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Drug ‘life-changing’ for CLL patients in phase 1 trial
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.” 
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”
Multiple myeloma advances in diagnosis, staging, therapy extend survival
SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?
Diagnostic criteria
The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.
Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).
“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.
This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”
Staging criteria
The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.
The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).
“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”
Primary therapy
Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.
“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”
Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.
The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.
Risk-adapted management
Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”
There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).
“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.
Stem cell transplant
“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.
Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.
“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”
Maintenance therapy post transplant
The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.
“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.
Options for relapsed disease
Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.
Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”
A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).
The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.
Investigational agents
Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).
Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.
Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).
“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.
SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?
Diagnostic criteria
The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.
Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).
“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.
This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”
Staging criteria
The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.
The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).
“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”
Primary therapy
Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.
“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”
Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.
The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.
Risk-adapted management
Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”
There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).
“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.
Stem cell transplant
“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.
Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.
“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”
Maintenance therapy post transplant
The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.
“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.
Options for relapsed disease
Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.
Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”
A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).
The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.
Investigational agents
Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).
Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.
Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).
“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.
SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?
Diagnostic criteria
The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.
Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).
“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.
This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”
Staging criteria
The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.
The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).
“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”
Primary therapy
Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.
“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”
Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.
The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.
Risk-adapted management
Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”
There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).
“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.
Stem cell transplant
“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.
Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.
“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”
Maintenance therapy post transplant
The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.
“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.
Options for relapsed disease
Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.
Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”
A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).
The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.
Investigational agents
Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).
Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.
Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).
“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.
EXPERT ANALYSIS FROM NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
CCSs have increased risk of autoimmune diseases
Photo by Bill Branson
Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.
CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.
Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing
an autoimmune disease.
Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.
They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.
The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.
The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).
In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.
So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.
SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).
SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).
The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.
The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.
They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.
The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.
Photo by Bill Branson
Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.
CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.
Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing
an autoimmune disease.
Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.
They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.
The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.
The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).
In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.
So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.
SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).
SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).
The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.
The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.
They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.
The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.
Photo by Bill Branson
Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.
CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.
Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing
an autoimmune disease.
Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.
They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.
The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.
The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).
In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.
So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.
SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).
SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).
The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.
The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.
They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.
The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.
ITC 2015: Review IDs features to aid thyroid lymphoma diagnosis
LAKE BUENA VISTA, FLA. – Rapidly enlarging thyroid masses with compressive symptoms may signal thyroid lymphoma, according to findings from a review of cases at the Mayo Clinic.
Radiologically, these masses tend to present as large, unilateral, thyroid-centered masses that are hypoechoic on ultrasound and that expand into adjacent soft tissue, Dr. Anu Sharma reported at the International Thyroid Congress.
The findings are based on a review of 75 patients with biopsy-proven thyroid lymphoma – a relatively rare disease, accounting for between 1% and 5% of all thyroid malignancies, and less than 1% of all lymphomas – who presented to the Mayo Clinic between 2000 and 2014.
“Thyroid lymphoma can sometimes present very similar to anaplastic carcinoma, and we wanted to see if there are any unique identification factors that you can use to increase your suspicion of thyroid lymphoma,” Dr. Sharma of the Mayo Clinic, Rochester, Minn., said.
Indeed, rapid enlargement and compressive symptoms are also common presenting features of anaplastic carcinoma, she said.
Of the 75 cases included in the review – compromising all cases presenting during the study period – 70.7% involved primary thyroid lymphoma. A neck mass was present in 88% of cases, dysphagia in 45%, and hoarseness in 37%.
The typical presentation included a solid, hypoechoic mass with mildly increased vascularity, no internal calcifications, and edge characteristics that ranged from well-defined (80%) to ill-defined (20%). Median tumor volume was 64 cm3, Dr. Sharma said.
This differs from anaplastic carcinoma in that most patients with anaplastic carcinoma have ill-defined edges, she noted.
Another difference between thyroid lymphoma and anaplastic carcinoma as noted in this study involves necrosis; none of the patients in the current study had areas of necrosis, whereas 78% of anaplastic carcinoma patients in another study had areas of necrosis, she explained.
The patients in the current study had a median age of 67 years, although the ages varied widely. About half (50.7%) were men, and 54.7% had a history of Hashimoto’s thyroiditis. Fifty-seven of the patients had an ultrasound before treatment.
The first diagnostic procedure performed was fine needle aspiration (FNA) in 65 subjects, and the FNA biopsies were abnormal in 69% of those, with 42% suggesting a specific lymphoma subtype. The subtype diagnosis was accurate, based on final tissue analysis, in 89% of those.
“While this is quite impressive, all patients who had FNA ended up having further tissue biopsy for subtype confirmation and for treatment, and this is important, because the subtype of the lymphoma is important in determining the type of treatment uses as well as determining prognosis,” she said.
The diagnosis was confirmed by core biopsy in 46.7% of cases, by incisional biopsy in 9.3%, by partial or total thyroidectomy in 25.3%, and by lymph node biopsy in 13.3%; percentages total 94.6% due to downward rounding. Histologic subtypes included diffuse large B-cell lymphoma (DLBCL) in 73.3% of cases, follicular lymphoma in 5.3%, mucosa-associated lymphoid tissue (MALT) in 10.7%, MALT/DLBCL in 2.6%, T-cell lymphoma in 2.6%, and Hodgkin’s lymphoma in 1.3%; percentages total 95.8% rather than 100% due to downward rounding.
In addition to rapid enlargement of a neck mass with compressive symptoms, findings that should raise suspicion of thyroid lymphoma include a history of Hashimoto’s thyroiditis and the ultrasound findings characterized by this study, Dr. Sharma said.
“Once you have that increased suspicion, you should move toward going to core biopsy rather than FNA to save the patient from having two diagnostic steps rather than one,” she concluded.
Dr. Sharma reported having no disclosures.
LAKE BUENA VISTA, FLA. – Rapidly enlarging thyroid masses with compressive symptoms may signal thyroid lymphoma, according to findings from a review of cases at the Mayo Clinic.
Radiologically, these masses tend to present as large, unilateral, thyroid-centered masses that are hypoechoic on ultrasound and that expand into adjacent soft tissue, Dr. Anu Sharma reported at the International Thyroid Congress.
The findings are based on a review of 75 patients with biopsy-proven thyroid lymphoma – a relatively rare disease, accounting for between 1% and 5% of all thyroid malignancies, and less than 1% of all lymphomas – who presented to the Mayo Clinic between 2000 and 2014.
“Thyroid lymphoma can sometimes present very similar to anaplastic carcinoma, and we wanted to see if there are any unique identification factors that you can use to increase your suspicion of thyroid lymphoma,” Dr. Sharma of the Mayo Clinic, Rochester, Minn., said.
Indeed, rapid enlargement and compressive symptoms are also common presenting features of anaplastic carcinoma, she said.
Of the 75 cases included in the review – compromising all cases presenting during the study period – 70.7% involved primary thyroid lymphoma. A neck mass was present in 88% of cases, dysphagia in 45%, and hoarseness in 37%.
The typical presentation included a solid, hypoechoic mass with mildly increased vascularity, no internal calcifications, and edge characteristics that ranged from well-defined (80%) to ill-defined (20%). Median tumor volume was 64 cm3, Dr. Sharma said.
This differs from anaplastic carcinoma in that most patients with anaplastic carcinoma have ill-defined edges, she noted.
Another difference between thyroid lymphoma and anaplastic carcinoma as noted in this study involves necrosis; none of the patients in the current study had areas of necrosis, whereas 78% of anaplastic carcinoma patients in another study had areas of necrosis, she explained.
The patients in the current study had a median age of 67 years, although the ages varied widely. About half (50.7%) were men, and 54.7% had a history of Hashimoto’s thyroiditis. Fifty-seven of the patients had an ultrasound before treatment.
The first diagnostic procedure performed was fine needle aspiration (FNA) in 65 subjects, and the FNA biopsies were abnormal in 69% of those, with 42% suggesting a specific lymphoma subtype. The subtype diagnosis was accurate, based on final tissue analysis, in 89% of those.
“While this is quite impressive, all patients who had FNA ended up having further tissue biopsy for subtype confirmation and for treatment, and this is important, because the subtype of the lymphoma is important in determining the type of treatment uses as well as determining prognosis,” she said.
The diagnosis was confirmed by core biopsy in 46.7% of cases, by incisional biopsy in 9.3%, by partial or total thyroidectomy in 25.3%, and by lymph node biopsy in 13.3%; percentages total 94.6% due to downward rounding. Histologic subtypes included diffuse large B-cell lymphoma (DLBCL) in 73.3% of cases, follicular lymphoma in 5.3%, mucosa-associated lymphoid tissue (MALT) in 10.7%, MALT/DLBCL in 2.6%, T-cell lymphoma in 2.6%, and Hodgkin’s lymphoma in 1.3%; percentages total 95.8% rather than 100% due to downward rounding.
In addition to rapid enlargement of a neck mass with compressive symptoms, findings that should raise suspicion of thyroid lymphoma include a history of Hashimoto’s thyroiditis and the ultrasound findings characterized by this study, Dr. Sharma said.
“Once you have that increased suspicion, you should move toward going to core biopsy rather than FNA to save the patient from having two diagnostic steps rather than one,” she concluded.
Dr. Sharma reported having no disclosures.
LAKE BUENA VISTA, FLA. – Rapidly enlarging thyroid masses with compressive symptoms may signal thyroid lymphoma, according to findings from a review of cases at the Mayo Clinic.
Radiologically, these masses tend to present as large, unilateral, thyroid-centered masses that are hypoechoic on ultrasound and that expand into adjacent soft tissue, Dr. Anu Sharma reported at the International Thyroid Congress.
The findings are based on a review of 75 patients with biopsy-proven thyroid lymphoma – a relatively rare disease, accounting for between 1% and 5% of all thyroid malignancies, and less than 1% of all lymphomas – who presented to the Mayo Clinic between 2000 and 2014.
“Thyroid lymphoma can sometimes present very similar to anaplastic carcinoma, and we wanted to see if there are any unique identification factors that you can use to increase your suspicion of thyroid lymphoma,” Dr. Sharma of the Mayo Clinic, Rochester, Minn., said.
Indeed, rapid enlargement and compressive symptoms are also common presenting features of anaplastic carcinoma, she said.
Of the 75 cases included in the review – compromising all cases presenting during the study period – 70.7% involved primary thyroid lymphoma. A neck mass was present in 88% of cases, dysphagia in 45%, and hoarseness in 37%.
The typical presentation included a solid, hypoechoic mass with mildly increased vascularity, no internal calcifications, and edge characteristics that ranged from well-defined (80%) to ill-defined (20%). Median tumor volume was 64 cm3, Dr. Sharma said.
This differs from anaplastic carcinoma in that most patients with anaplastic carcinoma have ill-defined edges, she noted.
Another difference between thyroid lymphoma and anaplastic carcinoma as noted in this study involves necrosis; none of the patients in the current study had areas of necrosis, whereas 78% of anaplastic carcinoma patients in another study had areas of necrosis, she explained.
The patients in the current study had a median age of 67 years, although the ages varied widely. About half (50.7%) were men, and 54.7% had a history of Hashimoto’s thyroiditis. Fifty-seven of the patients had an ultrasound before treatment.
The first diagnostic procedure performed was fine needle aspiration (FNA) in 65 subjects, and the FNA biopsies were abnormal in 69% of those, with 42% suggesting a specific lymphoma subtype. The subtype diagnosis was accurate, based on final tissue analysis, in 89% of those.
“While this is quite impressive, all patients who had FNA ended up having further tissue biopsy for subtype confirmation and for treatment, and this is important, because the subtype of the lymphoma is important in determining the type of treatment uses as well as determining prognosis,” she said.
The diagnosis was confirmed by core biopsy in 46.7% of cases, by incisional biopsy in 9.3%, by partial or total thyroidectomy in 25.3%, and by lymph node biopsy in 13.3%; percentages total 94.6% due to downward rounding. Histologic subtypes included diffuse large B-cell lymphoma (DLBCL) in 73.3% of cases, follicular lymphoma in 5.3%, mucosa-associated lymphoid tissue (MALT) in 10.7%, MALT/DLBCL in 2.6%, T-cell lymphoma in 2.6%, and Hodgkin’s lymphoma in 1.3%; percentages total 95.8% rather than 100% due to downward rounding.
In addition to rapid enlargement of a neck mass with compressive symptoms, findings that should raise suspicion of thyroid lymphoma include a history of Hashimoto’s thyroiditis and the ultrasound findings characterized by this study, Dr. Sharma said.
“Once you have that increased suspicion, you should move toward going to core biopsy rather than FNA to save the patient from having two diagnostic steps rather than one,” she concluded.
Dr. Sharma reported having no disclosures.
AT ITC 2015
Key clinical point: Rapidly enlarging thyroid masses with compressive symptoms may signal thyroid lymphoma, according to findings from a review of cases at the Mayo Clinic.
Major finding: Typical presentation included a solid, hypoechoic mass with mildly increased vascularity, no internal calcifications, and edge characteristics that ranged from well-defined (80%) to ill-defined (20%).
Data source: A retrospective review of 75 cases.
Disclosures: Dr. Sharma reported having no disclosures.
Drug protects fertility in chemo-treated mice
Photo courtesy of UW Health
The heart medication dexrazoxane can protect fertility and improve survival in female mice receiving the chemotherapeutic agent doxorubicin, according to research published in PLOS ONE.
Dexrazoxane prevented ovarian damage, increased the number of healthy offspring mice had, and prolonged their survival.
If dexrazoxane has the same effects in humans, it could save young lives while also overcoming limitations to fertility treatments currently used during cancer treatment, according to study author Sana Salih, MD, of the University of Wisconsin School of Medicine and Public Health in Madison.
“Fertility preservation following chemotherapy for children and women diagnosed with cancer is a formidable challenge,” Dr Salih said. “For pre-pubescent girls, the only option to prevent chemo-induced ovarian failure is to preserve ovarian tissue by freezing.”
Unfortunately, that is an experimental procedure that requires surgery to harvest and again to re-implant the tissue after cancer treatment. The transplantation carries a small risk of cancer recurrence and provides only a short-term solution.
“The transplanted ovarian tissue can only function for 3 to 7 years,” Dr Salih said.
So she was pleased to discover that pre-administration of dexrazoxane diminished ovarian damage and preserved ovarian function and fertility in mice whose ovaries were exposed to doxorubicin.
“What really surprised us is that a very small dose of dexrazoxane was enough to give full ovarian protection,” Dr Salih said.
Mice treated with dexrazoxane also gave birth to healthier litters, with more pups and higher birth weights than mice that received doxorubicin alone.
In addition, the mice that received dexrazoxane and doxorubicin lived much longer than mice that only received doxorubicin. And mice given only dexrazoxane lived longer than control mice receiving no interventions.
“The [US Food and Drug Administration] currently limits the use of dexrazoxane to adults to protect their hearts from the toxic side effects of chemotherapy,” Dr Salih said. “But these patients are receiving very high doses of dexrazoxane that may actually be contributing to increased toxicity, leading to decreased survival in some patients.”
Dr Salih and her colleagues found they could achieve high mouse survival rates, ovarian protection, and birthing successes using a dose of dexrazoxane 10 times lower than what is used for adult human cardiac protection. Post-mortem studies on the mice showed protection of ovarian, heart, and other cells and tissues.
“This is exciting,” Dr Salih said. “We are now submitting a grant to look at low-dose dexrazoxane protection in nonhuman primates as a stepping stone to clinical translation in pediatric cancer patients.”
Dr Salih has begun studies needed to show that safe doses of dexrazoxane can protect developing primate ovaries. Nonhuman primate ovarian development, cycle time, and gestation are very similar to that of humans.
“My goal is to present data so that physicians can come up with dosage recommendations and safety profiles for early clinical trials in humans,” Dr Salih said. “Up to 6% of young girls with childhood cancers and 50% of women with breast cancer who endure chemotherapy face ovarian failure. We need to give more cancer survivors real hope that they can conceive a healthy child.”
Photo courtesy of UW Health
The heart medication dexrazoxane can protect fertility and improve survival in female mice receiving the chemotherapeutic agent doxorubicin, according to research published in PLOS ONE.
Dexrazoxane prevented ovarian damage, increased the number of healthy offspring mice had, and prolonged their survival.
If dexrazoxane has the same effects in humans, it could save young lives while also overcoming limitations to fertility treatments currently used during cancer treatment, according to study author Sana Salih, MD, of the University of Wisconsin School of Medicine and Public Health in Madison.
“Fertility preservation following chemotherapy for children and women diagnosed with cancer is a formidable challenge,” Dr Salih said. “For pre-pubescent girls, the only option to prevent chemo-induced ovarian failure is to preserve ovarian tissue by freezing.”
Unfortunately, that is an experimental procedure that requires surgery to harvest and again to re-implant the tissue after cancer treatment. The transplantation carries a small risk of cancer recurrence and provides only a short-term solution.
“The transplanted ovarian tissue can only function for 3 to 7 years,” Dr Salih said.
So she was pleased to discover that pre-administration of dexrazoxane diminished ovarian damage and preserved ovarian function and fertility in mice whose ovaries were exposed to doxorubicin.
“What really surprised us is that a very small dose of dexrazoxane was enough to give full ovarian protection,” Dr Salih said.
Mice treated with dexrazoxane also gave birth to healthier litters, with more pups and higher birth weights than mice that received doxorubicin alone.
In addition, the mice that received dexrazoxane and doxorubicin lived much longer than mice that only received doxorubicin. And mice given only dexrazoxane lived longer than control mice receiving no interventions.
“The [US Food and Drug Administration] currently limits the use of dexrazoxane to adults to protect their hearts from the toxic side effects of chemotherapy,” Dr Salih said. “But these patients are receiving very high doses of dexrazoxane that may actually be contributing to increased toxicity, leading to decreased survival in some patients.”
Dr Salih and her colleagues found they could achieve high mouse survival rates, ovarian protection, and birthing successes using a dose of dexrazoxane 10 times lower than what is used for adult human cardiac protection. Post-mortem studies on the mice showed protection of ovarian, heart, and other cells and tissues.
“This is exciting,” Dr Salih said. “We are now submitting a grant to look at low-dose dexrazoxane protection in nonhuman primates as a stepping stone to clinical translation in pediatric cancer patients.”
Dr Salih has begun studies needed to show that safe doses of dexrazoxane can protect developing primate ovaries. Nonhuman primate ovarian development, cycle time, and gestation are very similar to that of humans.
“My goal is to present data so that physicians can come up with dosage recommendations and safety profiles for early clinical trials in humans,” Dr Salih said. “Up to 6% of young girls with childhood cancers and 50% of women with breast cancer who endure chemotherapy face ovarian failure. We need to give more cancer survivors real hope that they can conceive a healthy child.”
Photo courtesy of UW Health
The heart medication dexrazoxane can protect fertility and improve survival in female mice receiving the chemotherapeutic agent doxorubicin, according to research published in PLOS ONE.
Dexrazoxane prevented ovarian damage, increased the number of healthy offspring mice had, and prolonged their survival.
If dexrazoxane has the same effects in humans, it could save young lives while also overcoming limitations to fertility treatments currently used during cancer treatment, according to study author Sana Salih, MD, of the University of Wisconsin School of Medicine and Public Health in Madison.
“Fertility preservation following chemotherapy for children and women diagnosed with cancer is a formidable challenge,” Dr Salih said. “For pre-pubescent girls, the only option to prevent chemo-induced ovarian failure is to preserve ovarian tissue by freezing.”
Unfortunately, that is an experimental procedure that requires surgery to harvest and again to re-implant the tissue after cancer treatment. The transplantation carries a small risk of cancer recurrence and provides only a short-term solution.
“The transplanted ovarian tissue can only function for 3 to 7 years,” Dr Salih said.
So she was pleased to discover that pre-administration of dexrazoxane diminished ovarian damage and preserved ovarian function and fertility in mice whose ovaries were exposed to doxorubicin.
“What really surprised us is that a very small dose of dexrazoxane was enough to give full ovarian protection,” Dr Salih said.
Mice treated with dexrazoxane also gave birth to healthier litters, with more pups and higher birth weights than mice that received doxorubicin alone.
In addition, the mice that received dexrazoxane and doxorubicin lived much longer than mice that only received doxorubicin. And mice given only dexrazoxane lived longer than control mice receiving no interventions.
“The [US Food and Drug Administration] currently limits the use of dexrazoxane to adults to protect their hearts from the toxic side effects of chemotherapy,” Dr Salih said. “But these patients are receiving very high doses of dexrazoxane that may actually be contributing to increased toxicity, leading to decreased survival in some patients.”
Dr Salih and her colleagues found they could achieve high mouse survival rates, ovarian protection, and birthing successes using a dose of dexrazoxane 10 times lower than what is used for adult human cardiac protection. Post-mortem studies on the mice showed protection of ovarian, heart, and other cells and tissues.
“This is exciting,” Dr Salih said. “We are now submitting a grant to look at low-dose dexrazoxane protection in nonhuman primates as a stepping stone to clinical translation in pediatric cancer patients.”
Dr Salih has begun studies needed to show that safe doses of dexrazoxane can protect developing primate ovaries. Nonhuman primate ovarian development, cycle time, and gestation are very similar to that of humans.
“My goal is to present data so that physicians can come up with dosage recommendations and safety profiles for early clinical trials in humans,” Dr Salih said. “Up to 6% of young girls with childhood cancers and 50% of women with breast cancer who endure chemotherapy face ovarian failure. We need to give more cancer survivors real hope that they can conceive a healthy child.”
FDA grants drug priority review as FL therapy
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
The US Food and Drug Administration (FDA) has accepted for priority review a supplemental biologics license application for obinutuzumab (Gazyva) to treat patients with follicular lymphoma (FL) who have relapsed after or are refractory to a rituximab-containing regimen.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells.
The drug is already FDA-approved for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia.
A priority review designation is granted to drugs thought to have the potential to provide significant improvements in the treatment, prevention, or diagnosis of a disease.
The designation means the FDA’s goal is to take action on a drug application within 6 months, compared to 10 months under standard review.
The FDA has accepted the supplemental application for obinutuzumab in FL based on results of the phase 3 GADOLIN study.
Interim results from this trial were presented at the 2015 ASCO Annual Meeting (abstract LBA8502). Additional data are scheduled to be presented at the 2015 ASH Annual Meeting in December (abstracts 1532 and 3978).
GADOLIN study
The trial included 413 patients with rituximab-refractory non-Hodgkin lymphoma, including FL, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia.
The patients were randomized to receive bendamustine alone (control arm) or a combination of bendamustine and obinutuzumab (OB) followed by obinutuzumab maintenance (every 2 months for 2 years or until progression).
In all, 156 patients completed induction in the OB arm, as did 129 patients in the control arm. Thirty-six patients completed maintenance with obinutuzumab, and 46 were still receiving maintenance at the time of the interim analysis.
According to an independent radiology facility, 69.2% of patients in the OB arm had responded to treatment at the end of induction, as had 63% of the control arm. The best overall response by the 12-month mark was 78.7% and 76.6%, respectively.
According to the radiology facility, the median progression-free survival (PFS) had not been reached in the OB arm at a median follow-up of 21 months. In the control arm, the median PFS was 14.9 months (P<0.0001).
According to investigators, the median PFS was 29.2 months and 14 months, respectively (P<0.0001).
The median overall survival had not been reached in either arm (P=0.4017). Thirty-four patients (18%) in the OB arm died, as did 41 (20%) in the control arm.
About 99% of patients in the OB arm experienced at least 1 adverse event (AE), as did 98% of patients in the control arm. Severe AEs occurred in 38.1% and 32.8% of patients, respectively, and grade 3/4 AEs occurred in 67% and 62.1%, respectively.
AEs leading to treatment withdrawal occurred in 18% and 15.7% of patients, respectively. And AEs leading to death occurred in 6.2% and 6.1%, respectively.
Breast cancer drug may also work in MCL, myeloma
showing multiple myeloma
NEW YORK—Targeting the cell cycle with cyclin-dependent kinase (CDK) inhibitors may be an effective strategy to treat lymphoma and myeloma, according to a presentation at Lymphoma & Myeloma 2015.
Palbociclib, an inhibitor of CDK4 and CDK6, received accelerated approval from the US Food and Drug Administration to treat advanced breast cancer.
Now, it is showing promise in mantle cell lymphoma (MCL) and multiple myeloma (MM) as well.
CDK family members are important regulators of cell-cycle progression. Dysregulation of CDK4 and CDK6 is one of the most common genomic aberrations in human cancer, including myeloma, lymphoma, leukemia, breast cancer, metastatic lung adenocarcinoma, and glioblastoma.
MCL, which accounts for 6% of non-Hodgkin lymphomas, has an overall poor prognosis, with most patients eventually becoming resistant to drugs. MCL expresses cyclin D1 as a consequence of the t(11;14) translocation and overexpresses CDK4.
“So this is a perfect disease for the development of targeting CDK4,” said Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, New York, who presented this information at the meeting.
CDK4 and CDK6 signaling occur at the beginning of the cell cycle and bring the cell from the resting state into early G2.
“If we could control that,” Dr Chen-Kiang explained, “we reasoned that we could control the DNA replication and cell division” and increase tumor-specific cell death.
Palbociclib (PD0332991; Ibrance), an orally bioavailable, selective CDK4/CDK6 inhibitor, induces early G1 arrest. It is reversible and low in toxicity, according to Dr Chen-Kiang.
Currently, it’s being tested in phase 1 trials in MCL with ibrutinib and in MM with lenalidomide-dexamethasone. Phase 1 trials have also been completed at Cornell with palbociclib as a single agent in MCL, with bortezomib in MCL, and with bortezomib-dexamethasone in MM.
Palbociclib in MCL
Investigators conducted a phase 1, single-agent study of palbociclib to determine whether it could be tolerated in humans.
“CDK4/CDK6 is expressed in every cell,” Dr Chen-Kiang noted, “and you are targeting 2 proteins that are needed for every cell.”
Seventeen patients received 125 mg of palbociclib per day for 21 of 28 days.
“And surprisingly,” Dr Chen-Kiang said, “it’s very well tolerated.”
The most common adverse events were neutropenia, fatigue, and diarrhea.
“And even more surprising,” she added “is that we actually had a complete response (CR) [and] 2 partial responses, in addition to 5 stable diseases.”
The investigators hypothesized that blocking the cell cycle in G1 creates an imbalance in gene expression.
They then conducted a trial of palbociclib plus bortezomib in 17 patients with recurrent MCL. Patients received palbociclib on days 1–12 and low-dose bortezomib on days 8, 11, 15, and 18.
The palbociclib dose ranged from 75 mg to 125 mg, and the bortezomib dose ranged from 1.0 mg/m2 to 1.3 mg/m2.
Eleven patients experienced a reduction in tumor volume, the majority at the 125-mg dose.
Using whole-exome and whole-transcriptome sequencing of serial biopsies, investigators determined that CDK4/CDK6 inhibition induces early G1 arrest in MCL cells in both responders and non-responders initially.
This may occur because the cell cycle is perfectly controlled, and there’s no mutation in CDK4 in any of the patients.
Investigators attempted to identify genes that could differentiate sensitivity from resistance to CDK4 targeting. They found that a very small number of genes display opposite regulation in prolonged early G1 arrest in responding versus non-responding patients.
These genes are involved in metabolism and redox homeostasis and include a gene called PIK3IP1, an inhibitor of PI3 kinase.
In earlier analyses, the investigators had discovered a relapse-specific C481S mutation at the ibrutinib binding site of Bruton’s tyrosine kinase (BTK) in MCL cells. The mutation occurred at progression following a durable response to ibrutinib.
The mutation is absent, however, in patients with transient ibrutinib responses or in primary resistance.
The team observed that early cell-cycle arrest by CDK4 inhibition reprograms MCL cells for killing by ibrutinib. This occurs through inhibition of BTK and AKT (protein kinase B).
So the investigators undertook to study palbociclib in combination with ibrutinib, “with extraordinary results,” Dr Chen-Kiang said.
The trial is ongoing and, at the moment, has a 60% CR rate with durable responses.
“We’re very happy with this,” Dr Chen-Kiang said.
Palbociclib in MM
In addition to the phase 1/2 study of palbociclib with bortezomib and dexamethasone, investigators are also pursuing palbociclib in combination with lenalidomide and dexamethasone, which Dr Chen-Kiang briefly elaborated upon.
Lenalidomide rarely produces a complete remission on its own, she explained, so the team decided to study palbociclib in combination with immunomodulatory drugs in MM (NCT02030483).
The strategy is to prime the cell cycle with palbociclib and then use lenalidomide and dexamethasone to increase efficacy.
Twenty patients have received this combination thus far, and investigators found that palbociclib enhances the activity of lenalidomide in the killing of primary bone marrow myeloma cells.
Lenalidomide reduces the MEIS2/CRBN ratio in these cells. The drug changes the ratio, reduces the blocker, and allows the CRBN to work.
“The whole principle here is to control the gene coupling to the cell cycle and induce imbalance in gene expression,” Dr Chen-Kiang said. “And this weakens the tumor cells.”
Two-thirds of the samples respond to palboclib, she said, and those patients go on to be treated with lenalidomide or pomalidomide.
One third will not respond, but their in vivo clinical response and the ex vivo responders’ purified cells mimic one another.
“Now, this is very exciting to us,” she said.
The combination study with lenalidomide and dexamethasone is currently underway.
Palbociclib is being developed by Pfizer.
showing multiple myeloma
NEW YORK—Targeting the cell cycle with cyclin-dependent kinase (CDK) inhibitors may be an effective strategy to treat lymphoma and myeloma, according to a presentation at Lymphoma & Myeloma 2015.
Palbociclib, an inhibitor of CDK4 and CDK6, received accelerated approval from the US Food and Drug Administration to treat advanced breast cancer.
Now, it is showing promise in mantle cell lymphoma (MCL) and multiple myeloma (MM) as well.
CDK family members are important regulators of cell-cycle progression. Dysregulation of CDK4 and CDK6 is one of the most common genomic aberrations in human cancer, including myeloma, lymphoma, leukemia, breast cancer, metastatic lung adenocarcinoma, and glioblastoma.
MCL, which accounts for 6% of non-Hodgkin lymphomas, has an overall poor prognosis, with most patients eventually becoming resistant to drugs. MCL expresses cyclin D1 as a consequence of the t(11;14) translocation and overexpresses CDK4.
“So this is a perfect disease for the development of targeting CDK4,” said Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, New York, who presented this information at the meeting.
CDK4 and CDK6 signaling occur at the beginning of the cell cycle and bring the cell from the resting state into early G2.
“If we could control that,” Dr Chen-Kiang explained, “we reasoned that we could control the DNA replication and cell division” and increase tumor-specific cell death.
Palbociclib (PD0332991; Ibrance), an orally bioavailable, selective CDK4/CDK6 inhibitor, induces early G1 arrest. It is reversible and low in toxicity, according to Dr Chen-Kiang.
Currently, it’s being tested in phase 1 trials in MCL with ibrutinib and in MM with lenalidomide-dexamethasone. Phase 1 trials have also been completed at Cornell with palbociclib as a single agent in MCL, with bortezomib in MCL, and with bortezomib-dexamethasone in MM.
Palbociclib in MCL
Investigators conducted a phase 1, single-agent study of palbociclib to determine whether it could be tolerated in humans.
“CDK4/CDK6 is expressed in every cell,” Dr Chen-Kiang noted, “and you are targeting 2 proteins that are needed for every cell.”
Seventeen patients received 125 mg of palbociclib per day for 21 of 28 days.
“And surprisingly,” Dr Chen-Kiang said, “it’s very well tolerated.”
The most common adverse events were neutropenia, fatigue, and diarrhea.
“And even more surprising,” she added “is that we actually had a complete response (CR) [and] 2 partial responses, in addition to 5 stable diseases.”
The investigators hypothesized that blocking the cell cycle in G1 creates an imbalance in gene expression.
They then conducted a trial of palbociclib plus bortezomib in 17 patients with recurrent MCL. Patients received palbociclib on days 1–12 and low-dose bortezomib on days 8, 11, 15, and 18.
The palbociclib dose ranged from 75 mg to 125 mg, and the bortezomib dose ranged from 1.0 mg/m2 to 1.3 mg/m2.
Eleven patients experienced a reduction in tumor volume, the majority at the 125-mg dose.
Using whole-exome and whole-transcriptome sequencing of serial biopsies, investigators determined that CDK4/CDK6 inhibition induces early G1 arrest in MCL cells in both responders and non-responders initially.
This may occur because the cell cycle is perfectly controlled, and there’s no mutation in CDK4 in any of the patients.
Investigators attempted to identify genes that could differentiate sensitivity from resistance to CDK4 targeting. They found that a very small number of genes display opposite regulation in prolonged early G1 arrest in responding versus non-responding patients.
These genes are involved in metabolism and redox homeostasis and include a gene called PIK3IP1, an inhibitor of PI3 kinase.
In earlier analyses, the investigators had discovered a relapse-specific C481S mutation at the ibrutinib binding site of Bruton’s tyrosine kinase (BTK) in MCL cells. The mutation occurred at progression following a durable response to ibrutinib.
The mutation is absent, however, in patients with transient ibrutinib responses or in primary resistance.
The team observed that early cell-cycle arrest by CDK4 inhibition reprograms MCL cells for killing by ibrutinib. This occurs through inhibition of BTK and AKT (protein kinase B).
So the investigators undertook to study palbociclib in combination with ibrutinib, “with extraordinary results,” Dr Chen-Kiang said.
The trial is ongoing and, at the moment, has a 60% CR rate with durable responses.
“We’re very happy with this,” Dr Chen-Kiang said.
Palbociclib in MM
In addition to the phase 1/2 study of palbociclib with bortezomib and dexamethasone, investigators are also pursuing palbociclib in combination with lenalidomide and dexamethasone, which Dr Chen-Kiang briefly elaborated upon.
Lenalidomide rarely produces a complete remission on its own, she explained, so the team decided to study palbociclib in combination with immunomodulatory drugs in MM (NCT02030483).
The strategy is to prime the cell cycle with palbociclib and then use lenalidomide and dexamethasone to increase efficacy.
Twenty patients have received this combination thus far, and investigators found that palbociclib enhances the activity of lenalidomide in the killing of primary bone marrow myeloma cells.
Lenalidomide reduces the MEIS2/CRBN ratio in these cells. The drug changes the ratio, reduces the blocker, and allows the CRBN to work.
“The whole principle here is to control the gene coupling to the cell cycle and induce imbalance in gene expression,” Dr Chen-Kiang said. “And this weakens the tumor cells.”
Two-thirds of the samples respond to palboclib, she said, and those patients go on to be treated with lenalidomide or pomalidomide.
One third will not respond, but their in vivo clinical response and the ex vivo responders’ purified cells mimic one another.
“Now, this is very exciting to us,” she said.
The combination study with lenalidomide and dexamethasone is currently underway.
Palbociclib is being developed by Pfizer.
showing multiple myeloma
NEW YORK—Targeting the cell cycle with cyclin-dependent kinase (CDK) inhibitors may be an effective strategy to treat lymphoma and myeloma, according to a presentation at Lymphoma & Myeloma 2015.
Palbociclib, an inhibitor of CDK4 and CDK6, received accelerated approval from the US Food and Drug Administration to treat advanced breast cancer.
Now, it is showing promise in mantle cell lymphoma (MCL) and multiple myeloma (MM) as well.
CDK family members are important regulators of cell-cycle progression. Dysregulation of CDK4 and CDK6 is one of the most common genomic aberrations in human cancer, including myeloma, lymphoma, leukemia, breast cancer, metastatic lung adenocarcinoma, and glioblastoma.
MCL, which accounts for 6% of non-Hodgkin lymphomas, has an overall poor prognosis, with most patients eventually becoming resistant to drugs. MCL expresses cyclin D1 as a consequence of the t(11;14) translocation and overexpresses CDK4.
“So this is a perfect disease for the development of targeting CDK4,” said Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, New York, who presented this information at the meeting.
CDK4 and CDK6 signaling occur at the beginning of the cell cycle and bring the cell from the resting state into early G2.
“If we could control that,” Dr Chen-Kiang explained, “we reasoned that we could control the DNA replication and cell division” and increase tumor-specific cell death.
Palbociclib (PD0332991; Ibrance), an orally bioavailable, selective CDK4/CDK6 inhibitor, induces early G1 arrest. It is reversible and low in toxicity, according to Dr Chen-Kiang.
Currently, it’s being tested in phase 1 trials in MCL with ibrutinib and in MM with lenalidomide-dexamethasone. Phase 1 trials have also been completed at Cornell with palbociclib as a single agent in MCL, with bortezomib in MCL, and with bortezomib-dexamethasone in MM.
Palbociclib in MCL
Investigators conducted a phase 1, single-agent study of palbociclib to determine whether it could be tolerated in humans.
“CDK4/CDK6 is expressed in every cell,” Dr Chen-Kiang noted, “and you are targeting 2 proteins that are needed for every cell.”
Seventeen patients received 125 mg of palbociclib per day for 21 of 28 days.
“And surprisingly,” Dr Chen-Kiang said, “it’s very well tolerated.”
The most common adverse events were neutropenia, fatigue, and diarrhea.
“And even more surprising,” she added “is that we actually had a complete response (CR) [and] 2 partial responses, in addition to 5 stable diseases.”
The investigators hypothesized that blocking the cell cycle in G1 creates an imbalance in gene expression.
They then conducted a trial of palbociclib plus bortezomib in 17 patients with recurrent MCL. Patients received palbociclib on days 1–12 and low-dose bortezomib on days 8, 11, 15, and 18.
The palbociclib dose ranged from 75 mg to 125 mg, and the bortezomib dose ranged from 1.0 mg/m2 to 1.3 mg/m2.
Eleven patients experienced a reduction in tumor volume, the majority at the 125-mg dose.
Using whole-exome and whole-transcriptome sequencing of serial biopsies, investigators determined that CDK4/CDK6 inhibition induces early G1 arrest in MCL cells in both responders and non-responders initially.
This may occur because the cell cycle is perfectly controlled, and there’s no mutation in CDK4 in any of the patients.
Investigators attempted to identify genes that could differentiate sensitivity from resistance to CDK4 targeting. They found that a very small number of genes display opposite regulation in prolonged early G1 arrest in responding versus non-responding patients.
These genes are involved in metabolism and redox homeostasis and include a gene called PIK3IP1, an inhibitor of PI3 kinase.
In earlier analyses, the investigators had discovered a relapse-specific C481S mutation at the ibrutinib binding site of Bruton’s tyrosine kinase (BTK) in MCL cells. The mutation occurred at progression following a durable response to ibrutinib.
The mutation is absent, however, in patients with transient ibrutinib responses or in primary resistance.
The team observed that early cell-cycle arrest by CDK4 inhibition reprograms MCL cells for killing by ibrutinib. This occurs through inhibition of BTK and AKT (protein kinase B).
So the investigators undertook to study palbociclib in combination with ibrutinib, “with extraordinary results,” Dr Chen-Kiang said.
The trial is ongoing and, at the moment, has a 60% CR rate with durable responses.
“We’re very happy with this,” Dr Chen-Kiang said.
Palbociclib in MM
In addition to the phase 1/2 study of palbociclib with bortezomib and dexamethasone, investigators are also pursuing palbociclib in combination with lenalidomide and dexamethasone, which Dr Chen-Kiang briefly elaborated upon.
Lenalidomide rarely produces a complete remission on its own, she explained, so the team decided to study palbociclib in combination with immunomodulatory drugs in MM (NCT02030483).
The strategy is to prime the cell cycle with palbociclib and then use lenalidomide and dexamethasone to increase efficacy.
Twenty patients have received this combination thus far, and investigators found that palbociclib enhances the activity of lenalidomide in the killing of primary bone marrow myeloma cells.
Lenalidomide reduces the MEIS2/CRBN ratio in these cells. The drug changes the ratio, reduces the blocker, and allows the CRBN to work.
“The whole principle here is to control the gene coupling to the cell cycle and induce imbalance in gene expression,” Dr Chen-Kiang said. “And this weakens the tumor cells.”
Two-thirds of the samples respond to palboclib, she said, and those patients go on to be treated with lenalidomide or pomalidomide.
One third will not respond, but their in vivo clinical response and the ex vivo responders’ purified cells mimic one another.
“Now, this is very exciting to us,” she said.
The combination study with lenalidomide and dexamethasone is currently underway.
Palbociclib is being developed by Pfizer.
New therapies finding their place in management of follicular lymphoma
SAN FRANCISCO – A variety of emerging therapies are being incorporated into the management of follicular lymphoma, which is typically a long-term endeavor requiring strategic use of multiple treatments, Dr. Andrew D. Zelenetz said at the National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies.
“Follicular lymphoma is a disease of paradox. The reality is that overall survival is excellent, but patients are not going to be able to do that with one treatment; they are going to get a series of treatments,” he said. “Survival is the sum of your exposures to treatment, time on active therapy, time in remission, and actually time with relapse not needing treatment.”
Risk stratification
Overall survival for patients with follicular lymphoma diagnosed today and treated with modern therapy is only slightly inferior to that for age-matched controls, noted Dr. Zelenetz of the department of medicine at Memorial Sloan-Kettering Cancer Center and professor of medicine at Cornell University, both in New York.
But patients who are faring poorly at 12 months (American Society of Hematology [ASH] 2014, Abstract 1664) or at 24 months (J Clin Oncol. 2015;33[23]:2516-22) into care have a much worse prognosis. “This shows the importance of identifying those patients with poor biology, and [the question of] whether we can identify them without treating them first and having them progress,” he said.
Hematologists have historically looked to the Follicular Lymphoma International Prognostic Index (FLIPI) to estimate outcome. “The FLIPI clearly works; it’s an important clinical tool. But the FLIPI high-risk patients are still identifying more than those very high-risk patients,” he said.
Therefore, a clinicogenomic risk model was developed that incorporates seven mutations having poor prognostic impact, the m7-FLIPI (Lancet Oncol. 2015;16[9]:1111-22). Adding the mutations split the previously defined high-risk patients into a group with a prognosis similar to that of low-risk patients and a small group with a very poor prognosis.
“This actually represents something very close to the 20% of patients that we think have bad biology,” Dr. Zelenetz noted. “There will be some additional data at ASH looking at this exact question, because the holy grail is to know when you diagnose someone if they are in that bad-risk group because those are the patients you want to do novel clinical trials on. If your overall survival is equivalent to the general population, it’s going to be hard to ever prove an overall survival advantage for an intervention in an unselected group of patients.”
Advanced-stage disease with low tumor bulk
For patients who have advanced-stage follicular lymphoma but with low tumor bulk, the NCCN endorses a modification of criteria developed by the Follicular Lymphoma Study Group (GELF) in deciding when to start treatment (J Clin Oncol. 1998;16[7]:2332-8).
Roughly a fifth of patients who are eligible for and managed with a watch-and-wait approach will not need chemotherapy or die of their disease in the next 10 years (Lancet. 2003;362[9383]:516-22). Furthermore, this strategy nets a median delay in the need for chemotherapy of 2.6 years.
Compared with observation, treatment with the anti-CD20 antibody rituximab (Rituxan) improves progression-free survival but not overall survival in this setting (ASH 2010, Abstract 6). “Though in selected patients, rituximab may be appropriate as initial treatment for the observable patient, I would argue for the observable patient with no survival disadvantage, the standard of care remains observation,” Dr. Zelenetz said.
Advanced-stage disease requiring treatment
A meta-analysis has shown a clear survival benefit from adding rituximab to chemotherapy (R-chemo) in patients with advanced follicular lymphoma who need treatment (J Natl Cancer Inst. 2007;99[9]:706-14). “Based on the results, it is the standard of care to add rituximab to a chemotherapy backbone, but the optimum R-chemo actually remains undefined and would be customized to the individual clinical situation,” he commented.
A variety of emerging agents are being tested in this setting. Among the subset of patients with untreated follicular lymphoma in a single-center trial, the combination of rituximab with the immunomodulator lenalidomide (Revlimid) yielded an overall response rate of 98% and a complete response rate of 87%, as well as excellent progression-free and overall survival (Lancet Oncol. 2014;15[12]:1311-8). The main grade 3 or 4 toxicity was neutropenia, seen in 35% of all patients studied. Efficacy results were much the same in a multicenter trial (International Conference on Malignant Lymphoma [ICML] 2013, Abstract 63).
This combination is now being tested as front-line therapy for follicular lymphoma in the RELEVANCE (Rituximab and Lenalidomide Versus Any Chemotherapy) phase III trial. “The trial is now done, but we don’t have results, and we won’t have results until 2019, so don’t hold your breath,” Dr. Zelenetz commented. “That’s because this was an unselected trial; we took all patients, all comers. And if you don’t try to identify bad-risk patients, you actually have to do very large trials, and the effect size is relatively small.”
Relapsed and refractory disease
“Many times when patients with follicular lymphoma relapse, they are immediately started on treatment. It’s not necessary and probably in most cases not appropriate. If patients are asymptomatic and have a low tumor burden, they can have a second and a third and even a fourth period of observation, where they don’t need active treatment,” he said. “So I would encourage you to …wait until they actually meet GELF criteria again.”
A key question in this setting is whether patients previously given rituximab can derive benefit from an alternative anti-CD20 antibody. Taking on this question, the GADOLIN trial tested the addition of obinutuzumab (induction plus maintenance) to bendamustine among patients with rituximab-refractory disease (American Society of Clinical Oncology [ASCO] 2015, Abstract LBA8502; ICML 2015, Abstract 123).
Toxicities were generally similar by arm, except for a higher rate of infusion-related reactions with obinutuzumab. The overall response rates were comparable for the two arms, but progression-free survival was better with the combination (median event-free survival, not reached, vs. 14.9 months; hazard ratio, 0.55), and there was a trend for overall survival.
“These curves start separating after 6 months, and 6 months is the time of chemotherapy,” Dr. Zelenetz noted. “So I would argue from these data that the obinutuzumab didn’t add very much to the bendamustine backbone, but actually the obinutuzumab maintenance was effective even in rituximab-refractory patients.”
The combination of lenalidomide and rituximab has been compared with lenalidomide alone in patients with relapsed follicular lymphoma (ASCO 2012, Abstract 8000). The results showed a trend toward better median event-free survival with the combination (2.0 vs. 1.2 years; hazard ratio, 1.9; P = .061) but not overall survival.
In a phase II trial, idelalisib (Zydelig) was tested among patients with indolent non-Hodgkin lymphomas (60% with follicular lymphoma) that were refractory to both rituximab and an alkylator (N Engl J Med. 2014;370:1008-18). Noteworthy grade 3 or worse toxicities included pneumonia and transaminase elevations. The overall response rate was 57%, and the complete response rate was 6%; median progression-free survival was 11 months.
“Idelalisib can be safely combined with other agents including rituximab and bendamustine,” Dr. Zelenetz added (ASH 2014, Abstract 3063). “Interestingly, the overall response seems to be a little higher when you combine it, but it doesn’t seem to matter which drug you combine it with – rituximab, bendamustine, or [both] – you get good overall responses,” ranging from 71% to 85%.
The BCL-2 inhibitor venetoclax (formerly ABT-199/GDC-199) has been tested in non-Hodgkin lymphomas, where it has not been associated with the life-threatening tumor lysis syndrome seen in some other hematologic malignancies (European Hematology Association [EHA] 2015, Davis et al). It yielded an overall response rate of 31% in patients with relatively refractory follicular lymphoma. “This will lead to additional studies in this area,” he predicted.
Finally, nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, has been evaluated in a phase I study in relapsed or refractory hematologic malignancies, where it was well tolerated (ASH 2014, Abstract 291). Among the small subset of patients with follicular lymphoma, the overall response rate was 40%, prompting initiation of more trials.
Although chimeric antigen receptor (CAR) T-cell therapy is showing promise in various malignancies, Dr. Zelenetz said that other options are probably better avenues for research in follicular lymphoma at present.
“I’m much more interested in the tools that we have now, between the checkpoint inhibitors, the T-cell activators, and the bispecific monoclonal antibodies. I think I can [apply these therapies] with less money for probably less toxicity without the complexity of having to make a customized drug for the patient,” he said. “So I’m not very enthusiastic about CAR T cells in follicular lymphoma.”
SAN FRANCISCO – A variety of emerging therapies are being incorporated into the management of follicular lymphoma, which is typically a long-term endeavor requiring strategic use of multiple treatments, Dr. Andrew D. Zelenetz said at the National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies.
“Follicular lymphoma is a disease of paradox. The reality is that overall survival is excellent, but patients are not going to be able to do that with one treatment; they are going to get a series of treatments,” he said. “Survival is the sum of your exposures to treatment, time on active therapy, time in remission, and actually time with relapse not needing treatment.”
Risk stratification
Overall survival for patients with follicular lymphoma diagnosed today and treated with modern therapy is only slightly inferior to that for age-matched controls, noted Dr. Zelenetz of the department of medicine at Memorial Sloan-Kettering Cancer Center and professor of medicine at Cornell University, both in New York.
But patients who are faring poorly at 12 months (American Society of Hematology [ASH] 2014, Abstract 1664) or at 24 months (J Clin Oncol. 2015;33[23]:2516-22) into care have a much worse prognosis. “This shows the importance of identifying those patients with poor biology, and [the question of] whether we can identify them without treating them first and having them progress,” he said.
Hematologists have historically looked to the Follicular Lymphoma International Prognostic Index (FLIPI) to estimate outcome. “The FLIPI clearly works; it’s an important clinical tool. But the FLIPI high-risk patients are still identifying more than those very high-risk patients,” he said.
Therefore, a clinicogenomic risk model was developed that incorporates seven mutations having poor prognostic impact, the m7-FLIPI (Lancet Oncol. 2015;16[9]:1111-22). Adding the mutations split the previously defined high-risk patients into a group with a prognosis similar to that of low-risk patients and a small group with a very poor prognosis.
“This actually represents something very close to the 20% of patients that we think have bad biology,” Dr. Zelenetz noted. “There will be some additional data at ASH looking at this exact question, because the holy grail is to know when you diagnose someone if they are in that bad-risk group because those are the patients you want to do novel clinical trials on. If your overall survival is equivalent to the general population, it’s going to be hard to ever prove an overall survival advantage for an intervention in an unselected group of patients.”
Advanced-stage disease with low tumor bulk
For patients who have advanced-stage follicular lymphoma but with low tumor bulk, the NCCN endorses a modification of criteria developed by the Follicular Lymphoma Study Group (GELF) in deciding when to start treatment (J Clin Oncol. 1998;16[7]:2332-8).
Roughly a fifth of patients who are eligible for and managed with a watch-and-wait approach will not need chemotherapy or die of their disease in the next 10 years (Lancet. 2003;362[9383]:516-22). Furthermore, this strategy nets a median delay in the need for chemotherapy of 2.6 years.
Compared with observation, treatment with the anti-CD20 antibody rituximab (Rituxan) improves progression-free survival but not overall survival in this setting (ASH 2010, Abstract 6). “Though in selected patients, rituximab may be appropriate as initial treatment for the observable patient, I would argue for the observable patient with no survival disadvantage, the standard of care remains observation,” Dr. Zelenetz said.
Advanced-stage disease requiring treatment
A meta-analysis has shown a clear survival benefit from adding rituximab to chemotherapy (R-chemo) in patients with advanced follicular lymphoma who need treatment (J Natl Cancer Inst. 2007;99[9]:706-14). “Based on the results, it is the standard of care to add rituximab to a chemotherapy backbone, but the optimum R-chemo actually remains undefined and would be customized to the individual clinical situation,” he commented.
A variety of emerging agents are being tested in this setting. Among the subset of patients with untreated follicular lymphoma in a single-center trial, the combination of rituximab with the immunomodulator lenalidomide (Revlimid) yielded an overall response rate of 98% and a complete response rate of 87%, as well as excellent progression-free and overall survival (Lancet Oncol. 2014;15[12]:1311-8). The main grade 3 or 4 toxicity was neutropenia, seen in 35% of all patients studied. Efficacy results were much the same in a multicenter trial (International Conference on Malignant Lymphoma [ICML] 2013, Abstract 63).
This combination is now being tested as front-line therapy for follicular lymphoma in the RELEVANCE (Rituximab and Lenalidomide Versus Any Chemotherapy) phase III trial. “The trial is now done, but we don’t have results, and we won’t have results until 2019, so don’t hold your breath,” Dr. Zelenetz commented. “That’s because this was an unselected trial; we took all patients, all comers. And if you don’t try to identify bad-risk patients, you actually have to do very large trials, and the effect size is relatively small.”
Relapsed and refractory disease
“Many times when patients with follicular lymphoma relapse, they are immediately started on treatment. It’s not necessary and probably in most cases not appropriate. If patients are asymptomatic and have a low tumor burden, they can have a second and a third and even a fourth period of observation, where they don’t need active treatment,” he said. “So I would encourage you to …wait until they actually meet GELF criteria again.”
A key question in this setting is whether patients previously given rituximab can derive benefit from an alternative anti-CD20 antibody. Taking on this question, the GADOLIN trial tested the addition of obinutuzumab (induction plus maintenance) to bendamustine among patients with rituximab-refractory disease (American Society of Clinical Oncology [ASCO] 2015, Abstract LBA8502; ICML 2015, Abstract 123).
Toxicities were generally similar by arm, except for a higher rate of infusion-related reactions with obinutuzumab. The overall response rates were comparable for the two arms, but progression-free survival was better with the combination (median event-free survival, not reached, vs. 14.9 months; hazard ratio, 0.55), and there was a trend for overall survival.
“These curves start separating after 6 months, and 6 months is the time of chemotherapy,” Dr. Zelenetz noted. “So I would argue from these data that the obinutuzumab didn’t add very much to the bendamustine backbone, but actually the obinutuzumab maintenance was effective even in rituximab-refractory patients.”
The combination of lenalidomide and rituximab has been compared with lenalidomide alone in patients with relapsed follicular lymphoma (ASCO 2012, Abstract 8000). The results showed a trend toward better median event-free survival with the combination (2.0 vs. 1.2 years; hazard ratio, 1.9; P = .061) but not overall survival.
In a phase II trial, idelalisib (Zydelig) was tested among patients with indolent non-Hodgkin lymphomas (60% with follicular lymphoma) that were refractory to both rituximab and an alkylator (N Engl J Med. 2014;370:1008-18). Noteworthy grade 3 or worse toxicities included pneumonia and transaminase elevations. The overall response rate was 57%, and the complete response rate was 6%; median progression-free survival was 11 months.
“Idelalisib can be safely combined with other agents including rituximab and bendamustine,” Dr. Zelenetz added (ASH 2014, Abstract 3063). “Interestingly, the overall response seems to be a little higher when you combine it, but it doesn’t seem to matter which drug you combine it with – rituximab, bendamustine, or [both] – you get good overall responses,” ranging from 71% to 85%.
The BCL-2 inhibitor venetoclax (formerly ABT-199/GDC-199) has been tested in non-Hodgkin lymphomas, where it has not been associated with the life-threatening tumor lysis syndrome seen in some other hematologic malignancies (European Hematology Association [EHA] 2015, Davis et al). It yielded an overall response rate of 31% in patients with relatively refractory follicular lymphoma. “This will lead to additional studies in this area,” he predicted.
Finally, nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, has been evaluated in a phase I study in relapsed or refractory hematologic malignancies, where it was well tolerated (ASH 2014, Abstract 291). Among the small subset of patients with follicular lymphoma, the overall response rate was 40%, prompting initiation of more trials.
Although chimeric antigen receptor (CAR) T-cell therapy is showing promise in various malignancies, Dr. Zelenetz said that other options are probably better avenues for research in follicular lymphoma at present.
“I’m much more interested in the tools that we have now, between the checkpoint inhibitors, the T-cell activators, and the bispecific monoclonal antibodies. I think I can [apply these therapies] with less money for probably less toxicity without the complexity of having to make a customized drug for the patient,” he said. “So I’m not very enthusiastic about CAR T cells in follicular lymphoma.”
SAN FRANCISCO – A variety of emerging therapies are being incorporated into the management of follicular lymphoma, which is typically a long-term endeavor requiring strategic use of multiple treatments, Dr. Andrew D. Zelenetz said at the National Comprehensive Cancer Network (NCCN) 10th Annual Congress: Hematologic Malignancies.
“Follicular lymphoma is a disease of paradox. The reality is that overall survival is excellent, but patients are not going to be able to do that with one treatment; they are going to get a series of treatments,” he said. “Survival is the sum of your exposures to treatment, time on active therapy, time in remission, and actually time with relapse not needing treatment.”
Risk stratification
Overall survival for patients with follicular lymphoma diagnosed today and treated with modern therapy is only slightly inferior to that for age-matched controls, noted Dr. Zelenetz of the department of medicine at Memorial Sloan-Kettering Cancer Center and professor of medicine at Cornell University, both in New York.
But patients who are faring poorly at 12 months (American Society of Hematology [ASH] 2014, Abstract 1664) or at 24 months (J Clin Oncol. 2015;33[23]:2516-22) into care have a much worse prognosis. “This shows the importance of identifying those patients with poor biology, and [the question of] whether we can identify them without treating them first and having them progress,” he said.
Hematologists have historically looked to the Follicular Lymphoma International Prognostic Index (FLIPI) to estimate outcome. “The FLIPI clearly works; it’s an important clinical tool. But the FLIPI high-risk patients are still identifying more than those very high-risk patients,” he said.
Therefore, a clinicogenomic risk model was developed that incorporates seven mutations having poor prognostic impact, the m7-FLIPI (Lancet Oncol. 2015;16[9]:1111-22). Adding the mutations split the previously defined high-risk patients into a group with a prognosis similar to that of low-risk patients and a small group with a very poor prognosis.
“This actually represents something very close to the 20% of patients that we think have bad biology,” Dr. Zelenetz noted. “There will be some additional data at ASH looking at this exact question, because the holy grail is to know when you diagnose someone if they are in that bad-risk group because those are the patients you want to do novel clinical trials on. If your overall survival is equivalent to the general population, it’s going to be hard to ever prove an overall survival advantage for an intervention in an unselected group of patients.”
Advanced-stage disease with low tumor bulk
For patients who have advanced-stage follicular lymphoma but with low tumor bulk, the NCCN endorses a modification of criteria developed by the Follicular Lymphoma Study Group (GELF) in deciding when to start treatment (J Clin Oncol. 1998;16[7]:2332-8).
Roughly a fifth of patients who are eligible for and managed with a watch-and-wait approach will not need chemotherapy or die of their disease in the next 10 years (Lancet. 2003;362[9383]:516-22). Furthermore, this strategy nets a median delay in the need for chemotherapy of 2.6 years.
Compared with observation, treatment with the anti-CD20 antibody rituximab (Rituxan) improves progression-free survival but not overall survival in this setting (ASH 2010, Abstract 6). “Though in selected patients, rituximab may be appropriate as initial treatment for the observable patient, I would argue for the observable patient with no survival disadvantage, the standard of care remains observation,” Dr. Zelenetz said.
Advanced-stage disease requiring treatment
A meta-analysis has shown a clear survival benefit from adding rituximab to chemotherapy (R-chemo) in patients with advanced follicular lymphoma who need treatment (J Natl Cancer Inst. 2007;99[9]:706-14). “Based on the results, it is the standard of care to add rituximab to a chemotherapy backbone, but the optimum R-chemo actually remains undefined and would be customized to the individual clinical situation,” he commented.
A variety of emerging agents are being tested in this setting. Among the subset of patients with untreated follicular lymphoma in a single-center trial, the combination of rituximab with the immunomodulator lenalidomide (Revlimid) yielded an overall response rate of 98% and a complete response rate of 87%, as well as excellent progression-free and overall survival (Lancet Oncol. 2014;15[12]:1311-8). The main grade 3 or 4 toxicity was neutropenia, seen in 35% of all patients studied. Efficacy results were much the same in a multicenter trial (International Conference on Malignant Lymphoma [ICML] 2013, Abstract 63).
This combination is now being tested as front-line therapy for follicular lymphoma in the RELEVANCE (Rituximab and Lenalidomide Versus Any Chemotherapy) phase III trial. “The trial is now done, but we don’t have results, and we won’t have results until 2019, so don’t hold your breath,” Dr. Zelenetz commented. “That’s because this was an unselected trial; we took all patients, all comers. And if you don’t try to identify bad-risk patients, you actually have to do very large trials, and the effect size is relatively small.”
Relapsed and refractory disease
“Many times when patients with follicular lymphoma relapse, they are immediately started on treatment. It’s not necessary and probably in most cases not appropriate. If patients are asymptomatic and have a low tumor burden, they can have a second and a third and even a fourth period of observation, where they don’t need active treatment,” he said. “So I would encourage you to …wait until they actually meet GELF criteria again.”
A key question in this setting is whether patients previously given rituximab can derive benefit from an alternative anti-CD20 antibody. Taking on this question, the GADOLIN trial tested the addition of obinutuzumab (induction plus maintenance) to bendamustine among patients with rituximab-refractory disease (American Society of Clinical Oncology [ASCO] 2015, Abstract LBA8502; ICML 2015, Abstract 123).
Toxicities were generally similar by arm, except for a higher rate of infusion-related reactions with obinutuzumab. The overall response rates were comparable for the two arms, but progression-free survival was better with the combination (median event-free survival, not reached, vs. 14.9 months; hazard ratio, 0.55), and there was a trend for overall survival.
“These curves start separating after 6 months, and 6 months is the time of chemotherapy,” Dr. Zelenetz noted. “So I would argue from these data that the obinutuzumab didn’t add very much to the bendamustine backbone, but actually the obinutuzumab maintenance was effective even in rituximab-refractory patients.”
The combination of lenalidomide and rituximab has been compared with lenalidomide alone in patients with relapsed follicular lymphoma (ASCO 2012, Abstract 8000). The results showed a trend toward better median event-free survival with the combination (2.0 vs. 1.2 years; hazard ratio, 1.9; P = .061) but not overall survival.
In a phase II trial, idelalisib (Zydelig) was tested among patients with indolent non-Hodgkin lymphomas (60% with follicular lymphoma) that were refractory to both rituximab and an alkylator (N Engl J Med. 2014;370:1008-18). Noteworthy grade 3 or worse toxicities included pneumonia and transaminase elevations. The overall response rate was 57%, and the complete response rate was 6%; median progression-free survival was 11 months.
“Idelalisib can be safely combined with other agents including rituximab and bendamustine,” Dr. Zelenetz added (ASH 2014, Abstract 3063). “Interestingly, the overall response seems to be a little higher when you combine it, but it doesn’t seem to matter which drug you combine it with – rituximab, bendamustine, or [both] – you get good overall responses,” ranging from 71% to 85%.
The BCL-2 inhibitor venetoclax (formerly ABT-199/GDC-199) has been tested in non-Hodgkin lymphomas, where it has not been associated with the life-threatening tumor lysis syndrome seen in some other hematologic malignancies (European Hematology Association [EHA] 2015, Davis et al). It yielded an overall response rate of 31% in patients with relatively refractory follicular lymphoma. “This will lead to additional studies in this area,” he predicted.
Finally, nivolumab (Opdivo), a PD-1 immune checkpoint inhibitor, has been evaluated in a phase I study in relapsed or refractory hematologic malignancies, where it was well tolerated (ASH 2014, Abstract 291). Among the small subset of patients with follicular lymphoma, the overall response rate was 40%, prompting initiation of more trials.
Although chimeric antigen receptor (CAR) T-cell therapy is showing promise in various malignancies, Dr. Zelenetz said that other options are probably better avenues for research in follicular lymphoma at present.
“I’m much more interested in the tools that we have now, between the checkpoint inhibitors, the T-cell activators, and the bispecific monoclonal antibodies. I think I can [apply these therapies] with less money for probably less toxicity without the complexity of having to make a customized drug for the patient,” he said. “So I’m not very enthusiastic about CAR T cells in follicular lymphoma.”
AT NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
Lenalidomide plus rituximab achieves 87% response rate
First-line combination biologic therapy with lenalidomide plus rituximab produced an 87% overall response rate in stage 3-4 mantle cell lymphoma, in an industry-sponsored, phase II clinical trial reported online Nov. 5 in the New England Journal of Medicine.
Mantle cell lymphoma is generally incurable, and patients have a median survival of 4-5 years. Initial therapy is usually very intensive, involving high-dose chemotherapy and hematopoietic cell transplantation. Since the malignancy primarily affects older adults who aren’t suitable candidates for intensive regimens, treatment “remains a clinical challenge,” said Dr. Jia Ruan of the Meyer Cancer Center and the division of biostatistics and epidemiology, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, and her associates.
Reasoning that biologic therapy might offer effective disease control with fewer and less intense adverse effects, the investigators performed the open-label, single-group trial over a 3-year period. They treated 38 patients whose mean age was 65 years (range, 42-86 years), most of whom were at intermediate or high risk for imminent progression. These participants received a 12-cycle induction phase of lenalidomide plus rituximab, followed by a maintenance phase until disease progressed, unacceptable adverse effects developed, or patients withdrew from the study. The median follow-up was 30 months (range, 10-42 months).
The primary endpoint – overall response rate – was 87% in the intention-to-treat population, and the complete response rate was 61%. The number of complete responses increased over time with continuing treatment: the median time to a partial response was 3 months, and the median time to a complete response was 11 months. Two-year progression-free survival was 85%, and 2-year overall survival was 97%, the investigators said (New Engl. J. Med. 2015 Nov 5. doi: 10.1056/NEJMoa1505237).
Only eight patients showed progression of mantle cell lymphoma while taking lenalidomide plus rituximab, two of whom died from their disease. The other six patients responded to second-line therapy and remain alive, indicating that this first-line combination biologic therapy doesn’t compromise outcomes after subsequent treatments, Dr. Ruan and her associates said.
Almost as important as these favorable survival results were the findings concerning adverse effects. Scores on several quality-of-life measures either remained stable or improved throughout the induction and maintenance phases of treatment. As expected, grade 3 or 4 hematologic adverse effects included neutropenia (50% of patients), thrombocytopenia (13%), and anemia (11%), all of which resolved; grade 3 or 4 nonhematologic adverse effects included rash (29%), tumor flare (11%), serum sickness (8%), and fatigue (8%), all of which also resolved. All the serious infections that developed during the maintenance phase of treatment, which included pneumonia, cholangitis, and West Nile viral encephalitis, also resolved with antibiotics and supportive care.
Secondary cancers that developed during follow-up included two squamous cell skin cancers, one basal cell skin cancer, two cases of melanoma in situ, one Merkel cell carcinoma, and one pancreatic cancer.
“Our data show that a lower-intensity approach for initial therapy than that usually used in the case of patients with this cancer can be highly active, with durable responses observed in most patients,” Dr. Ruan and her associates said.
This study was supported by Celgene, maker of lenalidomide, and a Weill Cornell Medical College Clinical Translational Science Center grant. Dr. Ruan reported ties to Celgene, and her associates reported ties to numerous industry sources.
First-line combination biologic therapy with lenalidomide plus rituximab produced an 87% overall response rate in stage 3-4 mantle cell lymphoma, in an industry-sponsored, phase II clinical trial reported online Nov. 5 in the New England Journal of Medicine.
Mantle cell lymphoma is generally incurable, and patients have a median survival of 4-5 years. Initial therapy is usually very intensive, involving high-dose chemotherapy and hematopoietic cell transplantation. Since the malignancy primarily affects older adults who aren’t suitable candidates for intensive regimens, treatment “remains a clinical challenge,” said Dr. Jia Ruan of the Meyer Cancer Center and the division of biostatistics and epidemiology, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, and her associates.
Reasoning that biologic therapy might offer effective disease control with fewer and less intense adverse effects, the investigators performed the open-label, single-group trial over a 3-year period. They treated 38 patients whose mean age was 65 years (range, 42-86 years), most of whom were at intermediate or high risk for imminent progression. These participants received a 12-cycle induction phase of lenalidomide plus rituximab, followed by a maintenance phase until disease progressed, unacceptable adverse effects developed, or patients withdrew from the study. The median follow-up was 30 months (range, 10-42 months).
The primary endpoint – overall response rate – was 87% in the intention-to-treat population, and the complete response rate was 61%. The number of complete responses increased over time with continuing treatment: the median time to a partial response was 3 months, and the median time to a complete response was 11 months. Two-year progression-free survival was 85%, and 2-year overall survival was 97%, the investigators said (New Engl. J. Med. 2015 Nov 5. doi: 10.1056/NEJMoa1505237).
Only eight patients showed progression of mantle cell lymphoma while taking lenalidomide plus rituximab, two of whom died from their disease. The other six patients responded to second-line therapy and remain alive, indicating that this first-line combination biologic therapy doesn’t compromise outcomes after subsequent treatments, Dr. Ruan and her associates said.
Almost as important as these favorable survival results were the findings concerning adverse effects. Scores on several quality-of-life measures either remained stable or improved throughout the induction and maintenance phases of treatment. As expected, grade 3 or 4 hematologic adverse effects included neutropenia (50% of patients), thrombocytopenia (13%), and anemia (11%), all of which resolved; grade 3 or 4 nonhematologic adverse effects included rash (29%), tumor flare (11%), serum sickness (8%), and fatigue (8%), all of which also resolved. All the serious infections that developed during the maintenance phase of treatment, which included pneumonia, cholangitis, and West Nile viral encephalitis, also resolved with antibiotics and supportive care.
Secondary cancers that developed during follow-up included two squamous cell skin cancers, one basal cell skin cancer, two cases of melanoma in situ, one Merkel cell carcinoma, and one pancreatic cancer.
“Our data show that a lower-intensity approach for initial therapy than that usually used in the case of patients with this cancer can be highly active, with durable responses observed in most patients,” Dr. Ruan and her associates said.
This study was supported by Celgene, maker of lenalidomide, and a Weill Cornell Medical College Clinical Translational Science Center grant. Dr. Ruan reported ties to Celgene, and her associates reported ties to numerous industry sources.
First-line combination biologic therapy with lenalidomide plus rituximab produced an 87% overall response rate in stage 3-4 mantle cell lymphoma, in an industry-sponsored, phase II clinical trial reported online Nov. 5 in the New England Journal of Medicine.
Mantle cell lymphoma is generally incurable, and patients have a median survival of 4-5 years. Initial therapy is usually very intensive, involving high-dose chemotherapy and hematopoietic cell transplantation. Since the malignancy primarily affects older adults who aren’t suitable candidates for intensive regimens, treatment “remains a clinical challenge,” said Dr. Jia Ruan of the Meyer Cancer Center and the division of biostatistics and epidemiology, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, and her associates.
Reasoning that biologic therapy might offer effective disease control with fewer and less intense adverse effects, the investigators performed the open-label, single-group trial over a 3-year period. They treated 38 patients whose mean age was 65 years (range, 42-86 years), most of whom were at intermediate or high risk for imminent progression. These participants received a 12-cycle induction phase of lenalidomide plus rituximab, followed by a maintenance phase until disease progressed, unacceptable adverse effects developed, or patients withdrew from the study. The median follow-up was 30 months (range, 10-42 months).
The primary endpoint – overall response rate – was 87% in the intention-to-treat population, and the complete response rate was 61%. The number of complete responses increased over time with continuing treatment: the median time to a partial response was 3 months, and the median time to a complete response was 11 months. Two-year progression-free survival was 85%, and 2-year overall survival was 97%, the investigators said (New Engl. J. Med. 2015 Nov 5. doi: 10.1056/NEJMoa1505237).
Only eight patients showed progression of mantle cell lymphoma while taking lenalidomide plus rituximab, two of whom died from their disease. The other six patients responded to second-line therapy and remain alive, indicating that this first-line combination biologic therapy doesn’t compromise outcomes after subsequent treatments, Dr. Ruan and her associates said.
Almost as important as these favorable survival results were the findings concerning adverse effects. Scores on several quality-of-life measures either remained stable or improved throughout the induction and maintenance phases of treatment. As expected, grade 3 or 4 hematologic adverse effects included neutropenia (50% of patients), thrombocytopenia (13%), and anemia (11%), all of which resolved; grade 3 or 4 nonhematologic adverse effects included rash (29%), tumor flare (11%), serum sickness (8%), and fatigue (8%), all of which also resolved. All the serious infections that developed during the maintenance phase of treatment, which included pneumonia, cholangitis, and West Nile viral encephalitis, also resolved with antibiotics and supportive care.
Secondary cancers that developed during follow-up included two squamous cell skin cancers, one basal cell skin cancer, two cases of melanoma in situ, one Merkel cell carcinoma, and one pancreatic cancer.
“Our data show that a lower-intensity approach for initial therapy than that usually used in the case of patients with this cancer can be highly active, with durable responses observed in most patients,” Dr. Ruan and her associates said.
This study was supported by Celgene, maker of lenalidomide, and a Weill Cornell Medical College Clinical Translational Science Center grant. Dr. Ruan reported ties to Celgene, and her associates reported ties to numerous industry sources.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: First-line combination biologic therapy with lenalidomide plus rituximab produced an 87% overall response rate in stage 3 or 4 mantle cell lymphoma.
Major finding: The primary endpoint – overall response rate – was 87%, and the complete response rate was 61%.
Data source: A multicenter, industry-sponsored, open-label, phase II study involving 38 patients with mantle cell lymphoma followed for a median of 30 months.
Disclosures: This study was supported by Celgene, maker of lenalidomide, and a Weill Cornell Medical College Clinical Translational Science Center grant. Dr. Ruan reported ties to Celgene, and her associates reported ties to numerous industry sources.
Post-ibrutinib management in MCL unclear, speaker says
NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.
So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.
Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.
Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%.
The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.
“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”
Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months.
In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.
Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).
The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.
“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.”
The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide.
“There was no statistical association between survival and choice of therapy,” Dr Martin said.
What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).
“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.
However, he did make a few suggestions for treating high-risk patients.
Treatment suggestions after ibrutinib failure
Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.
Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.
Dr Martin admitted that what to do following ibrutinib failure remains cloudy.
“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”
In addition, on average 80% have expression of Ki67.
Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.
So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.
A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.
Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.
“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”
Overcoming ibrutinib resistance
Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”
Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers.
A number of trials are underway to hit some of these pathways, Dr Martin said.
Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.
The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.
There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.
“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”
Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination.
He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed.
“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”
NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.
So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.
Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.
Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%.
The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.
“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”
Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months.
In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.
Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).
The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.
“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.”
The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide.
“There was no statistical association between survival and choice of therapy,” Dr Martin said.
What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).
“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.
However, he did make a few suggestions for treating high-risk patients.
Treatment suggestions after ibrutinib failure
Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.
Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.
Dr Martin admitted that what to do following ibrutinib failure remains cloudy.
“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”
In addition, on average 80% have expression of Ki67.
Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.
So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.
A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.
Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.
“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”
Overcoming ibrutinib resistance
Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”
Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers.
A number of trials are underway to hit some of these pathways, Dr Martin said.
Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.
The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.
There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.
“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”
Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination.
He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed.
“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”
NEW YORK—Despite an “unprecedented” single-agent response rate and progression-free survival (PFS) in previously treated mantle cell lymphoma (MCL) patients, those with multiple risk factors have a dismal outcome following ibrutinib failure.
So after ibrutinib, what’s next in MCL? That was the question asked at Lymphoma & Myeloma 2015.
Peter Martin, MD, of Weill Cornell Medical College in New York, New York, discussed some possibilities.
Ibrutinib (Imbruvica) was approved by the US Food and Drug Administration for MCL based on the PCYC-1104 trial, which showed an overall response rate of 68%. In the MCL2001 trial, the overall response rate was 63%.
The median PFS for MCL was 13 months in PCYC-1104 and 10.5 months in MCL2001. The median overall survival (OS) was close to 2 years in PCYC-1104 and 18 months in MCL2001.
“So this is where I think it starts to get interesting,” Dr Martin said. “People were able to live for several months after progressing on ibrutinib. [However,] our experience at Cornell was not necessarily consistent with that.”
Cornell investigators, along with colleagues from Ohio State University, compiled data on patients who had been treated in clinical trials at their institutions and reviewed their survival after progression on ibrutinib. These patients had a median OS of 4 months.
In reviewing the patients’ Mantle Cell Lymphoma International Prognostic Index (MIPI) scores, Dr Martin said they were arguably a higher-risk population.
Dr Martin collected data on 114 relapsed/refractory MCL patients from centers around the world and found they had a lower response rate (50%) with ibrutinib overall and a lower duration of ibrutinib therapy (4.7 months).
The median OS after stopping ibrutinib was 2.9 months for the entire group. For patients who did not receive any subsequent therapy after failure, it was 0.8 months. Patients who received treatment after ibrutinib failure had a median OS of 5.8 months.
“And it didn’t seem to matter what we gave,” Dr Martin said. “Those treatments were pretty short-lived.”
The median time to next treatment with the first subsequent therapy was 2.4 months. These therapies included bendamustine, cytarabine, and lenalidomide.
“There was no statistical association between survival and choice of therapy,” Dr Martin said.
What was significant, by univariate Cox regression analysis, was the patients’ MIPI prior to ibrutinib therapy (P=0.0002) and the duration of ibrutinib treatment (P=0.0465).
“So at this point in time, I think it’s fair to say that there is insufficient data to recommend any specific treatment following ibrutinib failure,” Dr Martin said.
However, he did make a few suggestions for treating high-risk patients.
Treatment suggestions after ibrutinib failure
Dr Martin’s first suggestion is to focus on symptom management rather than active therapy for the older, frailer patients. Second, consider allogeneic stem cell transplant in any high-risk patient responding to ibrutinib.
Third, consider continuing ibrutinib therapy while starting the next therapy. And fourth, consider some form of continuous therapy that does not depend on TP53.
Dr Martin admitted that what to do following ibrutinib failure remains cloudy.
“Conducting a clinical trial will be tricky,” he said, “because the median time from ibrutinib failure to the next therapy was 9 days, and we’re targeting a very high-risk patient population.”
In addition, on average 80% have expression of Ki67.
Currently, a phase 2 trial of copanlisib (NCT02455297) is the only post-ibrutinib clinical trial in MCL open. Copanlisib is a potent and reversible phosphatidylinositol-3-kinase (PI3K) inhibitor with activity against both alpha and delta isoforms of PI3K. Preliminary results of the trial demonstrated response in 5 of 7 MCL patients.
So perhaps the best approach, Dr Martin suggested, would be to improve response and prevent relapse while on ibrutinib using combination therapies.
A phase 1/1b trial of ibrutinib with bendamustine and rituximab (BR) is underway. Of 17 MCL patients treated thus far, 94% have responded, and 76% have achieved a CR. But 25% developed grade 3 rash.
Ibrutinib is also being studied in combination with rituximab in MCL. The combination has produced an overall response rate of 88%, with 40% of patients achieving a CR.
“My interpretation from all these studies is you can probably add ibrutinib to any other effective anti-MCL therapy and improve that therapy,” Dr Martin said. “But there are questions, obviously, that still arise.”
Overcoming ibrutinib resistance
Dr Martin explained that, to use combinations rationally, we need to understand mechanisms of ibrutinib resistance, “and that’s not so straightforward.”
Mutations in MCL likely have multiple mechanisms of resistance. Mutations occur predominantly in 3 groups of genes involving NF-kB, PIM/mTOR, and epigenetic modifiers.
A number of trials are underway to hit some of these pathways, Dr Martin said.
Researchers at Cornell are studying ibrutinib plus palbociclib, an inhibitor of CDK4/CDK6 approved for advanced breast cancer, in a phase 1 trial of MCL patients.
The combination “very early on, has seen a high number of complete responses, which have been exciting,” Dr Martin said.
There are many ongoing ibrutinib trials in previously treated patients, including ones with carfilzomib, palbociclib, bortezomib, venetoclax, lenalidomide, and TGR-1202. In addition, the frontline trial of BR +/- ibrutinib is expected to have results soon.
“[A]nd once that happens, my guess is that this frontline trial, once it’s read out, essentially, makes all these other trials irrelevant because the minute ibrutinib moves into the frontline setting, it makes it very difficult to evaluate in a subsequent setting,” Dr Martin said. “So within a couple of years, it will be standard in the frontline setting.”
Dr Martin is concerned that resources are insufficient—there are too many studies, too few patients, and too little time—to find another, potentially more effective agent or combination.
He said there won’t be a one-size-fits-all approach to MCL either before or after ibrutinib, and collaboration among institutions, companies, and cooperative groups will be needed.
“Management in the post-ibrutinib setting remains unclear,” he said, “and these patients should be treated in a clinical trial if possible.”