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Gene editing aims to recreate beneficial mutation in SCD, beta-thalassemia
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
MADRID – With some genetic sleight-of-hand, investigators hope to mimic a rare, naturally occurring mutation that protects some patients with beta-thalassemia or sickle-cell disease (SCD) from becoming symptomatic.
Although human studies have yet to begin, investigators in a biotech company report that they can use CRISPR/Cas9 gene editing to recreate the rare condition known as hereditary persistence of fetal hemoglobin, or HPFH, which causes some patients with SCD or beta-thalassemia to continue to produce the fully functional fetal rather than adult form of hemoglobin into adulthood.
To date, there have been no detectable undesirable off-target genetic modifications seen by targeted deep sequencing for the two leading guide RNAs (gRNA) in development, he said at the annual congress of the European Hematology Association.
“Patients with sickle-cell disease and beta-thalassemia are not sick when they are first born, but symptoms develop shortly after birth as the fetal hemoglobin levels decline, and as adult hemoglobin rises,” Dr. Lundberg said.
Fetal hemoglobin has been shown to reduce the risk of sickle events in SCD, and reduce symptoms and morbidity of beta-thalassemia.
“Modest amounts of fetal hemoglobin are beneficial, and more appears to be better,” he said.
In rare instances, the genetic switch to turn off fetal hemoglobin fails, leading to HPFH. It is this rare circumstance that the investigators hope to copy.
CRISPR/Cas9 technology copies a bacterial defense mechanism using clustered regularly interspaced short palindromic (CRISPR) repeats of DNA as a template for adaptive immunity against viruses and plasmids. The system allows bacteria to prevent the activation of invading nucleic acids by effectively snipping out target sequences of foreign DNA.
The investigators plan to harvest hematopoietic stem cells from patients with SCD and beta-thalassemia and use CRISPR/Cas9 technology to modify the cells to express the fetal form of hemoglobin. The reintroduced stem cells would, ideally, proliferate and help protect patients against painful crises and debilitating symptoms of the hemoglobinopathies.
Dr. Lundberg said that to date they have been able to edit blood stem cells with more than 80% on-target efficiency, and that the editing leads to “clinically meaningful” levels of protective fetal hemoglobin, in the range of 30%.
As noted, the investigators have to date seen no evidence of off-target editing that could lead to undesirable or dangerous complications. When introduced into an immunodeficient mouse model (NOD scid gamma, or NSG mice), the edited human cells persisted for long periods.
Finally, the investigators have been able to demonstrate that the modified stem cells are able to differentiate and reconstitute different types of cells in blood.
The company plans to submit a clinical trial application in 2017, and start clinical trials in 2018, Dr. Lundberg said.
At a media briefing where he discussed his research prior to his presentation of data in a symposium, Dr. Lundberg said that to date they have worked only with mouse models and with cells from healthy donors.
He pointed out, however, that there are many thousands of patients with inherited hemoglobin disorders worldwide and beta-thalassemia, and asked “how do you proceed to implement this very expensive treatment?”
Dr. Lundberg acknowledged that the diseases are common in both the developing world and in wealthy countries. He said that the technique relies as much as possible on existing technologies, and pointed out that if the treatment is successful, it’s costs could be at least partially offset by reducing the costs of other forms of therapy.
The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
AT EHA 2017
Key clinical point: The fetal form of hemoglobin is protective against symptoms of sickle-cell disease (SCD) and beta-thalassemia.
Major finding: Human blood stem cells modified by CRISPR/Cas9 gene editing produced fetal hemoglobin without observable off-target effects.
Data source: Summary of preclinical studies with blood from healthy human volunteers and mouse models.
Disclosures: The work is supported by CRISPR Therapeutics. Dr. Lundberg is an employee and shareholder in the company. Dr. Hagenbeek reported having no relevant conflicts of interest.
Ibrutinib dons new anti-GVHD hat
MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.
Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.
Corticosteroids are the most commonly used therapy for cGVHD in the United States, but for those patients for whom corticosteroids are a bust, there is no established second-line therapy, and patients with refractory cGVHD are usually recommended for clinical trials, Dr. Pusic said.
The therapeutic rationale underpinning the use of ibrutinib in cGVHD, a condition marked by extensive immune dysregulation, is that the agent is an irreversible inhibitor of Bruton’s tyrosine kinase and interleukin-2 inducible T-cell kinase, and thus has wide-ranging immune-dampening activity, Dr. Pusic said.
She and colleagues in a multicenter study enrolled 42 patients with cGVHD that corticosteroids had failed to treat adequately, and treated them with oral ibrutinib 420 mg daily until cGVHD progression or unacceptable toxicity.
At a median follow-up of 13.9 months, a total of 28 patients (67%) had a response according to 2005 National Institutes of Health (NIH) criteria, including nine with a complete response, and 19 with partial responses.
Of the patients with responses, 79% had a response at the time of the first assessment for response, and 71% of responders had responses lasting at least 5 months.
Among patients with multiorgan involvement, responses were seen in two or more organs.
Grade 3 or greater adverse events included fatigue, diarrhea, muscles spasms, pneumonia, pyrexia, and headache. Two patients died on study, one from multilobular pneumonia and one from bronchopulmonary aspergillosis.
In general, the safety profile of ibrutinib was similar to that seen in studies of the drug in B-cell malignancies and to that seen with corticosteroid therapy for patients with cGVHD, Dr. Pusic said.
Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.
The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.
MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.
Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.
Corticosteroids are the most commonly used therapy for cGVHD in the United States, but for those patients for whom corticosteroids are a bust, there is no established second-line therapy, and patients with refractory cGVHD are usually recommended for clinical trials, Dr. Pusic said.
The therapeutic rationale underpinning the use of ibrutinib in cGVHD, a condition marked by extensive immune dysregulation, is that the agent is an irreversible inhibitor of Bruton’s tyrosine kinase and interleukin-2 inducible T-cell kinase, and thus has wide-ranging immune-dampening activity, Dr. Pusic said.
She and colleagues in a multicenter study enrolled 42 patients with cGVHD that corticosteroids had failed to treat adequately, and treated them with oral ibrutinib 420 mg daily until cGVHD progression or unacceptable toxicity.
At a median follow-up of 13.9 months, a total of 28 patients (67%) had a response according to 2005 National Institutes of Health (NIH) criteria, including nine with a complete response, and 19 with partial responses.
Of the patients with responses, 79% had a response at the time of the first assessment for response, and 71% of responders had responses lasting at least 5 months.
Among patients with multiorgan involvement, responses were seen in two or more organs.
Grade 3 or greater adverse events included fatigue, diarrhea, muscles spasms, pneumonia, pyrexia, and headache. Two patients died on study, one from multilobular pneumonia and one from bronchopulmonary aspergillosis.
In general, the safety profile of ibrutinib was similar to that seen in studies of the drug in B-cell malignancies and to that seen with corticosteroid therapy for patients with cGVHD, Dr. Pusic said.
Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.
The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.
MADRID – Talk about versatility: Ibrutinib (Imbruvica), a drug with marked activity against B-cell malignancies, also appears to be a safe and acceptable option for the treatment of patients with chronic graft vs. host disease (cGVHD) for whom frontline therapies have failed.
Among 42 patients in a phase II study with steroid-refractory cGVHD, the overall response rate with ibrutinib was 67%, with one-third of responders having a complete response, reported Iskra Pusic, MD, from Washington University School of Medicine in St. Louis.
Corticosteroids are the most commonly used therapy for cGVHD in the United States, but for those patients for whom corticosteroids are a bust, there is no established second-line therapy, and patients with refractory cGVHD are usually recommended for clinical trials, Dr. Pusic said.
The therapeutic rationale underpinning the use of ibrutinib in cGVHD, a condition marked by extensive immune dysregulation, is that the agent is an irreversible inhibitor of Bruton’s tyrosine kinase and interleukin-2 inducible T-cell kinase, and thus has wide-ranging immune-dampening activity, Dr. Pusic said.
She and colleagues in a multicenter study enrolled 42 patients with cGVHD that corticosteroids had failed to treat adequately, and treated them with oral ibrutinib 420 mg daily until cGVHD progression or unacceptable toxicity.
At a median follow-up of 13.9 months, a total of 28 patients (67%) had a response according to 2005 National Institutes of Health (NIH) criteria, including nine with a complete response, and 19 with partial responses.
Of the patients with responses, 79% had a response at the time of the first assessment for response, and 71% of responders had responses lasting at least 5 months.
Among patients with multiorgan involvement, responses were seen in two or more organs.
Grade 3 or greater adverse events included fatigue, diarrhea, muscles spasms, pneumonia, pyrexia, and headache. Two patients died on study, one from multilobular pneumonia and one from bronchopulmonary aspergillosis.
In general, the safety profile of ibrutinib was similar to that seen in studies of the drug in B-cell malignancies and to that seen with corticosteroid therapy for patients with cGVHD, Dr. Pusic said.
Investigators are currently enrolling patients in a double-blind clinical trial comparing ibrutinib or placebo in combination with corticosteroids in patients with newly diagnosed cGVHD, she noted.
The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.
AT EHA 2017
Key clinical point: The tyrosine kinase inhibitor ibrutinib was associated with complete and partial responses in two-thirds of patients with steroid-refractory chronic graft vs. host disease (cGVHD).
Major finding: A total of 28 patients (67%) had responses, including 9 complete responses.
Data source: Phase II clinical trial in 42 patients with cGVHD for whom corticosteroids had failed.
Disclosures: The study was supported by Pharmacyclics. Dr. Pusic did not report disclosures.
Overall survival better in advanced Hodgkin lymphoma with shorter eBEACOPP
MADRID – Patients with advanced Hodgkin lymphoma who have a metabolic response after the first two cycles of extended-dose(e)BEACOPP can be spared from undergoing more than two additional cycles of the highly intensive and toxic regimen, investigators from the German Hodgkin Study Group (GHSG) contend.
Among 1,005 patients with Hodgkin lymphoma who had negative PET scans after the second cycle of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, prednisone, procarbazine), progression-free survival (PFS) was virtually identical whether patients were randomized to undergo a total of six-to-eight cycles or only four cycles, reported Peter Borchmann, MD, from the University of Cologne, Germany.
“For patients with negative PET-2 after initial treatment with eBEACOPP. Therapy with only two additional cycles of eBEACOPP is very effective, obviously, very safe, very short – it just takes 12 weeks – and it’s affordable,” he said.
“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far. That’s why we recommend this treatment, PET-guided extended BEACOPP in patients with newly diagnosed, advanced-stage Hodgkin lymphoma,” he added.
Although most patients in the United States with newly diagnosed Hodgkin lymphoma receive ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), BEACOPP is sometimes used for high-risk patients. BEACOPP is associated with considerable toxicities, however, including increased risk of secondary malignancies.
To see whether select patients could be cured with fewer cycles of therapy, the GHSG investigators designed the GHSG HD18 study in which patient with metabolic responses determined by fluorodeoxyglucose-PET after two eBEACOPP cycles were randomized to either two or six-to-eight additional cycles.
A total of 2,101 patients from the ages of 18-60 years with newly diagnosed advanced-stage Hodgkin lymphoma were enrolled from centers in Germany, Switzerland, Austria, the Czech Republic, and the Netherlands.
After the second cycle of therapy, patients underwent fluorodeoxyglucose-PET scans, and those with negative results were then randomized.
The trial was designed and powered for noninferiority of the shortened regimen, with a maximum allowable difference of 6%.
The trial met its primary endpoint and then some. After a median observation time of 53 months, the 5-year PFS rate for patients who received only four cycles was 91.2%, compared with 91.8% for patients who underwent six-to-eight cycles. As shown on a Kaplan-Meier curve, the two lines were superimposable and virtually impossible to tell apart.
Interestingly, 5-year overall survival was significantly better with the shorter, less toxic regimen, at 97.6% vs. 95.4%, respectively, translating into a hazard ratio favoring the shorter regimen of 0.36 (P = .006).
In addition, the four-cycle regimen was associated with fewer severe infections (8% vs 15%), and lower degrees of organ toxicity (8% vs. 18%). In addition, the rate of secondary acute myeloid leukemia or the myelodysplastic syndrome was 0.4% among the 501 patients treated with only four cycles, compared with 1.6% for the 504 patients who received six to eight cycles.
There were no treatment-related deaths among patients who underwent four cycles, compared with six deaths among patients treated with additional cycles.
In an interview, Dr. Borchmann said that the findings are likely to change the standard of care for those centers that use the BEACOPP regimen. He acknowledged that the regimen is highly toxic and requires intensive patient surveillance and management, which may be more practical in Europe where patients generally live closer to major cancer centers than in the more spacious United States.
The study was supported by German Cancer Aid, the Swiss State Secratariate for Education, Research and Innovation, and by Roche Pharma AG. Dr, Borchmann reported having no relevant disclosures.
MADRID – Patients with advanced Hodgkin lymphoma who have a metabolic response after the first two cycles of extended-dose(e)BEACOPP can be spared from undergoing more than two additional cycles of the highly intensive and toxic regimen, investigators from the German Hodgkin Study Group (GHSG) contend.
Among 1,005 patients with Hodgkin lymphoma who had negative PET scans after the second cycle of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, prednisone, procarbazine), progression-free survival (PFS) was virtually identical whether patients were randomized to undergo a total of six-to-eight cycles or only four cycles, reported Peter Borchmann, MD, from the University of Cologne, Germany.
“For patients with negative PET-2 after initial treatment with eBEACOPP. Therapy with only two additional cycles of eBEACOPP is very effective, obviously, very safe, very short – it just takes 12 weeks – and it’s affordable,” he said.
“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far. That’s why we recommend this treatment, PET-guided extended BEACOPP in patients with newly diagnosed, advanced-stage Hodgkin lymphoma,” he added.
Although most patients in the United States with newly diagnosed Hodgkin lymphoma receive ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), BEACOPP is sometimes used for high-risk patients. BEACOPP is associated with considerable toxicities, however, including increased risk of secondary malignancies.
To see whether select patients could be cured with fewer cycles of therapy, the GHSG investigators designed the GHSG HD18 study in which patient with metabolic responses determined by fluorodeoxyglucose-PET after two eBEACOPP cycles were randomized to either two or six-to-eight additional cycles.
A total of 2,101 patients from the ages of 18-60 years with newly diagnosed advanced-stage Hodgkin lymphoma were enrolled from centers in Germany, Switzerland, Austria, the Czech Republic, and the Netherlands.
After the second cycle of therapy, patients underwent fluorodeoxyglucose-PET scans, and those with negative results were then randomized.
The trial was designed and powered for noninferiority of the shortened regimen, with a maximum allowable difference of 6%.
The trial met its primary endpoint and then some. After a median observation time of 53 months, the 5-year PFS rate for patients who received only four cycles was 91.2%, compared with 91.8% for patients who underwent six-to-eight cycles. As shown on a Kaplan-Meier curve, the two lines were superimposable and virtually impossible to tell apart.
Interestingly, 5-year overall survival was significantly better with the shorter, less toxic regimen, at 97.6% vs. 95.4%, respectively, translating into a hazard ratio favoring the shorter regimen of 0.36 (P = .006).
In addition, the four-cycle regimen was associated with fewer severe infections (8% vs 15%), and lower degrees of organ toxicity (8% vs. 18%). In addition, the rate of secondary acute myeloid leukemia or the myelodysplastic syndrome was 0.4% among the 501 patients treated with only four cycles, compared with 1.6% for the 504 patients who received six to eight cycles.
There were no treatment-related deaths among patients who underwent four cycles, compared with six deaths among patients treated with additional cycles.
In an interview, Dr. Borchmann said that the findings are likely to change the standard of care for those centers that use the BEACOPP regimen. He acknowledged that the regimen is highly toxic and requires intensive patient surveillance and management, which may be more practical in Europe where patients generally live closer to major cancer centers than in the more spacious United States.
The study was supported by German Cancer Aid, the Swiss State Secratariate for Education, Research and Innovation, and by Roche Pharma AG. Dr, Borchmann reported having no relevant disclosures.
MADRID – Patients with advanced Hodgkin lymphoma who have a metabolic response after the first two cycles of extended-dose(e)BEACOPP can be spared from undergoing more than two additional cycles of the highly intensive and toxic regimen, investigators from the German Hodgkin Study Group (GHSG) contend.
Among 1,005 patients with Hodgkin lymphoma who had negative PET scans after the second cycle of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, prednisone, procarbazine), progression-free survival (PFS) was virtually identical whether patients were randomized to undergo a total of six-to-eight cycles or only four cycles, reported Peter Borchmann, MD, from the University of Cologne, Germany.
“For patients with negative PET-2 after initial treatment with eBEACOPP. Therapy with only two additional cycles of eBEACOPP is very effective, obviously, very safe, very short – it just takes 12 weeks – and it’s affordable,” he said.
“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far. That’s why we recommend this treatment, PET-guided extended BEACOPP in patients with newly diagnosed, advanced-stage Hodgkin lymphoma,” he added.
Although most patients in the United States with newly diagnosed Hodgkin lymphoma receive ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), BEACOPP is sometimes used for high-risk patients. BEACOPP is associated with considerable toxicities, however, including increased risk of secondary malignancies.
To see whether select patients could be cured with fewer cycles of therapy, the GHSG investigators designed the GHSG HD18 study in which patient with metabolic responses determined by fluorodeoxyglucose-PET after two eBEACOPP cycles were randomized to either two or six-to-eight additional cycles.
A total of 2,101 patients from the ages of 18-60 years with newly diagnosed advanced-stage Hodgkin lymphoma were enrolled from centers in Germany, Switzerland, Austria, the Czech Republic, and the Netherlands.
After the second cycle of therapy, patients underwent fluorodeoxyglucose-PET scans, and those with negative results were then randomized.
The trial was designed and powered for noninferiority of the shortened regimen, with a maximum allowable difference of 6%.
The trial met its primary endpoint and then some. After a median observation time of 53 months, the 5-year PFS rate for patients who received only four cycles was 91.2%, compared with 91.8% for patients who underwent six-to-eight cycles. As shown on a Kaplan-Meier curve, the two lines were superimposable and virtually impossible to tell apart.
Interestingly, 5-year overall survival was significantly better with the shorter, less toxic regimen, at 97.6% vs. 95.4%, respectively, translating into a hazard ratio favoring the shorter regimen of 0.36 (P = .006).
In addition, the four-cycle regimen was associated with fewer severe infections (8% vs 15%), and lower degrees of organ toxicity (8% vs. 18%). In addition, the rate of secondary acute myeloid leukemia or the myelodysplastic syndrome was 0.4% among the 501 patients treated with only four cycles, compared with 1.6% for the 504 patients who received six to eight cycles.
There were no treatment-related deaths among patients who underwent four cycles, compared with six deaths among patients treated with additional cycles.
In an interview, Dr. Borchmann said that the findings are likely to change the standard of care for those centers that use the BEACOPP regimen. He acknowledged that the regimen is highly toxic and requires intensive patient surveillance and management, which may be more practical in Europe where patients generally live closer to major cancer centers than in the more spacious United States.
The study was supported by German Cancer Aid, the Swiss State Secratariate for Education, Research and Innovation, and by Roche Pharma AG. Dr, Borchmann reported having no relevant disclosures.
AT EHA 2017
Key clinical point: For patients with newly diagnosed advanced Hodgkin lymphoma with PET-confirmed metabolic responses, four cycles of BEACOPP were at least as good as six to eight cycles for progression-free and overall survival.
Major finding: 5-year overall survival with four cycles of extended-dose BEACOPP was 97.6%, compared with. 95.4% for six to eight cycles (P = .006).
Data source: Randomized trial in 1,005 patients with newly diagnosed Hodgkin lymphoma from five European nations.
Disclosures: The study was supported by German Cancer Aid, the Swiss State Secretariate for Education, Research and Innovation, and by Roche Pharma AG. Dr. Borchmann reported having no relevant disclosures.
Major bleeding deaths may outweigh VTE risk in older cancer patients
MADRID – Look before you leap into anticoagulation therapy for older cancer patients, results from a Canadian cohort study suggest.
Among patients 65 and older with cancer and a venous thromboembolic event (VTE) within 6 months of the cancer diagnosis, the 7-day mortality rate from VTE was 0.5%, compared with an 11% rate of death from a major bleeding episode, reported Alejandro Lazo-Langner MD, MSc from Western University in London, Canada.
If their findings are confirmed in further studies, “it would actually change what we do in terms of the treatment of thrombosis,” he said.
Risks for both VTE and for bleeding are known to be higher among patients with cancer than in the general population. Although a previously published systematic review suggested that mortality rates from recurrent VTE and major bleeding events were similar in the first 6 months of anticoagulation therapy, those results were limited by the heterogeneity of designs in the various studies included in the review, and by differences in outcome measures and the types of populations included, Dr. Lazo-Langner said.
To get a better idea of the case fatality rates of VTE recurrence and major bleeding and the case fatality rate ratio for each, the authors conducted a retrospective population-based cohort study in the Province of Ontario using de-identified linked administrative health care databases.
They assembled a cohort of patients 65 years of age and older who had a VTE event within 6 months of an initial cancer diagnosis. Recurrent VTE and major bleeding events were assessed within 180 days of the index date.
They found that from 2004 through 2014 there were 6,967 VTEs in cancer patients over 65 years of age (mean age 75) that were treated with an anticoagulant, either low-molecular-weight heparin (LMWH), LMWH plus warfarin, warfarin alone, or rivaroxaban (Xarelto).
Six months after the index VTE events, 235 patients (3%) had experienced a major bleeding event, and 1,184 (17%) had a recurrent VTE.
Within 7 days of the outcome event the mortality rate due to major bleeding was 11%, compared with 0.5% for recurrent VTEs. This translated into a mortality rate ratio for major bleeding vs. VTE of 21.8
Elizabeth Macintyre, MD, from the Hôpital Necker-Enfants Malades and University of Paris, France, who was not involved in the study, said in an interview that the results indicate that clinicians should not automatically assume that anticoagulation is a good idea for every older cancer patient.
“We now need to consider whether we should be reducing the time of anticoagulation, but that obviously depends on all sorts of other risk factors, so it has to be an individual patient decision. But the message is clearly don’t just anticoagulate to avoid the risk of thrombosis, and do in bear in mind that the other side of the coin could be just as serious,” she said.
The study was supported by the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Lazo-Langner and Dr. Macintyre reported having no conflicts of interest to disclose.
MADRID – Look before you leap into anticoagulation therapy for older cancer patients, results from a Canadian cohort study suggest.
Among patients 65 and older with cancer and a venous thromboembolic event (VTE) within 6 months of the cancer diagnosis, the 7-day mortality rate from VTE was 0.5%, compared with an 11% rate of death from a major bleeding episode, reported Alejandro Lazo-Langner MD, MSc from Western University in London, Canada.
If their findings are confirmed in further studies, “it would actually change what we do in terms of the treatment of thrombosis,” he said.
Risks for both VTE and for bleeding are known to be higher among patients with cancer than in the general population. Although a previously published systematic review suggested that mortality rates from recurrent VTE and major bleeding events were similar in the first 6 months of anticoagulation therapy, those results were limited by the heterogeneity of designs in the various studies included in the review, and by differences in outcome measures and the types of populations included, Dr. Lazo-Langner said.
To get a better idea of the case fatality rates of VTE recurrence and major bleeding and the case fatality rate ratio for each, the authors conducted a retrospective population-based cohort study in the Province of Ontario using de-identified linked administrative health care databases.
They assembled a cohort of patients 65 years of age and older who had a VTE event within 6 months of an initial cancer diagnosis. Recurrent VTE and major bleeding events were assessed within 180 days of the index date.
They found that from 2004 through 2014 there were 6,967 VTEs in cancer patients over 65 years of age (mean age 75) that were treated with an anticoagulant, either low-molecular-weight heparin (LMWH), LMWH plus warfarin, warfarin alone, or rivaroxaban (Xarelto).
Six months after the index VTE events, 235 patients (3%) had experienced a major bleeding event, and 1,184 (17%) had a recurrent VTE.
Within 7 days of the outcome event the mortality rate due to major bleeding was 11%, compared with 0.5% for recurrent VTEs. This translated into a mortality rate ratio for major bleeding vs. VTE of 21.8
Elizabeth Macintyre, MD, from the Hôpital Necker-Enfants Malades and University of Paris, France, who was not involved in the study, said in an interview that the results indicate that clinicians should not automatically assume that anticoagulation is a good idea for every older cancer patient.
“We now need to consider whether we should be reducing the time of anticoagulation, but that obviously depends on all sorts of other risk factors, so it has to be an individual patient decision. But the message is clearly don’t just anticoagulate to avoid the risk of thrombosis, and do in bear in mind that the other side of the coin could be just as serious,” she said.
The study was supported by the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Lazo-Langner and Dr. Macintyre reported having no conflicts of interest to disclose.
MADRID – Look before you leap into anticoagulation therapy for older cancer patients, results from a Canadian cohort study suggest.
Among patients 65 and older with cancer and a venous thromboembolic event (VTE) within 6 months of the cancer diagnosis, the 7-day mortality rate from VTE was 0.5%, compared with an 11% rate of death from a major bleeding episode, reported Alejandro Lazo-Langner MD, MSc from Western University in London, Canada.
If their findings are confirmed in further studies, “it would actually change what we do in terms of the treatment of thrombosis,” he said.
Risks for both VTE and for bleeding are known to be higher among patients with cancer than in the general population. Although a previously published systematic review suggested that mortality rates from recurrent VTE and major bleeding events were similar in the first 6 months of anticoagulation therapy, those results were limited by the heterogeneity of designs in the various studies included in the review, and by differences in outcome measures and the types of populations included, Dr. Lazo-Langner said.
To get a better idea of the case fatality rates of VTE recurrence and major bleeding and the case fatality rate ratio for each, the authors conducted a retrospective population-based cohort study in the Province of Ontario using de-identified linked administrative health care databases.
They assembled a cohort of patients 65 years of age and older who had a VTE event within 6 months of an initial cancer diagnosis. Recurrent VTE and major bleeding events were assessed within 180 days of the index date.
They found that from 2004 through 2014 there were 6,967 VTEs in cancer patients over 65 years of age (mean age 75) that were treated with an anticoagulant, either low-molecular-weight heparin (LMWH), LMWH plus warfarin, warfarin alone, or rivaroxaban (Xarelto).
Six months after the index VTE events, 235 patients (3%) had experienced a major bleeding event, and 1,184 (17%) had a recurrent VTE.
Within 7 days of the outcome event the mortality rate due to major bleeding was 11%, compared with 0.5% for recurrent VTEs. This translated into a mortality rate ratio for major bleeding vs. VTE of 21.8
Elizabeth Macintyre, MD, from the Hôpital Necker-Enfants Malades and University of Paris, France, who was not involved in the study, said in an interview that the results indicate that clinicians should not automatically assume that anticoagulation is a good idea for every older cancer patient.
“We now need to consider whether we should be reducing the time of anticoagulation, but that obviously depends on all sorts of other risk factors, so it has to be an individual patient decision. But the message is clearly don’t just anticoagulate to avoid the risk of thrombosis, and do in bear in mind that the other side of the coin could be just as serious,” she said.
The study was supported by the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Lazo-Langner and Dr. Macintyre reported having no conflicts of interest to disclose.
AT EHA 2017
Key clinical point: In cancer patients older than 65, the risk of major bleeding from anticoagulants may outweigh the risk of venous thromboembolism.
Major finding: 7-day mortality rates were 11% for major bleeding vs 0.5% for recurrent VTE.
Data source: Retrospective cohort study of 6,967 cancer patients age 65 and older from Ontario, Canada.
Disclosures: The study was supported by the Institute for Clinical Evaluative Sciences, funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Lazo-Langner and Dr. Macintyre reported having no conflicts of interest to disclose.
Infections may trigger leukemia in the genetically susceptible
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
MADRID – The evidence thus far comes only from animal models, but commonly encountered childhood infections may be able to trigger the development of leukemia in those children with certain genetic predispositions to B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
Mice genetically modified to mimic BCP-ALL susceptibility and its most common subtype (ETV6-RUNX1 BCP-ALL) developed leukemia only after exposure to a common infectious environment.
“The mechanism that takes place in preleukemic cells after the mice were exposed to infection was different in the two mouse models,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.
“This is another piece that will, hopefully, contribute to the picture of how exposure to infection can contribute to leukemic development” and may lead to novel approaches for leukemia prevention, she added.
The possibility that exposure to infectious pathogens could trigger leukemia has been bandied about for a century, based in part on observations that leukemia is the most common malignancy in children, with a still unexplained peak incidence between the ages of 2 and 6 years, Dr. Hauer noted.
To explore a possible link, she and her colleagues developed and characterized the aforementioned mice mimicking BCP-ALL with the BCR-ABL1 transcription and ETV6-RUNX1 BCP-ALL, in addition to a previously described Pax5+/- infection model. Some of all three mouse models were exposed not to specific pathogens but to a common laboratory environment, where they could be expected to acquire various infections at 2-3 months of age, and some were kept in a sterile environment designed to reduce transmission of pathogens. Wild-type mice were used as controls.
They observed that the Pax5+/- and ETV6-RUNX1 mice developed BCP-ALL only after exposure to common pathogens. In contrast, the BCR-ABL1p190 mice developed BCP-ALL independent of exposure to common infection.
They also determined that the mechanism leading to leukemia in the Pax5+/- mice was related to constitutive activations of mutations in the Janus kinase (JAK)3 pathway in susceptible B cell precursors, whereas the ETV6-RUNX1 mice developed BCP-ALL at a low penetrance (10.75%, 10 of 93) with a CD19-positive, B220-positive, immunoglobulin M-negative cell surface phenotype, manifested by blast cells in peripheral blood and a clonal immature B-cell receptor rearrangement.
In mice, norovirus and hepatitis C virus may be some of the pathogens most closely linked to risk of leukemia, but it’s likely that other viruses and parasitic infections will turn out to be the culprits in humans, Dr. Hauer said.
The findings raise the possibility of an unexpected link between leukemia and the so-called “hygiene hypothesis” linking childhood asthma, allergies, and atopic skin conditions to a lack of early exposure to a multiplicity of pathogens. In many developed countries, children are relatively protected from exposure to many different pathogens and may not encounter infectious agents until entering preschool or kindergarten, Dr. Hauer commented.
The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
AT EHA 2017
Key clinical point: This study suggests a link between acute lymphocytic leukemia development and infections in some genetically predisposed children.
Major finding: Mouse models of two types of B-cell precursor ALL developed leukemia only after exposure to infections.
Data source: A study of factors related to the development of childhood ALL using genetically modified mouse models.
Disclosures: The study was supported by German Cancer Aid, the Jose Carreras Leukemia Foundation, and other charitable agencies. Dr. Hauer reported no relevant disclosures.
Twofer drug blocks SYK/JAK pathways in advanced NHL
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.
The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.
“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.
Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.
In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.
In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.
The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.
As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.
In addition, the investigators identified one complete response in the first enrolled patient with PTCL.
“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.
Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.
The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.
The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.
In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.
Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.
The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
AT EHA 2017
Key clinical point: Cerdulatinib, an inhibitor of the SYK and JAK pathways, has shown efficacy against relapsed/refractory non-Hodgkin lymphomas.
Major finding: The overall response rate was 50%, including one complete response in a patient with peripheral T-cell lymphoma.
Data source: An open label, phase II study in 47 patients with non-Hodgkin lymphoma or peripheral T-cell lymphoma.
Disclosures: The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant roles for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.
Chemo-free induction in MCL keeps getting better
Lugano, Switzerland – It’s not the end of chemotherapy for young patients with newly diagnosed mantle cell lymphoma (MCL), but it’s a start.
For these patients, induction with a combination of ibrutinib and rituximab, followed by shorter cycles of chemoimmunotherapy, was associated in an early study with an objective response rate of 100%, including 90% complete responses (CR), reported Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This is the first time for a chemo-free therapy – ibrutinib/rituximab – to achieve an overall response rate of 100%. This has an unprecedented efficacy in the frontline in young patients with mantle-cell lymphoma,” he said at the 14th International Congress on Malignant Lymphoma.
In patients with relapsed or refractory MCL, the combination of ibrutinib and rituximab has been associated with durable responses in 88% of patients. The success of the combination suggests that fit patients younger than age 65 years with newly diagnosed MCL might benefit from a chemotherapy-free induction regimen with ibrutinib and rituximab, followed by consolidation with a short but intense course of chemoimmunotherapy, Dr. Wang said.
He presented updated results from the phase II Window I study, first results of which were reported at the 2016 meeting of the American Society of Hematology.
“Frontline therapy is the most important therapy for mantle cell lymphoma, because mantle cell lymphoma cells are most vulnerable to frontline attack. If the frontline therapy is good enough, it could kill all the mantle cell lymphoma cells, therefore leaving no chance for secondary resistance, and thereby (resulting in) long-term survival. And it is really my belief that if we ideally optimized the frontline therapy, that would be a shortcut to a cure,” he said.
To test this idea, Dr. Wang and MD Anderson colleagues initiated a phase II trial at their institution with 50 patients age 65 years or under with newly diagnosed, CD20-positive and Cyclin D1-positive MCL.
A total of 50 patients age 65 years or younger (median age 54) with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib 560 mg, plus rituximab 375 mg/m2 administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating every 28 days with rituximab plus high-dose methotrexate–cytarabine.
Patients who had complete responses to induction received four cycles of chemoimmunotherapy, while those who experienced disease progression and those who had partial responses received chemoimmunotherapy for two cycles beyond the point of complete remissions.
At the time of the presentation, all 50 patients were evaluable for the induction phase (part 2), and 47 were evaluable for both induction and consolidation (part 2) .Of the evaluable patients, the overall response rate (ORR) to chemotherapy-free induction therapy alone (Part 1 ) was 100% (50), with CR in 90% of patients and partial responses (PR) in 10%. Of the 47 patients evaluable for part 2 (chemoimmunotherapy), all had CRs, for an ORR of 100%.
Dr. Wang noted that one patient had a dramatic radiographic reduction in spleen size following just two cycles of chemotherapy-free induction, and two other patients had similar reductions after four and six cycles, respectively.
After a median follow-up of 15.9 months, neither the median duration of response, progression-free survival, nor overall survival have been reached. There have been no deaths and only one case of disease progression after one year of therapy.
The patients generally tolerated the regimen very well, Dr. Wang said. There were no cases of lymphocytosis, bleeding, or atrial fibrillation after 332 combined cycles.
Nonhematological adverse events were primarily grade 1 or 2. Grade 3 fatigue was reported in approximately 10% of patients. There were no grade 4 adverse events.
“This study may provide a window of opportunity to reduce the frontline therapies and reduce the long-term toxicities such as secondary malignancies.” Dr. Wang said.
He acknowledged that four cycles of intensive chemotherapy is still toxic and that further efforts to reduce these toxicities are needed. The investigators are currently planning the Window II study, in which a fraction of patients will be treated with no chemotherapy at all, he said.
The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
Lugano, Switzerland – It’s not the end of chemotherapy for young patients with newly diagnosed mantle cell lymphoma (MCL), but it’s a start.
For these patients, induction with a combination of ibrutinib and rituximab, followed by shorter cycles of chemoimmunotherapy, was associated in an early study with an objective response rate of 100%, including 90% complete responses (CR), reported Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This is the first time for a chemo-free therapy – ibrutinib/rituximab – to achieve an overall response rate of 100%. This has an unprecedented efficacy in the frontline in young patients with mantle-cell lymphoma,” he said at the 14th International Congress on Malignant Lymphoma.
In patients with relapsed or refractory MCL, the combination of ibrutinib and rituximab has been associated with durable responses in 88% of patients. The success of the combination suggests that fit patients younger than age 65 years with newly diagnosed MCL might benefit from a chemotherapy-free induction regimen with ibrutinib and rituximab, followed by consolidation with a short but intense course of chemoimmunotherapy, Dr. Wang said.
He presented updated results from the phase II Window I study, first results of which were reported at the 2016 meeting of the American Society of Hematology.
“Frontline therapy is the most important therapy for mantle cell lymphoma, because mantle cell lymphoma cells are most vulnerable to frontline attack. If the frontline therapy is good enough, it could kill all the mantle cell lymphoma cells, therefore leaving no chance for secondary resistance, and thereby (resulting in) long-term survival. And it is really my belief that if we ideally optimized the frontline therapy, that would be a shortcut to a cure,” he said.
To test this idea, Dr. Wang and MD Anderson colleagues initiated a phase II trial at their institution with 50 patients age 65 years or under with newly diagnosed, CD20-positive and Cyclin D1-positive MCL.
A total of 50 patients age 65 years or younger (median age 54) with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib 560 mg, plus rituximab 375 mg/m2 administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating every 28 days with rituximab plus high-dose methotrexate–cytarabine.
Patients who had complete responses to induction received four cycles of chemoimmunotherapy, while those who experienced disease progression and those who had partial responses received chemoimmunotherapy for two cycles beyond the point of complete remissions.
At the time of the presentation, all 50 patients were evaluable for the induction phase (part 2), and 47 were evaluable for both induction and consolidation (part 2) .Of the evaluable patients, the overall response rate (ORR) to chemotherapy-free induction therapy alone (Part 1 ) was 100% (50), with CR in 90% of patients and partial responses (PR) in 10%. Of the 47 patients evaluable for part 2 (chemoimmunotherapy), all had CRs, for an ORR of 100%.
Dr. Wang noted that one patient had a dramatic radiographic reduction in spleen size following just two cycles of chemotherapy-free induction, and two other patients had similar reductions after four and six cycles, respectively.
After a median follow-up of 15.9 months, neither the median duration of response, progression-free survival, nor overall survival have been reached. There have been no deaths and only one case of disease progression after one year of therapy.
The patients generally tolerated the regimen very well, Dr. Wang said. There were no cases of lymphocytosis, bleeding, or atrial fibrillation after 332 combined cycles.
Nonhematological adverse events were primarily grade 1 or 2. Grade 3 fatigue was reported in approximately 10% of patients. There were no grade 4 adverse events.
“This study may provide a window of opportunity to reduce the frontline therapies and reduce the long-term toxicities such as secondary malignancies.” Dr. Wang said.
He acknowledged that four cycles of intensive chemotherapy is still toxic and that further efforts to reduce these toxicities are needed. The investigators are currently planning the Window II study, in which a fraction of patients will be treated with no chemotherapy at all, he said.
The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
Lugano, Switzerland – It’s not the end of chemotherapy for young patients with newly diagnosed mantle cell lymphoma (MCL), but it’s a start.
For these patients, induction with a combination of ibrutinib and rituximab, followed by shorter cycles of chemoimmunotherapy, was associated in an early study with an objective response rate of 100%, including 90% complete responses (CR), reported Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston.
“This is the first time for a chemo-free therapy – ibrutinib/rituximab – to achieve an overall response rate of 100%. This has an unprecedented efficacy in the frontline in young patients with mantle-cell lymphoma,” he said at the 14th International Congress on Malignant Lymphoma.
In patients with relapsed or refractory MCL, the combination of ibrutinib and rituximab has been associated with durable responses in 88% of patients. The success of the combination suggests that fit patients younger than age 65 years with newly diagnosed MCL might benefit from a chemotherapy-free induction regimen with ibrutinib and rituximab, followed by consolidation with a short but intense course of chemoimmunotherapy, Dr. Wang said.
He presented updated results from the phase II Window I study, first results of which were reported at the 2016 meeting of the American Society of Hematology.
“Frontline therapy is the most important therapy for mantle cell lymphoma, because mantle cell lymphoma cells are most vulnerable to frontline attack. If the frontline therapy is good enough, it could kill all the mantle cell lymphoma cells, therefore leaving no chance for secondary resistance, and thereby (resulting in) long-term survival. And it is really my belief that if we ideally optimized the frontline therapy, that would be a shortcut to a cure,” he said.
To test this idea, Dr. Wang and MD Anderson colleagues initiated a phase II trial at their institution with 50 patients age 65 years or under with newly diagnosed, CD20-positive and Cyclin D1-positive MCL.
A total of 50 patients age 65 years or younger (median age 54) with newly diagnosed, untreated MCL underwent induction with continuous daily ibrutinib 560 mg, plus rituximab 375 mg/m2 administered weekly for 4 weeks during cycle 1 and on day 1 of cycles 3-12. Consolidation consisted of rituximab plus hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating every 28 days with rituximab plus high-dose methotrexate–cytarabine.
Patients who had complete responses to induction received four cycles of chemoimmunotherapy, while those who experienced disease progression and those who had partial responses received chemoimmunotherapy for two cycles beyond the point of complete remissions.
At the time of the presentation, all 50 patients were evaluable for the induction phase (part 2), and 47 were evaluable for both induction and consolidation (part 2) .Of the evaluable patients, the overall response rate (ORR) to chemotherapy-free induction therapy alone (Part 1 ) was 100% (50), with CR in 90% of patients and partial responses (PR) in 10%. Of the 47 patients evaluable for part 2 (chemoimmunotherapy), all had CRs, for an ORR of 100%.
Dr. Wang noted that one patient had a dramatic radiographic reduction in spleen size following just two cycles of chemotherapy-free induction, and two other patients had similar reductions after four and six cycles, respectively.
After a median follow-up of 15.9 months, neither the median duration of response, progression-free survival, nor overall survival have been reached. There have been no deaths and only one case of disease progression after one year of therapy.
The patients generally tolerated the regimen very well, Dr. Wang said. There were no cases of lymphocytosis, bleeding, or atrial fibrillation after 332 combined cycles.
Nonhematological adverse events were primarily grade 1 or 2. Grade 3 fatigue was reported in approximately 10% of patients. There were no grade 4 adverse events.
“This study may provide a window of opportunity to reduce the frontline therapies and reduce the long-term toxicities such as secondary malignancies.” Dr. Wang said.
He acknowledged that four cycles of intensive chemotherapy is still toxic and that further efforts to reduce these toxicities are needed. The investigators are currently planning the Window II study, in which a fraction of patients will be treated with no chemotherapy at all, he said.
The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
AT14-ICML
Key clinical point: A chemotherapy-free induction regimen with ibrutinib and rituximab was associated with high response rates in patients with newly diagnosed mantle cell lymphoma (MCL).
Major finding: The overall response rate after induction was 100%, including 90% complete responses.
Data source: Update results from phase II investigator-initiated study in 50 patients aged 65 years and younger with MCL.
Disclosures: The study was supported by Pharmacyclics and Janssen. Dr. Wang disclosed receiving research grants and honoraria and serving as a consultant for the companies.
Lenalidomide-rituximab induces high CR rate in untreated follicular lymphoma
LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.
Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.
“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.
In the 50803 study, the investigators enrolled 66 treatment-naive patients. The median age was 53 years (range 32-79). Patients were eligible if they had grade 1-3a, stage 3-4 or bulky stage 2 untreated follicular lymphoma, with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0-2.
They received lenalidomide 20 mg/day on days 1 through 21 of each 28-day cycle for 12 cycles, plus rituximab administered once weekly for each week of cycle 1, and on the first day of cycles 4, 6, 8 and 10.
The investigators also evaluated polymorphisms in the Fc fragment of immunoglobulin G receptor IIa and IIIa (FcGR2A/FcGR3A).
One of the 66 patients never started treatment, leaving 65 for the response analysis.
As noted, the overall response rate was 95%, including 94% of 21 patients with FLIPI 0 or 1 disease, and 96% of 44 patients with FLIPI 2 or 3. There were no associations between FLIPI score and likelihood of achieving a complete response, and no associations between FcR polymorphism or change in angiogenic markers and either complete responses or PFS, Dr. Leonard said.
Complete responses, the primary endpoint, were seen in 15 of the 21 (71%) of patients with FLIPI 0-1, and in 32 of the 44 (73%) with FLIPI 2-3, for an overall complete response rate of 72%.
Partial responses occurred in 5 patients (23%) with FLIPI 0-1 and 10 patients (23%) with FLIPI 2-3, for an overall PR rate of 23%.
Respective rates of stable disease were 0, 2%, and 2%. One patient in each FLIPI group was not evaluated because of adverse events.
After a median follow-up of 5 years, the progression free survival rate was 70%.
The most common grade 3 or 4 adverse events were neutropenia, seen in 21% of patients, and infections, seen in 40% (including one grade 3 febrile neutropenia).
Grade 1-2 fatigue was reported by 51 patients, and grade 3 fatigue was reported by 4.
Other grade 3 or 4 events seen in more than 5% of patients included rash in 9%, and hyperglycemia, hypophosphatemia, or hypertension, each in 6% of patients.
Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.
Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.
“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.
In the 50803 study, the investigators enrolled 66 treatment-naive patients. The median age was 53 years (range 32-79). Patients were eligible if they had grade 1-3a, stage 3-4 or bulky stage 2 untreated follicular lymphoma, with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0-2.
They received lenalidomide 20 mg/day on days 1 through 21 of each 28-day cycle for 12 cycles, plus rituximab administered once weekly for each week of cycle 1, and on the first day of cycles 4, 6, 8 and 10.
The investigators also evaluated polymorphisms in the Fc fragment of immunoglobulin G receptor IIa and IIIa (FcGR2A/FcGR3A).
One of the 66 patients never started treatment, leaving 65 for the response analysis.
As noted, the overall response rate was 95%, including 94% of 21 patients with FLIPI 0 or 1 disease, and 96% of 44 patients with FLIPI 2 or 3. There were no associations between FLIPI score and likelihood of achieving a complete response, and no associations between FcR polymorphism or change in angiogenic markers and either complete responses or PFS, Dr. Leonard said.
Complete responses, the primary endpoint, were seen in 15 of the 21 (71%) of patients with FLIPI 0-1, and in 32 of the 44 (73%) with FLIPI 2-3, for an overall complete response rate of 72%.
Partial responses occurred in 5 patients (23%) with FLIPI 0-1 and 10 patients (23%) with FLIPI 2-3, for an overall PR rate of 23%.
Respective rates of stable disease were 0, 2%, and 2%. One patient in each FLIPI group was not evaluated because of adverse events.
After a median follow-up of 5 years, the progression free survival rate was 70%.
The most common grade 3 or 4 adverse events were neutropenia, seen in 21% of patients, and infections, seen in 40% (including one grade 3 febrile neutropenia).
Grade 1-2 fatigue was reported by 51 patients, and grade 3 fatigue was reported by 4.
Other grade 3 or 4 events seen in more than 5% of patients included rash in 9%, and hyperglycemia, hypophosphatemia, or hypertension, each in 6% of patients.
Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
LUGANO, SWITZERLAND – The chemotherapy-free combination of lenalidomide (Revlimid) and rituximab was highly active as frontline therapy for patients with low- and intermediate-risk follicular lymphoma in a multicenter phase II trial.
Among 66 patients with previously untreated follicular lymphoma, the overall response rate to the combination was 95%, including complete responses in 72% of patients. The 5-year progression-free survival (PFS) rate was 70%, reported John P. Leonard, MD, of Weill Cornell Medicine, New York.
“I think this overall is a useful validation – confirmation of the single-center data that showed that this [combination] in a multicenter setting can be a highly effective and reasonably well-tolerated treatment approach for patients with untreated follicular lymphoma,” he said at the International Conference on Malignant Lymphoma, on behalf of colleagues in the National Cancer Institute Alliance for Clinical Trials in Oncology and Cancer and Leukemia Group B (CALGB) 50803 trial.
In the 50803 study, the investigators enrolled 66 treatment-naive patients. The median age was 53 years (range 32-79). Patients were eligible if they had grade 1-3a, stage 3-4 or bulky stage 2 untreated follicular lymphoma, with Follicular Lymphoma International Prognostic Index (FLIPI) scores of 0-2.
They received lenalidomide 20 mg/day on days 1 through 21 of each 28-day cycle for 12 cycles, plus rituximab administered once weekly for each week of cycle 1, and on the first day of cycles 4, 6, 8 and 10.
The investigators also evaluated polymorphisms in the Fc fragment of immunoglobulin G receptor IIa and IIIa (FcGR2A/FcGR3A).
One of the 66 patients never started treatment, leaving 65 for the response analysis.
As noted, the overall response rate was 95%, including 94% of 21 patients with FLIPI 0 or 1 disease, and 96% of 44 patients with FLIPI 2 or 3. There were no associations between FLIPI score and likelihood of achieving a complete response, and no associations between FcR polymorphism or change in angiogenic markers and either complete responses or PFS, Dr. Leonard said.
Complete responses, the primary endpoint, were seen in 15 of the 21 (71%) of patients with FLIPI 0-1, and in 32 of the 44 (73%) with FLIPI 2-3, for an overall complete response rate of 72%.
Partial responses occurred in 5 patients (23%) with FLIPI 0-1 and 10 patients (23%) with FLIPI 2-3, for an overall PR rate of 23%.
Respective rates of stable disease were 0, 2%, and 2%. One patient in each FLIPI group was not evaluated because of adverse events.
After a median follow-up of 5 years, the progression free survival rate was 70%.
The most common grade 3 or 4 adverse events were neutropenia, seen in 21% of patients, and infections, seen in 40% (including one grade 3 febrile neutropenia).
Grade 1-2 fatigue was reported by 51 patients, and grade 3 fatigue was reported by 4.
Other grade 3 or 4 events seen in more than 5% of patients included rash in 9%, and hyperglycemia, hypophosphatemia, or hypertension, each in 6% of patients.
Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
AT 14-ICML
Key clinical point: The combination of lenalidomide and rituximab was highly active against previously untreated follicular lymphoma.
Major finding: The overall response rate was 95%; 5-year progression-free survival was 70%.
Data source: Open-label prospective study of lenalidomide-rituximab in 66 patients with previously untreated follicular lymphoma.
Disclosures: Celgene and Genentech supported the study. Dr. Leonard has served as an adviser/consultant to Celgene and other companies.
Sequential triple therapy produces high response rates in CLL
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
Lugano, Switzerland– It’s in the BAG: For patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, a regimen consisting of debulking with bendamustine (Treanda) followed sequentially by obinutuzumab (Gazyva) and venetoclax (Venclexta) was associated with a high overall response rate and a large majority of patients being negative for minimal residual disease (MRD) in peripheral blood.
In the open-label, phase II CLL2-BAG study in 66 patients, the overall response rate at the end of induction was 95%, and 87% of patients were negative for MRD, reported Paula Cramer, MD, of the University of Cologne (Germany).
“This sequential treatment of bendamustine followed by obinutuzumab and venetoclax does not lead to any cumulative or unexpected toxicity. As compared to other trials, it’s important to point out that only one laboratory TLS [tumor lysis syndrome] occurred with venetoclax. Maybe that’s explained by the sequential start of all three drugs,” she said at the International Conference on Malignant Lymphoma.
The trial is based on a concept the investigators call “sequential triple-T” (tailored and targeted treatment) aimed at complete eradication of MRD.
The 66 patients (median age, 59 years) had either previously untreated or relapsed/refractory CLL; 34 of the treatment-naive and 29 of the relapsed/refractory patients were evaluable for response.
At enrollment, patients who had an absolute lymphocyte count of 25,000/mcL or greater and/or lymph nodes 5 cm or larger received two cycles of debulking with bendamustine 70 mg/m2 on days 1 and 2 every 28 days, unless this was contraindicated.
The induction phase consisted of obinutuzumab 1,000 mg administered three times in cycle 1, then every 4 weeks for cycles 2 through 6. Venetoclax was started during cycle 2 with a dose escalation to 400 mg daily over a period of 5 weeks.
Maintenance therapy consisted of daily venetoclax and obinutuzumab every 3 months until MRD negativity or up to 24 months.
A total of 45 patients (31 who were treatment naive and 14 with relapsed/refractory disease) underwent debulking. Of this group 36 patients received both cycles, and 9 discontinued early because of either adverse events (5 patients), disease progression (1), or unknown reasons (3).
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
Responses
In all, 24 patients (53%) who had debulking had a response during that phase based on International Workshop on CLL (IWCLL) criteria, for an overall response rate (ORR) of 53%. Thirteen patients had stable disease after debulking, and four had disease progression.
Responses after induction according to IWCLL criteria, the primary endpoint, included five patients with a complete response (three treatment-naive and two relapsed/refractory patients), and 20 patients (14 treatment-naive and six relapsed/refractory patients) with an unconfirmed or clinical complete response or a complete response with incomplete recovery of counts.
In addition, 35 patients (17 who were treatment naive and 18 with relapsed/refractory disease) had a partial response. No patients had stable disease, and three patients, all with relapsed/refractory disease, had disease progression.
Of the 63 patients who had at least two cycles of therapy, 87% were MRD negative. Eight patients had MRD assessments by bone marrow, and all eight were MRD negative.
The maintenance phase of the trial is ongoing and the data are not mature, but 56 patients (30 who were treatment naive and 26 with relapsed/refractory disease) have started on maintenance therapy. Of this group, 28 have stopped maintenance, including 21 patients who stopped because they achieved MRD negativity, 5 who discontinued because of adverse events, and 2 with disease progression or Richter’s transformation.
At 15 months of follow-up, progression-free survival was 100% in patients who received the combination as the frontline therapy, and 83% in the patients with relapsed/refractory disease.
Adverse events
In the debulking phase, 34 patients (72%) experienced adverse events of any grade, including 16 patients with grade 3 or 4 events
Adverse events associated with debulking included neutropenia and anemia, each seen in five patients, thrombocytopenia and infection each seen in three patients, and coronary artery disorders, rash, tumor lysis syndrome, vomiting, and pyrexia in one patient each.
Sixty of the 66 patients received the full six induction cycles. Three patients who had fewer than two cycles were excluded according to protocol. Of these three, two heavily pretreated patients died of sepsis and one of myocardial infarction in cycle 1.
All but 3 of the 63 patients had an adverse event, and 44 patients had at least one grade 3 or 4 adverse event.
Cytopenias, infections, infusion-related reactions, and neoplasms were the most common adverse events.
There were three grade 3 laboratory-confirmed cases of tumor lysis syndrome, one each occurring during bendamustine debulking, obinutuzumab administration, and venetoclax administration.
Something other than venetoclax?
Davide Rossi, MD, PhD, of the Oncology Institute of Southern Switzerland in Bellinzona, the invited discussant, questioned whether venetoclax is the best agent to use in sequential triple-T therapy.
“We know that venetoclax is more active in blood and bone marrow than in lymph nodes and, indeed, a proportion of cases achieving all the criteria for a CR [complete response] in the bone marrow and the peripheral blood, including MRD negativity, may still have some residual [disease in] lymph nodes,” he said.
Drugs that inhibit the B-cell receptor pathway may be more effective at eradicating MRD in the lymph node compartment, Dr. Cramer said.
The study was sponsored by the German CLL study group. Dr. Cramer disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
AT 14-ICML
Key clinical point: Sequential therapy with bendamustine, obinutuzumab, and venetoclax was associated with high response rates in patients with both treatment-naive and relapsed/refractory chronic lymphocytic leukemia.
Major finding: The overall response rate at the end of induction was 95%.
Data source: An open-label prospective study in 66 patients with CLL.
Disclosures: The study was sponsored by the German CLL study group. Dr. Cramer and her coauthors disclosed financial ties to multiple entities. Dr. Rossi did not report disclosures.
GALEN safe and effective in relapsed and refractory follicular lymphoma
LUGANO, SWITZERLAND – For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.
Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.
In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).
The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.
The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.
When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.
An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.
A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).
After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.
There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).
Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.
The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.
Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.
The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
LUGANO, SWITZERLAND – For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.
Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.
In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).
The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.
The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.
When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.
An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.
A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).
After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.
There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).
Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.
The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.
Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.
The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
LUGANO, SWITZERLAND – For patients with relapsed or refractory follicular lymphoma, a pairing of lenalidomide (Revlimid) and obinutuzumab (Gazyva) appeared to be especially useful among patients who had disease progression within 24 months, based on results from a Lymphoma Academic Research Organisation trial.
Among 86 patients who were enrolled in a phase II trial and were assessable for efficacy, overall response rates (ORR) with the combination therapy, nicknamed “GALEN,” were 80.2% by 1999 International Working Group criteria, and 74.4% according to the 2007 IWG criteria, reported Franck Morschhauser, MD, PhD, of the University of Lille, France.
The rationale for this combination is the known synergy between lenalidomide and rituximab in relapsed refractory non-Hodgkin lymphomas and in the frontline setting for patients with follicular lymphoma. Obinutuzumab, a follow-on to rituximab, is a unique type II glycoengineered monoclonal antibody directed against CD20, but with increased antibody-dependent cell-mediated cytotoxicity and increased direct cytotoxicity, compared with rituximab, he explained.
In the phase Ib part of the study, researchers settled on a dose of obinutuzumab 1000 mg and lenalidomide 20 mg. Obinutuzumab was administered on days 8, 15 and 22 and lenalidomide on days 1 to 21 of each 28 day cycle. Patients were evaluated for response after three cycles and at the end of induction (after completion of 4 to 6 cycles).
The maintenance phase consisted of obinutuzumab on day 1 of every other cycle beginning with cycle 1, and lenalidomide on days 1 through 22 for cycles 7 through 18. From cycles 19 through 24, obinutuzumab was given alone on the first day of every 56-day cycle.
The overall response rate (ORR) at the end of induction according to the IWG 1999 criteria, the primary endpoint, was 80.2%, including 39.5% complete or unconfirmed complete responses.
When the same patients were assessed according to 2007 IWG criteria, the ORR rate was slightly lower, at 74.4%, but the complete or unconfirmed complete response rate was slightly higher, at 44.2%.
An analysis of responses by time to relapse showed that the ORR among 24 patients with disease progression within 24 months was 70.8%, including 33.3% complete or unconfirmed complete responses by the 1999 criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
ORR among the 64 patients with disease progression after more than 24 months was 83.9% with 41.9% complete or unconfirmed complete responses by 1999 criteria, and 77.4% with 40.3% complete or unconfirmed complete responses by 2007 criteria. The differences between the groups with disease progression within 24 months and later relapse groups were not significant.
A subanalysis by refractory status, however, showed that the 63 nonrefractory patients fared significantly better, with 87.3% ORR and 41.3% complete or unconfirmed complete responses by 1999 criteria, and 81.0% with 49.2% complete or unconfirmed complete response rate by 2007 determinations, compared with respective rates among 23 refractory patients of 60.9%/34.8% complete or unconfirmed complete response rate and 56.5% with 30.4% complete or unconfirmed complete responses (P = .0212 by 1999 criteria, and P = .022 by 2007 criteria).
After a median follow-up of 18 months, 1-year progression-free survival (PFS) among all patients was 75.5%, and 1-year overall survival (OS) was 88.8%.
There were no significant differences in either progression-free survival or overall survival by time to relapse. Although there appeared to be a nonsignificant trend toward worse outcomes among patients with refractory vs. nonrefractory disease, there was a significantly lower 1-year overall survival rate among refractory patients, at 71.5% compared with 95% for nonrefractory patients (censored logrank P = .0098).
Dr. Morschhauser said that the combination had no unexpected toxicities. Hematologic toxicities of grade 3 or greater included neutropenia in 28.4%, thrombocytopenia in 11.4%, and anemia and lymphopenia in 3.4% each.
The most common nonhematologic toxicities of all grades included infections in 62.5% of patients (grade 3 or greater in 6.8%), and asthenia in 52.3% of patients (grade 3 or greater in 2.3%). The only other grade 3 or greater toxicities were peripheral neuropathy in 1.1%, and infusion related rash in 3.4%.
Additional follow-up will be need for evaluation of the full impact of maintenance on outcomes, he added.
The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
AT 14-ICML
Key clinical point: A combination of lenalidomide and obinutuzumab was safe and effective in patients with relapsed/refractory follicular lymphoma.
Major finding: The overall response rate according to 1999 International Working Group criteria was 80.2%, including 39.5% CR/CRu.
Data source: Single-arm phase II study with 86 patients evaluable for efficacy and 88 evaluable for safety.
Disclosures: The study was funded by Celgene and Roche. Dr. Morschhauser disclosed receiving honoraria from and serving on advisory boards for both companies.
