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Sharon Worcester is an award-winning medical journalist for MDedge News. She has been with the company since 1996, first as the Southeast Bureau Chief (1996-2009) when the company was known as International Medical News Group, then as a freelance writer (2010-2015) before returning as a reporter in 2015. She previously worked as a daily newspaper reporter covering health and local government. Sharon currently reports primarily on oncology and hematology. She has a BA from Eckerd College and an MA in Mass Communication/Print Journalism from the University of Florida. Connect with her via LinkedIn and follow her on twitter @SW_MedReporter.
FDA approves Sovaldi, Harvoni for HCV in ages 12-plus
The Food and Drug Administration has approved the use of Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir) for the treatment of hepatitis C virus (HCV) in children aged 12 years and older.
The drugs – the first direct-acting, potentially curative antiviral treatments approved for children and adolescents with HCV – previously were approved for adults. The supplemental applications submitted by Gilead Sciences, which markets the drugs, were approved by the FDA on April 7 and expand the use of these drugs to pediatric patients aged 12 and up who weigh at least 77 pounds, and who have either mild or no cirrhosis; Sovaldi is indicated for those with HCV genotypes 2 or 3, and Harvoni is indicated for those with HCV genotypes 1, 4, 5, or 6.
“These approvals will help change the landscape for HCV treatment by addressing an unmet need in children and adolescents,” Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said in a press statement.
Of note, hepatitis B virus (HBV) reactivation has been reported in adults with HCV/HBV coinfection who were treated with these drugs, but who were not receiving HBV antiviral therapy; therefore, all patients should be screened for evidence of current or prior HBV infection before starting treatment with Harvoni or Sovaldi, according to the FDA statement.
The Food and Drug Administration has approved the use of Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir) for the treatment of hepatitis C virus (HCV) in children aged 12 years and older.
The drugs – the first direct-acting, potentially curative antiviral treatments approved for children and adolescents with HCV – previously were approved for adults. The supplemental applications submitted by Gilead Sciences, which markets the drugs, were approved by the FDA on April 7 and expand the use of these drugs to pediatric patients aged 12 and up who weigh at least 77 pounds, and who have either mild or no cirrhosis; Sovaldi is indicated for those with HCV genotypes 2 or 3, and Harvoni is indicated for those with HCV genotypes 1, 4, 5, or 6.
“These approvals will help change the landscape for HCV treatment by addressing an unmet need in children and adolescents,” Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said in a press statement.
Of note, hepatitis B virus (HBV) reactivation has been reported in adults with HCV/HBV coinfection who were treated with these drugs, but who were not receiving HBV antiviral therapy; therefore, all patients should be screened for evidence of current or prior HBV infection before starting treatment with Harvoni or Sovaldi, according to the FDA statement.
The Food and Drug Administration has approved the use of Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir) for the treatment of hepatitis C virus (HCV) in children aged 12 years and older.
The drugs – the first direct-acting, potentially curative antiviral treatments approved for children and adolescents with HCV – previously were approved for adults. The supplemental applications submitted by Gilead Sciences, which markets the drugs, were approved by the FDA on April 7 and expand the use of these drugs to pediatric patients aged 12 and up who weigh at least 77 pounds, and who have either mild or no cirrhosis; Sovaldi is indicated for those with HCV genotypes 2 or 3, and Harvoni is indicated for those with HCV genotypes 1, 4, 5, or 6.
“These approvals will help change the landscape for HCV treatment by addressing an unmet need in children and adolescents,” Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, said in a press statement.
Of note, hepatitis B virus (HBV) reactivation has been reported in adults with HCV/HBV coinfection who were treated with these drugs, but who were not receiving HBV antiviral therapy; therefore, all patients should be screened for evidence of current or prior HBV infection before starting treatment with Harvoni or Sovaldi, according to the FDA statement.
Myelofibrosis therapies moving beyond ruxolitinib
ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.
“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.
Among those being considered specifically for myelofibrosis are pacritinib, momelotinib, PRM-151, and imetelstat, he said.
Pacritinib
This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.
Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.
PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.
The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.
Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.
Momelotinib
Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.
“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.
SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.
The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.
If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.
There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.
“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.
PRM-151
This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.
Imetelstat
This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.
The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.
According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.
If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.
Combination therapies
In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.
“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.
Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.
ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.
“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.
Among those being considered specifically for myelofibrosis are pacritinib, momelotinib, PRM-151, and imetelstat, he said.
Pacritinib
This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.
Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.
PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.
The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.
Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.
Momelotinib
Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.
“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.
SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.
The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.
If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.
There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.
“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.
PRM-151
This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.
Imetelstat
This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.
The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.
According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.
If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.
Combination therapies
In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.
“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.
Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.
ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.
“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.
Among those being considered specifically for myelofibrosis are pacritinib, momelotinib, PRM-151, and imetelstat, he said.
Pacritinib
This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.
Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.
PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.
The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.
Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.
Momelotinib
Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.
“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.
SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.
The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.
If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.
There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.
“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.
PRM-151
This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.
Imetelstat
This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.
The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.
According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.
If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.
Combination therapies
In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.
“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.
Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.
EXPERT ANALYSIS AT THE NCCN ANNUAL CONFERENCE
NCCN myelofibrosis guideline: Patient voice is key
ORLANDO – Referral to a specialized center with expertise in the management of myeloproliferative neoplasms is strongly recommended for all patients diagnosed with myelofibrosis, according to a new treatment guideline from the National Comprehensive Cancer Network.
The guideline is the first in a series addressing myeloproliferative neoplasms (MPNs), and it focuses on the diagnostic work-up of MPNs, as well as the treatment of myelofibrosis. The guideline panel, led by panel chair Ruben A. Mesa, MD, is working next on guidelines for the other two “core classic” Philadelphia chromosome–negative MPNs: polycythemia vera, and essential thrombocythemia.
Nearly two-thirds of myelofibrosis patients have intermediate-risk 2 or high-risk disease, and treatment decisions in these patients are complex and require patient input – particularly in candidates for allogeneic hematopoietic stem cell transplantation, he said.
“These diseases can be a little different than other malignant diseases,” Dr. Mesa said, explaining that while there is a clear risk of progression to acute myeloid leukemia, and from polycythemia vera and essential thrombocythemia to myelofibrosis, and while the diseases can be fatal, the burden patients face is not solely related to mortality.
There are implications in terms of health that are independent of that, such as the risk of thrombosis and bleeding, the potential for cytopenia, and severe splenomegaly that results in significant symptoms, he said.
Further, while molecular mutations and their implications for prognosis are a “rapidly moving part of the discussion,” the care of patients with MPNs involves far more than a molecular understanding of the disease.
In fact, the role of molecular changes in these patients is speculative, he said.
While such changes can be assessed and used for patient stratification, their role in myelofibrosis – unlike in other diseases such as chronic myeloid leukemia where the level of change in a target gene is highly relevant and prognostic, is not yet clear.
Thus, a core aspect of the guideline is inclusion of the voice of the patient in individualizing care, he said, noting that many factors should be considered, including how well the patient metabolizes drugs, and the symptom profile, psychosocial circumstances, support structure, and personal beliefs.
“It’s not solely about the tumor,” he stressed.
In fact, the answer to the question of whether a patient can be symptomatic enough to require a specific treatment is “no,” because of the potential for side effects, risk, expense, and other considerations.
“So the voice of the patient is always a key part [of the decision],” he said, noting also that as with all NCCN guidelines, this guideline is a partnership with the treating physician; deciding who is a transplant candidate is a nuanced issue for which the panel provides “discussion and guidance.”
“But clearly, these guidelines are the most useful and helpful in the setting of experienced providers bringing all of their experiences to bear,” he said.
In general, however, the guidelines call for allogeneic hematopoietic stem cell transplantation (HCT) in those with intermediate-risk 2 or high-risk disease who are transplant candidates, and treatment based on assessment of symptom burden (using the MPN–Symptom Assessment Form Total Symptom Score–10 Items) in those who are not HCT candidates. Those with platelets at 50,000 or below should be considered for clinical trial enrollment, and those with platelets above 50,000 should be considered for a clinical trial or treatment with the oral JAK1 and JAK2 inhibitor ruxolitinib, which has been shown to have beneficial effects on both symptoms and survival and which is approved for patients with platelets above 50,000. .
Treated patients should be monitored for response and for signs and symptoms of disease progression every 3-6 months. Treatment should continue in those who respond, as well as in those who do not – as long as there is no disease progression.
Those with progressive disease include patients who are moving toward acute leukemia, and those with overt acute leukemia.
“Here is where the key decision occurs. Are they or are they not a transplant candidate? If they are a candidate, we have a potentially curative track which would include cytoreduction followed by transplant,” Dr. Mesa said.
Cytoreduction can involve hypomethylating agents if the patient doesn’t have excess blast cells or too high a burden of disease.
Acute myeloid leukemia–like induction chemotherapy followed by allogeneic HCT is also an option in these patients.
As for treatment of low-risk myelofibrosis, the guideline states that asymptomatic patients can be observed or enrolled in a clinical trial and monitored for progression every 3-6 months, and that symptomatic patients should receive ruxolitinib or interferons (which are used off label), or be enrolled in a clinical trial. Treatment is important for patients with particularly difficult symptoms, he said, noting that some patients have had pruritus so severe that they have committed suicide. Treatment should continue unless monitoring shows signs of progression to intermediate risk 1, intermediate risk 2/high-risk, or advanced stage disease.
For those with intermediate risk 1 disease, the guideline calls for observation or ruxolitinib in those who are symptomatic, or clinical trial enrollment or allogeneic HCT. Treatment should continue unless monitoring shows disease progression, in which case the appropriate algorithm should be considered.
The guideline also addresses several special circumstances, including the management of anemia in myelofibrosis patients, which can be a difficult issue, he said.
Since the guideline was first published in December, two updates have been incorporated, and Dr. Mesa said that he anticipates regular updates given the rapidly evolving understanding of MPNs and new findings with respect to potential treatment strategies.
He noted that a number of drugs are currently in clinical trials involving patients with myelofibrosis, including the JAK2/FLT3 inhibitor pacritinib, the JAK1/JAK2 inhibitor momelotinib, the active antifibrosing agent PRM-151, and the telomerase inhibitor imetelstat, as well as numerous drug combinations.
Going forward, the guideline panel will be focusing on four different areas of assessment, including new therapies and new genetic therapies, improving transplant outcomes, MPN symptom and quality of life assessment, and nonpharmacologic interventions such as yoga.
“We certainly hope to complement things over time, to look not only at pharmacologic interventions, but others that patients may be able to utilize from a toolkit of resources,” he said.
COMFORT-1 update: ruxolitinib responses durable in myelofibrosis
To date, ruxolitinib is the only Food and Drug Administration–approved drug for the treatment of myelofibrosis.
The randomized controlled phase III COMFORT I and II trials conducted in the United States and Europe, respectively, demonstrated that the oral JAK1/JAK2 inhibitor has a rapid, beneficial impact on both survival and disease-associated enlargement of the spleen and improvement in related symptoms, Dr. Mesa said.
A 5-year update on data from 309 patients in the COMFORT-1 trial, as reported at the annual meeting of the American Society of Clinical Oncology in 2016, confirmed the durability of treatment responses to ruxolitinib in patients initially randomized to receive the drug, he said.
“We were able to demonstrate a continued survival advantage for those individuals receiving ruxolitinib,” he added.
At weeks 24 and 264, the mean spleen volume reduction was 31.6% and 37.6%, respectively, in those originally randomized to ruxolitinib. The median duration of at least 35% spleen volume reduction was 168.3 weeks.
Overall survival favored ruxolitinib (hazard ratio, 0.69). Median overall survival in the ruxolitinib group had not yet been reached.
“But we realize our work is not done. The survival curve does not plateau; we are not curing these patients. We’re having meaningful impact, but we have room to continue to improve,” he said.
Also, there is an initial drop in platelet counts that tends to stabilize, but not improve, and there is worsening of anemia (new onset grade 3 or 4 anemia was 25.2% with ruxolitinib, and 26.1% in 111 of 154 patients who crossed over from the placebo group), and although this tends to improve, these are among areas of unmet need, he added.
Further, long-term risks of treatment include cutaneous malignancies (basal cell carcinoma occurred in 7.7% and 9.0% of treatment and crossover patients, respectively), which are difficult to separate from baseline hydroxyurea use, and increased risk of herpes zoster (which occurred in 10.3% and 13.5% of treated and crossover patients).
However, there appears to be no increased risk – and there may be a slight decreased risk – of progression to acute leukemia, Dr. Mesa said.
Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.
A step toward harmonizing treatment
Myelofibrosis is a rare chronic leukemia with a complex biology. Disease heterogeneity poses several challenges in the appropriate selection and timing of treatments in this disorder. The NCCN Practice Guidelines in Myelofibrosis is an important step towards harmonizing clinical practice for treating this disease and improving the care of patients.
Vikas Gupta, MD, FRCP, FRCPath, is Director of The Elizabeth and Tony Comper MPN Program at Princess Margaret Cancer Centre in Toronto and a member of the editorial advisory board of Hematology News.
A step toward harmonizing treatment
Myelofibrosis is a rare chronic leukemia with a complex biology. Disease heterogeneity poses several challenges in the appropriate selection and timing of treatments in this disorder. The NCCN Practice Guidelines in Myelofibrosis is an important step towards harmonizing clinical practice for treating this disease and improving the care of patients.
Vikas Gupta, MD, FRCP, FRCPath, is Director of The Elizabeth and Tony Comper MPN Program at Princess Margaret Cancer Centre in Toronto and a member of the editorial advisory board of Hematology News.
A step toward harmonizing treatment
Myelofibrosis is a rare chronic leukemia with a complex biology. Disease heterogeneity poses several challenges in the appropriate selection and timing of treatments in this disorder. The NCCN Practice Guidelines in Myelofibrosis is an important step towards harmonizing clinical practice for treating this disease and improving the care of patients.
Vikas Gupta, MD, FRCP, FRCPath, is Director of The Elizabeth and Tony Comper MPN Program at Princess Margaret Cancer Centre in Toronto and a member of the editorial advisory board of Hematology News.
ORLANDO – Referral to a specialized center with expertise in the management of myeloproliferative neoplasms is strongly recommended for all patients diagnosed with myelofibrosis, according to a new treatment guideline from the National Comprehensive Cancer Network.
The guideline is the first in a series addressing myeloproliferative neoplasms (MPNs), and it focuses on the diagnostic work-up of MPNs, as well as the treatment of myelofibrosis. The guideline panel, led by panel chair Ruben A. Mesa, MD, is working next on guidelines for the other two “core classic” Philadelphia chromosome–negative MPNs: polycythemia vera, and essential thrombocythemia.
Nearly two-thirds of myelofibrosis patients have intermediate-risk 2 or high-risk disease, and treatment decisions in these patients are complex and require patient input – particularly in candidates for allogeneic hematopoietic stem cell transplantation, he said.
“These diseases can be a little different than other malignant diseases,” Dr. Mesa said, explaining that while there is a clear risk of progression to acute myeloid leukemia, and from polycythemia vera and essential thrombocythemia to myelofibrosis, and while the diseases can be fatal, the burden patients face is not solely related to mortality.
There are implications in terms of health that are independent of that, such as the risk of thrombosis and bleeding, the potential for cytopenia, and severe splenomegaly that results in significant symptoms, he said.
Further, while molecular mutations and their implications for prognosis are a “rapidly moving part of the discussion,” the care of patients with MPNs involves far more than a molecular understanding of the disease.
In fact, the role of molecular changes in these patients is speculative, he said.
While such changes can be assessed and used for patient stratification, their role in myelofibrosis – unlike in other diseases such as chronic myeloid leukemia where the level of change in a target gene is highly relevant and prognostic, is not yet clear.
Thus, a core aspect of the guideline is inclusion of the voice of the patient in individualizing care, he said, noting that many factors should be considered, including how well the patient metabolizes drugs, and the symptom profile, psychosocial circumstances, support structure, and personal beliefs.
“It’s not solely about the tumor,” he stressed.
In fact, the answer to the question of whether a patient can be symptomatic enough to require a specific treatment is “no,” because of the potential for side effects, risk, expense, and other considerations.
“So the voice of the patient is always a key part [of the decision],” he said, noting also that as with all NCCN guidelines, this guideline is a partnership with the treating physician; deciding who is a transplant candidate is a nuanced issue for which the panel provides “discussion and guidance.”
“But clearly, these guidelines are the most useful and helpful in the setting of experienced providers bringing all of their experiences to bear,” he said.
In general, however, the guidelines call for allogeneic hematopoietic stem cell transplantation (HCT) in those with intermediate-risk 2 or high-risk disease who are transplant candidates, and treatment based on assessment of symptom burden (using the MPN–Symptom Assessment Form Total Symptom Score–10 Items) in those who are not HCT candidates. Those with platelets at 50,000 or below should be considered for clinical trial enrollment, and those with platelets above 50,000 should be considered for a clinical trial or treatment with the oral JAK1 and JAK2 inhibitor ruxolitinib, which has been shown to have beneficial effects on both symptoms and survival and which is approved for patients with platelets above 50,000. .
Treated patients should be monitored for response and for signs and symptoms of disease progression every 3-6 months. Treatment should continue in those who respond, as well as in those who do not – as long as there is no disease progression.
Those with progressive disease include patients who are moving toward acute leukemia, and those with overt acute leukemia.
“Here is where the key decision occurs. Are they or are they not a transplant candidate? If they are a candidate, we have a potentially curative track which would include cytoreduction followed by transplant,” Dr. Mesa said.
Cytoreduction can involve hypomethylating agents if the patient doesn’t have excess blast cells or too high a burden of disease.
Acute myeloid leukemia–like induction chemotherapy followed by allogeneic HCT is also an option in these patients.
As for treatment of low-risk myelofibrosis, the guideline states that asymptomatic patients can be observed or enrolled in a clinical trial and monitored for progression every 3-6 months, and that symptomatic patients should receive ruxolitinib or interferons (which are used off label), or be enrolled in a clinical trial. Treatment is important for patients with particularly difficult symptoms, he said, noting that some patients have had pruritus so severe that they have committed suicide. Treatment should continue unless monitoring shows signs of progression to intermediate risk 1, intermediate risk 2/high-risk, or advanced stage disease.
For those with intermediate risk 1 disease, the guideline calls for observation or ruxolitinib in those who are symptomatic, or clinical trial enrollment or allogeneic HCT. Treatment should continue unless monitoring shows disease progression, in which case the appropriate algorithm should be considered.
The guideline also addresses several special circumstances, including the management of anemia in myelofibrosis patients, which can be a difficult issue, he said.
Since the guideline was first published in December, two updates have been incorporated, and Dr. Mesa said that he anticipates regular updates given the rapidly evolving understanding of MPNs and new findings with respect to potential treatment strategies.
He noted that a number of drugs are currently in clinical trials involving patients with myelofibrosis, including the JAK2/FLT3 inhibitor pacritinib, the JAK1/JAK2 inhibitor momelotinib, the active antifibrosing agent PRM-151, and the telomerase inhibitor imetelstat, as well as numerous drug combinations.
Going forward, the guideline panel will be focusing on four different areas of assessment, including new therapies and new genetic therapies, improving transplant outcomes, MPN symptom and quality of life assessment, and nonpharmacologic interventions such as yoga.
“We certainly hope to complement things over time, to look not only at pharmacologic interventions, but others that patients may be able to utilize from a toolkit of resources,” he said.
COMFORT-1 update: ruxolitinib responses durable in myelofibrosis
To date, ruxolitinib is the only Food and Drug Administration–approved drug for the treatment of myelofibrosis.
The randomized controlled phase III COMFORT I and II trials conducted in the United States and Europe, respectively, demonstrated that the oral JAK1/JAK2 inhibitor has a rapid, beneficial impact on both survival and disease-associated enlargement of the spleen and improvement in related symptoms, Dr. Mesa said.
A 5-year update on data from 309 patients in the COMFORT-1 trial, as reported at the annual meeting of the American Society of Clinical Oncology in 2016, confirmed the durability of treatment responses to ruxolitinib in patients initially randomized to receive the drug, he said.
“We were able to demonstrate a continued survival advantage for those individuals receiving ruxolitinib,” he added.
At weeks 24 and 264, the mean spleen volume reduction was 31.6% and 37.6%, respectively, in those originally randomized to ruxolitinib. The median duration of at least 35% spleen volume reduction was 168.3 weeks.
Overall survival favored ruxolitinib (hazard ratio, 0.69). Median overall survival in the ruxolitinib group had not yet been reached.
“But we realize our work is not done. The survival curve does not plateau; we are not curing these patients. We’re having meaningful impact, but we have room to continue to improve,” he said.
Also, there is an initial drop in platelet counts that tends to stabilize, but not improve, and there is worsening of anemia (new onset grade 3 or 4 anemia was 25.2% with ruxolitinib, and 26.1% in 111 of 154 patients who crossed over from the placebo group), and although this tends to improve, these are among areas of unmet need, he added.
Further, long-term risks of treatment include cutaneous malignancies (basal cell carcinoma occurred in 7.7% and 9.0% of treatment and crossover patients, respectively), which are difficult to separate from baseline hydroxyurea use, and increased risk of herpes zoster (which occurred in 10.3% and 13.5% of treated and crossover patients).
However, there appears to be no increased risk – and there may be a slight decreased risk – of progression to acute leukemia, Dr. Mesa said.
Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.
ORLANDO – Referral to a specialized center with expertise in the management of myeloproliferative neoplasms is strongly recommended for all patients diagnosed with myelofibrosis, according to a new treatment guideline from the National Comprehensive Cancer Network.
The guideline is the first in a series addressing myeloproliferative neoplasms (MPNs), and it focuses on the diagnostic work-up of MPNs, as well as the treatment of myelofibrosis. The guideline panel, led by panel chair Ruben A. Mesa, MD, is working next on guidelines for the other two “core classic” Philadelphia chromosome–negative MPNs: polycythemia vera, and essential thrombocythemia.
Nearly two-thirds of myelofibrosis patients have intermediate-risk 2 or high-risk disease, and treatment decisions in these patients are complex and require patient input – particularly in candidates for allogeneic hematopoietic stem cell transplantation, he said.
“These diseases can be a little different than other malignant diseases,” Dr. Mesa said, explaining that while there is a clear risk of progression to acute myeloid leukemia, and from polycythemia vera and essential thrombocythemia to myelofibrosis, and while the diseases can be fatal, the burden patients face is not solely related to mortality.
There are implications in terms of health that are independent of that, such as the risk of thrombosis and bleeding, the potential for cytopenia, and severe splenomegaly that results in significant symptoms, he said.
Further, while molecular mutations and their implications for prognosis are a “rapidly moving part of the discussion,” the care of patients with MPNs involves far more than a molecular understanding of the disease.
In fact, the role of molecular changes in these patients is speculative, he said.
While such changes can be assessed and used for patient stratification, their role in myelofibrosis – unlike in other diseases such as chronic myeloid leukemia where the level of change in a target gene is highly relevant and prognostic, is not yet clear.
Thus, a core aspect of the guideline is inclusion of the voice of the patient in individualizing care, he said, noting that many factors should be considered, including how well the patient metabolizes drugs, and the symptom profile, psychosocial circumstances, support structure, and personal beliefs.
“It’s not solely about the tumor,” he stressed.
In fact, the answer to the question of whether a patient can be symptomatic enough to require a specific treatment is “no,” because of the potential for side effects, risk, expense, and other considerations.
“So the voice of the patient is always a key part [of the decision],” he said, noting also that as with all NCCN guidelines, this guideline is a partnership with the treating physician; deciding who is a transplant candidate is a nuanced issue for which the panel provides “discussion and guidance.”
“But clearly, these guidelines are the most useful and helpful in the setting of experienced providers bringing all of their experiences to bear,” he said.
In general, however, the guidelines call for allogeneic hematopoietic stem cell transplantation (HCT) in those with intermediate-risk 2 or high-risk disease who are transplant candidates, and treatment based on assessment of symptom burden (using the MPN–Symptom Assessment Form Total Symptom Score–10 Items) in those who are not HCT candidates. Those with platelets at 50,000 or below should be considered for clinical trial enrollment, and those with platelets above 50,000 should be considered for a clinical trial or treatment with the oral JAK1 and JAK2 inhibitor ruxolitinib, which has been shown to have beneficial effects on both symptoms and survival and which is approved for patients with platelets above 50,000. .
Treated patients should be monitored for response and for signs and symptoms of disease progression every 3-6 months. Treatment should continue in those who respond, as well as in those who do not – as long as there is no disease progression.
Those with progressive disease include patients who are moving toward acute leukemia, and those with overt acute leukemia.
“Here is where the key decision occurs. Are they or are they not a transplant candidate? If they are a candidate, we have a potentially curative track which would include cytoreduction followed by transplant,” Dr. Mesa said.
Cytoreduction can involve hypomethylating agents if the patient doesn’t have excess blast cells or too high a burden of disease.
Acute myeloid leukemia–like induction chemotherapy followed by allogeneic HCT is also an option in these patients.
As for treatment of low-risk myelofibrosis, the guideline states that asymptomatic patients can be observed or enrolled in a clinical trial and monitored for progression every 3-6 months, and that symptomatic patients should receive ruxolitinib or interferons (which are used off label), or be enrolled in a clinical trial. Treatment is important for patients with particularly difficult symptoms, he said, noting that some patients have had pruritus so severe that they have committed suicide. Treatment should continue unless monitoring shows signs of progression to intermediate risk 1, intermediate risk 2/high-risk, or advanced stage disease.
For those with intermediate risk 1 disease, the guideline calls for observation or ruxolitinib in those who are symptomatic, or clinical trial enrollment or allogeneic HCT. Treatment should continue unless monitoring shows disease progression, in which case the appropriate algorithm should be considered.
The guideline also addresses several special circumstances, including the management of anemia in myelofibrosis patients, which can be a difficult issue, he said.
Since the guideline was first published in December, two updates have been incorporated, and Dr. Mesa said that he anticipates regular updates given the rapidly evolving understanding of MPNs and new findings with respect to potential treatment strategies.
He noted that a number of drugs are currently in clinical trials involving patients with myelofibrosis, including the JAK2/FLT3 inhibitor pacritinib, the JAK1/JAK2 inhibitor momelotinib, the active antifibrosing agent PRM-151, and the telomerase inhibitor imetelstat, as well as numerous drug combinations.
Going forward, the guideline panel will be focusing on four different areas of assessment, including new therapies and new genetic therapies, improving transplant outcomes, MPN symptom and quality of life assessment, and nonpharmacologic interventions such as yoga.
“We certainly hope to complement things over time, to look not only at pharmacologic interventions, but others that patients may be able to utilize from a toolkit of resources,” he said.
COMFORT-1 update: ruxolitinib responses durable in myelofibrosis
To date, ruxolitinib is the only Food and Drug Administration–approved drug for the treatment of myelofibrosis.
The randomized controlled phase III COMFORT I and II trials conducted in the United States and Europe, respectively, demonstrated that the oral JAK1/JAK2 inhibitor has a rapid, beneficial impact on both survival and disease-associated enlargement of the spleen and improvement in related symptoms, Dr. Mesa said.
A 5-year update on data from 309 patients in the COMFORT-1 trial, as reported at the annual meeting of the American Society of Clinical Oncology in 2016, confirmed the durability of treatment responses to ruxolitinib in patients initially randomized to receive the drug, he said.
“We were able to demonstrate a continued survival advantage for those individuals receiving ruxolitinib,” he added.
At weeks 24 and 264, the mean spleen volume reduction was 31.6% and 37.6%, respectively, in those originally randomized to ruxolitinib. The median duration of at least 35% spleen volume reduction was 168.3 weeks.
Overall survival favored ruxolitinib (hazard ratio, 0.69). Median overall survival in the ruxolitinib group had not yet been reached.
“But we realize our work is not done. The survival curve does not plateau; we are not curing these patients. We’re having meaningful impact, but we have room to continue to improve,” he said.
Also, there is an initial drop in platelet counts that tends to stabilize, but not improve, and there is worsening of anemia (new onset grade 3 or 4 anemia was 25.2% with ruxolitinib, and 26.1% in 111 of 154 patients who crossed over from the placebo group), and although this tends to improve, these are among areas of unmet need, he added.
Further, long-term risks of treatment include cutaneous malignancies (basal cell carcinoma occurred in 7.7% and 9.0% of treatment and crossover patients, respectively), which are difficult to separate from baseline hydroxyurea use, and increased risk of herpes zoster (which occurred in 10.3% and 13.5% of treated and crossover patients).
However, there appears to be no increased risk – and there may be a slight decreased risk – of progression to acute leukemia, Dr. Mesa said.
Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.
EXPERT ANALYSIS AT THE NCCN ANNUAL CONFERENCE
Safety of N9-GP for hemophilia B needs further study, FDA committee agrees
Concerns about a possible safety issue with the investigational glycoPEGylated factor IX product nonacog beta pegol (N9-GP) for the treatment of hemophilia B left members of the Blood Products Advisory Committee of the Food and Drug Administration divided during an April 4 committee meeting about whether additional study should take place prior to FDA approval of a Biologics Licensing Application or in the postmarketing setting.
The committee was not asked to vote on a recommendation for approval of N9-GP. Committee members agreed that if N9-GP is approved, standardized postmarketing monitoring would be needed, particularly in very young and very old patients.
As a result, the FDA asked the advisory committee to consider the clinical significance of the preclinical findings, the nature and level of any safety concerns in various populations, the sufficiency of evidence from toxicology and clinical studies for intermittent and chronic use, clinical or laboratory assessments that might help ensure patient safety, and recommendations for additional studies to support the safety of the product.
Novo Nordisk is specifically seeking FDA marketing approval of N9-GP, which is administered weekly, for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in adults and children. The company submitted evidence for these indications from three phase III trials and a phase III extension study in adults and children.
“The Office of Tissues and Advanced Therapies – OTAT – appreciates that hemophilia B is a serious disease and we need improved therapies to benefit patients. We also appreciate that this is a rare disease, which limits the availability of data to address issues of safety and effectiveness,” Wilson Bryan, MD, director of OTAT, which is part of the FDA’s Center for Biologics Evaluation and Research, told the advisory committee.
The committee then heard from Novo Nordisk representatives who spoke about the unmet public health need for hemophilia B treatments, and N9-GP clinical efficacy, long-term safety, and risk/benefit analyses.
Shawn Hoskin, senior director of regulatory affairs for Novo Nordisk, noted that with weekly dosing of N9-GP, no adverse effects were seen in preclinical studies at doses up to 42 times the human dose. Further, no adverse effects were reported in clinical studies, in which high levels of factor IX were achieved.
“Our trials demonstrated that the higher factor IX levels achieved with N9-GP lead to better outcomes for patients, including reduced annual bleed rate, reduction in the number of spontaneous bleeds, and resolution of target joints,” he said.
Stephanie Seremetis, MD, chief medical officer and corporate vice president for hemophilia at Novo Nordisk, said the company has proposed a postapproval monitoring plan and safety study.
The advisory committee also heard from patients invited by Novo Nordisk to share their experiences, and from Maria Lehtinen, PhD, of Boston Children’s Hospital, who was invited to speak about choroid plexus biology.
The patients agreed that there is an urgent need and desire for effective, long-acting treatments. Ben Shuldiner, for example, said he was part of the clinical trials for N9-GP, has never had as much success sticking to a treatment regimen, and “is in much better shape, much less pain.”
“The [hemophilia] community needs choice,” said Mr. Shuldiner, a professor at Hunter College in New York, and an activist. He stressed that what works for one patient doesn’t necessarily work for another.
Committee members didn’t question the efficacy or value of the long-acting product, but did express concern about the unknown effects of PEG accumulation. One member questioned whether it might be feasible to restrict licensing to children over age 6 years and to adults under age 65 years pending additional study. Other members said that approach would restrict treatment for patients who might benefit the most from N9-GP.
Meera B. Chitlur, MD, noted that most children with hemophilia B are treated prophylactically by age 1, or at least by the time they are walking, and suggested it might be better to allow use of the product in those who need it, while collecting data going forward.
“Only over the last couple years have our patients finally had the opportunity to have something that has substantially changed how they are managed or what they can do. This class of drugs is one that has made it possible for these patients to lead a better life, so I think it is really important for us,” said Dr. Chitlur of Wayne State University and Children’s Hospital of Michigan, Detroit.
“The youngest children will probably benefit the most. Yes, there are concerns ... but at the same time I think I haven’t heard anything today, or read anything, that has made me want to say it is not safe for the patients that I’m going to take care of,” she added, noting that informed consent is possible and important.
Dr. Chitlur said she completely agrees with the need for systematic data collection, and feels there are already mechanisms in place to achieve that goal.
“I feel comfortable taking this to my patients and saying that here is another option for you,” she said.
Laura Manuelidis, MD, of Yale University, New Haven, Conn., a temporary voting member of the committee, said she was “less sanguine,” about immediate approval. Additional studies of the effects of PEG accumulation in animals are feasible, she said, and could be performed rapidly before approving treatment in children under age 2 years.
Michael Dobbs, MD, of the University of Kentucky, Lexington, also a temporary voting member, agreed it would be valuable to test available cerebrospinal fluid of animals from the preclinical studies. He had no recommendation for additional studies, but agreed on the importance of extensive postmarketing surveillance. He added that patients who undergo CSF testing or magnetic resonance imaging for other clinical reasons should be evaluated for the possible effects of PEG accumulation.
“I think we should follow cognitive outcomes in the postmarket data, probably requiring more neurocognitive data in pediatrics with some validated, standardized tests. It would be reasonable to require a full neurological exam pre- and post-[treatment], especially in those at fixed developmental states,” he said.
It would also be reasonable to monitor children for signs and symptoms of hydrocephalus and for papilledema and other visual disturbances, he added.
“But again, most of all ... whatever we really do recommend, we need standardization, validation – to do this the same [way] for all of the patients,” he said.
Dr. Bryan, of OTAT, said the input from members and guests will be considered as the FDA proceeds with its review of the Biologics Licensing Application for N9-GP. The FDA is not bound by the committee’s guidance.
All members of the advisory committee have been screened and found to be in compliance with respect to potential conflicts of interest. No conflict of interest waivers were issued. Patients who spoke in favor of N9-GP received travel and/or other support from Novo Nordisk.
Concerns about a possible safety issue with the investigational glycoPEGylated factor IX product nonacog beta pegol (N9-GP) for the treatment of hemophilia B left members of the Blood Products Advisory Committee of the Food and Drug Administration divided during an April 4 committee meeting about whether additional study should take place prior to FDA approval of a Biologics Licensing Application or in the postmarketing setting.
The committee was not asked to vote on a recommendation for approval of N9-GP. Committee members agreed that if N9-GP is approved, standardized postmarketing monitoring would be needed, particularly in very young and very old patients.
As a result, the FDA asked the advisory committee to consider the clinical significance of the preclinical findings, the nature and level of any safety concerns in various populations, the sufficiency of evidence from toxicology and clinical studies for intermittent and chronic use, clinical or laboratory assessments that might help ensure patient safety, and recommendations for additional studies to support the safety of the product.
Novo Nordisk is specifically seeking FDA marketing approval of N9-GP, which is administered weekly, for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in adults and children. The company submitted evidence for these indications from three phase III trials and a phase III extension study in adults and children.
“The Office of Tissues and Advanced Therapies – OTAT – appreciates that hemophilia B is a serious disease and we need improved therapies to benefit patients. We also appreciate that this is a rare disease, which limits the availability of data to address issues of safety and effectiveness,” Wilson Bryan, MD, director of OTAT, which is part of the FDA’s Center for Biologics Evaluation and Research, told the advisory committee.
The committee then heard from Novo Nordisk representatives who spoke about the unmet public health need for hemophilia B treatments, and N9-GP clinical efficacy, long-term safety, and risk/benefit analyses.
Shawn Hoskin, senior director of regulatory affairs for Novo Nordisk, noted that with weekly dosing of N9-GP, no adverse effects were seen in preclinical studies at doses up to 42 times the human dose. Further, no adverse effects were reported in clinical studies, in which high levels of factor IX were achieved.
“Our trials demonstrated that the higher factor IX levels achieved with N9-GP lead to better outcomes for patients, including reduced annual bleed rate, reduction in the number of spontaneous bleeds, and resolution of target joints,” he said.
Stephanie Seremetis, MD, chief medical officer and corporate vice president for hemophilia at Novo Nordisk, said the company has proposed a postapproval monitoring plan and safety study.
The advisory committee also heard from patients invited by Novo Nordisk to share their experiences, and from Maria Lehtinen, PhD, of Boston Children’s Hospital, who was invited to speak about choroid plexus biology.
The patients agreed that there is an urgent need and desire for effective, long-acting treatments. Ben Shuldiner, for example, said he was part of the clinical trials for N9-GP, has never had as much success sticking to a treatment regimen, and “is in much better shape, much less pain.”
“The [hemophilia] community needs choice,” said Mr. Shuldiner, a professor at Hunter College in New York, and an activist. He stressed that what works for one patient doesn’t necessarily work for another.
Committee members didn’t question the efficacy or value of the long-acting product, but did express concern about the unknown effects of PEG accumulation. One member questioned whether it might be feasible to restrict licensing to children over age 6 years and to adults under age 65 years pending additional study. Other members said that approach would restrict treatment for patients who might benefit the most from N9-GP.
Meera B. Chitlur, MD, noted that most children with hemophilia B are treated prophylactically by age 1, or at least by the time they are walking, and suggested it might be better to allow use of the product in those who need it, while collecting data going forward.
“Only over the last couple years have our patients finally had the opportunity to have something that has substantially changed how they are managed or what they can do. This class of drugs is one that has made it possible for these patients to lead a better life, so I think it is really important for us,” said Dr. Chitlur of Wayne State University and Children’s Hospital of Michigan, Detroit.
“The youngest children will probably benefit the most. Yes, there are concerns ... but at the same time I think I haven’t heard anything today, or read anything, that has made me want to say it is not safe for the patients that I’m going to take care of,” she added, noting that informed consent is possible and important.
Dr. Chitlur said she completely agrees with the need for systematic data collection, and feels there are already mechanisms in place to achieve that goal.
“I feel comfortable taking this to my patients and saying that here is another option for you,” she said.
Laura Manuelidis, MD, of Yale University, New Haven, Conn., a temporary voting member of the committee, said she was “less sanguine,” about immediate approval. Additional studies of the effects of PEG accumulation in animals are feasible, she said, and could be performed rapidly before approving treatment in children under age 2 years.
Michael Dobbs, MD, of the University of Kentucky, Lexington, also a temporary voting member, agreed it would be valuable to test available cerebrospinal fluid of animals from the preclinical studies. He had no recommendation for additional studies, but agreed on the importance of extensive postmarketing surveillance. He added that patients who undergo CSF testing or magnetic resonance imaging for other clinical reasons should be evaluated for the possible effects of PEG accumulation.
“I think we should follow cognitive outcomes in the postmarket data, probably requiring more neurocognitive data in pediatrics with some validated, standardized tests. It would be reasonable to require a full neurological exam pre- and post-[treatment], especially in those at fixed developmental states,” he said.
It would also be reasonable to monitor children for signs and symptoms of hydrocephalus and for papilledema and other visual disturbances, he added.
“But again, most of all ... whatever we really do recommend, we need standardization, validation – to do this the same [way] for all of the patients,” he said.
Dr. Bryan, of OTAT, said the input from members and guests will be considered as the FDA proceeds with its review of the Biologics Licensing Application for N9-GP. The FDA is not bound by the committee’s guidance.
All members of the advisory committee have been screened and found to be in compliance with respect to potential conflicts of interest. No conflict of interest waivers were issued. Patients who spoke in favor of N9-GP received travel and/or other support from Novo Nordisk.
Concerns about a possible safety issue with the investigational glycoPEGylated factor IX product nonacog beta pegol (N9-GP) for the treatment of hemophilia B left members of the Blood Products Advisory Committee of the Food and Drug Administration divided during an April 4 committee meeting about whether additional study should take place prior to FDA approval of a Biologics Licensing Application or in the postmarketing setting.
The committee was not asked to vote on a recommendation for approval of N9-GP. Committee members agreed that if N9-GP is approved, standardized postmarketing monitoring would be needed, particularly in very young and very old patients.
As a result, the FDA asked the advisory committee to consider the clinical significance of the preclinical findings, the nature and level of any safety concerns in various populations, the sufficiency of evidence from toxicology and clinical studies for intermittent and chronic use, clinical or laboratory assessments that might help ensure patient safety, and recommendations for additional studies to support the safety of the product.
Novo Nordisk is specifically seeking FDA marketing approval of N9-GP, which is administered weekly, for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in adults and children. The company submitted evidence for these indications from three phase III trials and a phase III extension study in adults and children.
“The Office of Tissues and Advanced Therapies – OTAT – appreciates that hemophilia B is a serious disease and we need improved therapies to benefit patients. We also appreciate that this is a rare disease, which limits the availability of data to address issues of safety and effectiveness,” Wilson Bryan, MD, director of OTAT, which is part of the FDA’s Center for Biologics Evaluation and Research, told the advisory committee.
The committee then heard from Novo Nordisk representatives who spoke about the unmet public health need for hemophilia B treatments, and N9-GP clinical efficacy, long-term safety, and risk/benefit analyses.
Shawn Hoskin, senior director of regulatory affairs for Novo Nordisk, noted that with weekly dosing of N9-GP, no adverse effects were seen in preclinical studies at doses up to 42 times the human dose. Further, no adverse effects were reported in clinical studies, in which high levels of factor IX were achieved.
“Our trials demonstrated that the higher factor IX levels achieved with N9-GP lead to better outcomes for patients, including reduced annual bleed rate, reduction in the number of spontaneous bleeds, and resolution of target joints,” he said.
Stephanie Seremetis, MD, chief medical officer and corporate vice president for hemophilia at Novo Nordisk, said the company has proposed a postapproval monitoring plan and safety study.
The advisory committee also heard from patients invited by Novo Nordisk to share their experiences, and from Maria Lehtinen, PhD, of Boston Children’s Hospital, who was invited to speak about choroid plexus biology.
The patients agreed that there is an urgent need and desire for effective, long-acting treatments. Ben Shuldiner, for example, said he was part of the clinical trials for N9-GP, has never had as much success sticking to a treatment regimen, and “is in much better shape, much less pain.”
“The [hemophilia] community needs choice,” said Mr. Shuldiner, a professor at Hunter College in New York, and an activist. He stressed that what works for one patient doesn’t necessarily work for another.
Committee members didn’t question the efficacy or value of the long-acting product, but did express concern about the unknown effects of PEG accumulation. One member questioned whether it might be feasible to restrict licensing to children over age 6 years and to adults under age 65 years pending additional study. Other members said that approach would restrict treatment for patients who might benefit the most from N9-GP.
Meera B. Chitlur, MD, noted that most children with hemophilia B are treated prophylactically by age 1, or at least by the time they are walking, and suggested it might be better to allow use of the product in those who need it, while collecting data going forward.
“Only over the last couple years have our patients finally had the opportunity to have something that has substantially changed how they are managed or what they can do. This class of drugs is one that has made it possible for these patients to lead a better life, so I think it is really important for us,” said Dr. Chitlur of Wayne State University and Children’s Hospital of Michigan, Detroit.
“The youngest children will probably benefit the most. Yes, there are concerns ... but at the same time I think I haven’t heard anything today, or read anything, that has made me want to say it is not safe for the patients that I’m going to take care of,” she added, noting that informed consent is possible and important.
Dr. Chitlur said she completely agrees with the need for systematic data collection, and feels there are already mechanisms in place to achieve that goal.
“I feel comfortable taking this to my patients and saying that here is another option for you,” she said.
Laura Manuelidis, MD, of Yale University, New Haven, Conn., a temporary voting member of the committee, said she was “less sanguine,” about immediate approval. Additional studies of the effects of PEG accumulation in animals are feasible, she said, and could be performed rapidly before approving treatment in children under age 2 years.
Michael Dobbs, MD, of the University of Kentucky, Lexington, also a temporary voting member, agreed it would be valuable to test available cerebrospinal fluid of animals from the preclinical studies. He had no recommendation for additional studies, but agreed on the importance of extensive postmarketing surveillance. He added that patients who undergo CSF testing or magnetic resonance imaging for other clinical reasons should be evaluated for the possible effects of PEG accumulation.
“I think we should follow cognitive outcomes in the postmarket data, probably requiring more neurocognitive data in pediatrics with some validated, standardized tests. It would be reasonable to require a full neurological exam pre- and post-[treatment], especially in those at fixed developmental states,” he said.
It would also be reasonable to monitor children for signs and symptoms of hydrocephalus and for papilledema and other visual disturbances, he added.
“But again, most of all ... whatever we really do recommend, we need standardization, validation – to do this the same [way] for all of the patients,” he said.
Dr. Bryan, of OTAT, said the input from members and guests will be considered as the FDA proceeds with its review of the Biologics Licensing Application for N9-GP. The FDA is not bound by the committee’s guidance.
All members of the advisory committee have been screened and found to be in compliance with respect to potential conflicts of interest. No conflict of interest waivers were issued. Patients who spoke in favor of N9-GP received travel and/or other support from Novo Nordisk.
Tocilizumab shows promise for GVHD prevention
ORLANDO – Tocilizumab plus standard immune suppression appears to drive down the risk for graft-versus-host disease (GVHD), according to results from a phase II study of 35 adults undergoing allogeneic stem cell transplants.
The effect was particularly pronounced for prevention of GVHD in the colon, William Drobyski, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The incidence rate of grades II-IV and III-IV acute GVHD was 12% at day 100 in patients given standard prophylaxis of tacrolimus/methotrexate (Tac/MTX) and 3% in patients given Tac/MTX plus 8 mg/kg of tocilizumab (Toc, capped at 800 mg), said Dr. Drobyski of the Medical College of Wisconsin, Milwaukee.
To provide further context to the results, Dr. Drobyski and his colleagues performed a matched case-control analysis using contemporary controls in the Center for International Blood & Marrow Transplant Research from 2000 to 2014. The same eligibility criteria used for the trial were applied to the matched controls except for the use of Tac/MTX as GVHD prophylaxis. Patients were otherwise matched based on age, performance score, disease, and donor type.
The incidence of grades II-IV acute GVHD at day 100 was significantly lower in the Toc/Tac/MTX group than in the Tac/MTX control population (12% vs. 41%). The incidence of grades III-IV acute GVHD was slightly lower with tocilizumab, but the difference between the groups was not statistically significant, Dr. Drobyski said.
The probability of grade II-IV acute GVHD–free survival, which was the primary endpoint of the study, was significantly higher in the Toc/Tac/MTX group (79% vs 52%), he said.
Five patients developed grade 2 acute GVHD of the skin or upper GI tract, and one patient died of grade 4 acute GVHD of the skin in the first 100 days. Notably, there were no cases of acute GVHD of the lower GI tract during that time, although two cases did occur between days 130 and 180, he said.
“There was no difference in transplant-related mortality, relapse, disease-free survival, or overall survival,” he said, adding that preliminary data suggest there were no differences in chronic GVHD between the groups.
Causes of death also were similar between the two cohorts with respect to disease- and transplant-related complications.
Patients in the tocilizumab study were enrolled between January 2015 and June 2016; the median age was 66 years. Diseases represented in the cohort included de novo acute myeloid leukemia (13 patients), AML (6 patients), chronic myelomonocytic leukemia (6 patients), acute lymphoblastic leukemia (4 patients), myelodysplastic syndrome (3 patients), and T-cell lymphoma, chronic myeloid leukemia, and NK/T cell lymphoma (in 1 patient each). Most patients were classified as high risk (9 patients) or intermediate risk (22 patients) by the disease risk index.
Conditioning was entirely busulfan based. Myeloablative conditioning was with busulfan and cyclophosphamide (Cytoxan) in 5 patients, or fludarabine and 4 days of busulfan in 10 patients, and reduced-intensity conditioning was with fludarabine and 2 days of busulfan in 18 patients. Transplants were with either HLA-matched related or unrelated donor grafts. Most patients (29 of 35) received peripheral stem cell grafts.
Tocilizumab, an interleuken-6 receptor blocker that is approved for treatment of rheumatoid arthritis, was administered after completion of conditioning and on the day prior to stem cell infusion.
In a pilot clinical trial of tocilizumab for the treatment of steroid-resistant acute GVHD in patients who had primarily had lower GI tract disease, “we were able to demonstrate responses in a majority of these patients,” Dr. Drobyski said, noting that a recent study presented at the 2016 annual meeting of the American Society of Hematology also showed efficacy in the treatment of lower tract GI GVHD, “providing evidence that tocilizumab had activity in acute GVHD, and perhaps in the treatment of steroid-refractory lower GI GVHD.”
Elevated IL-6 levels in the peripheral blood are correlated with an increased incidence and severity of GVHD; administration of an anti-IL-6 receptor antibody has been shown in preclinical studies to protect mice from lethal GVHD. The current open-label study was performed to “try to advance this concept” by assessing whether inhibition of IL-6 signaling could also prevent acute GVHD.
The findings confirm those of a 2014 study by Kennedy et al. in Lancet Oncology (2014;15:1451-9), and imply that tocilizumab warrants a randomized trial as prophylaxis for acute GVHD, he concluded.
Dr. Drobyski reported having no disclosures.
ORLANDO – Tocilizumab plus standard immune suppression appears to drive down the risk for graft-versus-host disease (GVHD), according to results from a phase II study of 35 adults undergoing allogeneic stem cell transplants.
The effect was particularly pronounced for prevention of GVHD in the colon, William Drobyski, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The incidence rate of grades II-IV and III-IV acute GVHD was 12% at day 100 in patients given standard prophylaxis of tacrolimus/methotrexate (Tac/MTX) and 3% in patients given Tac/MTX plus 8 mg/kg of tocilizumab (Toc, capped at 800 mg), said Dr. Drobyski of the Medical College of Wisconsin, Milwaukee.
To provide further context to the results, Dr. Drobyski and his colleagues performed a matched case-control analysis using contemporary controls in the Center for International Blood & Marrow Transplant Research from 2000 to 2014. The same eligibility criteria used for the trial were applied to the matched controls except for the use of Tac/MTX as GVHD prophylaxis. Patients were otherwise matched based on age, performance score, disease, and donor type.
The incidence of grades II-IV acute GVHD at day 100 was significantly lower in the Toc/Tac/MTX group than in the Tac/MTX control population (12% vs. 41%). The incidence of grades III-IV acute GVHD was slightly lower with tocilizumab, but the difference between the groups was not statistically significant, Dr. Drobyski said.
The probability of grade II-IV acute GVHD–free survival, which was the primary endpoint of the study, was significantly higher in the Toc/Tac/MTX group (79% vs 52%), he said.
Five patients developed grade 2 acute GVHD of the skin or upper GI tract, and one patient died of grade 4 acute GVHD of the skin in the first 100 days. Notably, there were no cases of acute GVHD of the lower GI tract during that time, although two cases did occur between days 130 and 180, he said.
“There was no difference in transplant-related mortality, relapse, disease-free survival, or overall survival,” he said, adding that preliminary data suggest there were no differences in chronic GVHD between the groups.
Causes of death also were similar between the two cohorts with respect to disease- and transplant-related complications.
Patients in the tocilizumab study were enrolled between January 2015 and June 2016; the median age was 66 years. Diseases represented in the cohort included de novo acute myeloid leukemia (13 patients), AML (6 patients), chronic myelomonocytic leukemia (6 patients), acute lymphoblastic leukemia (4 patients), myelodysplastic syndrome (3 patients), and T-cell lymphoma, chronic myeloid leukemia, and NK/T cell lymphoma (in 1 patient each). Most patients were classified as high risk (9 patients) or intermediate risk (22 patients) by the disease risk index.
Conditioning was entirely busulfan based. Myeloablative conditioning was with busulfan and cyclophosphamide (Cytoxan) in 5 patients, or fludarabine and 4 days of busulfan in 10 patients, and reduced-intensity conditioning was with fludarabine and 2 days of busulfan in 18 patients. Transplants were with either HLA-matched related or unrelated donor grafts. Most patients (29 of 35) received peripheral stem cell grafts.
Tocilizumab, an interleuken-6 receptor blocker that is approved for treatment of rheumatoid arthritis, was administered after completion of conditioning and on the day prior to stem cell infusion.
In a pilot clinical trial of tocilizumab for the treatment of steroid-resistant acute GVHD in patients who had primarily had lower GI tract disease, “we were able to demonstrate responses in a majority of these patients,” Dr. Drobyski said, noting that a recent study presented at the 2016 annual meeting of the American Society of Hematology also showed efficacy in the treatment of lower tract GI GVHD, “providing evidence that tocilizumab had activity in acute GVHD, and perhaps in the treatment of steroid-refractory lower GI GVHD.”
Elevated IL-6 levels in the peripheral blood are correlated with an increased incidence and severity of GVHD; administration of an anti-IL-6 receptor antibody has been shown in preclinical studies to protect mice from lethal GVHD. The current open-label study was performed to “try to advance this concept” by assessing whether inhibition of IL-6 signaling could also prevent acute GVHD.
The findings confirm those of a 2014 study by Kennedy et al. in Lancet Oncology (2014;15:1451-9), and imply that tocilizumab warrants a randomized trial as prophylaxis for acute GVHD, he concluded.
Dr. Drobyski reported having no disclosures.
ORLANDO – Tocilizumab plus standard immune suppression appears to drive down the risk for graft-versus-host disease (GVHD), according to results from a phase II study of 35 adults undergoing allogeneic stem cell transplants.
The effect was particularly pronounced for prevention of GVHD in the colon, William Drobyski, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The incidence rate of grades II-IV and III-IV acute GVHD was 12% at day 100 in patients given standard prophylaxis of tacrolimus/methotrexate (Tac/MTX) and 3% in patients given Tac/MTX plus 8 mg/kg of tocilizumab (Toc, capped at 800 mg), said Dr. Drobyski of the Medical College of Wisconsin, Milwaukee.
To provide further context to the results, Dr. Drobyski and his colleagues performed a matched case-control analysis using contemporary controls in the Center for International Blood & Marrow Transplant Research from 2000 to 2014. The same eligibility criteria used for the trial were applied to the matched controls except for the use of Tac/MTX as GVHD prophylaxis. Patients were otherwise matched based on age, performance score, disease, and donor type.
The incidence of grades II-IV acute GVHD at day 100 was significantly lower in the Toc/Tac/MTX group than in the Tac/MTX control population (12% vs. 41%). The incidence of grades III-IV acute GVHD was slightly lower with tocilizumab, but the difference between the groups was not statistically significant, Dr. Drobyski said.
The probability of grade II-IV acute GVHD–free survival, which was the primary endpoint of the study, was significantly higher in the Toc/Tac/MTX group (79% vs 52%), he said.
Five patients developed grade 2 acute GVHD of the skin or upper GI tract, and one patient died of grade 4 acute GVHD of the skin in the first 100 days. Notably, there were no cases of acute GVHD of the lower GI tract during that time, although two cases did occur between days 130 and 180, he said.
“There was no difference in transplant-related mortality, relapse, disease-free survival, or overall survival,” he said, adding that preliminary data suggest there were no differences in chronic GVHD between the groups.
Causes of death also were similar between the two cohorts with respect to disease- and transplant-related complications.
Patients in the tocilizumab study were enrolled between January 2015 and June 2016; the median age was 66 years. Diseases represented in the cohort included de novo acute myeloid leukemia (13 patients), AML (6 patients), chronic myelomonocytic leukemia (6 patients), acute lymphoblastic leukemia (4 patients), myelodysplastic syndrome (3 patients), and T-cell lymphoma, chronic myeloid leukemia, and NK/T cell lymphoma (in 1 patient each). Most patients were classified as high risk (9 patients) or intermediate risk (22 patients) by the disease risk index.
Conditioning was entirely busulfan based. Myeloablative conditioning was with busulfan and cyclophosphamide (Cytoxan) in 5 patients, or fludarabine and 4 days of busulfan in 10 patients, and reduced-intensity conditioning was with fludarabine and 2 days of busulfan in 18 patients. Transplants were with either HLA-matched related or unrelated donor grafts. Most patients (29 of 35) received peripheral stem cell grafts.
Tocilizumab, an interleuken-6 receptor blocker that is approved for treatment of rheumatoid arthritis, was administered after completion of conditioning and on the day prior to stem cell infusion.
In a pilot clinical trial of tocilizumab for the treatment of steroid-resistant acute GVHD in patients who had primarily had lower GI tract disease, “we were able to demonstrate responses in a majority of these patients,” Dr. Drobyski said, noting that a recent study presented at the 2016 annual meeting of the American Society of Hematology also showed efficacy in the treatment of lower tract GI GVHD, “providing evidence that tocilizumab had activity in acute GVHD, and perhaps in the treatment of steroid-refractory lower GI GVHD.”
Elevated IL-6 levels in the peripheral blood are correlated with an increased incidence and severity of GVHD; administration of an anti-IL-6 receptor antibody has been shown in preclinical studies to protect mice from lethal GVHD. The current open-label study was performed to “try to advance this concept” by assessing whether inhibition of IL-6 signaling could also prevent acute GVHD.
The findings confirm those of a 2014 study by Kennedy et al. in Lancet Oncology (2014;15:1451-9), and imply that tocilizumab warrants a randomized trial as prophylaxis for acute GVHD, he concluded.
Dr. Drobyski reported having no disclosures.
Key clinical point:
Major finding: The probability of grade II-IV acute GVHD-free survival was 79% vs. 52% in the tocilizumab group vs. age-matched controls.
Data source: An open-label phase II study of 35 patients.
Disclosures: Dr. Drobyski reported having no disclosures.
AGA releases POWER – an obesity practice guide for gastroenterologists
The obesity epidemic has reached critical proportions. A new practice guide from the American Gastroenterological Association aims to help gastroenterologists engage in a multidisciplinary effort to tackle the problem.
The guide, entitled “POWER: Practice Guide on Obesity and Weight Management, Education and Resources,” includes a comprehensive clinical process for assessing and safely and effectively managing patients with obesity, as well as a framework focused on helping practitioners navigate the business operational issues related to the management of obesity. Both are in press for the May issue of Clinical Gastroenterology and Hepatology (2016. doi: 10.1016/j.cgh.2016.10.023).
The POWER model recognizes obesity as an epidemic and as an economic and societal burden that should be embraced as a chronic, relapsing disease best managed across a flexible care cycle using a team approach.
“Every single gastroenterologist is at the front line of this obesity epidemic. Before patients develop diabetes or joint problems or cardiovascular disease, they are already in our clinics, they already have [gastroesophageal reflux disease], they have nonalcoholic fatty liver disease, they have colon cancer – and those conditions present even earlier than the other complications of obesity,” said Dr. Acosta of the Mayo Clinic, Rochester, Minn.
The guide is a model for addressing obesity – the root cause of many of these conditions – rather than simply treating its symptoms, he added.
The approach to obesity management promoted by POWER involves four phases along a continuum of care: assessment, intensive weight loss intervention, weight stabilization and reintensification when needed, and prevention of weight regain.
Lifestyle changes are the cornerstones of obesity management and maintenance of weight loss, but the POWER model includes much more, as it incorporates guidance on the use of pharmacotherapy, bariatric endoscopy, and surgery.
“We tried to make it extremely simple, bringing it down to the busy clinician level,” Dr. Acosta said. “We want to be able to embrace and tackle obesity... in a very straightforward manner.”
Gastroenterologists shouldn’t be afraid of taking on obesity, he added.
“We feel comfortable managing extremely complicated medications, so we should be able to handle the obesity medications. We are already endoscopists... so we want all gastroenterologists to say, ‘I can do this, too; I can incorporate this into my practice,’ ” he said.
Further, gastroenterologists already have a relationship with bariatric surgeons, so referring those with obesity for surgery if appropriate is also simple, he added.
When it comes to moving through the four phases of care, each should be addressed separately using the best evidence available. Realistic goals should be set, and only when those goals are met should care move to the next phase, according to the guide. Learn how to implement the AGA Obesity Practice Guide at www.gastro.org/obesity.
The assessment phase should include a medical evaluation to identify underlying etiologies, screen for causes of secondary weight gain, and identify related comorbidities. A nutrition evaluation should focus not only on nutritional status and appetite, but also on the patient’s relationship with food, food allergies and intolerances, and food environment. A physical activity/exercise evaluation should explore the patient’s activity level and preferences, as well as limiting factors such as joint disease.
A psychosocial evaluation is particularly important, as behavioral modification is a critical component of successful obesity management, and some patients – such as those with a low score on the weight Efficacy Lifestyle Questionnaire Short-Form – may benefit from referral to a health care professional experienced in obesity counseling and behavioral therapy.
Gastroenterologists already work with other specialists, including nutritionists, psychiatrists, and psychologists within their institutions and communities, so the POWER model is an extension of that.
“That’s what this proposes – a multidisciplinary team effort,” he said.
The approach to treatment should be based on the findings of these assessments.
“Physicians should discuss all the appropriate options and their expected weight loss, potential side effects, and figure in the patient’s wishes and goals. Furthermore, physicians should recognize special comorbidities that may favor one intervention over another,” the authors wrote.
The intensive weight loss intervention phase should be based on modest initial weight loss goals, which increase the likelihood of success, increase patient confidence, and encourage ongoing efforts to lose weight. Further, modest weight loss vs. larger amounts of weight loss is more easily achieved and maintained. In addition to lifestyle changes, an evaluation of whether other interventions are needed is important, particularly in patients with weight regain or plateaus in weight loss.
The weight stabilization and intensification therapy for relapse phase is essential to prevent weight regain and its associated consequences. This phase introduces patients to the attitudes and behaviors that are likely to lead to long-term maintenance of weight loss, the authors note.
The prevention of weight regain phase – a maintenance phase – is unique among obesity care guidelines, and is a critical component of obesity management, Dr. Acosta said.
“Helping patients lose weight and keep it off requires a comprehensive and sustained effort that involves devising an individualized approach to diet, behavior, and exercise,” he and his colleagues wrote.
In addition to detailed steps and tips for moving through this care cycle, the POWER guide also details the various tools to facilitate adherence to a healthier diet and lifestyle. Various medications, including phentermine, extended-release phentermine/topiramate, lorcaserin, and liraglutide are described, as are various types of bariatric endoscopy and bariatric surgery.
A section on addressing the unique needs of obese children and adolescents is also included in the guide for those gastroenterologists who treat children.
“Obesity really begins in childhood, so it is a pediatric disease in its origin, so it was important to us to incorporate issues unique to children for our pediatric GI colleagues,” Dr. Streett said.
Importantly, the practice guide was developed with input from the Society of American Gastrointestinal and Endoscopic Surgeons, The Obesity Society, the Academy of Nutrition and Dietetics, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. and the program has been endorsed with additional input by the American Society for Gastrointestinal Endoscopy, American Society for Metabolic and Bariatric Surgery, American Association for the Study of Liver Diseases, and the Obesity Medicine Association.
This collaborative approach is also unique among existing guidelines, and is important, given the need for practitioners across the care spectrum to work together to address obesity, she said.
“What we’ve been doing [individually] hasn’t worked successfully, so that is something that people recognize in the field of medicine: Obesity is something that has physiological, nutritional, dietetic, socioeconomic, and behavioral aspects and we need to have a multipronged approach for success. We need patients to be hearing similar messages and having their care integrated,” she said, adding that “as we move toward a value-based schema, this is the perfect disorder to address in that way.”
Dr. Acosta is a stockholder of Gila Therapeutics and serves on the scientific advisory board or board of directors of Gila Therapeutics, Inversago, and General Mills. Dr. Streett reported having no disclosures.
The obesity epidemic has reached critical proportions. A new practice guide from the American Gastroenterological Association aims to help gastroenterologists engage in a multidisciplinary effort to tackle the problem.
The guide, entitled “POWER: Practice Guide on Obesity and Weight Management, Education and Resources,” includes a comprehensive clinical process for assessing and safely and effectively managing patients with obesity, as well as a framework focused on helping practitioners navigate the business operational issues related to the management of obesity. Both are in press for the May issue of Clinical Gastroenterology and Hepatology (2016. doi: 10.1016/j.cgh.2016.10.023).
The POWER model recognizes obesity as an epidemic and as an economic and societal burden that should be embraced as a chronic, relapsing disease best managed across a flexible care cycle using a team approach.
“Every single gastroenterologist is at the front line of this obesity epidemic. Before patients develop diabetes or joint problems or cardiovascular disease, they are already in our clinics, they already have [gastroesophageal reflux disease], they have nonalcoholic fatty liver disease, they have colon cancer – and those conditions present even earlier than the other complications of obesity,” said Dr. Acosta of the Mayo Clinic, Rochester, Minn.
The guide is a model for addressing obesity – the root cause of many of these conditions – rather than simply treating its symptoms, he added.
The approach to obesity management promoted by POWER involves four phases along a continuum of care: assessment, intensive weight loss intervention, weight stabilization and reintensification when needed, and prevention of weight regain.
Lifestyle changes are the cornerstones of obesity management and maintenance of weight loss, but the POWER model includes much more, as it incorporates guidance on the use of pharmacotherapy, bariatric endoscopy, and surgery.
“We tried to make it extremely simple, bringing it down to the busy clinician level,” Dr. Acosta said. “We want to be able to embrace and tackle obesity... in a very straightforward manner.”
Gastroenterologists shouldn’t be afraid of taking on obesity, he added.
“We feel comfortable managing extremely complicated medications, so we should be able to handle the obesity medications. We are already endoscopists... so we want all gastroenterologists to say, ‘I can do this, too; I can incorporate this into my practice,’ ” he said.
Further, gastroenterologists already have a relationship with bariatric surgeons, so referring those with obesity for surgery if appropriate is also simple, he added.
When it comes to moving through the four phases of care, each should be addressed separately using the best evidence available. Realistic goals should be set, and only when those goals are met should care move to the next phase, according to the guide. Learn how to implement the AGA Obesity Practice Guide at www.gastro.org/obesity.
The assessment phase should include a medical evaluation to identify underlying etiologies, screen for causes of secondary weight gain, and identify related comorbidities. A nutrition evaluation should focus not only on nutritional status and appetite, but also on the patient’s relationship with food, food allergies and intolerances, and food environment. A physical activity/exercise evaluation should explore the patient’s activity level and preferences, as well as limiting factors such as joint disease.
A psychosocial evaluation is particularly important, as behavioral modification is a critical component of successful obesity management, and some patients – such as those with a low score on the weight Efficacy Lifestyle Questionnaire Short-Form – may benefit from referral to a health care professional experienced in obesity counseling and behavioral therapy.
Gastroenterologists already work with other specialists, including nutritionists, psychiatrists, and psychologists within their institutions and communities, so the POWER model is an extension of that.
“That’s what this proposes – a multidisciplinary team effort,” he said.
The approach to treatment should be based on the findings of these assessments.
“Physicians should discuss all the appropriate options and their expected weight loss, potential side effects, and figure in the patient’s wishes and goals. Furthermore, physicians should recognize special comorbidities that may favor one intervention over another,” the authors wrote.
The intensive weight loss intervention phase should be based on modest initial weight loss goals, which increase the likelihood of success, increase patient confidence, and encourage ongoing efforts to lose weight. Further, modest weight loss vs. larger amounts of weight loss is more easily achieved and maintained. In addition to lifestyle changes, an evaluation of whether other interventions are needed is important, particularly in patients with weight regain or plateaus in weight loss.
The weight stabilization and intensification therapy for relapse phase is essential to prevent weight regain and its associated consequences. This phase introduces patients to the attitudes and behaviors that are likely to lead to long-term maintenance of weight loss, the authors note.
The prevention of weight regain phase – a maintenance phase – is unique among obesity care guidelines, and is a critical component of obesity management, Dr. Acosta said.
“Helping patients lose weight and keep it off requires a comprehensive and sustained effort that involves devising an individualized approach to diet, behavior, and exercise,” he and his colleagues wrote.
In addition to detailed steps and tips for moving through this care cycle, the POWER guide also details the various tools to facilitate adherence to a healthier diet and lifestyle. Various medications, including phentermine, extended-release phentermine/topiramate, lorcaserin, and liraglutide are described, as are various types of bariatric endoscopy and bariatric surgery.
A section on addressing the unique needs of obese children and adolescents is also included in the guide for those gastroenterologists who treat children.
“Obesity really begins in childhood, so it is a pediatric disease in its origin, so it was important to us to incorporate issues unique to children for our pediatric GI colleagues,” Dr. Streett said.
Importantly, the practice guide was developed with input from the Society of American Gastrointestinal and Endoscopic Surgeons, The Obesity Society, the Academy of Nutrition and Dietetics, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. and the program has been endorsed with additional input by the American Society for Gastrointestinal Endoscopy, American Society for Metabolic and Bariatric Surgery, American Association for the Study of Liver Diseases, and the Obesity Medicine Association.
This collaborative approach is also unique among existing guidelines, and is important, given the need for practitioners across the care spectrum to work together to address obesity, she said.
“What we’ve been doing [individually] hasn’t worked successfully, so that is something that people recognize in the field of medicine: Obesity is something that has physiological, nutritional, dietetic, socioeconomic, and behavioral aspects and we need to have a multipronged approach for success. We need patients to be hearing similar messages and having their care integrated,” she said, adding that “as we move toward a value-based schema, this is the perfect disorder to address in that way.”
Dr. Acosta is a stockholder of Gila Therapeutics and serves on the scientific advisory board or board of directors of Gila Therapeutics, Inversago, and General Mills. Dr. Streett reported having no disclosures.
The obesity epidemic has reached critical proportions. A new practice guide from the American Gastroenterological Association aims to help gastroenterologists engage in a multidisciplinary effort to tackle the problem.
The guide, entitled “POWER: Practice Guide on Obesity and Weight Management, Education and Resources,” includes a comprehensive clinical process for assessing and safely and effectively managing patients with obesity, as well as a framework focused on helping practitioners navigate the business operational issues related to the management of obesity. Both are in press for the May issue of Clinical Gastroenterology and Hepatology (2016. doi: 10.1016/j.cgh.2016.10.023).
The POWER model recognizes obesity as an epidemic and as an economic and societal burden that should be embraced as a chronic, relapsing disease best managed across a flexible care cycle using a team approach.
“Every single gastroenterologist is at the front line of this obesity epidemic. Before patients develop diabetes or joint problems or cardiovascular disease, they are already in our clinics, they already have [gastroesophageal reflux disease], they have nonalcoholic fatty liver disease, they have colon cancer – and those conditions present even earlier than the other complications of obesity,” said Dr. Acosta of the Mayo Clinic, Rochester, Minn.
The guide is a model for addressing obesity – the root cause of many of these conditions – rather than simply treating its symptoms, he added.
The approach to obesity management promoted by POWER involves four phases along a continuum of care: assessment, intensive weight loss intervention, weight stabilization and reintensification when needed, and prevention of weight regain.
Lifestyle changes are the cornerstones of obesity management and maintenance of weight loss, but the POWER model includes much more, as it incorporates guidance on the use of pharmacotherapy, bariatric endoscopy, and surgery.
“We tried to make it extremely simple, bringing it down to the busy clinician level,” Dr. Acosta said. “We want to be able to embrace and tackle obesity... in a very straightforward manner.”
Gastroenterologists shouldn’t be afraid of taking on obesity, he added.
“We feel comfortable managing extremely complicated medications, so we should be able to handle the obesity medications. We are already endoscopists... so we want all gastroenterologists to say, ‘I can do this, too; I can incorporate this into my practice,’ ” he said.
Further, gastroenterologists already have a relationship with bariatric surgeons, so referring those with obesity for surgery if appropriate is also simple, he added.
When it comes to moving through the four phases of care, each should be addressed separately using the best evidence available. Realistic goals should be set, and only when those goals are met should care move to the next phase, according to the guide. Learn how to implement the AGA Obesity Practice Guide at www.gastro.org/obesity.
The assessment phase should include a medical evaluation to identify underlying etiologies, screen for causes of secondary weight gain, and identify related comorbidities. A nutrition evaluation should focus not only on nutritional status and appetite, but also on the patient’s relationship with food, food allergies and intolerances, and food environment. A physical activity/exercise evaluation should explore the patient’s activity level and preferences, as well as limiting factors such as joint disease.
A psychosocial evaluation is particularly important, as behavioral modification is a critical component of successful obesity management, and some patients – such as those with a low score on the weight Efficacy Lifestyle Questionnaire Short-Form – may benefit from referral to a health care professional experienced in obesity counseling and behavioral therapy.
Gastroenterologists already work with other specialists, including nutritionists, psychiatrists, and psychologists within their institutions and communities, so the POWER model is an extension of that.
“That’s what this proposes – a multidisciplinary team effort,” he said.
The approach to treatment should be based on the findings of these assessments.
“Physicians should discuss all the appropriate options and their expected weight loss, potential side effects, and figure in the patient’s wishes and goals. Furthermore, physicians should recognize special comorbidities that may favor one intervention over another,” the authors wrote.
The intensive weight loss intervention phase should be based on modest initial weight loss goals, which increase the likelihood of success, increase patient confidence, and encourage ongoing efforts to lose weight. Further, modest weight loss vs. larger amounts of weight loss is more easily achieved and maintained. In addition to lifestyle changes, an evaluation of whether other interventions are needed is important, particularly in patients with weight regain or plateaus in weight loss.
The weight stabilization and intensification therapy for relapse phase is essential to prevent weight regain and its associated consequences. This phase introduces patients to the attitudes and behaviors that are likely to lead to long-term maintenance of weight loss, the authors note.
The prevention of weight regain phase – a maintenance phase – is unique among obesity care guidelines, and is a critical component of obesity management, Dr. Acosta said.
“Helping patients lose weight and keep it off requires a comprehensive and sustained effort that involves devising an individualized approach to diet, behavior, and exercise,” he and his colleagues wrote.
In addition to detailed steps and tips for moving through this care cycle, the POWER guide also details the various tools to facilitate adherence to a healthier diet and lifestyle. Various medications, including phentermine, extended-release phentermine/topiramate, lorcaserin, and liraglutide are described, as are various types of bariatric endoscopy and bariatric surgery.
A section on addressing the unique needs of obese children and adolescents is also included in the guide for those gastroenterologists who treat children.
“Obesity really begins in childhood, so it is a pediatric disease in its origin, so it was important to us to incorporate issues unique to children for our pediatric GI colleagues,” Dr. Streett said.
Importantly, the practice guide was developed with input from the Society of American Gastrointestinal and Endoscopic Surgeons, The Obesity Society, the Academy of Nutrition and Dietetics, and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition. and the program has been endorsed with additional input by the American Society for Gastrointestinal Endoscopy, American Society for Metabolic and Bariatric Surgery, American Association for the Study of Liver Diseases, and the Obesity Medicine Association.
This collaborative approach is also unique among existing guidelines, and is important, given the need for practitioners across the care spectrum to work together to address obesity, she said.
“What we’ve been doing [individually] hasn’t worked successfully, so that is something that people recognize in the field of medicine: Obesity is something that has physiological, nutritional, dietetic, socioeconomic, and behavioral aspects and we need to have a multipronged approach for success. We need patients to be hearing similar messages and having their care integrated,” she said, adding that “as we move toward a value-based schema, this is the perfect disorder to address in that way.”
Dr. Acosta is a stockholder of Gila Therapeutics and serves on the scientific advisory board or board of directors of Gila Therapeutics, Inversago, and General Mills. Dr. Streett reported having no disclosures.
Venetoclax produces durable effects in relapsed/refractory CLL
ORLANDO – In patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the results with venetoclax continue to be encouraging, and recent findings from a multicenter phase Ib study hint that venetoclax may also provide durable responses – even with treatment discontinuation.
Venetoclax is an orally bioavailable selective BCL2 inhibitor that is typically given in an open-ended fashion. Toxicity – including tumor lysis syndrome – is always a concern, however, and the issue of whether open-ended administration is necessary is an important question, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.
In one phase II multicenter study of venetoclax monotherapy in 107 patients with relapsed/refractory CLL with del(17p) at 31 centers in the United States, Canada, and Europe, the overall response rate was 79.4% based on an independent review committee assessment, (Lancet Oncol. 2016[17]:768-78).
Treatment included once-daily venetoclax beginning with a dose of 20 mg that was ramped up to 50, 100, 200, and 400 mg over 4-5 weeks, followed by daily 400 mg continuous dosing until disease progression or discontinuation for another reason.
Notably, 18 of 85 patients from the study who achieved an objective response were minimal residual disease (MRD)–negative in peripheral blood samples – an outcome that has not been seen with tyrosine kinase inhibitors, noted Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York.
The durability of venetoclax’s activity in the study was 84.7% at 12 months in all responders; 100% in those who achieved complete response, complete response with incomplete recovery of blood counts, or nodular partial remission; and 94.4% in the MRD-negative patients.
The authors concluded that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, and that given the distinct mechanism of action of this new therapeutic option for these very poor-prognosis patients, it deserves further investigation as part of a combination or as part of sequential treatment with other novel targeted agents.
The finding that patients on venetoclax can achieve MRD negativity also raised the question of whether treatment can be stopped, Dr. Zelenetz said.
“Because who wants to be on a drug forever? Nobody,” he added.
This question was explored in a study published in February by Seymour et al., which provided early evidence that stopping treatment may indeed be feasible in some patients (Lancet Oncol. 2017;18[2]:230-40).
Venetoclax in this study was given in a dose-escalating fashion to target doses of 200-600 mg daily, in 49 patients with relapsed or refractory “moderately heavily pretreated” CLL. Rituximab was added at a dose of 375 mg/m2 in month 1 and 500 mg/m2 in months 2-6.
Patients had the option of stopping treatment if they achieved a complete response.
The overall response rate was 86%, including a complete response in 51% of patients. Two-year estimates for progression-free survival and ongoing response were 82% and 89% respectively.
MRD negativity was attained in 80% of complete responders and 57% of patients overall. Thirteen responders discontinued all treatment, and at the time of publication, 11 MRD-negative responders who discontinued therapy remained progression free off therapy. Two MRD-positive patients who achieved complete response and discontinued therapy progressed after 2 years, but were able to recapture response once they restarted the drug.
“So it’s really quite interesting. We might have durable responses after discontinuation of this drug in an MRD-negative state,” Dr. Zelenetz said.
Of note, the latest update to the NCCN guidelines for the treatment of CLL/SLL (small lymphocytic lymphoma) included the addition of “+/– rituximab” as part of the “suggested treatment regimen” of venetoclax in the relapsed/refractory disease setting. This recommendation is category 2A, meaning it is based on lower level evidence with uniform NCCN consensus that the intervention is appropriate.
Venetoclax: adverse events of special interest
In these studies, venetoclax was considered well tolerated, but attention to adverse events and their prevention and management – particularly with respect to tumor lysis syndrome – is essential, Dr. Zelenetz said.
In the phase II study by Stilgenbauer et al., adverse events of special interest included grade 3/4 neutropenia, which occurred in 40% of patients. This was manageable with dose interruptions (five patients) or reductions (four patients), or with granulocyte–colony stimulating factor and antibiotics (six patients, including one who received only antibiotics). None of the patients permanently discontinued treatment.
Infections occurred in 72% of patients, and grade 3 or greater infections occurred in 20% of patients. The most common overall were upper respiratory infections (15%), nasopharyngitis (14%), and urinary tract infections (9%).
Serious infections occurring in two or more patients were pneumonia, lower respiratory tract infection, and upper respiratory tract infection. One patient died from septic shock, 10 had infections leading to venetoclax interruption, and 2 had infections leading to dose reduction.
No mandated infection prophylaxis was used in this study.
Serious adverse events occurred in 59 patients (55%). The most common, occurring in at least 5% of patients, were pyrexia, autoimmune hemolytic anemia, pneumonia, and febrile neutropenia. Thirteen had adverse events leading to dose reductions, most commonly due to neutropenia, thrombocytopenia, and febrile neutropenia.
Laboratory-confirmed tumor lysis syndrome was reported in five patients during the ramp-up period, including four who developed the syndrome within the first 2 days of treatment. All cases resolved without clinical sequelae. Treatment was continued without interruption in three patients with tumor lysis syndrome, who received only electrolyte management, and two patients had a 1-day treatment interruption. Both resumed dosing the next day.
In the phase Ib study by Seymour et al., common grade 1-2 toxicities included upper respiratory tract infections, diarrhea, and nausea occurring in 57%, 55%, and 53% of patients, respectively. Grade 3-4 adverse events occurred in 76% of 49 patients, and most often included neutropenia (12% of patients), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%). The most common serious adverse events were pyrexia (12%), febrile neutropenia (10%), lower respiratory tract infection (6%), and pneumonia (6%). Clinical tumor lysis syndrome occurred in two patients who initiated venetoclax at 50 mg, one of whom died as a result.
After enhancement of tumor lysis syndrome prophylaxis measures and reduction of the starting dose of venetoclax to 20 mg, no additional cases occurred, the authors reported.
Mitigating tumor lysis syndrome risk
General measures for mitigating the risk of tumor lysis syndrome include identification of patients at increased risk, initiation of prophylaxis with hydration and a uric acid reducing agent, and initiation of venetoclax at a 20 mg dose for 1 week, with gradual step-wise ramp-up over 5 weeks to the target dose, Dr. Zelenetz noted.
As reported by Stilgenbauer, et al., patients with a nodal mass less than 5 cm and absolute lymphocyte count (ALC) of 25,000 or less are considered at low risk for tumor lysis syndrome, those with a nodal mass of 5 cm to less than 10 cm or ALC greater than 25,000 are at medium risk, and those with a nodal mass of 10 cm or greater or nodal mass of 5 cm or greater and ALC of greater than 25,000 are considered to be at high risk.
High-risk patients in the study received inpatient venetoclax dosing and monitoring at 4, 8, 12, and 24 hours with 20 mg and 50 mg dosing, as well as outpatient intravenous hydration at 100 mg if there was no indication to hospitalize, and post-dose 8-24 hour laboratory monitoring at 100 mg and above.
Medium-risk patients received IV hydration at 20 and 50 mg dosing, inpatient care if creatinine clearance was less than 80 mL/min or if there was a high tumor burden, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose escalations. Low-risk patients received outpatient dosing at all dose levels in the absence of an indication to hospitalize, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose increases.
“Unfortunately, the dose-limiting toxicity of venetoclax is fatal tumor lysis,” Dr. Zelenetz said, adding that by increasing the dose slowly over time according to current treatment recommendations – from 20 mg, to 50, 100, 200, and 400 mg at weekly intervals, this complication can be avoided.
Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Genentech, the maker of venetoclax (Venclexta), and a wide variety of other drug companies.
ORLANDO – In patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the results with venetoclax continue to be encouraging, and recent findings from a multicenter phase Ib study hint that venetoclax may also provide durable responses – even with treatment discontinuation.
Venetoclax is an orally bioavailable selective BCL2 inhibitor that is typically given in an open-ended fashion. Toxicity – including tumor lysis syndrome – is always a concern, however, and the issue of whether open-ended administration is necessary is an important question, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.
In one phase II multicenter study of venetoclax monotherapy in 107 patients with relapsed/refractory CLL with del(17p) at 31 centers in the United States, Canada, and Europe, the overall response rate was 79.4% based on an independent review committee assessment, (Lancet Oncol. 2016[17]:768-78).
Treatment included once-daily venetoclax beginning with a dose of 20 mg that was ramped up to 50, 100, 200, and 400 mg over 4-5 weeks, followed by daily 400 mg continuous dosing until disease progression or discontinuation for another reason.
Notably, 18 of 85 patients from the study who achieved an objective response were minimal residual disease (MRD)–negative in peripheral blood samples – an outcome that has not been seen with tyrosine kinase inhibitors, noted Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York.
The durability of venetoclax’s activity in the study was 84.7% at 12 months in all responders; 100% in those who achieved complete response, complete response with incomplete recovery of blood counts, or nodular partial remission; and 94.4% in the MRD-negative patients.
The authors concluded that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, and that given the distinct mechanism of action of this new therapeutic option for these very poor-prognosis patients, it deserves further investigation as part of a combination or as part of sequential treatment with other novel targeted agents.
The finding that patients on venetoclax can achieve MRD negativity also raised the question of whether treatment can be stopped, Dr. Zelenetz said.
“Because who wants to be on a drug forever? Nobody,” he added.
This question was explored in a study published in February by Seymour et al., which provided early evidence that stopping treatment may indeed be feasible in some patients (Lancet Oncol. 2017;18[2]:230-40).
Venetoclax in this study was given in a dose-escalating fashion to target doses of 200-600 mg daily, in 49 patients with relapsed or refractory “moderately heavily pretreated” CLL. Rituximab was added at a dose of 375 mg/m2 in month 1 and 500 mg/m2 in months 2-6.
Patients had the option of stopping treatment if they achieved a complete response.
The overall response rate was 86%, including a complete response in 51% of patients. Two-year estimates for progression-free survival and ongoing response were 82% and 89% respectively.
MRD negativity was attained in 80% of complete responders and 57% of patients overall. Thirteen responders discontinued all treatment, and at the time of publication, 11 MRD-negative responders who discontinued therapy remained progression free off therapy. Two MRD-positive patients who achieved complete response and discontinued therapy progressed after 2 years, but were able to recapture response once they restarted the drug.
“So it’s really quite interesting. We might have durable responses after discontinuation of this drug in an MRD-negative state,” Dr. Zelenetz said.
Of note, the latest update to the NCCN guidelines for the treatment of CLL/SLL (small lymphocytic lymphoma) included the addition of “+/– rituximab” as part of the “suggested treatment regimen” of venetoclax in the relapsed/refractory disease setting. This recommendation is category 2A, meaning it is based on lower level evidence with uniform NCCN consensus that the intervention is appropriate.
Venetoclax: adverse events of special interest
In these studies, venetoclax was considered well tolerated, but attention to adverse events and their prevention and management – particularly with respect to tumor lysis syndrome – is essential, Dr. Zelenetz said.
In the phase II study by Stilgenbauer et al., adverse events of special interest included grade 3/4 neutropenia, which occurred in 40% of patients. This was manageable with dose interruptions (five patients) or reductions (four patients), or with granulocyte–colony stimulating factor and antibiotics (six patients, including one who received only antibiotics). None of the patients permanently discontinued treatment.
Infections occurred in 72% of patients, and grade 3 or greater infections occurred in 20% of patients. The most common overall were upper respiratory infections (15%), nasopharyngitis (14%), and urinary tract infections (9%).
Serious infections occurring in two or more patients were pneumonia, lower respiratory tract infection, and upper respiratory tract infection. One patient died from septic shock, 10 had infections leading to venetoclax interruption, and 2 had infections leading to dose reduction.
No mandated infection prophylaxis was used in this study.
Serious adverse events occurred in 59 patients (55%). The most common, occurring in at least 5% of patients, were pyrexia, autoimmune hemolytic anemia, pneumonia, and febrile neutropenia. Thirteen had adverse events leading to dose reductions, most commonly due to neutropenia, thrombocytopenia, and febrile neutropenia.
Laboratory-confirmed tumor lysis syndrome was reported in five patients during the ramp-up period, including four who developed the syndrome within the first 2 days of treatment. All cases resolved without clinical sequelae. Treatment was continued without interruption in three patients with tumor lysis syndrome, who received only electrolyte management, and two patients had a 1-day treatment interruption. Both resumed dosing the next day.
In the phase Ib study by Seymour et al., common grade 1-2 toxicities included upper respiratory tract infections, diarrhea, and nausea occurring in 57%, 55%, and 53% of patients, respectively. Grade 3-4 adverse events occurred in 76% of 49 patients, and most often included neutropenia (12% of patients), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%). The most common serious adverse events were pyrexia (12%), febrile neutropenia (10%), lower respiratory tract infection (6%), and pneumonia (6%). Clinical tumor lysis syndrome occurred in two patients who initiated venetoclax at 50 mg, one of whom died as a result.
After enhancement of tumor lysis syndrome prophylaxis measures and reduction of the starting dose of venetoclax to 20 mg, no additional cases occurred, the authors reported.
Mitigating tumor lysis syndrome risk
General measures for mitigating the risk of tumor lysis syndrome include identification of patients at increased risk, initiation of prophylaxis with hydration and a uric acid reducing agent, and initiation of venetoclax at a 20 mg dose for 1 week, with gradual step-wise ramp-up over 5 weeks to the target dose, Dr. Zelenetz noted.
As reported by Stilgenbauer, et al., patients with a nodal mass less than 5 cm and absolute lymphocyte count (ALC) of 25,000 or less are considered at low risk for tumor lysis syndrome, those with a nodal mass of 5 cm to less than 10 cm or ALC greater than 25,000 are at medium risk, and those with a nodal mass of 10 cm or greater or nodal mass of 5 cm or greater and ALC of greater than 25,000 are considered to be at high risk.
High-risk patients in the study received inpatient venetoclax dosing and monitoring at 4, 8, 12, and 24 hours with 20 mg and 50 mg dosing, as well as outpatient intravenous hydration at 100 mg if there was no indication to hospitalize, and post-dose 8-24 hour laboratory monitoring at 100 mg and above.
Medium-risk patients received IV hydration at 20 and 50 mg dosing, inpatient care if creatinine clearance was less than 80 mL/min or if there was a high tumor burden, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose escalations. Low-risk patients received outpatient dosing at all dose levels in the absence of an indication to hospitalize, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose increases.
“Unfortunately, the dose-limiting toxicity of venetoclax is fatal tumor lysis,” Dr. Zelenetz said, adding that by increasing the dose slowly over time according to current treatment recommendations – from 20 mg, to 50, 100, 200, and 400 mg at weekly intervals, this complication can be avoided.
Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Genentech, the maker of venetoclax (Venclexta), and a wide variety of other drug companies.
ORLANDO – In patients with relapsed or refractory chronic lymphocytic leukemia (CLL), the results with venetoclax continue to be encouraging, and recent findings from a multicenter phase Ib study hint that venetoclax may also provide durable responses – even with treatment discontinuation.
Venetoclax is an orally bioavailable selective BCL2 inhibitor that is typically given in an open-ended fashion. Toxicity – including tumor lysis syndrome – is always a concern, however, and the issue of whether open-ended administration is necessary is an important question, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.
In one phase II multicenter study of venetoclax monotherapy in 107 patients with relapsed/refractory CLL with del(17p) at 31 centers in the United States, Canada, and Europe, the overall response rate was 79.4% based on an independent review committee assessment, (Lancet Oncol. 2016[17]:768-78).
Treatment included once-daily venetoclax beginning with a dose of 20 mg that was ramped up to 50, 100, 200, and 400 mg over 4-5 weeks, followed by daily 400 mg continuous dosing until disease progression or discontinuation for another reason.
Notably, 18 of 85 patients from the study who achieved an objective response were minimal residual disease (MRD)–negative in peripheral blood samples – an outcome that has not been seen with tyrosine kinase inhibitors, noted Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York.
The durability of venetoclax’s activity in the study was 84.7% at 12 months in all responders; 100% in those who achieved complete response, complete response with incomplete recovery of blood counts, or nodular partial remission; and 94.4% in the MRD-negative patients.
The authors concluded that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukemia, and that given the distinct mechanism of action of this new therapeutic option for these very poor-prognosis patients, it deserves further investigation as part of a combination or as part of sequential treatment with other novel targeted agents.
The finding that patients on venetoclax can achieve MRD negativity also raised the question of whether treatment can be stopped, Dr. Zelenetz said.
“Because who wants to be on a drug forever? Nobody,” he added.
This question was explored in a study published in February by Seymour et al., which provided early evidence that stopping treatment may indeed be feasible in some patients (Lancet Oncol. 2017;18[2]:230-40).
Venetoclax in this study was given in a dose-escalating fashion to target doses of 200-600 mg daily, in 49 patients with relapsed or refractory “moderately heavily pretreated” CLL. Rituximab was added at a dose of 375 mg/m2 in month 1 and 500 mg/m2 in months 2-6.
Patients had the option of stopping treatment if they achieved a complete response.
The overall response rate was 86%, including a complete response in 51% of patients. Two-year estimates for progression-free survival and ongoing response were 82% and 89% respectively.
MRD negativity was attained in 80% of complete responders and 57% of patients overall. Thirteen responders discontinued all treatment, and at the time of publication, 11 MRD-negative responders who discontinued therapy remained progression free off therapy. Two MRD-positive patients who achieved complete response and discontinued therapy progressed after 2 years, but were able to recapture response once they restarted the drug.
“So it’s really quite interesting. We might have durable responses after discontinuation of this drug in an MRD-negative state,” Dr. Zelenetz said.
Of note, the latest update to the NCCN guidelines for the treatment of CLL/SLL (small lymphocytic lymphoma) included the addition of “+/– rituximab” as part of the “suggested treatment regimen” of venetoclax in the relapsed/refractory disease setting. This recommendation is category 2A, meaning it is based on lower level evidence with uniform NCCN consensus that the intervention is appropriate.
Venetoclax: adverse events of special interest
In these studies, venetoclax was considered well tolerated, but attention to adverse events and their prevention and management – particularly with respect to tumor lysis syndrome – is essential, Dr. Zelenetz said.
In the phase II study by Stilgenbauer et al., adverse events of special interest included grade 3/4 neutropenia, which occurred in 40% of patients. This was manageable with dose interruptions (five patients) or reductions (four patients), or with granulocyte–colony stimulating factor and antibiotics (six patients, including one who received only antibiotics). None of the patients permanently discontinued treatment.
Infections occurred in 72% of patients, and grade 3 or greater infections occurred in 20% of patients. The most common overall were upper respiratory infections (15%), nasopharyngitis (14%), and urinary tract infections (9%).
Serious infections occurring in two or more patients were pneumonia, lower respiratory tract infection, and upper respiratory tract infection. One patient died from septic shock, 10 had infections leading to venetoclax interruption, and 2 had infections leading to dose reduction.
No mandated infection prophylaxis was used in this study.
Serious adverse events occurred in 59 patients (55%). The most common, occurring in at least 5% of patients, were pyrexia, autoimmune hemolytic anemia, pneumonia, and febrile neutropenia. Thirteen had adverse events leading to dose reductions, most commonly due to neutropenia, thrombocytopenia, and febrile neutropenia.
Laboratory-confirmed tumor lysis syndrome was reported in five patients during the ramp-up period, including four who developed the syndrome within the first 2 days of treatment. All cases resolved without clinical sequelae. Treatment was continued without interruption in three patients with tumor lysis syndrome, who received only electrolyte management, and two patients had a 1-day treatment interruption. Both resumed dosing the next day.
In the phase Ib study by Seymour et al., common grade 1-2 toxicities included upper respiratory tract infections, diarrhea, and nausea occurring in 57%, 55%, and 53% of patients, respectively. Grade 3-4 adverse events occurred in 76% of 49 patients, and most often included neutropenia (12% of patients), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%). The most common serious adverse events were pyrexia (12%), febrile neutropenia (10%), lower respiratory tract infection (6%), and pneumonia (6%). Clinical tumor lysis syndrome occurred in two patients who initiated venetoclax at 50 mg, one of whom died as a result.
After enhancement of tumor lysis syndrome prophylaxis measures and reduction of the starting dose of venetoclax to 20 mg, no additional cases occurred, the authors reported.
Mitigating tumor lysis syndrome risk
General measures for mitigating the risk of tumor lysis syndrome include identification of patients at increased risk, initiation of prophylaxis with hydration and a uric acid reducing agent, and initiation of venetoclax at a 20 mg dose for 1 week, with gradual step-wise ramp-up over 5 weeks to the target dose, Dr. Zelenetz noted.
As reported by Stilgenbauer, et al., patients with a nodal mass less than 5 cm and absolute lymphocyte count (ALC) of 25,000 or less are considered at low risk for tumor lysis syndrome, those with a nodal mass of 5 cm to less than 10 cm or ALC greater than 25,000 are at medium risk, and those with a nodal mass of 10 cm or greater or nodal mass of 5 cm or greater and ALC of greater than 25,000 are considered to be at high risk.
High-risk patients in the study received inpatient venetoclax dosing and monitoring at 4, 8, 12, and 24 hours with 20 mg and 50 mg dosing, as well as outpatient intravenous hydration at 100 mg if there was no indication to hospitalize, and post-dose 8-24 hour laboratory monitoring at 100 mg and above.
Medium-risk patients received IV hydration at 20 and 50 mg dosing, inpatient care if creatinine clearance was less than 80 mL/min or if there was a high tumor burden, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose escalations. Low-risk patients received outpatient dosing at all dose levels in the absence of an indication to hospitalize, and postdose 8- and 24-hour laboratory monitoring after the initial dose and at dose increases.
“Unfortunately, the dose-limiting toxicity of venetoclax is fatal tumor lysis,” Dr. Zelenetz said, adding that by increasing the dose slowly over time according to current treatment recommendations – from 20 mg, to 50, 100, 200, and 400 mg at weekly intervals, this complication can be avoided.
Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Genentech, the maker of venetoclax (Venclexta), and a wide variety of other drug companies.
EXPERT ANALYSIS AT THE NCCN ANNUAL CONFERENCE
Advanced CLL treatment approach depends on comorbidity burden
ORLANDO – The choice of first-line therapy in symptomatic chronic lymphocytic leukemia patients depends largely on comorbidity burden, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.
“This is a disease of elderly patients. Frequently they have comorbidities,” he said. Categorizing these patients as having a low or high comorbidity burden can be done with the Cumulative Index Rating Scale score, which involves scoring of all organ systems on a 0-5 scale representing “not affected” to “extremely disabled.”
“We use this to determine first-line therapy,” said Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York. Dr. Zelenetz is chair of the NCCN Non-Hodgkin Lymphoma Guidelines panel.
Patients with a score of greater than 12 on the 0- to 56-point scale, are “no-go” patients with respect to therapy, and are typically treated only with palliative approaches. Those with a score of 7-12 (“slow-go” patients) have a significant comorbidity burden, but can undergo treatment, thought typically to be at reduced intensity. Those with a score of 0-6 are “go-go” patients with respect to treatment, as they are physically fit, have excellent renal function, and have no significant comorbidities, he said.
Treatment options for ‘go-go’ CLL patients
Among the treatment options for the latter is FCR–the combination of fludarabine, cyclophosphamide, and rituximab, which was shown in the phase III CLL10 trial of patients with advanced CLL to be associated with improved complete response rates compared with the popular regimen of bendamustine and rituximab (BR), both overall and in patients under age 65. In older patients, the advantage disappeared, Dr. Zelenetz said.
FCR was also associated with improved outcomes vs. BR in patients with del(11q).
The primary endpoint of the study was progression-free survival, which favored FCR (median of 55.2 vs. 41.7 months; hazard ratio, 1.643), he said, noting that no difference was seen between the two regimens in terms of overall survival.
In a recent publication, MD Anderson Cancer Center reported its experience with its first 300 CLL patients treated with FCR. With long-term follow-up of at least 9-10 years (median of 12.8 years), patients in this trial have done extremely well.
“But interestingly, when you stratify these patients by whether they have IGHV [immunoglobulin heavy chain variable] mutated or unmutated [disease], the IGHV mutated patients have something that looks a whole lot like a survival plateau, and that survival plateau is not trivial – it’s about 60%,” he said. “So there is a group of patients with CLL who are, in fact, curable with conventional chemoimmunotherapy.
“This is an appropriate treatment for a young, fit, ‘go-go’ patient, and it has a big implication,” he said. That is, patients who are young and fit require IGHV mutation testing, as “you will absolutely choose FCR chemotherapy for the fit, young patients who has IGHV mutated disease.
“In that setting IGHV testing is now mandatory,” he stressed, noting that the benefits in this population extend to overall survival as well as progression-free survival.
Dr. Zelenetz also emphasized the need for increasing the single dose of rituximab from 375 mg/m2 during cycle 1 to 500 mg/m2 during cycles 2-6 in those receiving FCR, as this is often forgotten.
The data demonstrating the efficacy of FCR were based on this approach, he said.
Fludarabine is to be given at a dose of 25 mg/m2, and cyclophosphamide at a dose of 250 mg/m2 – both for 2-4 days during cycle 1 and for 1-3 days during cycles 2-6.
Treatment options for ‘slow-go’ CLL patients
In “slow-go” patients, an interesting approach is to use new anti-CD20 antibodies such as ofatumumab and obinutuzumab, which have features that are distinct from rituximab.
Both have been studied in CLL. The CLL11 trial compared chlorambucil, rituximab+chlorambucil, and obinutuzumab+chlorambucil, and the latest analysis showed substantial improvement in progression-free survival with obinutuzumab+chlorambucil vs. the other two regimens (26.7 months vs. 11.1 and 16.3 months, respectively), Dr. Zelenetz said, noting that rituximab+chlorambucil was also superior to chlorambucil alone, but that only the obinutuzumab regimen had an overall survival advantage vs. chlorambucil alone.
An updated analysis to be reported soon will show emerging evidence of a survival advantage of obinutuzumab+chlorambucil vs. rituximab+chlorambucil, he said.
“This suggests that obinutuzumab is a far better antibody,” he added, noting that the reasons for that are under debate, “but the way it’s given, it works better in CLL, and that, I think is unequivocal.”
A similar study looking at chlorambucil with and without ofatumumab in “slow-go” patients also demonstrated an improvement in PFS with ofatumumab, but showed “no difference whatsoever in overall survival.”
“This is actually very similar to the rituximab result, and I actually call this the ‘death of ofatumumab’ study, because clearly obinutuzumab in CLL is, I think, a superior anti-CD20 antibody,” Dr. Zelenetz said.
Studies in which obinutuzumab is substituted for rituximab in the FCR combination are currently underway as are a number of other studies of obinutuzumab, he noted.
Another treatment option in the up-front setting is ibrutinib, which was shown to be effective in the RESONATE 2 trial .
“But notice, a very, very small [complete response rate]. CRs are very difficult to achieve with ibrutinib alone, so this drug is given continuously, lifelong,” Dr. Zelenetz said, noting that it was, however, associated with an overall survival advantage vs. chlorambucil.
“Should this be the standard of care? I think it is in patients who have del(17p) or mutation of TP53. Outside of that setting, I’m still concerned about the cost of long-term tolerability of the agent,” he said.
Future of first-line CLL treatment
Avoidance of long-term therapy and conventional chemotherapy in patients with CLL is a goal, he added, noting that new understanding from studies in patients in the relapsed/refractory CLL setting – such as recent findings from a phase Ib study of venetoclax plus rituximab, which demonstrated potentially durable responses after treatment discontinuation in minimal residual disease (MRD)–negative patients – are providing insights into achieving MRD negativity that could be applied in the front line treatment setting.
“We’re still trying to figure out how to best use this. We want to try to use some of this knowledge about achievement of MRD negativity in the up-front setting so we don’t have to give patients long-term therapy, and we would like to avoid conventional chemotherapy,” he said. “So I’m hoping we’re going to be able to replace chronic long-term therapy of CLL with a defined course of treatment with high levels of MRD negativity.”
Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Acerta Pharma, Amgen Inc., BeiGene, Bristol-Myers Squibb, Celgene Corporation, Genentech, Gilead Sciences, Janssen Pharmaceutica Products, MEI Pharma, NanoString Technologies, Pharmacyclics, Portola Pharmaceuticals, Roche Laboratories, and Takeda Pharmaceuticals North America.
ORLANDO – The choice of first-line therapy in symptomatic chronic lymphocytic leukemia patients depends largely on comorbidity burden, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.
“This is a disease of elderly patients. Frequently they have comorbidities,” he said. Categorizing these patients as having a low or high comorbidity burden can be done with the Cumulative Index Rating Scale score, which involves scoring of all organ systems on a 0-5 scale representing “not affected” to “extremely disabled.”
“We use this to determine first-line therapy,” said Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York. Dr. Zelenetz is chair of the NCCN Non-Hodgkin Lymphoma Guidelines panel.
Patients with a score of greater than 12 on the 0- to 56-point scale, are “no-go” patients with respect to therapy, and are typically treated only with palliative approaches. Those with a score of 7-12 (“slow-go” patients) have a significant comorbidity burden, but can undergo treatment, thought typically to be at reduced intensity. Those with a score of 0-6 are “go-go” patients with respect to treatment, as they are physically fit, have excellent renal function, and have no significant comorbidities, he said.
Treatment options for ‘go-go’ CLL patients
Among the treatment options for the latter is FCR–the combination of fludarabine, cyclophosphamide, and rituximab, which was shown in the phase III CLL10 trial of patients with advanced CLL to be associated with improved complete response rates compared with the popular regimen of bendamustine and rituximab (BR), both overall and in patients under age 65. In older patients, the advantage disappeared, Dr. Zelenetz said.
FCR was also associated with improved outcomes vs. BR in patients with del(11q).
The primary endpoint of the study was progression-free survival, which favored FCR (median of 55.2 vs. 41.7 months; hazard ratio, 1.643), he said, noting that no difference was seen between the two regimens in terms of overall survival.
In a recent publication, MD Anderson Cancer Center reported its experience with its first 300 CLL patients treated with FCR. With long-term follow-up of at least 9-10 years (median of 12.8 years), patients in this trial have done extremely well.
“But interestingly, when you stratify these patients by whether they have IGHV [immunoglobulin heavy chain variable] mutated or unmutated [disease], the IGHV mutated patients have something that looks a whole lot like a survival plateau, and that survival plateau is not trivial – it’s about 60%,” he said. “So there is a group of patients with CLL who are, in fact, curable with conventional chemoimmunotherapy.
“This is an appropriate treatment for a young, fit, ‘go-go’ patient, and it has a big implication,” he said. That is, patients who are young and fit require IGHV mutation testing, as “you will absolutely choose FCR chemotherapy for the fit, young patients who has IGHV mutated disease.
“In that setting IGHV testing is now mandatory,” he stressed, noting that the benefits in this population extend to overall survival as well as progression-free survival.
Dr. Zelenetz also emphasized the need for increasing the single dose of rituximab from 375 mg/m2 during cycle 1 to 500 mg/m2 during cycles 2-6 in those receiving FCR, as this is often forgotten.
The data demonstrating the efficacy of FCR were based on this approach, he said.
Fludarabine is to be given at a dose of 25 mg/m2, and cyclophosphamide at a dose of 250 mg/m2 – both for 2-4 days during cycle 1 and for 1-3 days during cycles 2-6.
Treatment options for ‘slow-go’ CLL patients
In “slow-go” patients, an interesting approach is to use new anti-CD20 antibodies such as ofatumumab and obinutuzumab, which have features that are distinct from rituximab.
Both have been studied in CLL. The CLL11 trial compared chlorambucil, rituximab+chlorambucil, and obinutuzumab+chlorambucil, and the latest analysis showed substantial improvement in progression-free survival with obinutuzumab+chlorambucil vs. the other two regimens (26.7 months vs. 11.1 and 16.3 months, respectively), Dr. Zelenetz said, noting that rituximab+chlorambucil was also superior to chlorambucil alone, but that only the obinutuzumab regimen had an overall survival advantage vs. chlorambucil alone.
An updated analysis to be reported soon will show emerging evidence of a survival advantage of obinutuzumab+chlorambucil vs. rituximab+chlorambucil, he said.
“This suggests that obinutuzumab is a far better antibody,” he added, noting that the reasons for that are under debate, “but the way it’s given, it works better in CLL, and that, I think is unequivocal.”
A similar study looking at chlorambucil with and without ofatumumab in “slow-go” patients also demonstrated an improvement in PFS with ofatumumab, but showed “no difference whatsoever in overall survival.”
“This is actually very similar to the rituximab result, and I actually call this the ‘death of ofatumumab’ study, because clearly obinutuzumab in CLL is, I think, a superior anti-CD20 antibody,” Dr. Zelenetz said.
Studies in which obinutuzumab is substituted for rituximab in the FCR combination are currently underway as are a number of other studies of obinutuzumab, he noted.
Another treatment option in the up-front setting is ibrutinib, which was shown to be effective in the RESONATE 2 trial .
“But notice, a very, very small [complete response rate]. CRs are very difficult to achieve with ibrutinib alone, so this drug is given continuously, lifelong,” Dr. Zelenetz said, noting that it was, however, associated with an overall survival advantage vs. chlorambucil.
“Should this be the standard of care? I think it is in patients who have del(17p) or mutation of TP53. Outside of that setting, I’m still concerned about the cost of long-term tolerability of the agent,” he said.
Future of first-line CLL treatment
Avoidance of long-term therapy and conventional chemotherapy in patients with CLL is a goal, he added, noting that new understanding from studies in patients in the relapsed/refractory CLL setting – such as recent findings from a phase Ib study of venetoclax plus rituximab, which demonstrated potentially durable responses after treatment discontinuation in minimal residual disease (MRD)–negative patients – are providing insights into achieving MRD negativity that could be applied in the front line treatment setting.
“We’re still trying to figure out how to best use this. We want to try to use some of this knowledge about achievement of MRD negativity in the up-front setting so we don’t have to give patients long-term therapy, and we would like to avoid conventional chemotherapy,” he said. “So I’m hoping we’re going to be able to replace chronic long-term therapy of CLL with a defined course of treatment with high levels of MRD negativity.”
Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Acerta Pharma, Amgen Inc., BeiGene, Bristol-Myers Squibb, Celgene Corporation, Genentech, Gilead Sciences, Janssen Pharmaceutica Products, MEI Pharma, NanoString Technologies, Pharmacyclics, Portola Pharmaceuticals, Roche Laboratories, and Takeda Pharmaceuticals North America.
ORLANDO – The choice of first-line therapy in symptomatic chronic lymphocytic leukemia patients depends largely on comorbidity burden, Andrew D. Zelenetz, MD, PhD, said at the annual conference of the National Comprehensive Cancer Network.
“This is a disease of elderly patients. Frequently they have comorbidities,” he said. Categorizing these patients as having a low or high comorbidity burden can be done with the Cumulative Index Rating Scale score, which involves scoring of all organ systems on a 0-5 scale representing “not affected” to “extremely disabled.”
“We use this to determine first-line therapy,” said Dr. Zelenetz of Memorial Sloan Kettering Cancer Center, New York. Dr. Zelenetz is chair of the NCCN Non-Hodgkin Lymphoma Guidelines panel.
Patients with a score of greater than 12 on the 0- to 56-point scale, are “no-go” patients with respect to therapy, and are typically treated only with palliative approaches. Those with a score of 7-12 (“slow-go” patients) have a significant comorbidity burden, but can undergo treatment, thought typically to be at reduced intensity. Those with a score of 0-6 are “go-go” patients with respect to treatment, as they are physically fit, have excellent renal function, and have no significant comorbidities, he said.
Treatment options for ‘go-go’ CLL patients
Among the treatment options for the latter is FCR–the combination of fludarabine, cyclophosphamide, and rituximab, which was shown in the phase III CLL10 trial of patients with advanced CLL to be associated with improved complete response rates compared with the popular regimen of bendamustine and rituximab (BR), both overall and in patients under age 65. In older patients, the advantage disappeared, Dr. Zelenetz said.
FCR was also associated with improved outcomes vs. BR in patients with del(11q).
The primary endpoint of the study was progression-free survival, which favored FCR (median of 55.2 vs. 41.7 months; hazard ratio, 1.643), he said, noting that no difference was seen between the two regimens in terms of overall survival.
In a recent publication, MD Anderson Cancer Center reported its experience with its first 300 CLL patients treated with FCR. With long-term follow-up of at least 9-10 years (median of 12.8 years), patients in this trial have done extremely well.
“But interestingly, when you stratify these patients by whether they have IGHV [immunoglobulin heavy chain variable] mutated or unmutated [disease], the IGHV mutated patients have something that looks a whole lot like a survival plateau, and that survival plateau is not trivial – it’s about 60%,” he said. “So there is a group of patients with CLL who are, in fact, curable with conventional chemoimmunotherapy.
“This is an appropriate treatment for a young, fit, ‘go-go’ patient, and it has a big implication,” he said. That is, patients who are young and fit require IGHV mutation testing, as “you will absolutely choose FCR chemotherapy for the fit, young patients who has IGHV mutated disease.
“In that setting IGHV testing is now mandatory,” he stressed, noting that the benefits in this population extend to overall survival as well as progression-free survival.
Dr. Zelenetz also emphasized the need for increasing the single dose of rituximab from 375 mg/m2 during cycle 1 to 500 mg/m2 during cycles 2-6 in those receiving FCR, as this is often forgotten.
The data demonstrating the efficacy of FCR were based on this approach, he said.
Fludarabine is to be given at a dose of 25 mg/m2, and cyclophosphamide at a dose of 250 mg/m2 – both for 2-4 days during cycle 1 and for 1-3 days during cycles 2-6.
Treatment options for ‘slow-go’ CLL patients
In “slow-go” patients, an interesting approach is to use new anti-CD20 antibodies such as ofatumumab and obinutuzumab, which have features that are distinct from rituximab.
Both have been studied in CLL. The CLL11 trial compared chlorambucil, rituximab+chlorambucil, and obinutuzumab+chlorambucil, and the latest analysis showed substantial improvement in progression-free survival with obinutuzumab+chlorambucil vs. the other two regimens (26.7 months vs. 11.1 and 16.3 months, respectively), Dr. Zelenetz said, noting that rituximab+chlorambucil was also superior to chlorambucil alone, but that only the obinutuzumab regimen had an overall survival advantage vs. chlorambucil alone.
An updated analysis to be reported soon will show emerging evidence of a survival advantage of obinutuzumab+chlorambucil vs. rituximab+chlorambucil, he said.
“This suggests that obinutuzumab is a far better antibody,” he added, noting that the reasons for that are under debate, “but the way it’s given, it works better in CLL, and that, I think is unequivocal.”
A similar study looking at chlorambucil with and without ofatumumab in “slow-go” patients also demonstrated an improvement in PFS with ofatumumab, but showed “no difference whatsoever in overall survival.”
“This is actually very similar to the rituximab result, and I actually call this the ‘death of ofatumumab’ study, because clearly obinutuzumab in CLL is, I think, a superior anti-CD20 antibody,” Dr. Zelenetz said.
Studies in which obinutuzumab is substituted for rituximab in the FCR combination are currently underway as are a number of other studies of obinutuzumab, he noted.
Another treatment option in the up-front setting is ibrutinib, which was shown to be effective in the RESONATE 2 trial .
“But notice, a very, very small [complete response rate]. CRs are very difficult to achieve with ibrutinib alone, so this drug is given continuously, lifelong,” Dr. Zelenetz said, noting that it was, however, associated with an overall survival advantage vs. chlorambucil.
“Should this be the standard of care? I think it is in patients who have del(17p) or mutation of TP53. Outside of that setting, I’m still concerned about the cost of long-term tolerability of the agent,” he said.
Future of first-line CLL treatment
Avoidance of long-term therapy and conventional chemotherapy in patients with CLL is a goal, he added, noting that new understanding from studies in patients in the relapsed/refractory CLL setting – such as recent findings from a phase Ib study of venetoclax plus rituximab, which demonstrated potentially durable responses after treatment discontinuation in minimal residual disease (MRD)–negative patients – are providing insights into achieving MRD negativity that could be applied in the front line treatment setting.
“We’re still trying to figure out how to best use this. We want to try to use some of this knowledge about achievement of MRD negativity in the up-front setting so we don’t have to give patients long-term therapy, and we would like to avoid conventional chemotherapy,” he said. “So I’m hoping we’re going to be able to replace chronic long-term therapy of CLL with a defined course of treatment with high levels of MRD negativity.”
Dr. Zelenetz reported receiving consulting fees, honoraria, and/or grant/research support from Acerta Pharma, Amgen Inc., BeiGene, Bristol-Myers Squibb, Celgene Corporation, Genentech, Gilead Sciences, Janssen Pharmaceutica Products, MEI Pharma, NanoString Technologies, Pharmacyclics, Portola Pharmaceuticals, Roche Laboratories, and Takeda Pharmaceuticals North America.
EXPERT ANALYSIS FROM THE NCCN ANNUAL CONFERENCE
NCCN: Myelofibrosis guideline is first in series on MPNs
ORLANDO – A guideline published late last year for the diagnostic work-up of myeloproliferative neoplasms and for the management of myelofibrosis in particular is just the first in a series of National Comprehensive Cancer Network guidelines on this “family of myeloid neoplasms,” according to the guideline panel chair, Ruben A. Mesa, MD.
The myeloproliferative neoplasm (MPN) guideline panel first worked to develop a framework based on existing understanding of the MPNs. Members consulted with two other panels working in the area of chronic myeloid diseases, including chronic myeloid leukemia and myelodysplastic syndrome.
“We were in agreement that these are different entities, and our treatments are different, our guidelines are different,” Dr. Mesa of the Mayo Clinic Cancer Center, Phoenix, said at the annual conference of the National Comprehensive Cancer Network.
That said, there are also some shared circumstances. For example, all three sets of diseases can progress to acute myeloid leukemia.
“Indeed, I view this very much as pieces in a jigsaw puzzle. … It is important that we recognize their interdependencies as well as those aspects that are disease specific,” he said.
In essence, however, the MPN guideline development is a from-scratch effort, as these are the first guidelines for these disorders, he noted.
The effort is timely, as the diagnosis and management of patients with MPNs have rapidly evolved since the identification of mutations that activate the JAK pathway, including JAK2, CALR, and MPL mutations. Further, the development of targeted therapies – such as the JAK1 and JAK2 inhibitor ruxolitinib, which was the first drug approved for the treatment of myelofibrosis – has resulted in significant improvements in disease-related symptoms and quality of life.
The panel is focusing first on the “core classic” Philadelphia chromosome–negative MPNs: myelofibrosis, polycythemia vera, and essential thrombocythemia. The first piece to be placed in the MPN puzzle was the guideline for the diagnostic work-up of these entities and for risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, which the panel considered “the greatest unmet need and the most urgent in terms of guidance,” Dr. Mesa said.
This initial MPN guideline was published in December (J Natl Compr Canc Netw. 2016;14:1572-611) and, because of the evolving understanding of MPNs, updates are already under consideration as additional MPN guidelines are being developed.
“We have been actively working … to develop the next set of treatment guidelines, which are the treatment guidelines for polycythemia vera and essential thrombocythemia. Finally, we will work to include the atypical MPNs,” he said, noting that the latter include hypereosinophilic disease, systemic mast cell disease, and other atypical illnesses.
These represent a small number of patients, but “their management is key, it’s distinct from the others, and there is no good guidance,” Dr. Mesa said.
“Once this is fleshed out, we will then have a fully developed set of guidelines that then will be maintained along the traditional process that NCCN follows, which is first an annual review, but second, a monitoring in real time of key developments that could impact the guidelines during the off-cycle,” he said.
Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.
ORLANDO – A guideline published late last year for the diagnostic work-up of myeloproliferative neoplasms and for the management of myelofibrosis in particular is just the first in a series of National Comprehensive Cancer Network guidelines on this “family of myeloid neoplasms,” according to the guideline panel chair, Ruben A. Mesa, MD.
The myeloproliferative neoplasm (MPN) guideline panel first worked to develop a framework based on existing understanding of the MPNs. Members consulted with two other panels working in the area of chronic myeloid diseases, including chronic myeloid leukemia and myelodysplastic syndrome.
“We were in agreement that these are different entities, and our treatments are different, our guidelines are different,” Dr. Mesa of the Mayo Clinic Cancer Center, Phoenix, said at the annual conference of the National Comprehensive Cancer Network.
That said, there are also some shared circumstances. For example, all three sets of diseases can progress to acute myeloid leukemia.
“Indeed, I view this very much as pieces in a jigsaw puzzle. … It is important that we recognize their interdependencies as well as those aspects that are disease specific,” he said.
In essence, however, the MPN guideline development is a from-scratch effort, as these are the first guidelines for these disorders, he noted.
The effort is timely, as the diagnosis and management of patients with MPNs have rapidly evolved since the identification of mutations that activate the JAK pathway, including JAK2, CALR, and MPL mutations. Further, the development of targeted therapies – such as the JAK1 and JAK2 inhibitor ruxolitinib, which was the first drug approved for the treatment of myelofibrosis – has resulted in significant improvements in disease-related symptoms and quality of life.
The panel is focusing first on the “core classic” Philadelphia chromosome–negative MPNs: myelofibrosis, polycythemia vera, and essential thrombocythemia. The first piece to be placed in the MPN puzzle was the guideline for the diagnostic work-up of these entities and for risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, which the panel considered “the greatest unmet need and the most urgent in terms of guidance,” Dr. Mesa said.
This initial MPN guideline was published in December (J Natl Compr Canc Netw. 2016;14:1572-611) and, because of the evolving understanding of MPNs, updates are already under consideration as additional MPN guidelines are being developed.
“We have been actively working … to develop the next set of treatment guidelines, which are the treatment guidelines for polycythemia vera and essential thrombocythemia. Finally, we will work to include the atypical MPNs,” he said, noting that the latter include hypereosinophilic disease, systemic mast cell disease, and other atypical illnesses.
These represent a small number of patients, but “their management is key, it’s distinct from the others, and there is no good guidance,” Dr. Mesa said.
“Once this is fleshed out, we will then have a fully developed set of guidelines that then will be maintained along the traditional process that NCCN follows, which is first an annual review, but second, a monitoring in real time of key developments that could impact the guidelines during the off-cycle,” he said.
Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.
ORLANDO – A guideline published late last year for the diagnostic work-up of myeloproliferative neoplasms and for the management of myelofibrosis in particular is just the first in a series of National Comprehensive Cancer Network guidelines on this “family of myeloid neoplasms,” according to the guideline panel chair, Ruben A. Mesa, MD.
The myeloproliferative neoplasm (MPN) guideline panel first worked to develop a framework based on existing understanding of the MPNs. Members consulted with two other panels working in the area of chronic myeloid diseases, including chronic myeloid leukemia and myelodysplastic syndrome.
“We were in agreement that these are different entities, and our treatments are different, our guidelines are different,” Dr. Mesa of the Mayo Clinic Cancer Center, Phoenix, said at the annual conference of the National Comprehensive Cancer Network.
That said, there are also some shared circumstances. For example, all three sets of diseases can progress to acute myeloid leukemia.
“Indeed, I view this very much as pieces in a jigsaw puzzle. … It is important that we recognize their interdependencies as well as those aspects that are disease specific,” he said.
In essence, however, the MPN guideline development is a from-scratch effort, as these are the first guidelines for these disorders, he noted.
The effort is timely, as the diagnosis and management of patients with MPNs have rapidly evolved since the identification of mutations that activate the JAK pathway, including JAK2, CALR, and MPL mutations. Further, the development of targeted therapies – such as the JAK1 and JAK2 inhibitor ruxolitinib, which was the first drug approved for the treatment of myelofibrosis – has resulted in significant improvements in disease-related symptoms and quality of life.
The panel is focusing first on the “core classic” Philadelphia chromosome–negative MPNs: myelofibrosis, polycythemia vera, and essential thrombocythemia. The first piece to be placed in the MPN puzzle was the guideline for the diagnostic work-up of these entities and for risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, which the panel considered “the greatest unmet need and the most urgent in terms of guidance,” Dr. Mesa said.
This initial MPN guideline was published in December (J Natl Compr Canc Netw. 2016;14:1572-611) and, because of the evolving understanding of MPNs, updates are already under consideration as additional MPN guidelines are being developed.
“We have been actively working … to develop the next set of treatment guidelines, which are the treatment guidelines for polycythemia vera and essential thrombocythemia. Finally, we will work to include the atypical MPNs,” he said, noting that the latter include hypereosinophilic disease, systemic mast cell disease, and other atypical illnesses.
These represent a small number of patients, but “their management is key, it’s distinct from the others, and there is no good guidance,” Dr. Mesa said.
“Once this is fleshed out, we will then have a fully developed set of guidelines that then will be maintained along the traditional process that NCCN follows, which is first an annual review, but second, a monitoring in real time of key developments that could impact the guidelines during the off-cycle,” he said.
Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.
AT THE NCCN ANNUAL CONFERENCE
VIDEO: Striking improvement in PFS with olaparib for ovarian cancer
NATIONAL HARBOR, MD. – Maintenance therapy with the first-in-class PARP inhibitor olaparib was associated with a striking improvement in progression-free survival in patients with platinum-sensitive relapsed ovarian cancer and BRCA 1/2 mutation in the randomized, placebo-controlled phase III SOLO2 trial.
Compared with placebo, the tablet formulation of olaparib was associated with investigator-assessed PFS of 19.1 months in 196 patients, compared with 5.5 months in 99 patients who received placebo (hazard ratio, 0.30), Dr. Eric Pujade-Lauraine reported at the annual meeting of the Society of Gynecologic Oncology.
The SOLO2 results were both clinically meaningful and highly statistically significant, said Dr. Pujade-Lauraine of Hopital Hotel-Dieu, Paris.
Active treatment, which involved a twice-daily 300-mg oral dose of olaparib, was well tolerated; 75% of patients completed the study without dose reduction, he noted.
In this video interview, Dr. Pujade-Lauraine discussed the SOLO2 study and findings, which confirmed those of the phase II Study 19. Study 19 looked at olaparib in all-comers with platinum-sensitive relapsed ovarian cancer and involved a different formulation of the drug, which required that patients take 16 capsules each day to achieve a twice-daily dose of 400 mg. Patients with BRCA mutations were found in that study to derive the most benefit from olaparib.
The current findings are practice changing, Dr. Pujade-Lauraine said, concluding that “it is important to test BRCA, and if this test is positive, to offer olaparib in patients who are platinum sensitive.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NATIONAL HARBOR, MD. – Maintenance therapy with the first-in-class PARP inhibitor olaparib was associated with a striking improvement in progression-free survival in patients with platinum-sensitive relapsed ovarian cancer and BRCA 1/2 mutation in the randomized, placebo-controlled phase III SOLO2 trial.
Compared with placebo, the tablet formulation of olaparib was associated with investigator-assessed PFS of 19.1 months in 196 patients, compared with 5.5 months in 99 patients who received placebo (hazard ratio, 0.30), Dr. Eric Pujade-Lauraine reported at the annual meeting of the Society of Gynecologic Oncology.
The SOLO2 results were both clinically meaningful and highly statistically significant, said Dr. Pujade-Lauraine of Hopital Hotel-Dieu, Paris.
Active treatment, which involved a twice-daily 300-mg oral dose of olaparib, was well tolerated; 75% of patients completed the study without dose reduction, he noted.
In this video interview, Dr. Pujade-Lauraine discussed the SOLO2 study and findings, which confirmed those of the phase II Study 19. Study 19 looked at olaparib in all-comers with platinum-sensitive relapsed ovarian cancer and involved a different formulation of the drug, which required that patients take 16 capsules each day to achieve a twice-daily dose of 400 mg. Patients with BRCA mutations were found in that study to derive the most benefit from olaparib.
The current findings are practice changing, Dr. Pujade-Lauraine said, concluding that “it is important to test BRCA, and if this test is positive, to offer olaparib in patients who are platinum sensitive.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NATIONAL HARBOR, MD. – Maintenance therapy with the first-in-class PARP inhibitor olaparib was associated with a striking improvement in progression-free survival in patients with platinum-sensitive relapsed ovarian cancer and BRCA 1/2 mutation in the randomized, placebo-controlled phase III SOLO2 trial.
Compared with placebo, the tablet formulation of olaparib was associated with investigator-assessed PFS of 19.1 months in 196 patients, compared with 5.5 months in 99 patients who received placebo (hazard ratio, 0.30), Dr. Eric Pujade-Lauraine reported at the annual meeting of the Society of Gynecologic Oncology.
The SOLO2 results were both clinically meaningful and highly statistically significant, said Dr. Pujade-Lauraine of Hopital Hotel-Dieu, Paris.
Active treatment, which involved a twice-daily 300-mg oral dose of olaparib, was well tolerated; 75% of patients completed the study without dose reduction, he noted.
In this video interview, Dr. Pujade-Lauraine discussed the SOLO2 study and findings, which confirmed those of the phase II Study 19. Study 19 looked at olaparib in all-comers with platinum-sensitive relapsed ovarian cancer and involved a different formulation of the drug, which required that patients take 16 capsules each day to achieve a twice-daily dose of 400 mg. Patients with BRCA mutations were found in that study to derive the most benefit from olaparib.
The current findings are practice changing, Dr. Pujade-Lauraine said, concluding that “it is important to test BRCA, and if this test is positive, to offer olaparib in patients who are platinum sensitive.”
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT THE ANNUAL MEETING ON WOMEN'S CANCER
