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VIDEO: Good responses with antibody-drug conjugate in third-line metastatic TNBC therapy
SAN ANTONIO – Fully one-third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) had a response to therapy with a novel antibody-drug conjugate called sacituzumab govitecan. The conjugate consists of the active metabolites of the topoisomerase I inhibitor irinotecan linked to a humanized monoclonal antibody target Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
Aditya Bardia, MD, from Massachusetts General Hospital in Boston, previously reported results of a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
In this video interview, he discusses the conjugate’s activity in the third-line or greater setting for patients with metastatic TNBC, with an overall response rate of 34%, including some complete responses according to independent reviewers, and describes planned clinical trials pitting the agent against standard-of-care single-drug therapies.
The trial was supported by Immunomedics. Dr. Bardia reported institutional funding from the company, but no other conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Fully one-third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) had a response to therapy with a novel antibody-drug conjugate called sacituzumab govitecan. The conjugate consists of the active metabolites of the topoisomerase I inhibitor irinotecan linked to a humanized monoclonal antibody target Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
Aditya Bardia, MD, from Massachusetts General Hospital in Boston, previously reported results of a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
In this video interview, he discusses the conjugate’s activity in the third-line or greater setting for patients with metastatic TNBC, with an overall response rate of 34%, including some complete responses according to independent reviewers, and describes planned clinical trials pitting the agent against standard-of-care single-drug therapies.
The trial was supported by Immunomedics. Dr. Bardia reported institutional funding from the company, but no other conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
SAN ANTONIO – Fully one-third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC) had a response to therapy with a novel antibody-drug conjugate called sacituzumab govitecan. The conjugate consists of the active metabolites of the topoisomerase I inhibitor irinotecan linked to a humanized monoclonal antibody target Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
Aditya Bardia, MD, from Massachusetts General Hospital in Boston, previously reported results of a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
In this video interview, he discusses the conjugate’s activity in the third-line or greater setting for patients with metastatic TNBC, with an overall response rate of 34%, including some complete responses according to independent reviewers, and describes planned clinical trials pitting the agent against standard-of-care single-drug therapies.
The trial was supported by Immunomedics. Dr. Bardia reported institutional funding from the company, but no other conflicts of interest.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
REPORTING FROM SABCS 2017
ASCO platelet transfusion guidelines updated
A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.
“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.
Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.
For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).
The authors caution, however, that the recommendation applies to adults only.
Other updated recommendations include:
• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.
• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.
“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.
They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.
To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.
The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.
The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.
“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.
Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.
For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).
The authors caution, however, that the recommendation applies to adults only.
Other updated recommendations include:
• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.
• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.
“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.
They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.
To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.
The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.
The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
A lot has happened in oncology since the American Society of Clinical Oncology (ASCO) first issued its guidelines on platelet transfusion for patients with cancer in 2001, noted the authors of the updated recommendations.
“The expense of platelet transfusions, coupled with potential adverse effects such as febrile and allergic reactions, transfusion-related acute lung injury, and bacterial contamination point to the importance of evidence-based transfusion practice,” wrote Charles A Schiffer, MD, of Wayne State Michigan, Detroit, and his colleagues in the updated guidelines.
Many of the original recommendations remain unchanged, but there are updated evidence-based recommendations in five key areas.
For example, regarding platelet transfusion thresholds in the setting of hematologic stem-cell transplantation in adults, the guidelines incorporate evidence from randomized clinical trials showing that among adults who have received autologous hematologic stem-cell transplantation, bleeding rates with decreased use of platelets are similar whether patients are treated prophylactically or at the first sign of bleeding, “and this approach may be used in experienced centers,” wrote Dr. Schiffer and his colleagues (J Clin Oncol. 2017 Nov 28. doi: 10.1200/JCO.2017.76.1734).
The authors caution, however, that the recommendation applies to adults only.
Other updated recommendations include:
• Rhesus D alloimmunization from platelet transfusions to RhD-negative patients can be prevented through either exclusive use of platelet products from RhD-negative donors or immunoprophylaxis. The guidelines note that there is a low rate of RhD alloimmunization in cancer patients in general, but state that prevention may be used in girls and in women of child-bearing age who are being treated with curative intent.
• For patients with acute myeloid leukemia, receiving induction chemotherapy, the use of leukoreduced platelet and red blood cell products can reduce the likelihood that patients will develop alloantibody-mediated refractory reactions to plate transfusions.
“It is therefore appropriate to provide leukoreduced blood products to patients with [acute myeloid leukemia] from the time of diagnosis to ameliorate this important clinical problem,” the investigators wrote.
They noted that leukoreduction to prevent alloimmunization might benefit patients with other leukemia histologies and with other types of cancer who are undergoing chemotherapy, but added that there is a lack of evidence to support this as a recommendation outside of acute myeloid leukemia.
To reduce the risk of bleeding due to thrombocytopenia in patients with solid tumors who are undergoing chemotherapy, the panelists recommend transfusing patients when their platelet levels fall below 10 x 109 per liter. It is appropriate to give platelet transfusions to patients with higher levels when there is active localized bleeding, they stated.
The guideline authors also recommend that when refractoriness to platelet infusions is suspected, clinicians should perform platelet counts from 10 to 60 minutes after the transfusion is completed. A refractoriness determination should be made only after two or more infusions of ABO-compatible units that have been stored for less than 72 hours result in poor increments, they advised.
The guideline development process is supported by ASCO. Dr. Schiffer and six other guideline authors disclosed consulting or advisory roles, research funding, honoraria and/or fees with various pharmaceutical companies or other corporate entities.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
ASCO larynx-preservation guidelines reflect important practice changes
The latest edition of the clinical practice guideline on larynx preservation strategies for the treatment of laryngeal cancer from the American Society of Clinical Oncology (ASCO) emphasizes that larynx preservation in patients with early stage disease does not compromise survival compared with total laryngectomy.
“The nuances of treatment selection, assessments of pretreatment voice and swallowing, and public awareness of new organ-preservation treatment and decision making have increased to the point that careful and individualized discussion with patients and families with the multidisciplinary treatment team is a critical element of modern care,” wrote Arlene A. Forastiere, MD, of Johns Hopkins Medicine in Baltimore, and her colleagues. The report was published in the Journal of Clinical Oncology.
Changes since the last guideline on the subject, issued in 2006, include evidence-based support for the use of endoscopic resection in patients with limited stage (T1 and T2) disease, and as an initial total laryngectomy therapy both in patients with stage T4a disease, and in those with severe laryngeal dysfunction prior to treatment.
Also new since the last guideline are recommendations for the use of positron-emission tomography imaging for evaluating the status of regional nodes after treatment, as well as guidance on the best techniques for evaluating voice and swallowing function.
While the initial recommendation that all patients with T1 and T2 laryngeal cancer should be treated with the intent to preserve the larynx has not changed, there is a new recommendation (1.3) stating that surgery may be more effective than radiotherapy for initial larynx preservation therapy, although this recommendation is based on retrospective data and may be affected by patient selection factors, the authors acknowledged. The new recommendation also notes that in an experienced operator’s hands, endoscopic resections can have outcomes that are equal to or better than those with open partial laryngectomy.
The initial recommendation stating that “[e]very effort should be made to avoid combining surgery with radiation therapy because functional outcomes may be compromised by combined-modality therapy; single-modality treatment is effective for limited-stage, invasive cancer of the larynx” remains unchanged.
There is also an updated recommendation that tumor-free margins should be the goal when surgery with larynx preservation intent is performed (1.4).
“Surgery that anticipates the need for postoperative [radiation therapy] to treat close or involved tumor margins or widespread dysplasia is not an acceptable treatment approach,” the guideline authors noted.
There are two other new recommendations including the opinion, based on evidence of benefits vs. harms, that total laryngectomy rather than larynx preservation may be associated with better survival and quality of life in patients with extensive T3 lesions, large T4 lesions, or in those who have poor pretreatment laryngeal function.
The third new recommendation is that “[a]s part of a comprehensive pretreatment evaluation, all patients should undergo a baseline assessment of voice and swallowing function, voice (use and requirements), and counseling with regard to the potential effect of treatment options on voice, swallowing, and quality of life.”
Among the updated recommendations are the following:
• An emphasis on the importance of considering a multiplicity of factors when choosing therapy for patients with limited-stage disease (1.7).
• The option of specialized organ-preservation procedures for a small number of patients with T3 or T4 primary site disease (2.4).
• A strong recommendation for the use of concurrent chemoradiotherapy compared with radiotherapy alone or sequential therapy (2.5).
• Elective neck dissection is not required for patients with clinically involved regional cervical nodes treated with definitive radiotherapy of chemoradiotherapy who have complete clinical, radiologic, and metabolic imaging (3.3).
• “Selection of therapy for an individual patient requires assessment by the multidisciplinary team as well as consideration of voice and swallowing function; patient comorbidity, psychosocial situation, and preferences; and local therapeutic expertise” (4.2).
The guideline development process was supported by ASCO. Dr, Forastiere disclosed employment and stock ownership in NantHealth. Many of her coauthors disclosed institutional funding, consultation/advising, travel support and expenses, honoraria, and or patents/royalties with multiple entities.
The latest edition of the clinical practice guideline on larynx preservation strategies for the treatment of laryngeal cancer from the American Society of Clinical Oncology (ASCO) emphasizes that larynx preservation in patients with early stage disease does not compromise survival compared with total laryngectomy.
“The nuances of treatment selection, assessments of pretreatment voice and swallowing, and public awareness of new organ-preservation treatment and decision making have increased to the point that careful and individualized discussion with patients and families with the multidisciplinary treatment team is a critical element of modern care,” wrote Arlene A. Forastiere, MD, of Johns Hopkins Medicine in Baltimore, and her colleagues. The report was published in the Journal of Clinical Oncology.
Changes since the last guideline on the subject, issued in 2006, include evidence-based support for the use of endoscopic resection in patients with limited stage (T1 and T2) disease, and as an initial total laryngectomy therapy both in patients with stage T4a disease, and in those with severe laryngeal dysfunction prior to treatment.
Also new since the last guideline are recommendations for the use of positron-emission tomography imaging for evaluating the status of regional nodes after treatment, as well as guidance on the best techniques for evaluating voice and swallowing function.
While the initial recommendation that all patients with T1 and T2 laryngeal cancer should be treated with the intent to preserve the larynx has not changed, there is a new recommendation (1.3) stating that surgery may be more effective than radiotherapy for initial larynx preservation therapy, although this recommendation is based on retrospective data and may be affected by patient selection factors, the authors acknowledged. The new recommendation also notes that in an experienced operator’s hands, endoscopic resections can have outcomes that are equal to or better than those with open partial laryngectomy.
The initial recommendation stating that “[e]very effort should be made to avoid combining surgery with radiation therapy because functional outcomes may be compromised by combined-modality therapy; single-modality treatment is effective for limited-stage, invasive cancer of the larynx” remains unchanged.
There is also an updated recommendation that tumor-free margins should be the goal when surgery with larynx preservation intent is performed (1.4).
“Surgery that anticipates the need for postoperative [radiation therapy] to treat close or involved tumor margins or widespread dysplasia is not an acceptable treatment approach,” the guideline authors noted.
There are two other new recommendations including the opinion, based on evidence of benefits vs. harms, that total laryngectomy rather than larynx preservation may be associated with better survival and quality of life in patients with extensive T3 lesions, large T4 lesions, or in those who have poor pretreatment laryngeal function.
The third new recommendation is that “[a]s part of a comprehensive pretreatment evaluation, all patients should undergo a baseline assessment of voice and swallowing function, voice (use and requirements), and counseling with regard to the potential effect of treatment options on voice, swallowing, and quality of life.”
Among the updated recommendations are the following:
• An emphasis on the importance of considering a multiplicity of factors when choosing therapy for patients with limited-stage disease (1.7).
• The option of specialized organ-preservation procedures for a small number of patients with T3 or T4 primary site disease (2.4).
• A strong recommendation for the use of concurrent chemoradiotherapy compared with radiotherapy alone or sequential therapy (2.5).
• Elective neck dissection is not required for patients with clinically involved regional cervical nodes treated with definitive radiotherapy of chemoradiotherapy who have complete clinical, radiologic, and metabolic imaging (3.3).
• “Selection of therapy for an individual patient requires assessment by the multidisciplinary team as well as consideration of voice and swallowing function; patient comorbidity, psychosocial situation, and preferences; and local therapeutic expertise” (4.2).
The guideline development process was supported by ASCO. Dr, Forastiere disclosed employment and stock ownership in NantHealth. Many of her coauthors disclosed institutional funding, consultation/advising, travel support and expenses, honoraria, and or patents/royalties with multiple entities.
The latest edition of the clinical practice guideline on larynx preservation strategies for the treatment of laryngeal cancer from the American Society of Clinical Oncology (ASCO) emphasizes that larynx preservation in patients with early stage disease does not compromise survival compared with total laryngectomy.
“The nuances of treatment selection, assessments of pretreatment voice and swallowing, and public awareness of new organ-preservation treatment and decision making have increased to the point that careful and individualized discussion with patients and families with the multidisciplinary treatment team is a critical element of modern care,” wrote Arlene A. Forastiere, MD, of Johns Hopkins Medicine in Baltimore, and her colleagues. The report was published in the Journal of Clinical Oncology.
Changes since the last guideline on the subject, issued in 2006, include evidence-based support for the use of endoscopic resection in patients with limited stage (T1 and T2) disease, and as an initial total laryngectomy therapy both in patients with stage T4a disease, and in those with severe laryngeal dysfunction prior to treatment.
Also new since the last guideline are recommendations for the use of positron-emission tomography imaging for evaluating the status of regional nodes after treatment, as well as guidance on the best techniques for evaluating voice and swallowing function.
While the initial recommendation that all patients with T1 and T2 laryngeal cancer should be treated with the intent to preserve the larynx has not changed, there is a new recommendation (1.3) stating that surgery may be more effective than radiotherapy for initial larynx preservation therapy, although this recommendation is based on retrospective data and may be affected by patient selection factors, the authors acknowledged. The new recommendation also notes that in an experienced operator’s hands, endoscopic resections can have outcomes that are equal to or better than those with open partial laryngectomy.
The initial recommendation stating that “[e]very effort should be made to avoid combining surgery with radiation therapy because functional outcomes may be compromised by combined-modality therapy; single-modality treatment is effective for limited-stage, invasive cancer of the larynx” remains unchanged.
There is also an updated recommendation that tumor-free margins should be the goal when surgery with larynx preservation intent is performed (1.4).
“Surgery that anticipates the need for postoperative [radiation therapy] to treat close or involved tumor margins or widespread dysplasia is not an acceptable treatment approach,” the guideline authors noted.
There are two other new recommendations including the opinion, based on evidence of benefits vs. harms, that total laryngectomy rather than larynx preservation may be associated with better survival and quality of life in patients with extensive T3 lesions, large T4 lesions, or in those who have poor pretreatment laryngeal function.
The third new recommendation is that “[a]s part of a comprehensive pretreatment evaluation, all patients should undergo a baseline assessment of voice and swallowing function, voice (use and requirements), and counseling with regard to the potential effect of treatment options on voice, swallowing, and quality of life.”
Among the updated recommendations are the following:
• An emphasis on the importance of considering a multiplicity of factors when choosing therapy for patients with limited-stage disease (1.7).
• The option of specialized organ-preservation procedures for a small number of patients with T3 or T4 primary site disease (2.4).
• A strong recommendation for the use of concurrent chemoradiotherapy compared with radiotherapy alone or sequential therapy (2.5).
• Elective neck dissection is not required for patients with clinically involved regional cervical nodes treated with definitive radiotherapy of chemoradiotherapy who have complete clinical, radiologic, and metabolic imaging (3.3).
• “Selection of therapy for an individual patient requires assessment by the multidisciplinary team as well as consideration of voice and swallowing function; patient comorbidity, psychosocial situation, and preferences; and local therapeutic expertise” (4.2).
The guideline development process was supported by ASCO. Dr, Forastiere disclosed employment and stock ownership in NantHealth. Many of her coauthors disclosed institutional funding, consultation/advising, travel support and expenses, honoraria, and or patents/royalties with multiple entities.
FROM JCO
ASCT or novel therapies in early relapsing follicular lymphoma?
NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.
But That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
Dr. Casulo: ASCT
“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.
“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.
To lay out her argument for ASCT, Dr. Casulo pointed to four studies suggesting that about 20% of patients with follicular lymphoma will experience disease progression within 24 months of chemoimmunotherapy. Similar patterns of progression at 24 months were seen with R-CHOP in the SWOG S0016 trial, with both bendamustine-rituximab and R-CHOP in the StiL Study, with lenalidomide (Revlimid) and rituximab in a phase 3 clinical trial, and with one of three rituximab-based immunochemotherapy regimens in the PRIMA trial.
The results from these trials suggest that “there is an inherent biology to this population that relapses early, regardless of what induction strategy is used. However, what’s not known, until now, is whether early relapse implies poor survival in this disease,” she said.
To examine this question Dr. Casulo and her colleagues performed an analysis of time to progression among patients with newly-diagnosed follicular lymphoma treated with R-CHOP who were enrolled in the National LymphoCare Study (NLCS). “What we found was that there were very poor outcomes associated with early-relapsing follicular lymphoma,” she said.
Overall survival (OS) at 8 years was 50% for patients with disease progression within 24 months of therapy, compared with 90% for patients who did not have early progression, a finding that was validated in a cohort of patients from the University of Iowa and the Mayo Clinic in which 8-year OS for early progressors was 34%, compared with 90% for other patients. The results held up when the researchers controlled for Follicular Lymphoma International Prognostic Index scores and in patients treated with rituximab and the cyclophosphamide, vincristine, and prednisone regimen rather than CHOP, Dr. Casulo noted.
“So, given these findings, how does one navigate the treatment landscape for patients with early relapsing follicular lymphoma? The reality is that there is really no standard of care or best approach,” she said.
“Ultimately, the goal of therapy, at least in my opinion, should be overcoming the chemoresistance that’s inherent to this biology, and establishing durable disease control, and there are a couple of strategies that might be able to achieve that,” she added.
There have been only two clinical trials of ASCT in patients with relapsed follicular lymphoma.
In the CUP trial, initiated prior to the introduction of rituximab, 89 patients with relapsed follicular lymphoma were treated with three cycles of CHOP, and those with a response were then randomized to either purged or unpurged ASCT, or to three additional cycles of CHOP. Four-year OS in this study was 70% for patients who underwent ASCT vs. 50% for those who received six cycles of CHOP.
In the EBMT LYM1 trial, 280 rituximab-naive patients with relapsed follicular lymphoma after a partial or complete remission were randomized to rituximab-purged or unpurged ASCT, followed by randomization to observation or rituximab maintenance. In this trial, the 10-year OS with ASCT ranged from 68% to 73%.
A Spanish registry study presented in a poster session at the 14th International Conference on Malignant Lymphoma in Lugano, Italy, showed long-term efficacy of ASCT in relapsed follicular lymphoma, with plateaus in both PFS and OS about 9 years after transplant for both rituximab-exposed and rituximab-naive patients, “suggesting that perhaps a subset of patients with relapsed follicular lymphoma can be cured with this approach,” Dr. Casulo said.
Similarly, a trial from the German Low Grade Lymphoma Studies group, presented at the 2016 American Society of Hematology annual meeting, showed 5-year OS of 77% with ASCT vs. 46% for patients who did not receive a transplant.
Dr. Casulo and her colleagues collaborated with investigators at the Center for International Blood and Marrow Transplant Research and the NLCS to see whether ASCT can improve OS compared with no transplant in patients with early-relapsed follicular lymphoma. They found that patients who received ASCT within 1 year of therapy failure had a 5-year OS of 73%, compared with 60% for those who did not receive ASCT (P = .02).
She acknowledged that toxicities associated with ASCT are a concern, pointing to a 2007 study looking at long-term follow-up of myeloablative ASCT for follicular lymphoma at the time of second or subsequent remission. The investigators found that rates of myelodysplasia were as high as 20% at 10 years, especially among patients who had undergone total body irradiation, a practice that has since fallen out of favor.
A separate study led by Matt Kalaycio, MD, of the Cleveland Clinic, showed that more lines of prior therapy (4-6 vs. 1-3) and radiation were both risk factors for subsequent myelodysplastic syndrome and acute myeloid leukemia.
“I hope we have demonstrated that autologous transplant can have durable response in these patients, with possibly a cure in a subset; but, ultimately, I think strategies that combine novel agents and autologous transplant in a clinical trial are the way to go to improve outcomes,” she said.
Dr. Link: Novel agents
“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.
“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.
He cited data from the University of Iowa/Mayo Clinic series, validated in a cohort of patients from Lyon, France, showing that high-risk patients with early progression after immunochemotherapy had “especially poor outcomes.” In contrast, patients who were not early progressors fared quite well.
“It suggested that with agents that were available as of 2015, if you’re not an early progressor, your survival at least matches, or essentially matches with statistical power, that of the expected age- and gender-matched populations. So, novel agents are not required necessarily nor are clinical trials necessarily required for people who have good early outcomes,” Dr. Link said.
The best snapshot of current practice for high-risk patients comes from unpublished data from the NLCS showing that after a median follow-up of 8 years, 889 of 2,652 patients had received a second line of therapy, with the choice of agents or approaches generally similar between early progressors and others.
Early progressors were slightly less likely to receive rituximab monotherapy (30% vs. 36%) or an investigational agent (4.4% vs. 5.5%), whereas they were slightly more likely to receive an anthracycline (18% vs. 13%) or to undergo ASCT (3.5% vs. 1.1%).
In the treatment of patients with high-risk follicular lymphoma, a novel agent can be considered as one that was either not available or had not been used in follicular lymphoma when the previously mentioned survival data were generated, including immunomodulators such as thalidomide analogues, targeted kinase inhibitors, new anti-CD20 antibodies such as obinutuzumab (Gazyva), and immune checkpoint inhibitors.
For example, in Alliance 50803, a phase 2 trial in patients with previously untreated stage II-IV follicular lymphoma, the combination of lenalidomide (Revlimid) and rituximab was associated with a 95% overall response rate (ORR), including 72% complete response, and 5-year PFS rate of 70%, comparable to trials with rituximab plus bendamustine, CHOP, or cyclophosphamide-vincristine-prednisone, Dr. Link said.
In the phase 2 GALEN study, the combination of lenalidomide and obinutuzumab was associated with an ORR of 74% among 86 patients with relapsed/refractory follicular lymphoma, with a 1-year PFS rate of 76%.
An analysis of responses by time to relapse in GALEN 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 International Working Group criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
Idelalisib, an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), was granted accelerated approval in 2014 for treatment of patients with follicular lymphoma after two or more prior lines of therapy, but toxicities associated with this agent caused the drug maker Gilead to dial back its development of this agent.
“But idelalisib is not the only PI3 kinase inhibitor on the block,” Dr. Link said, noting that more than a dozen similar agents are currently in development.
In clinical trials, PI3 kinase inhibitors have been associated with ORRs of about 60% in patients who experience early disease progression on other therapies, “suggesting an uncoupling between the paradigm that says that early progressors are going to have a less effective outcome than late progressors, perhaps, with targeted therapies.
The best evidence for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) comes from the DAWN study, a phase 2 trial in patients with follicular lymphoma refractory to immunochemotherapy. The drug showed some biologic activity, but only a 21% ORR.
Dr. Link noted that the S1608 trial, currently recruiting patients, may give clinicians a better idea of which novel agent is most effective. The phase 2 trial is enrolling patients with early-progressing or refractory follicular lymphoma who will be randomized to receive obinutuzumab with either the investigational PI3 kinase inhibitor TGR-1202, lenalidomide, or CHOP chemotherapy.
“High-risk follicular lymphoma is a bad hombre,” Dr. Link said. “If we want to be any smarter as a society 10 years from now, we should incorporate clinical trials with novel therapies as standard operating practice into this setting of high-risk follicular lymphoma.”
Dr. Casulo reported serving on the speakers bureau for Gilead. Dr. Link reported serving as a consultant to AbbVie, Celgene, Genentech, and Gilead.
NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.
But That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
Dr. Casulo: ASCT
“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.
“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.
To lay out her argument for ASCT, Dr. Casulo pointed to four studies suggesting that about 20% of patients with follicular lymphoma will experience disease progression within 24 months of chemoimmunotherapy. Similar patterns of progression at 24 months were seen with R-CHOP in the SWOG S0016 trial, with both bendamustine-rituximab and R-CHOP in the StiL Study, with lenalidomide (Revlimid) and rituximab in a phase 3 clinical trial, and with one of three rituximab-based immunochemotherapy regimens in the PRIMA trial.
The results from these trials suggest that “there is an inherent biology to this population that relapses early, regardless of what induction strategy is used. However, what’s not known, until now, is whether early relapse implies poor survival in this disease,” she said.
To examine this question Dr. Casulo and her colleagues performed an analysis of time to progression among patients with newly-diagnosed follicular lymphoma treated with R-CHOP who were enrolled in the National LymphoCare Study (NLCS). “What we found was that there were very poor outcomes associated with early-relapsing follicular lymphoma,” she said.
Overall survival (OS) at 8 years was 50% for patients with disease progression within 24 months of therapy, compared with 90% for patients who did not have early progression, a finding that was validated in a cohort of patients from the University of Iowa and the Mayo Clinic in which 8-year OS for early progressors was 34%, compared with 90% for other patients. The results held up when the researchers controlled for Follicular Lymphoma International Prognostic Index scores and in patients treated with rituximab and the cyclophosphamide, vincristine, and prednisone regimen rather than CHOP, Dr. Casulo noted.
“So, given these findings, how does one navigate the treatment landscape for patients with early relapsing follicular lymphoma? The reality is that there is really no standard of care or best approach,” she said.
“Ultimately, the goal of therapy, at least in my opinion, should be overcoming the chemoresistance that’s inherent to this biology, and establishing durable disease control, and there are a couple of strategies that might be able to achieve that,” she added.
There have been only two clinical trials of ASCT in patients with relapsed follicular lymphoma.
In the CUP trial, initiated prior to the introduction of rituximab, 89 patients with relapsed follicular lymphoma were treated with three cycles of CHOP, and those with a response were then randomized to either purged or unpurged ASCT, or to three additional cycles of CHOP. Four-year OS in this study was 70% for patients who underwent ASCT vs. 50% for those who received six cycles of CHOP.
In the EBMT LYM1 trial, 280 rituximab-naive patients with relapsed follicular lymphoma after a partial or complete remission were randomized to rituximab-purged or unpurged ASCT, followed by randomization to observation or rituximab maintenance. In this trial, the 10-year OS with ASCT ranged from 68% to 73%.
A Spanish registry study presented in a poster session at the 14th International Conference on Malignant Lymphoma in Lugano, Italy, showed long-term efficacy of ASCT in relapsed follicular lymphoma, with plateaus in both PFS and OS about 9 years after transplant for both rituximab-exposed and rituximab-naive patients, “suggesting that perhaps a subset of patients with relapsed follicular lymphoma can be cured with this approach,” Dr. Casulo said.
Similarly, a trial from the German Low Grade Lymphoma Studies group, presented at the 2016 American Society of Hematology annual meeting, showed 5-year OS of 77% with ASCT vs. 46% for patients who did not receive a transplant.
Dr. Casulo and her colleagues collaborated with investigators at the Center for International Blood and Marrow Transplant Research and the NLCS to see whether ASCT can improve OS compared with no transplant in patients with early-relapsed follicular lymphoma. They found that patients who received ASCT within 1 year of therapy failure had a 5-year OS of 73%, compared with 60% for those who did not receive ASCT (P = .02).
She acknowledged that toxicities associated with ASCT are a concern, pointing to a 2007 study looking at long-term follow-up of myeloablative ASCT for follicular lymphoma at the time of second or subsequent remission. The investigators found that rates of myelodysplasia were as high as 20% at 10 years, especially among patients who had undergone total body irradiation, a practice that has since fallen out of favor.
A separate study led by Matt Kalaycio, MD, of the Cleveland Clinic, showed that more lines of prior therapy (4-6 vs. 1-3) and radiation were both risk factors for subsequent myelodysplastic syndrome and acute myeloid leukemia.
“I hope we have demonstrated that autologous transplant can have durable response in these patients, with possibly a cure in a subset; but, ultimately, I think strategies that combine novel agents and autologous transplant in a clinical trial are the way to go to improve outcomes,” she said.
Dr. Link: Novel agents
“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.
“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.
He cited data from the University of Iowa/Mayo Clinic series, validated in a cohort of patients from Lyon, France, showing that high-risk patients with early progression after immunochemotherapy had “especially poor outcomes.” In contrast, patients who were not early progressors fared quite well.
“It suggested that with agents that were available as of 2015, if you’re not an early progressor, your survival at least matches, or essentially matches with statistical power, that of the expected age- and gender-matched populations. So, novel agents are not required necessarily nor are clinical trials necessarily required for people who have good early outcomes,” Dr. Link said.
The best snapshot of current practice for high-risk patients comes from unpublished data from the NLCS showing that after a median follow-up of 8 years, 889 of 2,652 patients had received a second line of therapy, with the choice of agents or approaches generally similar between early progressors and others.
Early progressors were slightly less likely to receive rituximab monotherapy (30% vs. 36%) or an investigational agent (4.4% vs. 5.5%), whereas they were slightly more likely to receive an anthracycline (18% vs. 13%) or to undergo ASCT (3.5% vs. 1.1%).
In the treatment of patients with high-risk follicular lymphoma, a novel agent can be considered as one that was either not available or had not been used in follicular lymphoma when the previously mentioned survival data were generated, including immunomodulators such as thalidomide analogues, targeted kinase inhibitors, new anti-CD20 antibodies such as obinutuzumab (Gazyva), and immune checkpoint inhibitors.
For example, in Alliance 50803, a phase 2 trial in patients with previously untreated stage II-IV follicular lymphoma, the combination of lenalidomide (Revlimid) and rituximab was associated with a 95% overall response rate (ORR), including 72% complete response, and 5-year PFS rate of 70%, comparable to trials with rituximab plus bendamustine, CHOP, or cyclophosphamide-vincristine-prednisone, Dr. Link said.
In the phase 2 GALEN study, the combination of lenalidomide and obinutuzumab was associated with an ORR of 74% among 86 patients with relapsed/refractory follicular lymphoma, with a 1-year PFS rate of 76%.
An analysis of responses by time to relapse in GALEN 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 International Working Group criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
Idelalisib, an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), was granted accelerated approval in 2014 for treatment of patients with follicular lymphoma after two or more prior lines of therapy, but toxicities associated with this agent caused the drug maker Gilead to dial back its development of this agent.
“But idelalisib is not the only PI3 kinase inhibitor on the block,” Dr. Link said, noting that more than a dozen similar agents are currently in development.
In clinical trials, PI3 kinase inhibitors have been associated with ORRs of about 60% in patients who experience early disease progression on other therapies, “suggesting an uncoupling between the paradigm that says that early progressors are going to have a less effective outcome than late progressors, perhaps, with targeted therapies.
The best evidence for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) comes from the DAWN study, a phase 2 trial in patients with follicular lymphoma refractory to immunochemotherapy. The drug showed some biologic activity, but only a 21% ORR.
Dr. Link noted that the S1608 trial, currently recruiting patients, may give clinicians a better idea of which novel agent is most effective. The phase 2 trial is enrolling patients with early-progressing or refractory follicular lymphoma who will be randomized to receive obinutuzumab with either the investigational PI3 kinase inhibitor TGR-1202, lenalidomide, or CHOP chemotherapy.
“High-risk follicular lymphoma is a bad hombre,” Dr. Link said. “If we want to be any smarter as a society 10 years from now, we should incorporate clinical trials with novel therapies as standard operating practice into this setting of high-risk follicular lymphoma.”
Dr. Casulo reported serving on the speakers bureau for Gilead. Dr. Link reported serving as a consultant to AbbVie, Celgene, Genentech, and Gilead.
NEW YORK – For patients with newly diagnosed follicular lymphoma and other indolent non-Hodgkin lymphoma, the combination of bendamustine (Treanda) and rituximab is associated with significantly better progression-free survival (PFS) and longer time-to-next treatment than is rituximab plus CHOP chemotherapy, results of the BRIGHT study indicate.
But That was the question taken on in a debate at an international congress on hematologic malignancies by Carla Casulo, MD of the James P. Wilmot Cancer Institute at the University of Rochester (N.Y.), and Brian K. Link, MD, of the University of Iowa Hospitals & Clinics in Iowa City.
Dr. Casulo: ASCT
“Follicular lymphoma with a short remission duration has been established as a poor prognostic marker for survival, and the optimal therapy for these patients is really not known,” Dr. Casulo said.
“Of course, [novel] therapies can be considered, I think, for the appropriate patient, and hopefully in the context of a clinical study,” she added.
To lay out her argument for ASCT, Dr. Casulo pointed to four studies suggesting that about 20% of patients with follicular lymphoma will experience disease progression within 24 months of chemoimmunotherapy. Similar patterns of progression at 24 months were seen with R-CHOP in the SWOG S0016 trial, with both bendamustine-rituximab and R-CHOP in the StiL Study, with lenalidomide (Revlimid) and rituximab in a phase 3 clinical trial, and with one of three rituximab-based immunochemotherapy regimens in the PRIMA trial.
The results from these trials suggest that “there is an inherent biology to this population that relapses early, regardless of what induction strategy is used. However, what’s not known, until now, is whether early relapse implies poor survival in this disease,” she said.
To examine this question Dr. Casulo and her colleagues performed an analysis of time to progression among patients with newly-diagnosed follicular lymphoma treated with R-CHOP who were enrolled in the National LymphoCare Study (NLCS). “What we found was that there were very poor outcomes associated with early-relapsing follicular lymphoma,” she said.
Overall survival (OS) at 8 years was 50% for patients with disease progression within 24 months of therapy, compared with 90% for patients who did not have early progression, a finding that was validated in a cohort of patients from the University of Iowa and the Mayo Clinic in which 8-year OS for early progressors was 34%, compared with 90% for other patients. The results held up when the researchers controlled for Follicular Lymphoma International Prognostic Index scores and in patients treated with rituximab and the cyclophosphamide, vincristine, and prednisone regimen rather than CHOP, Dr. Casulo noted.
“So, given these findings, how does one navigate the treatment landscape for patients with early relapsing follicular lymphoma? The reality is that there is really no standard of care or best approach,” she said.
“Ultimately, the goal of therapy, at least in my opinion, should be overcoming the chemoresistance that’s inherent to this biology, and establishing durable disease control, and there are a couple of strategies that might be able to achieve that,” she added.
There have been only two clinical trials of ASCT in patients with relapsed follicular lymphoma.
In the CUP trial, initiated prior to the introduction of rituximab, 89 patients with relapsed follicular lymphoma were treated with three cycles of CHOP, and those with a response were then randomized to either purged or unpurged ASCT, or to three additional cycles of CHOP. Four-year OS in this study was 70% for patients who underwent ASCT vs. 50% for those who received six cycles of CHOP.
In the EBMT LYM1 trial, 280 rituximab-naive patients with relapsed follicular lymphoma after a partial or complete remission were randomized to rituximab-purged or unpurged ASCT, followed by randomization to observation or rituximab maintenance. In this trial, the 10-year OS with ASCT ranged from 68% to 73%.
A Spanish registry study presented in a poster session at the 14th International Conference on Malignant Lymphoma in Lugano, Italy, showed long-term efficacy of ASCT in relapsed follicular lymphoma, with plateaus in both PFS and OS about 9 years after transplant for both rituximab-exposed and rituximab-naive patients, “suggesting that perhaps a subset of patients with relapsed follicular lymphoma can be cured with this approach,” Dr. Casulo said.
Similarly, a trial from the German Low Grade Lymphoma Studies group, presented at the 2016 American Society of Hematology annual meeting, showed 5-year OS of 77% with ASCT vs. 46% for patients who did not receive a transplant.
Dr. Casulo and her colleagues collaborated with investigators at the Center for International Blood and Marrow Transplant Research and the NLCS to see whether ASCT can improve OS compared with no transplant in patients with early-relapsed follicular lymphoma. They found that patients who received ASCT within 1 year of therapy failure had a 5-year OS of 73%, compared with 60% for those who did not receive ASCT (P = .02).
She acknowledged that toxicities associated with ASCT are a concern, pointing to a 2007 study looking at long-term follow-up of myeloablative ASCT for follicular lymphoma at the time of second or subsequent remission. The investigators found that rates of myelodysplasia were as high as 20% at 10 years, especially among patients who had undergone total body irradiation, a practice that has since fallen out of favor.
A separate study led by Matt Kalaycio, MD, of the Cleveland Clinic, showed that more lines of prior therapy (4-6 vs. 1-3) and radiation were both risk factors for subsequent myelodysplastic syndrome and acute myeloid leukemia.
“I hope we have demonstrated that autologous transplant can have durable response in these patients, with possibly a cure in a subset; but, ultimately, I think strategies that combine novel agents and autologous transplant in a clinical trial are the way to go to improve outcomes,” she said.
Dr. Link: Novel agents
“I actually happen to agree with very much of what Carla had to share, but I do have a couple of caveats,” Dr. Link said.
“The focus of this discussion is on patients with high-risk follicular lymphoma, as Carla very carefully defined in her analysis of the NLCS. These are the early progressors,” he said.
He cited data from the University of Iowa/Mayo Clinic series, validated in a cohort of patients from Lyon, France, showing that high-risk patients with early progression after immunochemotherapy had “especially poor outcomes.” In contrast, patients who were not early progressors fared quite well.
“It suggested that with agents that were available as of 2015, if you’re not an early progressor, your survival at least matches, or essentially matches with statistical power, that of the expected age- and gender-matched populations. So, novel agents are not required necessarily nor are clinical trials necessarily required for people who have good early outcomes,” Dr. Link said.
The best snapshot of current practice for high-risk patients comes from unpublished data from the NLCS showing that after a median follow-up of 8 years, 889 of 2,652 patients had received a second line of therapy, with the choice of agents or approaches generally similar between early progressors and others.
Early progressors were slightly less likely to receive rituximab monotherapy (30% vs. 36%) or an investigational agent (4.4% vs. 5.5%), whereas they were slightly more likely to receive an anthracycline (18% vs. 13%) or to undergo ASCT (3.5% vs. 1.1%).
In the treatment of patients with high-risk follicular lymphoma, a novel agent can be considered as one that was either not available or had not been used in follicular lymphoma when the previously mentioned survival data were generated, including immunomodulators such as thalidomide analogues, targeted kinase inhibitors, new anti-CD20 antibodies such as obinutuzumab (Gazyva), and immune checkpoint inhibitors.
For example, in Alliance 50803, a phase 2 trial in patients with previously untreated stage II-IV follicular lymphoma, the combination of lenalidomide (Revlimid) and rituximab was associated with a 95% overall response rate (ORR), including 72% complete response, and 5-year PFS rate of 70%, comparable to trials with rituximab plus bendamustine, CHOP, or cyclophosphamide-vincristine-prednisone, Dr. Link said.
In the phase 2 GALEN study, the combination of lenalidomide and obinutuzumab was associated with an ORR of 74% among 86 patients with relapsed/refractory follicular lymphoma, with a 1-year PFS rate of 76%.
An analysis of responses by time to relapse in GALEN 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 International Working Group criteria, and 66.7% with 54.2% complete or unconfirmed complete responses by the 2007 criteria.
Idelalisib, an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), was granted accelerated approval in 2014 for treatment of patients with follicular lymphoma after two or more prior lines of therapy, but toxicities associated with this agent caused the drug maker Gilead to dial back its development of this agent.
“But idelalisib is not the only PI3 kinase inhibitor on the block,” Dr. Link said, noting that more than a dozen similar agents are currently in development.
In clinical trials, PI3 kinase inhibitors have been associated with ORRs of about 60% in patients who experience early disease progression on other therapies, “suggesting an uncoupling between the paradigm that says that early progressors are going to have a less effective outcome than late progressors, perhaps, with targeted therapies.
The best evidence for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) comes from the DAWN study, a phase 2 trial in patients with follicular lymphoma refractory to immunochemotherapy. The drug showed some biologic activity, but only a 21% ORR.
Dr. Link noted that the S1608 trial, currently recruiting patients, may give clinicians a better idea of which novel agent is most effective. The phase 2 trial is enrolling patients with early-progressing or refractory follicular lymphoma who will be randomized to receive obinutuzumab with either the investigational PI3 kinase inhibitor TGR-1202, lenalidomide, or CHOP chemotherapy.
“High-risk follicular lymphoma is a bad hombre,” Dr. Link said. “If we want to be any smarter as a society 10 years from now, we should incorporate clinical trials with novel therapies as standard operating practice into this setting of high-risk follicular lymphoma.”
Dr. Casulo reported serving on the speakers bureau for Gilead. Dr. Link reported serving as a consultant to AbbVie, Celgene, Genentech, and Gilead.
EXPERT ANALYSIS AT LYMPHOMA & MYELOMA
Novel therapies may expand anti-MZL toolbox
, Italian investigators reported.
Current treatment options for patients with MZL include antibiotics, radiotherapy, and single-agent immunotherapy, commonly with the CD20 inhibitor rituximab. For patients with localized, early stage disease, these therapies are often highly effective and capable of producing long-term remission, but there is no standard of care for patients with disseminated nodal or extranodal disease, wrote Pier Luigi Zinzani, MD, PhD, and Alessandro Broccoli, MD, of the University of Bologna, Italy.
“Several targeted agents have demonstrated their efficacy, with generally mild and reversible side effects, in patients with MZL, although clinical trials specifically involving this kind of subjects are lacking due to the rarity of the disease. Newer molecules targeting specific intracellular pathways involved in tumor proliferation, cell differentiation, motility and apoptosis represent attractive alternatives to conventional cytotoxic drugs and deserve further investigation,” they wrote in a review article (Best Pract Res Clin Haematol. 2017;30[1-2]:149-57).
They cited a study showing that single-agent lenalidomide (Revlimid), an immunomodulator that has become a mainstay of therapy for multiple myeloma, was associated with a 61% overall response rate (ORR), including 33% complete responses (CR) in patients with non–gastric mucosa–associated lymphoid tissue (MALT) lymphoma, or gastric MALT lymphoma that was either negative for Helicobacter pylori or was Helicobacter pylori positive but refractory to antibiotics (Haematologica 2013;98:353-6).
Lenalidomide plus rituximab was associated with an 89% ORR and 67% CR rate in patients with MZL enrolled in a clinical trial of patients with untreated advanced stage non-Hodgkin lymphomas.
Lenalidomide’s frequent partner, the proteasome inhibitor bortezomib (Velcade), has been tested alone in small studies in patients with MALT lymphoma, with one study showing an ORR of 80% in 16 patients with MALT lymphoma, although investigators noted an unexpectedly high rate of toxicities. In a different study, bortezomib was associated with an ORR of 48%, including nine CR and five partial responses in 29 patients with relapsed/refractory MALT lymphoma.
Other potential therapeutic options for patients with MZL include:
90Y-ibritumomab tiuxetan, a radiotherapeutic targeted to B-cell surface antigens, which has been associated with high CR rates and durable disease-free remissions in small series.
Obinutuzumab (Gazyva), an anti-CD20 monoclonal antibody, with data largely in other indolent lymphoma histologies.
Ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase that moderates B-cell receptor signaling, which has shown good activity against mantle cell lymphoma.
Idelalisib (Zydelig), an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), with activity against indolent non-Hodgkin lymphoma.
Other agents in early stages of investigation in MZL are venetoclax, an oral B-cell lymphoma protein-2; copanlisib, an inhibitor of both the alpha and delta isoforms of PI3K; and ublituximab, an anti-CD20 monoclonal antibody that has been combined with TGR-1202, a PI3K-delta inhibitor.
“Many of these new agents show synergism when combined together and with chemotherapy or immunotherapy, without significant cumulative toxicity. Chemo-free approaches in MZL are nowadays possible and worthwhile to be pursued,” the researchers wrote.
They reported having no financial disclosures.
, Italian investigators reported.
Current treatment options for patients with MZL include antibiotics, radiotherapy, and single-agent immunotherapy, commonly with the CD20 inhibitor rituximab. For patients with localized, early stage disease, these therapies are often highly effective and capable of producing long-term remission, but there is no standard of care for patients with disseminated nodal or extranodal disease, wrote Pier Luigi Zinzani, MD, PhD, and Alessandro Broccoli, MD, of the University of Bologna, Italy.
“Several targeted agents have demonstrated their efficacy, with generally mild and reversible side effects, in patients with MZL, although clinical trials specifically involving this kind of subjects are lacking due to the rarity of the disease. Newer molecules targeting specific intracellular pathways involved in tumor proliferation, cell differentiation, motility and apoptosis represent attractive alternatives to conventional cytotoxic drugs and deserve further investigation,” they wrote in a review article (Best Pract Res Clin Haematol. 2017;30[1-2]:149-57).
They cited a study showing that single-agent lenalidomide (Revlimid), an immunomodulator that has become a mainstay of therapy for multiple myeloma, was associated with a 61% overall response rate (ORR), including 33% complete responses (CR) in patients with non–gastric mucosa–associated lymphoid tissue (MALT) lymphoma, or gastric MALT lymphoma that was either negative for Helicobacter pylori or was Helicobacter pylori positive but refractory to antibiotics (Haematologica 2013;98:353-6).
Lenalidomide plus rituximab was associated with an 89% ORR and 67% CR rate in patients with MZL enrolled in a clinical trial of patients with untreated advanced stage non-Hodgkin lymphomas.
Lenalidomide’s frequent partner, the proteasome inhibitor bortezomib (Velcade), has been tested alone in small studies in patients with MALT lymphoma, with one study showing an ORR of 80% in 16 patients with MALT lymphoma, although investigators noted an unexpectedly high rate of toxicities. In a different study, bortezomib was associated with an ORR of 48%, including nine CR and five partial responses in 29 patients with relapsed/refractory MALT lymphoma.
Other potential therapeutic options for patients with MZL include:
90Y-ibritumomab tiuxetan, a radiotherapeutic targeted to B-cell surface antigens, which has been associated with high CR rates and durable disease-free remissions in small series.
Obinutuzumab (Gazyva), an anti-CD20 monoclonal antibody, with data largely in other indolent lymphoma histologies.
Ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase that moderates B-cell receptor signaling, which has shown good activity against mantle cell lymphoma.
Idelalisib (Zydelig), an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), with activity against indolent non-Hodgkin lymphoma.
Other agents in early stages of investigation in MZL are venetoclax, an oral B-cell lymphoma protein-2; copanlisib, an inhibitor of both the alpha and delta isoforms of PI3K; and ublituximab, an anti-CD20 monoclonal antibody that has been combined with TGR-1202, a PI3K-delta inhibitor.
“Many of these new agents show synergism when combined together and with chemotherapy or immunotherapy, without significant cumulative toxicity. Chemo-free approaches in MZL are nowadays possible and worthwhile to be pursued,” the researchers wrote.
They reported having no financial disclosures.
, Italian investigators reported.
Current treatment options for patients with MZL include antibiotics, radiotherapy, and single-agent immunotherapy, commonly with the CD20 inhibitor rituximab. For patients with localized, early stage disease, these therapies are often highly effective and capable of producing long-term remission, but there is no standard of care for patients with disseminated nodal or extranodal disease, wrote Pier Luigi Zinzani, MD, PhD, and Alessandro Broccoli, MD, of the University of Bologna, Italy.
“Several targeted agents have demonstrated their efficacy, with generally mild and reversible side effects, in patients with MZL, although clinical trials specifically involving this kind of subjects are lacking due to the rarity of the disease. Newer molecules targeting specific intracellular pathways involved in tumor proliferation, cell differentiation, motility and apoptosis represent attractive alternatives to conventional cytotoxic drugs and deserve further investigation,” they wrote in a review article (Best Pract Res Clin Haematol. 2017;30[1-2]:149-57).
They cited a study showing that single-agent lenalidomide (Revlimid), an immunomodulator that has become a mainstay of therapy for multiple myeloma, was associated with a 61% overall response rate (ORR), including 33% complete responses (CR) in patients with non–gastric mucosa–associated lymphoid tissue (MALT) lymphoma, or gastric MALT lymphoma that was either negative for Helicobacter pylori or was Helicobacter pylori positive but refractory to antibiotics (Haematologica 2013;98:353-6).
Lenalidomide plus rituximab was associated with an 89% ORR and 67% CR rate in patients with MZL enrolled in a clinical trial of patients with untreated advanced stage non-Hodgkin lymphomas.
Lenalidomide’s frequent partner, the proteasome inhibitor bortezomib (Velcade), has been tested alone in small studies in patients with MALT lymphoma, with one study showing an ORR of 80% in 16 patients with MALT lymphoma, although investigators noted an unexpectedly high rate of toxicities. In a different study, bortezomib was associated with an ORR of 48%, including nine CR and five partial responses in 29 patients with relapsed/refractory MALT lymphoma.
Other potential therapeutic options for patients with MZL include:
90Y-ibritumomab tiuxetan, a radiotherapeutic targeted to B-cell surface antigens, which has been associated with high CR rates and durable disease-free remissions in small series.
Obinutuzumab (Gazyva), an anti-CD20 monoclonal antibody, with data largely in other indolent lymphoma histologies.
Ibrutinib (Imbruvica), an inhibitor of Bruton’s tyrosine kinase that moderates B-cell receptor signaling, which has shown good activity against mantle cell lymphoma.
Idelalisib (Zydelig), an inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K), with activity against indolent non-Hodgkin lymphoma.
Other agents in early stages of investigation in MZL are venetoclax, an oral B-cell lymphoma protein-2; copanlisib, an inhibitor of both the alpha and delta isoforms of PI3K; and ublituximab, an anti-CD20 monoclonal antibody that has been combined with TGR-1202, a PI3K-delta inhibitor.
“Many of these new agents show synergism when combined together and with chemotherapy or immunotherapy, without significant cumulative toxicity. Chemo-free approaches in MZL are nowadays possible and worthwhile to be pursued,” the researchers wrote.
They reported having no financial disclosures.
FROM BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY
Rare epidermotropic MZL yields to rituximab
Epidermotropic marginal zone lymphoma (MZL), a rare cutaneous B-cell lymphoma identified in only eight patients to date, appears to be responsive to rituximab, according to authors of a case report.
A 69-year-old man who presented with a generalized papulosquamous eruption that was eventually diagnosed as epidermotropic MZL achieved a near total remission within 3 months of receiving four total weekly rituximab infusions, reported Cynthia M. Magro, MD, from Cornell University, New York, and her colleagues from the University of Arizona, Tucson (JAAD Case Rep. 2017 Sep 23;3[6]:474-6).
“Epidermotropic MZL represents a distinctive nosologic B-cell lymphoma that should be considered a diagnostic possibility in older men who present with an unexplained papulosquamous eruption resembling pityriasis rosea,” the researchers wrote.
“Epidermotropism refers to a state of abnormal colonization of the epidermis by leukocytes, which often reflects a clonal T-cell or monocyte dyscrasia. Epidermotropism is a distinctive pattern of passive migration into epithelial structures that is not otherwise attributable to the normal function of innate and adaptive immunity,” the researchers explained.
They described the case of the aforementioned patient, who presented with asymptomatic indurated, red-to-brown papules and plaques on his chest, abdomen, back, and buttocks, which gave the clinical impression of pityriasis rosea or a similarly appearing drug reaction.
Histopathologic examination of two biopsied lesions “demonstrated a dense superficial lymphocytic infiltrate that expanded and effaced the papillary and superficial reticular dermis.”
After epidermotropic MZL was diagnosed, the patient was evaluated for systemic disease with a bone marrow biopsy, which revealed a low-grade B-cell lymphoproliferative disorder, and with a PET scan showing lymphomatous infiltration of the spleen. The patient was treated with four weekly infusions of rituximab 375 mg/m2.
“Within 3 months, he experienced marked regression of his cutaneous disease. Repeat radiographic imaging found an interval decrease in the size of his spleen, signifying an objective response. Since achieving near total clinical remission, the patient remains under the close observation of medical oncology services,” the researchers wrote.
The investigators noted that if histopathology is the only method used to diagnosis the condition, epidermotropic MZL could be mistaken for a T-cell lymphoproliferative disorder, such as mycosis fungoides, because of the similar architecture at low resolution.
“In these settings, immunohistochemical staining for B-cell markers represents an indispensable diagnostic test,” they wrote.
The researchers reported having no conflicts of interest.
Epidermotropic marginal zone lymphoma (MZL), a rare cutaneous B-cell lymphoma identified in only eight patients to date, appears to be responsive to rituximab, according to authors of a case report.
A 69-year-old man who presented with a generalized papulosquamous eruption that was eventually diagnosed as epidermotropic MZL achieved a near total remission within 3 months of receiving four total weekly rituximab infusions, reported Cynthia M. Magro, MD, from Cornell University, New York, and her colleagues from the University of Arizona, Tucson (JAAD Case Rep. 2017 Sep 23;3[6]:474-6).
“Epidermotropic MZL represents a distinctive nosologic B-cell lymphoma that should be considered a diagnostic possibility in older men who present with an unexplained papulosquamous eruption resembling pityriasis rosea,” the researchers wrote.
“Epidermotropism refers to a state of abnormal colonization of the epidermis by leukocytes, which often reflects a clonal T-cell or monocyte dyscrasia. Epidermotropism is a distinctive pattern of passive migration into epithelial structures that is not otherwise attributable to the normal function of innate and adaptive immunity,” the researchers explained.
They described the case of the aforementioned patient, who presented with asymptomatic indurated, red-to-brown papules and plaques on his chest, abdomen, back, and buttocks, which gave the clinical impression of pityriasis rosea or a similarly appearing drug reaction.
Histopathologic examination of two biopsied lesions “demonstrated a dense superficial lymphocytic infiltrate that expanded and effaced the papillary and superficial reticular dermis.”
After epidermotropic MZL was diagnosed, the patient was evaluated for systemic disease with a bone marrow biopsy, which revealed a low-grade B-cell lymphoproliferative disorder, and with a PET scan showing lymphomatous infiltration of the spleen. The patient was treated with four weekly infusions of rituximab 375 mg/m2.
“Within 3 months, he experienced marked regression of his cutaneous disease. Repeat radiographic imaging found an interval decrease in the size of his spleen, signifying an objective response. Since achieving near total clinical remission, the patient remains under the close observation of medical oncology services,” the researchers wrote.
The investigators noted that if histopathology is the only method used to diagnosis the condition, epidermotropic MZL could be mistaken for a T-cell lymphoproliferative disorder, such as mycosis fungoides, because of the similar architecture at low resolution.
“In these settings, immunohistochemical staining for B-cell markers represents an indispensable diagnostic test,” they wrote.
The researchers reported having no conflicts of interest.
Epidermotropic marginal zone lymphoma (MZL), a rare cutaneous B-cell lymphoma identified in only eight patients to date, appears to be responsive to rituximab, according to authors of a case report.
A 69-year-old man who presented with a generalized papulosquamous eruption that was eventually diagnosed as epidermotropic MZL achieved a near total remission within 3 months of receiving four total weekly rituximab infusions, reported Cynthia M. Magro, MD, from Cornell University, New York, and her colleagues from the University of Arizona, Tucson (JAAD Case Rep. 2017 Sep 23;3[6]:474-6).
“Epidermotropic MZL represents a distinctive nosologic B-cell lymphoma that should be considered a diagnostic possibility in older men who present with an unexplained papulosquamous eruption resembling pityriasis rosea,” the researchers wrote.
“Epidermotropism refers to a state of abnormal colonization of the epidermis by leukocytes, which often reflects a clonal T-cell or monocyte dyscrasia. Epidermotropism is a distinctive pattern of passive migration into epithelial structures that is not otherwise attributable to the normal function of innate and adaptive immunity,” the researchers explained.
They described the case of the aforementioned patient, who presented with asymptomatic indurated, red-to-brown papules and plaques on his chest, abdomen, back, and buttocks, which gave the clinical impression of pityriasis rosea or a similarly appearing drug reaction.
Histopathologic examination of two biopsied lesions “demonstrated a dense superficial lymphocytic infiltrate that expanded and effaced the papillary and superficial reticular dermis.”
After epidermotropic MZL was diagnosed, the patient was evaluated for systemic disease with a bone marrow biopsy, which revealed a low-grade B-cell lymphoproliferative disorder, and with a PET scan showing lymphomatous infiltration of the spleen. The patient was treated with four weekly infusions of rituximab 375 mg/m2.
“Within 3 months, he experienced marked regression of his cutaneous disease. Repeat radiographic imaging found an interval decrease in the size of his spleen, signifying an objective response. Since achieving near total clinical remission, the patient remains under the close observation of medical oncology services,” the researchers wrote.
The investigators noted that if histopathology is the only method used to diagnosis the condition, epidermotropic MZL could be mistaken for a T-cell lymphoproliferative disorder, such as mycosis fungoides, because of the similar architecture at low resolution.
“In these settings, immunohistochemical staining for B-cell markers represents an indispensable diagnostic test,” they wrote.
The researchers reported having no conflicts of interest.
FROM JAAD CASE REPORTS
Key clinical point: Epidermotropic marginal zone lymphoma, a very rare B-cell disorder, can be effectively treated with rituximab.
Major finding: A patient with epidermotropic MZL had a near complete response to rituximab within 3 months.
Data source: Case study of a 69-year-old man presenting with an otherwise asymptomatic diffuse dermatologic eruption.
Disclosures: The researchers reported no conflicts of interest.
Upfront chemotherapy yields excellent survival in patients with MZLs
For patients with advanced or recurrent marginal zone lymphomas (MZL) typically treated with radiotherapy, antibiotics, single-agent therapy, or observation, upfront chemotherapy was associated with high rates of both failure-free and overall survival at 10 years.
A retrospective analysis of data on 44 patients with either extranodal MZL (MALT), splenic MZL (SMZL), or nodal MZL (NMZL) treated with either the standard of care (for early-stage MALT) or with chemotherapy plus rituximab (for patients with advanced MALT, SMZL, or NMZL) showed a projected 10-year failure-free survival rate of 80%, and an overall survival rate of 100%, reported José L. Ortega, MD, of the University of Puerto Rico in San Juan, and his colleagues (Clin Lymphoma Myeloma Leuk. 2017 Sep 23. pii: S2152-2650[17]30632-8. doi: 10.1016/j.clml.2017.09.014).
“Although the watch and wait modality is still the most-used strategy for patients with advanced MZLs, with chemotherapy traditionally reserved for relapsed or advanced symptomatic disease, our data suggest that upfront chemotherapy is very effective for patients with advanced MALT, SMZL, and NMZL. However, it was not possible to definitely exclude that a less-aggressive approach such as single-agent rituximab could yield similar results,” the investigators wrote.
The standard of care for patients with localized MALT has traditionally been either antibiotic therapy for gastric MALT, or radiotherapy when antibiotics are not feasible. There is no standard of care, however, for either SMZL or NMZL, which are typically managed with either observation or single-agent rituximab, the investigators stated.
To see whether upfront chemotherapy with either FND-R (fludarabine, mitoxantrone, dexamethasone, and rituximab) or CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) could improve outcomes in patients with advanced or recurrent MZLs, the investigators conducted a retrospective study of outcomes for 44 patients treated at their institution.
Group 1 comprised 22 patients with early-stage MALT treated with either radiotherapy or antibiotics, with or without surgery. Group 2 comprised 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Patients in this group underwent upfront chemotherapy with either FND-R (14 patients) or CHOP-R (8 patients). In addition, 16 patients in group 2 received maintenance rituximab.
All patients in each group had complete remissions. Two patients in group 1 had relapses (one at 70 months and one at 75 months) of stage I MALT that had previously been treated with radiotherapy. Both patients underwent salvage FND-R, and remained disease free at 27 and 39 months after relapse. There were no relapses in group 2.
The investigators deemed long-term toxicities to be “acceptable,” with most adverse effects in group 2 being hematologic in origin, including grade 3 or 4 neutropenia in 70%, thrombocytopenia in 22%, and anemia in 17%. Nonhematologic adverse events were mostly grade 1 or 2. There were no second malignancies reported at the most recent follow-up.
The investigators noted that the high complete remission rate and durable remissions with FND-R suggest that it has excellent activity against MZL, and that the long failure-free survival suggests the possibility of cure. They acknowledged, however, that their impressions were based on retrospective data and a small sample size, and that larger clinical trials are needed to confirm their results.
The investigators reported having no conflicts of interest.
For patients with advanced or recurrent marginal zone lymphomas (MZL) typically treated with radiotherapy, antibiotics, single-agent therapy, or observation, upfront chemotherapy was associated with high rates of both failure-free and overall survival at 10 years.
A retrospective analysis of data on 44 patients with either extranodal MZL (MALT), splenic MZL (SMZL), or nodal MZL (NMZL) treated with either the standard of care (for early-stage MALT) or with chemotherapy plus rituximab (for patients with advanced MALT, SMZL, or NMZL) showed a projected 10-year failure-free survival rate of 80%, and an overall survival rate of 100%, reported José L. Ortega, MD, of the University of Puerto Rico in San Juan, and his colleagues (Clin Lymphoma Myeloma Leuk. 2017 Sep 23. pii: S2152-2650[17]30632-8. doi: 10.1016/j.clml.2017.09.014).
“Although the watch and wait modality is still the most-used strategy for patients with advanced MZLs, with chemotherapy traditionally reserved for relapsed or advanced symptomatic disease, our data suggest that upfront chemotherapy is very effective for patients with advanced MALT, SMZL, and NMZL. However, it was not possible to definitely exclude that a less-aggressive approach such as single-agent rituximab could yield similar results,” the investigators wrote.
The standard of care for patients with localized MALT has traditionally been either antibiotic therapy for gastric MALT, or radiotherapy when antibiotics are not feasible. There is no standard of care, however, for either SMZL or NMZL, which are typically managed with either observation or single-agent rituximab, the investigators stated.
To see whether upfront chemotherapy with either FND-R (fludarabine, mitoxantrone, dexamethasone, and rituximab) or CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) could improve outcomes in patients with advanced or recurrent MZLs, the investigators conducted a retrospective study of outcomes for 44 patients treated at their institution.
Group 1 comprised 22 patients with early-stage MALT treated with either radiotherapy or antibiotics, with or without surgery. Group 2 comprised 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Patients in this group underwent upfront chemotherapy with either FND-R (14 patients) or CHOP-R (8 patients). In addition, 16 patients in group 2 received maintenance rituximab.
All patients in each group had complete remissions. Two patients in group 1 had relapses (one at 70 months and one at 75 months) of stage I MALT that had previously been treated with radiotherapy. Both patients underwent salvage FND-R, and remained disease free at 27 and 39 months after relapse. There were no relapses in group 2.
The investigators deemed long-term toxicities to be “acceptable,” with most adverse effects in group 2 being hematologic in origin, including grade 3 or 4 neutropenia in 70%, thrombocytopenia in 22%, and anemia in 17%. Nonhematologic adverse events were mostly grade 1 or 2. There were no second malignancies reported at the most recent follow-up.
The investigators noted that the high complete remission rate and durable remissions with FND-R suggest that it has excellent activity against MZL, and that the long failure-free survival suggests the possibility of cure. They acknowledged, however, that their impressions were based on retrospective data and a small sample size, and that larger clinical trials are needed to confirm their results.
The investigators reported having no conflicts of interest.
For patients with advanced or recurrent marginal zone lymphomas (MZL) typically treated with radiotherapy, antibiotics, single-agent therapy, or observation, upfront chemotherapy was associated with high rates of both failure-free and overall survival at 10 years.
A retrospective analysis of data on 44 patients with either extranodal MZL (MALT), splenic MZL (SMZL), or nodal MZL (NMZL) treated with either the standard of care (for early-stage MALT) or with chemotherapy plus rituximab (for patients with advanced MALT, SMZL, or NMZL) showed a projected 10-year failure-free survival rate of 80%, and an overall survival rate of 100%, reported José L. Ortega, MD, of the University of Puerto Rico in San Juan, and his colleagues (Clin Lymphoma Myeloma Leuk. 2017 Sep 23. pii: S2152-2650[17]30632-8. doi: 10.1016/j.clml.2017.09.014).
“Although the watch and wait modality is still the most-used strategy for patients with advanced MZLs, with chemotherapy traditionally reserved for relapsed or advanced symptomatic disease, our data suggest that upfront chemotherapy is very effective for patients with advanced MALT, SMZL, and NMZL. However, it was not possible to definitely exclude that a less-aggressive approach such as single-agent rituximab could yield similar results,” the investigators wrote.
The standard of care for patients with localized MALT has traditionally been either antibiotic therapy for gastric MALT, or radiotherapy when antibiotics are not feasible. There is no standard of care, however, for either SMZL or NMZL, which are typically managed with either observation or single-agent rituximab, the investigators stated.
To see whether upfront chemotherapy with either FND-R (fludarabine, mitoxantrone, dexamethasone, and rituximab) or CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab) could improve outcomes in patients with advanced or recurrent MZLs, the investigators conducted a retrospective study of outcomes for 44 patients treated at their institution.
Group 1 comprised 22 patients with early-stage MALT treated with either radiotherapy or antibiotics, with or without surgery. Group 2 comprised 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Patients in this group underwent upfront chemotherapy with either FND-R (14 patients) or CHOP-R (8 patients). In addition, 16 patients in group 2 received maintenance rituximab.
All patients in each group had complete remissions. Two patients in group 1 had relapses (one at 70 months and one at 75 months) of stage I MALT that had previously been treated with radiotherapy. Both patients underwent salvage FND-R, and remained disease free at 27 and 39 months after relapse. There were no relapses in group 2.
The investigators deemed long-term toxicities to be “acceptable,” with most adverse effects in group 2 being hematologic in origin, including grade 3 or 4 neutropenia in 70%, thrombocytopenia in 22%, and anemia in 17%. Nonhematologic adverse events were mostly grade 1 or 2. There were no second malignancies reported at the most recent follow-up.
The investigators noted that the high complete remission rate and durable remissions with FND-R suggest that it has excellent activity against MZL, and that the long failure-free survival suggests the possibility of cure. They acknowledged, however, that their impressions were based on retrospective data and a small sample size, and that larger clinical trials are needed to confirm their results.
The investigators reported having no conflicts of interest.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: The 10-year projected failure-free survival rate was 80%, and the overall survival rate was 100%.
Data source: Retrospective single-center study of 44 patients with marginal zone lymphomas.
Disclosures: The investigators reported having no conflicts of interest.
CAR T-cells gain ground against hematologic cancers
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
Chimeric antigen receptor (CAR) T-cell therapies are driving ever faster forward, with impressive response rates – including a high level of complete responses – in treatment of patients with lymphomas and multiple myeloma as shown by clinical trial results to be presented at the annual meeting of the American Society of Hematology.
Investigators will be presenting data on the first two CAR T constructs to receive Food and Drug Administration approval, each directed against CD19.
ZUMA-1 for non-Hodgkin lymphoma
Long-term follow-up results with the use of axicabtagene ciloleucel (Yescarta; axi-cel) in patients with refractory aggressive non-Hodgkin lymphoma will be presented by Sattva S. Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, on behalf of colleagues in the ZUMA-1 trial (Abstract 578).
At the 2017 European Hematology Association Congress in Madrid, ZUMA-1 investigators reported that axi-cel, an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. The 54% complete response rate was nearly sevenfold higher than that reported for historical controls, according to coinvestigator Yi Lin, MD, PhD, of the Mayo Clinic, Rochester, Minn.
The treatment was generally safe, with 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tocilizumab or steroids to control adverse events did not have a negative effect on responses.
This CAR T-cell construct received FDA approval in October 2017.
At ASH 2017, Dr. Neelapu will present 1-year follow-up data from the trial which will include both data on responses and toxicity, “but also some very interesting information on mechanisms of resistance, whether patients’ tumor cells become CD19 negative, or checkpoint, like PD-L1, positive,” said Kenneth Anderson, MD, of the Dana-Farber Cancer Institute in Boston, who discussed noteworthy abstracts in a media briefing prior to the meeting.
JULIET for DLBCL
Data on the use of another anti-CD19 CAR construct, tisagenlecleucel (Kymriah) in adults with relapsed or refractory DLBCL will be presented by Stephen J. Schuster, MD, of the University of Pennsylvania, Philadelphia, on behalf of investigators in the JULIET trial.
At the 2017 European Hematology Association Congress, coinvestigator Gilles Salles, MD, PhD, of the University of Lyon, France, reported an interim analysis from the trial, showing that the CAR T construct was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses in patients with relapsed or refractory DLBCL. The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.
Dr. Schuster will present the primary analysis of the global phase 2 pivotal trial at ASH 2017 (Abstract 577), looking at patients who received the product from the U.S. manufacturing site.
As of the data cutoff in March 2017, the best ORR among 81 patients with at least 3 months of follow-up, or earlier discontinuation, was 53.1% with 39.5% complete responses and 13.6% partial responses. For 46 patients evaluable at 6 months, the complete response rate was 30% and partial response rate was 7%.
The response rates were consistent across subgroups, including patients who had previously undergone autologous stem cell transplant and those with double-hit lymphoma (i.e, with mutation in MYC and BCL2 or BCL6).
The responses also appeared to be durable, with the median duration not reached. The 6-month probability of being relapse free was 73.5%. Similarly, median overall survival was not reached; the 6-month probability of overall survival was 64.5%, according to the published abstract.
Adverse events included CRS in 58% of infused patients, with 15% grade 3 and 8% grade 4 in severity. CRS was managed according to protocol with tocilizumab and/or corticosteroids. There were no deaths associated with either the CRS or neurologic toxicities.
“This is a multicenter trial: 27 centers, 10 countries, 4 continents, so it sort of demonstrates to all of us that this technology can be done in an international scope,” Dr. Anderson said.
Anti-BCMA for multiple myeloma
CAR T-cells are relative newcomers in the treatment of multiple myeloma, but James N. Kochenderfer, MD, of the National Cancer Institute, Bethesda, Md., will be presenting updated results from a multicenter study of bb2121, a CAR T-cell construct directed against B-cell maturation antigen (BCMA).
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. As previously reported, a different anti-BCMA T-cell product induced clinical remissions in 33 of 35 patients with relapsed/refractory multiple myeloma who were treated in an early clinical trial.
With the construct being investigated by Dr. Kochenderfer and colleagues, 21 patients (median 58 years old) with a median of 5 years since a diagnosis of multiple myeloma were infused with bb2121. One-month data on clinical response was available for 18 patients at the time of data cutoff in May 2017 (Abstract 740).
In this heavily pretreated population, the ORR was 89% overall, and was 100% for patients treated with doses of 150 x 106 CAR+ T cells or higher. At this dose range or higher no patients had disease progression at up to 54 weeks after infusion. Of the four patients evaluable for minimal residual disease (MRD), all were MRD negative.
As of the data cut-off there were no dose-limiting toxicities and no treatment-related grade 3 or higher neurotoxicities. CRS was primarily grade 1 or 2 and was reported in 15 of 21 patients. Two patients had grade 3 CRS that resolved in 24 hours, and four patients received tocilizumab (one with steroids) for CRS management.
There was one on-study death, from cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history. The death was judged to be unrelated to CAR T-cell therapy.
Dr. Kochenderfer will present data and analysis on an additional 5 months of follow-up.
“This abstract demonstrates that again, in patients, this time with myeloma with literally no other option, you can achieve very impressive response,” Dr. Anderson said.
The ZUMA-1 study is funded by Kite Pharma. Dr. Neelapu reported research funding from BMS, Poseida, Merck, Kite Pharma, and Cellectis. He reported consultancy and membership on the board of directors or advisory committees for Merck, Kite Pharma, and Celgene.
The JULIET study is funded by Novartis. Dr. Schuster reported consultancy and research funding from Novartis Pharmaceuticals, Celgene, Genentech, Bristol-Myers Squibb, Janssen R&D, and Gilead. He reported consultancy with Seattle Genetics and Nordic Nanovector, and research funding from Merck.
The multicenter study of bb2121 is sponsored by bluebird bio and Celgene. Dr. Kochenderfer reported research funding from bluebird bio and Kite Pharma. He reported having multiple patents in the CAR field.
Abstract 578 Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL) will be presented in session 626, Monday, Dec. 11, 2017, at 7:15 a.m.
Abstract 577 Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma will be presented in session 626, Monday, Dec. 11, 2017 at 7:00 a.m.
Abstract 740 Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-BCMA CAR T Cell Therapy will be presented in session 653, Monday, Dec. 11, 2017 at 3:00 p.m.
FROM ASH 2017
Studies need to address best follow-on therapy to ibrutinib in CLL
Reporting AT LYMPHOMA & MYELOMA 2017
NEW YORK – Clinical trials are needed to determine the best follow-on therapies when patients discontinue the ibrutinib due to adverse events or disease progression, according to a leading expert on chronic lymphocytic leukemia (CLL).
Anthony Mato, MD, MSCE, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, discussed how real-world experience with the use of ibrutinib (Imbruvica) can fill the gaps in knowledge left by clinical trials and point to the need for further study.
“Regulatory bodies around the world are more and more interested in what’s going on in the clinic, and there is a question about whether or not the experiences for patients that we take care of might actually answer some important questions that aren’t easily answered in the context of clinical research,” he said at the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies here.
“Are the experiences in practice with novel agents similar to experiences from clinical trials? I think that’s very important,” he added.
Other important questions that real-world experience may help to answer include whether it’s possible to refine adverse event profiles and reasons for ibrutinib discontinuation, what therapies should be prescribed after ibrutinib, and what is the optimal sequencing of therapies for CLL.
For example, in the RESONATE-2 trial, an open-label, international phase 3 study comparing ibrutinib with chlorambucil in previously untreated patients 65 and older, ibrutinib was found to be superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), response rate, and improvements in hematologic variables.
However, this trial excluded patients with the deleterious chromosome 17p deletion (del17p) and included only patients 65 and older, a population that does not necessarily reflect clinical experience.
To get a better sense of how ibrutinib is used to treat CLL in the front-line setting Dr. Mato and colleagues conducted a retrospective cohort study of 391 patients treated in 19 US and international academic and community centers.
The median age of the sample was 68 years, but 41% of the patients were younger than 65. In all, 62% were male, and 80% had Rai stage 2 or greater disease. Genetic analyses showed that 30% of the patients were positive for del17p, and 17% had both del17p and the 11q deletion (del11q). Mutations in TP53 were seen in 20% of patients, 23% had a complex karyotype, and 67% had an unmutated immuglobulin heavy chain variable region (IGHV). Only 57 patients (14.5%) were classified as genetically low risk.
Additionally, only 79 of the 391 patients had complete data for CLL International Prognostic Index (CLL-IPI) scoring, “which goes, I think, to show how often this is actually being tested and utilized in clinical practice,” Dr. Mato said.
Off-label use of ibrutinib in combination therapy was given to 16% of patients, most commonly with an anti-CD20 inhibitor such as rituximab.
In all, 17% of patients required permanent dose reductions; and 42% had a dose interruption, with a median hiatus of 12 days.
Grade 3 or 4 adverse events were uncommon, but more than 20% of patients experienced arthralgias or myalgias of any kind, about 19% reported fatigue, 18% had dermatologic toxicities, 18% reported bruising, 17% had diarrhea or colitis and 15% had infections.
The toxicities seen in RESONATE-2 were somewhat similar, but generally occurred in higher frequencies in the trial than in real-world practice.
Dr. Mato and colleagues found that at a median of 12 months of follow-up, 24% of patients had discontinued ibrutinib. In contrast, in RESONATE-2, after 18 months of follow-up, 13% of patients had discontinued the drug.
The most common reasons for discontinuation in clinical practice were for toxicities (59.5% of 94 discontinuations) including atrial fibrillation in 20% of the patients who discontinued, arthralgias/myalgias and skin toxicities in 14.5% each, and bleeding in 9.1%.
Other reasons for discontinuation included Richter’s transformation in 9.6%, doctor or patient preference in 7.4%, and deaths that were not secondary to CLL progression in 3.2%.
“We also tried to get a sense of whether or not cost was a factor for patients, and in this series and the relapsed refractory setting, 1% or less of patients discontinued due to financial issues,” Dr. Mato said.
Outcomes in the real word were quite good, he noted, with an overall response rate (ORR) of 81.7%, which included 17.4% complete responses (CR), Neither median PFS nor OS have been reached and the respective PFS and OS at 12 months were 92% and 95%. The respective PFS and OS rates for patients with del17p were 87% and 89%. An analysis of predictors of survival showed that only the presence of del17p was associated with inferior PFS (odds ratio 1.91, P = .035)
Dr. Mato noted that there was no clear standard treatment approach for patients who discontinued ibrutinib or for whom ibrutinib did not work. The top three second-line approaches used included an anti-CD20 agent combined with chlorambucil, venetoclax (Venclexta), or a different kinase inhibitor. Chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab was given to only 5 patients as a second line therapy.
Dr. Mato disclosed serving as a consultant for AbbVie, AstraZeneca, Janssen/Pharmacyclics, and TG Therapeutics.
Reporting AT LYMPHOMA & MYELOMA 2017
NEW YORK – Clinical trials are needed to determine the best follow-on therapies when patients discontinue the ibrutinib due to adverse events or disease progression, according to a leading expert on chronic lymphocytic leukemia (CLL).
Anthony Mato, MD, MSCE, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, discussed how real-world experience with the use of ibrutinib (Imbruvica) can fill the gaps in knowledge left by clinical trials and point to the need for further study.
“Regulatory bodies around the world are more and more interested in what’s going on in the clinic, and there is a question about whether or not the experiences for patients that we take care of might actually answer some important questions that aren’t easily answered in the context of clinical research,” he said at the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies here.
“Are the experiences in practice with novel agents similar to experiences from clinical trials? I think that’s very important,” he added.
Other important questions that real-world experience may help to answer include whether it’s possible to refine adverse event profiles and reasons for ibrutinib discontinuation, what therapies should be prescribed after ibrutinib, and what is the optimal sequencing of therapies for CLL.
For example, in the RESONATE-2 trial, an open-label, international phase 3 study comparing ibrutinib with chlorambucil in previously untreated patients 65 and older, ibrutinib was found to be superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), response rate, and improvements in hematologic variables.
However, this trial excluded patients with the deleterious chromosome 17p deletion (del17p) and included only patients 65 and older, a population that does not necessarily reflect clinical experience.
To get a better sense of how ibrutinib is used to treat CLL in the front-line setting Dr. Mato and colleagues conducted a retrospective cohort study of 391 patients treated in 19 US and international academic and community centers.
The median age of the sample was 68 years, but 41% of the patients were younger than 65. In all, 62% were male, and 80% had Rai stage 2 or greater disease. Genetic analyses showed that 30% of the patients were positive for del17p, and 17% had both del17p and the 11q deletion (del11q). Mutations in TP53 were seen in 20% of patients, 23% had a complex karyotype, and 67% had an unmutated immuglobulin heavy chain variable region (IGHV). Only 57 patients (14.5%) were classified as genetically low risk.
Additionally, only 79 of the 391 patients had complete data for CLL International Prognostic Index (CLL-IPI) scoring, “which goes, I think, to show how often this is actually being tested and utilized in clinical practice,” Dr. Mato said.
Off-label use of ibrutinib in combination therapy was given to 16% of patients, most commonly with an anti-CD20 inhibitor such as rituximab.
In all, 17% of patients required permanent dose reductions; and 42% had a dose interruption, with a median hiatus of 12 days.
Grade 3 or 4 adverse events were uncommon, but more than 20% of patients experienced arthralgias or myalgias of any kind, about 19% reported fatigue, 18% had dermatologic toxicities, 18% reported bruising, 17% had diarrhea or colitis and 15% had infections.
The toxicities seen in RESONATE-2 were somewhat similar, but generally occurred in higher frequencies in the trial than in real-world practice.
Dr. Mato and colleagues found that at a median of 12 months of follow-up, 24% of patients had discontinued ibrutinib. In contrast, in RESONATE-2, after 18 months of follow-up, 13% of patients had discontinued the drug.
The most common reasons for discontinuation in clinical practice were for toxicities (59.5% of 94 discontinuations) including atrial fibrillation in 20% of the patients who discontinued, arthralgias/myalgias and skin toxicities in 14.5% each, and bleeding in 9.1%.
Other reasons for discontinuation included Richter’s transformation in 9.6%, doctor or patient preference in 7.4%, and deaths that were not secondary to CLL progression in 3.2%.
“We also tried to get a sense of whether or not cost was a factor for patients, and in this series and the relapsed refractory setting, 1% or less of patients discontinued due to financial issues,” Dr. Mato said.
Outcomes in the real word were quite good, he noted, with an overall response rate (ORR) of 81.7%, which included 17.4% complete responses (CR), Neither median PFS nor OS have been reached and the respective PFS and OS at 12 months were 92% and 95%. The respective PFS and OS rates for patients with del17p were 87% and 89%. An analysis of predictors of survival showed that only the presence of del17p was associated with inferior PFS (odds ratio 1.91, P = .035)
Dr. Mato noted that there was no clear standard treatment approach for patients who discontinued ibrutinib or for whom ibrutinib did not work. The top three second-line approaches used included an anti-CD20 agent combined with chlorambucil, venetoclax (Venclexta), or a different kinase inhibitor. Chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab was given to only 5 patients as a second line therapy.
Dr. Mato disclosed serving as a consultant for AbbVie, AstraZeneca, Janssen/Pharmacyclics, and TG Therapeutics.
Reporting AT LYMPHOMA & MYELOMA 2017
NEW YORK – Clinical trials are needed to determine the best follow-on therapies when patients discontinue the ibrutinib due to adverse events or disease progression, according to a leading expert on chronic lymphocytic leukemia (CLL).
Anthony Mato, MD, MSCE, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, discussed how real-world experience with the use of ibrutinib (Imbruvica) can fill the gaps in knowledge left by clinical trials and point to the need for further study.
“Regulatory bodies around the world are more and more interested in what’s going on in the clinic, and there is a question about whether or not the experiences for patients that we take care of might actually answer some important questions that aren’t easily answered in the context of clinical research,” he said at the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies here.
“Are the experiences in practice with novel agents similar to experiences from clinical trials? I think that’s very important,” he added.
Other important questions that real-world experience may help to answer include whether it’s possible to refine adverse event profiles and reasons for ibrutinib discontinuation, what therapies should be prescribed after ibrutinib, and what is the optimal sequencing of therapies for CLL.
For example, in the RESONATE-2 trial, an open-label, international phase 3 study comparing ibrutinib with chlorambucil in previously untreated patients 65 and older, ibrutinib was found to be superior to chlorambucil in terms of progression-free survival (PFS), overall survival (OS), response rate, and improvements in hematologic variables.
However, this trial excluded patients with the deleterious chromosome 17p deletion (del17p) and included only patients 65 and older, a population that does not necessarily reflect clinical experience.
To get a better sense of how ibrutinib is used to treat CLL in the front-line setting Dr. Mato and colleagues conducted a retrospective cohort study of 391 patients treated in 19 US and international academic and community centers.
The median age of the sample was 68 years, but 41% of the patients were younger than 65. In all, 62% were male, and 80% had Rai stage 2 or greater disease. Genetic analyses showed that 30% of the patients were positive for del17p, and 17% had both del17p and the 11q deletion (del11q). Mutations in TP53 were seen in 20% of patients, 23% had a complex karyotype, and 67% had an unmutated immuglobulin heavy chain variable region (IGHV). Only 57 patients (14.5%) were classified as genetically low risk.
Additionally, only 79 of the 391 patients had complete data for CLL International Prognostic Index (CLL-IPI) scoring, “which goes, I think, to show how often this is actually being tested and utilized in clinical practice,” Dr. Mato said.
Off-label use of ibrutinib in combination therapy was given to 16% of patients, most commonly with an anti-CD20 inhibitor such as rituximab.
In all, 17% of patients required permanent dose reductions; and 42% had a dose interruption, with a median hiatus of 12 days.
Grade 3 or 4 adverse events were uncommon, but more than 20% of patients experienced arthralgias or myalgias of any kind, about 19% reported fatigue, 18% had dermatologic toxicities, 18% reported bruising, 17% had diarrhea or colitis and 15% had infections.
The toxicities seen in RESONATE-2 were somewhat similar, but generally occurred in higher frequencies in the trial than in real-world practice.
Dr. Mato and colleagues found that at a median of 12 months of follow-up, 24% of patients had discontinued ibrutinib. In contrast, in RESONATE-2, after 18 months of follow-up, 13% of patients had discontinued the drug.
The most common reasons for discontinuation in clinical practice were for toxicities (59.5% of 94 discontinuations) including atrial fibrillation in 20% of the patients who discontinued, arthralgias/myalgias and skin toxicities in 14.5% each, and bleeding in 9.1%.
Other reasons for discontinuation included Richter’s transformation in 9.6%, doctor or patient preference in 7.4%, and deaths that were not secondary to CLL progression in 3.2%.
“We also tried to get a sense of whether or not cost was a factor for patients, and in this series and the relapsed refractory setting, 1% or less of patients discontinued due to financial issues,” Dr. Mato said.
Outcomes in the real word were quite good, he noted, with an overall response rate (ORR) of 81.7%, which included 17.4% complete responses (CR), Neither median PFS nor OS have been reached and the respective PFS and OS at 12 months were 92% and 95%. The respective PFS and OS rates for patients with del17p were 87% and 89%. An analysis of predictors of survival showed that only the presence of del17p was associated with inferior PFS (odds ratio 1.91, P = .035)
Dr. Mato noted that there was no clear standard treatment approach for patients who discontinued ibrutinib or for whom ibrutinib did not work. The top three second-line approaches used included an anti-CD20 agent combined with chlorambucil, venetoclax (Venclexta), or a different kinase inhibitor. Chemoimmunotherapy with either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab was given to only 5 patients as a second line therapy.
Dr. Mato disclosed serving as a consultant for AbbVie, AstraZeneca, Janssen/Pharmacyclics, and TG Therapeutics.
Debate: Is MRD ready for prime time in multiple myeloma?
NEW YORK – Evidence of minimal residual disease (MRD) has been shown to be an important prognostic factor in several different hematologic malignancies, including acute and chronic myeloid leukemias, but its clinical utility in day-to-day practice in multiple myeloma is still uncertain.
At the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies, C. Ola Landgren, MD, PhD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Myeloma Center at the Dana-Farber Cancer Institute in Boston, debated the question: “Is MRD ready for prime time?”
Yes: Dr. Landgren
“As we all know, with older drugs for myeloma, only a small proportion of patients reached a complete response, so there was really no reason to talk about MRD. But this belongs to the past: using the modern combination therapies, about 100% of our patients have a response, an overall response, and up to 80% of patients are reaching a complete response. So it’s really necessary, a logical step to go forward, to look at MRD,” Dr. Landgren said.
He cited evidence from two meta-analyses showing that MRD negativity is a strong predictor of clinical outcomes, including long-term survival.
“Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma,” they wrote.
In a second meta-analysis, Nikhil Munshi, MD, from the Dana-Farber Cancer Institute, and his colleagues, reviewed PFS data from 14 studies with a total of 1,273 patients, and OS data from 12 studies with a total of 1,100 patients.
This second meta-analysis found that MRD negativity was associated with significantly better PFS (HR, 0.41; P less than .001), including among patients in studies looking specifically at complete response (CR) (HR, 0.44; P less than .001).
Munshi et al. also saw a significant benefit for MRD negativity among all patients in trials with OS as the endpoint (HR, 0.57; P less than .001) and in those focusing on patients with a CR (HR, 0.47; P less than .001).
They concluded that MRD-negative status after treatment for new newly diagnosed multiple myeloma is associated with long-term survival, and like Landgren et al. contended that their findings “provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.”
Dr. Landgren noted that 2016 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma, coauthored by both Dr. Landgren and Dr. Richardson, now incorporate MRD.
In addition, in the IFM/DFCI 2009 trial comparing induction therapy for patients with newly diagnosed multiple myeloma with or without autologous stem cell transplant after three cycles of lenalidomide, bortezomib, and dexamethasone, patients in each trial arm who were MRD negative had significantly better PFS than patients who were MRD positive after consolidation, regardless of assigned treatment, Dr. Landgren noted.
In the relapsed/refractory multiple myeloma setting, MRD negativity was associated with better PFS for patients in the POLLUX trial, whether subjects were assigned to receive daratumumab plus lenalidomide and dexamethasone, or len-dex alone.
“This raises an important question: Is MRD more important than treatment modality?” Dr. Landgren said.
“The debate is: Is MRD ready for prime time? And as I have shown you with all the data, the answer is ‘Yes’,” he concluded.
No: Dr. Richardson
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena. The question for me as a clinician in my clinic is: ‘Do I apply it to everyday practice?’ And I would simply suggest to you at this point we’re not ready for that, and we’re not ready for that for a variety of complex reasons,” Dr. Richardson said in his rebuttal.
He cited a definition of MRD offered by Simone Ferrero, MD, and his colleagues from the University of Turin (Italy) in 2011 in Hematological Oncology: “Any approach aimed at detecting and possibly quantifying residual tumor cells beyond the sensitivity level of routine imaging and laboratory techniques.”
“We recognize in hematologic malignancies in particular, and increasingly in myeloma, that achievement of complete clinical remission and assessing this needs a variety of different scenarios,” he said.
These scenarios may include establishing the full eradication of the neoplastic clone, determining the long-term persistence of quiescent or nonclonogenic or immunologically regulated tumor cells, or persistence of clonogenic cells capable of giving rise to a full clinical relapse within a number of years.
Myeloma specialists recognize that MRD is a real phenomenon, made more challenging by the “extraordinary” heterogeneity of myeloma, he said.
Determination of MRD using sensitive molecular techniques may allow analysis of treatments that induce a greater depth of response than others, and may also identify patients who are experiencing early relapse and will need further treatment, Dr. Richardson acknowledged.
“The question is, should it dictate what you and I do every afternoon in the clinic with a particular patient, for example, outside of a clinical trial?”
He noted that MRD is still a secondary endpoint in trials for acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, and chronic lymphocytic leukemia, although it has been accepted by the FDA as a primary endpoint to assess molecular responses to second-generation tyrosine kinase inhibitors.
MRD is also still a secondary endpoint in trials for therapies against follicular and mantle cell lymphomas as well.
“So my hypothesis, or suggestion to you this morning, is that whilst MRD clearly is a vital area of research – and I especially applaud Ola for being on the forefront of this, and I fully support all the points he made – I would just simply suggest to you that it’s less advanced than in leukemia and lymphoma, and we are currently at the point where MRD assessments are clearly secondary endpoints and an important research tool,” he said,
MRD remains a research tool in multiple myeloma because, despite the wealth of new therapies and combinations approved in just the past few years, “we’re not able to eradicate it completely, and cure remains in myeloma, frankly, evasive,” he added.
Immunotherapy, for example, is not the “mutationally agnostic” approach that clinicians had hoped for, with recent evidence suggesting that it cannot overcome every genetic variation that may give rise to multiple myeloma.
For MRD to become a useful clinical tool rather than a research/regulatory tool, standardization of testing methods will be needed. Flow cytometry until recently has been the mainstay for detecting MRD, but molecular strategies are currently being investigated, and rapid next-generation sequencing has the potential to become a gold standard, with its ability to identify and quantify all clonotypes in a sample.
“What’s critical is, therapeutic adjustment for what? What is the difference? For example, [if] one arm of a trial has 20% MRD positivity vs. 40% in another, what does that really mean for overall survival? These are enormous challenges that we still face,” Dr. Richardson said.
“I do think the lack of standardization broadly across the country is a challenge, and so with that in mind, I would simply suggest that it is not yet a standard of care in clinical practice, but may be,” he concluded.
Dr. Landgren disclosed serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene and Janssen. Dr. Richardson disclosed consulting for Celgene and Takeda.
NEW YORK – Evidence of minimal residual disease (MRD) has been shown to be an important prognostic factor in several different hematologic malignancies, including acute and chronic myeloid leukemias, but its clinical utility in day-to-day practice in multiple myeloma is still uncertain.
At the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies, C. Ola Landgren, MD, PhD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Myeloma Center at the Dana-Farber Cancer Institute in Boston, debated the question: “Is MRD ready for prime time?”
Yes: Dr. Landgren
“As we all know, with older drugs for myeloma, only a small proportion of patients reached a complete response, so there was really no reason to talk about MRD. But this belongs to the past: using the modern combination therapies, about 100% of our patients have a response, an overall response, and up to 80% of patients are reaching a complete response. So it’s really necessary, a logical step to go forward, to look at MRD,” Dr. Landgren said.
He cited evidence from two meta-analyses showing that MRD negativity is a strong predictor of clinical outcomes, including long-term survival.
“Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma,” they wrote.
In a second meta-analysis, Nikhil Munshi, MD, from the Dana-Farber Cancer Institute, and his colleagues, reviewed PFS data from 14 studies with a total of 1,273 patients, and OS data from 12 studies with a total of 1,100 patients.
This second meta-analysis found that MRD negativity was associated with significantly better PFS (HR, 0.41; P less than .001), including among patients in studies looking specifically at complete response (CR) (HR, 0.44; P less than .001).
Munshi et al. also saw a significant benefit for MRD negativity among all patients in trials with OS as the endpoint (HR, 0.57; P less than .001) and in those focusing on patients with a CR (HR, 0.47; P less than .001).
They concluded that MRD-negative status after treatment for new newly diagnosed multiple myeloma is associated with long-term survival, and like Landgren et al. contended that their findings “provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.”
Dr. Landgren noted that 2016 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma, coauthored by both Dr. Landgren and Dr. Richardson, now incorporate MRD.
In addition, in the IFM/DFCI 2009 trial comparing induction therapy for patients with newly diagnosed multiple myeloma with or without autologous stem cell transplant after three cycles of lenalidomide, bortezomib, and dexamethasone, patients in each trial arm who were MRD negative had significantly better PFS than patients who were MRD positive after consolidation, regardless of assigned treatment, Dr. Landgren noted.
In the relapsed/refractory multiple myeloma setting, MRD negativity was associated with better PFS for patients in the POLLUX trial, whether subjects were assigned to receive daratumumab plus lenalidomide and dexamethasone, or len-dex alone.
“This raises an important question: Is MRD more important than treatment modality?” Dr. Landgren said.
“The debate is: Is MRD ready for prime time? And as I have shown you with all the data, the answer is ‘Yes’,” he concluded.
No: Dr. Richardson
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena. The question for me as a clinician in my clinic is: ‘Do I apply it to everyday practice?’ And I would simply suggest to you at this point we’re not ready for that, and we’re not ready for that for a variety of complex reasons,” Dr. Richardson said in his rebuttal.
He cited a definition of MRD offered by Simone Ferrero, MD, and his colleagues from the University of Turin (Italy) in 2011 in Hematological Oncology: “Any approach aimed at detecting and possibly quantifying residual tumor cells beyond the sensitivity level of routine imaging and laboratory techniques.”
“We recognize in hematologic malignancies in particular, and increasingly in myeloma, that achievement of complete clinical remission and assessing this needs a variety of different scenarios,” he said.
These scenarios may include establishing the full eradication of the neoplastic clone, determining the long-term persistence of quiescent or nonclonogenic or immunologically regulated tumor cells, or persistence of clonogenic cells capable of giving rise to a full clinical relapse within a number of years.
Myeloma specialists recognize that MRD is a real phenomenon, made more challenging by the “extraordinary” heterogeneity of myeloma, he said.
Determination of MRD using sensitive molecular techniques may allow analysis of treatments that induce a greater depth of response than others, and may also identify patients who are experiencing early relapse and will need further treatment, Dr. Richardson acknowledged.
“The question is, should it dictate what you and I do every afternoon in the clinic with a particular patient, for example, outside of a clinical trial?”
He noted that MRD is still a secondary endpoint in trials for acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, and chronic lymphocytic leukemia, although it has been accepted by the FDA as a primary endpoint to assess molecular responses to second-generation tyrosine kinase inhibitors.
MRD is also still a secondary endpoint in trials for therapies against follicular and mantle cell lymphomas as well.
“So my hypothesis, or suggestion to you this morning, is that whilst MRD clearly is a vital area of research – and I especially applaud Ola for being on the forefront of this, and I fully support all the points he made – I would just simply suggest to you that it’s less advanced than in leukemia and lymphoma, and we are currently at the point where MRD assessments are clearly secondary endpoints and an important research tool,” he said,
MRD remains a research tool in multiple myeloma because, despite the wealth of new therapies and combinations approved in just the past few years, “we’re not able to eradicate it completely, and cure remains in myeloma, frankly, evasive,” he added.
Immunotherapy, for example, is not the “mutationally agnostic” approach that clinicians had hoped for, with recent evidence suggesting that it cannot overcome every genetic variation that may give rise to multiple myeloma.
For MRD to become a useful clinical tool rather than a research/regulatory tool, standardization of testing methods will be needed. Flow cytometry until recently has been the mainstay for detecting MRD, but molecular strategies are currently being investigated, and rapid next-generation sequencing has the potential to become a gold standard, with its ability to identify and quantify all clonotypes in a sample.
“What’s critical is, therapeutic adjustment for what? What is the difference? For example, [if] one arm of a trial has 20% MRD positivity vs. 40% in another, what does that really mean for overall survival? These are enormous challenges that we still face,” Dr. Richardson said.
“I do think the lack of standardization broadly across the country is a challenge, and so with that in mind, I would simply suggest that it is not yet a standard of care in clinical practice, but may be,” he concluded.
Dr. Landgren disclosed serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene and Janssen. Dr. Richardson disclosed consulting for Celgene and Takeda.
NEW YORK – Evidence of minimal residual disease (MRD) has been shown to be an important prognostic factor in several different hematologic malignancies, including acute and chronic myeloid leukemias, but its clinical utility in day-to-day practice in multiple myeloma is still uncertain.
At the annual Lymphoma & Myeloma International Congress on Hematologic Malignancies, C. Ola Landgren, MD, PhD, chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and Paul G. Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Myeloma Center at the Dana-Farber Cancer Institute in Boston, debated the question: “Is MRD ready for prime time?”
Yes: Dr. Landgren
“As we all know, with older drugs for myeloma, only a small proportion of patients reached a complete response, so there was really no reason to talk about MRD. But this belongs to the past: using the modern combination therapies, about 100% of our patients have a response, an overall response, and up to 80% of patients are reaching a complete response. So it’s really necessary, a logical step to go forward, to look at MRD,” Dr. Landgren said.
He cited evidence from two meta-analyses showing that MRD negativity is a strong predictor of clinical outcomes, including long-term survival.
“Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma,” they wrote.
In a second meta-analysis, Nikhil Munshi, MD, from the Dana-Farber Cancer Institute, and his colleagues, reviewed PFS data from 14 studies with a total of 1,273 patients, and OS data from 12 studies with a total of 1,100 patients.
This second meta-analysis found that MRD negativity was associated with significantly better PFS (HR, 0.41; P less than .001), including among patients in studies looking specifically at complete response (CR) (HR, 0.44; P less than .001).
Munshi et al. also saw a significant benefit for MRD negativity among all patients in trials with OS as the endpoint (HR, 0.57; P less than .001) and in those focusing on patients with a CR (HR, 0.47; P less than .001).
They concluded that MRD-negative status after treatment for new newly diagnosed multiple myeloma is associated with long-term survival, and like Landgren et al. contended that their findings “provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of multiple myeloma.”
Dr. Landgren noted that 2016 International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma, coauthored by both Dr. Landgren and Dr. Richardson, now incorporate MRD.
In addition, in the IFM/DFCI 2009 trial comparing induction therapy for patients with newly diagnosed multiple myeloma with or without autologous stem cell transplant after three cycles of lenalidomide, bortezomib, and dexamethasone, patients in each trial arm who were MRD negative had significantly better PFS than patients who were MRD positive after consolidation, regardless of assigned treatment, Dr. Landgren noted.
In the relapsed/refractory multiple myeloma setting, MRD negativity was associated with better PFS for patients in the POLLUX trial, whether subjects were assigned to receive daratumumab plus lenalidomide and dexamethasone, or len-dex alone.
“This raises an important question: Is MRD more important than treatment modality?” Dr. Landgren said.
“The debate is: Is MRD ready for prime time? And as I have shown you with all the data, the answer is ‘Yes’,” he concluded.
No: Dr. Richardson
“My position on this is that MRD testing is absolutely ready for prime time in the research and regulatory arena. The question for me as a clinician in my clinic is: ‘Do I apply it to everyday practice?’ And I would simply suggest to you at this point we’re not ready for that, and we’re not ready for that for a variety of complex reasons,” Dr. Richardson said in his rebuttal.
He cited a definition of MRD offered by Simone Ferrero, MD, and his colleagues from the University of Turin (Italy) in 2011 in Hematological Oncology: “Any approach aimed at detecting and possibly quantifying residual tumor cells beyond the sensitivity level of routine imaging and laboratory techniques.”
“We recognize in hematologic malignancies in particular, and increasingly in myeloma, that achievement of complete clinical remission and assessing this needs a variety of different scenarios,” he said.
These scenarios may include establishing the full eradication of the neoplastic clone, determining the long-term persistence of quiescent or nonclonogenic or immunologically regulated tumor cells, or persistence of clonogenic cells capable of giving rise to a full clinical relapse within a number of years.
Myeloma specialists recognize that MRD is a real phenomenon, made more challenging by the “extraordinary” heterogeneity of myeloma, he said.
Determination of MRD using sensitive molecular techniques may allow analysis of treatments that induce a greater depth of response than others, and may also identify patients who are experiencing early relapse and will need further treatment, Dr. Richardson acknowledged.
“The question is, should it dictate what you and I do every afternoon in the clinic with a particular patient, for example, outside of a clinical trial?”
He noted that MRD is still a secondary endpoint in trials for acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, and chronic lymphocytic leukemia, although it has been accepted by the FDA as a primary endpoint to assess molecular responses to second-generation tyrosine kinase inhibitors.
MRD is also still a secondary endpoint in trials for therapies against follicular and mantle cell lymphomas as well.
“So my hypothesis, or suggestion to you this morning, is that whilst MRD clearly is a vital area of research – and I especially applaud Ola for being on the forefront of this, and I fully support all the points he made – I would just simply suggest to you that it’s less advanced than in leukemia and lymphoma, and we are currently at the point where MRD assessments are clearly secondary endpoints and an important research tool,” he said,
MRD remains a research tool in multiple myeloma because, despite the wealth of new therapies and combinations approved in just the past few years, “we’re not able to eradicate it completely, and cure remains in myeloma, frankly, evasive,” he added.
Immunotherapy, for example, is not the “mutationally agnostic” approach that clinicians had hoped for, with recent evidence suggesting that it cannot overcome every genetic variation that may give rise to multiple myeloma.
For MRD to become a useful clinical tool rather than a research/regulatory tool, standardization of testing methods will be needed. Flow cytometry until recently has been the mainstay for detecting MRD, but molecular strategies are currently being investigated, and rapid next-generation sequencing has the potential to become a gold standard, with its ability to identify and quantify all clonotypes in a sample.
“What’s critical is, therapeutic adjustment for what? What is the difference? For example, [if] one arm of a trial has 20% MRD positivity vs. 40% in another, what does that really mean for overall survival? These are enormous challenges that we still face,” Dr. Richardson said.
“I do think the lack of standardization broadly across the country is a challenge, and so with that in mind, I would simply suggest that it is not yet a standard of care in clinical practice, but may be,” he concluded.
Dr. Landgren disclosed serving as a consultant to AbbVie, Amgen, Bristol-Myers Squibb, Celgene and Janssen. Dr. Richardson disclosed consulting for Celgene and Takeda.
AT LYMPHOMA & MYELOMA 2017