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Study Overview
Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R2 regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).
Design. Phase 3, multicenter, international, placebo controlled randomized trial.
Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.
Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.
Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.
Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R2 group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.
Main results. PFS was significantly improved for patients treated with the R2 regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R2 group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R2 group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R2 group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.
Conclusion. The R2 regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R2 regimen compared to rituximab/placebo.
Commentary
Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.1 Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.1 These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.
More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.2 The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.2 As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.
A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas2,3 and MZL.4 However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.
The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.5 The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.5 The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.6
RELEVANCE, a phase 3 trial, compared the R2 regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).7 Efficacy outcomes were similar between the comparators and R2 was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R2 regimen and who entered a plan to receive maintenance with rituximab.8
The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R2 regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.
As observed in other R2 regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.
The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R2 at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.
Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R2 arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R2 arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R2 regimen.
Applications for Clinical Practice
Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.
Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.
The evidence from this trial has yielded what is likely to be a practice changing regimen, with R2 replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R2 offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R2.
Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.
Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.9 Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.
In the R2 arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R2 group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R2 group, which may have been responsible for a lower incidence of febrile neutropenia.
Increased toxicities of tumor flare, rash, and constipation were observed in the R2 arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.
The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.10 Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R2 regimen may be cost prohibitive without financial assistance from charities.
Indolent NHL remains mostly incurable. The R2 approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.
—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS
1. Perry AM, Diebold J, Nathwani BN, et al. Classification of non-Hodgkin lymphoma in seven geographic regions around the world: review of 4539 cases from the International Non-Hodgkin Lymphoma Classification Project. Haematologica. 2016;101:1244-1250.
2. Armitage JO, Longo DL. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood. 2016;127:2804-2808.
3. Tan D, Horning SJ, Hoppe RT, et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: The Stanford University experience. Blood. 2013;122:981-987.
4. Olszewski AJ, Castillo JJ. Survival of patients with marginal zone lymphoma: Analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2013;119:629-638.
5. Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164:811-821.
6. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33:3635-3640.
7. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379:934-947.
8. Andorsky DJ, Coleman M, Yacoubeman A, et al. MAGNIFY: Phase IIIb interim analysis of induction R2 followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37 (suppl; abstr 7513).
9. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279-3289.
10. Revlimid prices, coupons and patient assistance programs. www.drugs.com/price-guide/revlimid. Accessed August 27, 2019.
Study Overview
Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R2 regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).
Design. Phase 3, multicenter, international, placebo controlled randomized trial.
Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.
Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.
Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.
Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R2 group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.
Main results. PFS was significantly improved for patients treated with the R2 regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R2 group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R2 group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R2 group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.
Conclusion. The R2 regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R2 regimen compared to rituximab/placebo.
Commentary
Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.1 Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.1 These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.
More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.2 The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.2 As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.
A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas2,3 and MZL.4 However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.
The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.5 The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.5 The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.6
RELEVANCE, a phase 3 trial, compared the R2 regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).7 Efficacy outcomes were similar between the comparators and R2 was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R2 regimen and who entered a plan to receive maintenance with rituximab.8
The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R2 regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.
As observed in other R2 regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.
The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R2 at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.
Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R2 arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R2 arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R2 regimen.
Applications for Clinical Practice
Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.
Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.
The evidence from this trial has yielded what is likely to be a practice changing regimen, with R2 replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R2 offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R2.
Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.
Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.9 Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.
In the R2 arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R2 group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R2 group, which may have been responsible for a lower incidence of febrile neutropenia.
Increased toxicities of tumor flare, rash, and constipation were observed in the R2 arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.
The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.10 Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R2 regimen may be cost prohibitive without financial assistance from charities.
Indolent NHL remains mostly incurable. The R2 approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.
—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS
Study Overview
Objective. To compare the efficacy and safety of lenalidomide in combination with rituximab (known as the R2 regimen) to rituximab plus placebo in patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma (MZL).
Design. Phase 3, multicenter, international, placebo controlled randomized trial.
Setting and participants. 358 patients with rituximab-sensitive relapsed or refractory grade 1-3a follicular lymphoma or MZL.
Intervention. Patients were randomly assigned 1:1 to receive lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5.
Main outcome measures. The primary endpoint was progression-free survival (PFS) as determined by independent radiology reviewers using intent-to-treat analysis. Secondary end points included overall response rate, complete response rate, duration of response, overall survival, event-free survival, and time to next anti-lymphoma therapy. Time to next chemotherapy treatment and histologic transformation were exploratory endpoints. Responses were assessed by participating investigators and independent reviewers. Computed tomography or magnetic resonance imaging was used to obtain tumor measurements. Positron emission tomography was not used. Complete remissions were confirmed by bone marrow biopsy, as bone marrow involvement is exceedingly common in these lymphomas. Gastrointestinal endoscopy was performed to obtain disease status if there was involvement by lymphoma initially.
Improvement in primary and secondary endpoints as well as extrapolatory endpoints were reported in the R2 group. Primary efficacy analyses were conducted in the intention-to-treat population primary endpoint of PFS at 1-sided α = 0.025 level.
Main results. PFS was significantly improved for patients treated with the R2 regimen compared to those who recieved placebo plus rituximab, with a hazard ratio of 0.46 (95% confidence interval [CI], 0.34-0.62; P < 0.001). Median duration of PFS in the R2 group was 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months) in the rituximab/placebo group. Overall response in the R2 group was 78% (95% CI, 71%-83%) versus 53% (95% CI, 46%-61%; P < 0.0001) in the rituximab/placebo group, with 34% (95% CI, 27%-41%) versus 18% (95% CI, 13%-25%) of patients achieving complete remission (P = 0.001). There were 15 deaths in the R2 group versus 26 deaths in the rituximab/placebo group. Overall survival data is not mature yet.
Conclusion. The R2 regimen was superior to rituximab and placebo in relapsed or recurrent follicular lymphomas. The regimen’s safety profile was acceptable, with higher events of usual and expected but manageable toxicities in the R2 regimen compared to rituximab/placebo.
Commentary
Nearly half of non-Hodgkins lymphomas (NHLs) diagnosed in the United States are classified as indolent B-cell lymphomas.1 Follicular lymphomas constitute about 50% of all indolent NHLs, while MZLs comprise less than 15%.1 These slowly progressive B-cell lymphomas are currently considered treatable but have very low cure rates. Cure is primarily limited to early stage I/II disease and may be possible in less than half of patients by applying involved-field radiation therapy with curative intent.
More than two thirds of indolent lymphomas present in advanced stages (III-IV). Despite an advanced stage at presentation, initial chemoimmunotherapy can induce complete remission in nearly 60% of patients. Unfortunately, nearly all patients relapse over the next 10 years.2 The wait-and-watch approach is a common strategy, and most patients are administered initial therapy or subsequent lines of therapy if they are symptomatic.2 As such, for the majority of these patients, the goal of therapy is to minimize toxicities, preserve quality of life, treat symptoms, and achieve a long PFS without an attempt to cure. Following each line of therapy, patients often revert to watchful surveillance, sometimes for more than a decade. With additional subsequent lines of therapy, lymphoma tends to get more refractory to treatment.
A median survival of nearly 2 decades has been achieved in advanced follicular lymphomas2,3 and MZL.4 However, wide variation in overall response, duration of response, and survival is reported based on the individual risk profile.
The drug of interest in the present study by Leonard and colleagues, lenalidomide, has immunomodulatory properties and antiproliferative effects, possibly related to its binding of the E3 ligase protein cereblon and subsequent ubiquitination of the transcription factors Aiolos and Ikaros.5 The benefits of combination lenalidomide/rituximab against follicular lymphoma in preclinical settings have been attributed to mechanisms mediated by tumor-infiltrating lymphocytes, natural killer cells, monocytes, and antibody-dependent cell-mediated toxicity.5 The combination has now been studied in first-line and subsequent lines of therapy for follicular lymphoma and MZL.6
RELEVANCE, a phase 3 trial, compared the R2 regimen in the upfront setting in advanced follicular lymphoma with rituximab and chemotherapy combination (including CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], CVP [cyclophosphamide, vincristine, prednisone], and bendamustine).7 Efficacy outcomes were similar between the comparators and R2 was noninferior. MAGNIFY, a phase 3b trial involving rituximab-sensitive and rituximab-refractory patients with previously treated follicular lymphoma and MZL, demonstrated an overall response rate of 73%, complete response rate of 45%, and median PFS of 36 months in patients who received the R2 regimen and who entered a plan to receive maintenance with rituximab.8
The AUGMENT trial was conducted at 97 centers in the United States and 14 Asian and European countries; it enrolled 358 patients, 82% of whom had a follicular lymphoma, between February 13, 2014 and January 26, 2017. The study was well conducted. The R2 regimen was compared to the often used second-line therapy of rituximab alone, and 1:1 randomization was done with stratification factors of prior rituximab use, marginal versus follicular histology, and time lapse of less than or greater than 2 years since last therapy. A limitation of this study is that it selected individuals with a better prognosis, as the study patients were not rituximab refractory and 57% had received only a single prior therapy.
As observed in other R2 regimen trials in follicular or marginal zone lymphomas, the most common adverse reactions (occurring in at least 20% of patients) were neutropenia, fatigue, and constipation. These were manageable with dose adjustments and interruptions, and, in the opinion of authors, did not take away from the overall benefits seen.
The authors acknowledge that a limitation of this study was a lower assessment of median PFS in both arms by investigators than by independent reviewers. The independent review committee assessed PFS for R2 at 39.4 months, whereas investigators assessed it at 25.4 months. The median PFS benefit remained at 14.1 months by both methods of assessment. This may highlight the differences of radiographic measurements in a central setting versus at individual centers.
Histologic transformation to a higher-grade aggressive lymphoma occurred in 2 patients in the R2 arm and 10 patients in the placebo/rituximab arm. After transformation, 1 patient in the R2 arm and 6 in the placebo plus rituximab arm died. A plausible mechanism for this variation has not been provided. If confirmed across a wider population, this may be one of the most significant benefits of the R2 regimen.
Applications for Clinical Practice
Therapy for relapsed and refractory indolent B-cell lymphomas continues to evolve. While chemotherapy remains an effective option, immunomodulation using non-chemotherapeutic intervention has emerged as an attractive strategy. The AUGMENT trial further solidifies adoption of the non-chemotherapy doublet option of rituximab/lenalidomide based on the premise of immunomodulation. Both the agents have been commercially available for more than a decade and are being used for other indications beyond the study population for this trial.
Based on the AUGMENT and MAGNIFY trials, lenalidomide combined with rituximab was approved by the Food and Drug Administration for use in relapsed and refractory follicular or marginal zone lymphomas soon after the AUGMENT study results were published. The recommended lenalidomide dose for both lymphomas is 20 mg once daily orally on days 1 to 21 of repeated 28-day cycles for up to 12 cycles.
The evidence from this trial has yielded what is likely to be a practice changing regimen, with R2 replacing single-agent rituximab for treating follicular lymphoma in the second line or beyond. The response rates and PFS periods were slightly lower in MZL. R2 offers advantages associated with a chemotherapy-free regimen and improved PFS. Also, in the AUGEMENT trial the secondary and exploratory endpoints of time to next therapy, overall response rates, and overall survival rates were improved in patients treated with R2.
Practitioners may choose lenalidomide plus rituximab over rituximab alone based on the AUGMENT study. When considering this regimen, several points should be kept in mind. A very careful selection of patients would be prudent, considering that the study’s follow-up of less than 4 years is short for a disease with long overall survival rates. The study was not powered to compare overall survival benefit. Also, practitioners are reminded to limit the use of lenalidomide to a maximum of 12 months, with planned interruptions and 8 doses of rituximab, replicating the trial schema. Additionally, as per the clinical trial design, the regimen is not intended for rituximab-refractory patients. Patients with MZL constituted only 18% of the study, and conclusions of superiority in this subgroup were not statistically significant. Lenalidomide is not approved for other indolent B cell lymphoproliferative malignancies, such as small lymphocytic lymphoma and chronic lymphocytic leukemia. The conclusion of the published study abstract suggests acceptable use in recurrent indolent lymphomas, but no such conclusion can be made due to lack of inclusion of all indolent lymphoma subtypes in this study.
Longer-term use of lenalidomide has been associated with a marginally increased risk of secondary hematologic malignancies in patients with multiple myeloma who were prescribed lenalidomide maintenance therapy for up to 2 years following high-dose chemotherapy and autologous hematopoietic stem cell transplant.9 Interestingly, in the AUGMENT study and other trials using lenalidomide/rituximab, no significant increase in secondary hematologic malignancies has been reported. The absence of prior myeloablative chemotherapy and a shorter duration of use (1 year) in this group of patients may be factors in why no additional risk of secondary hematologic malignancies was observed. Longer-term follow-up may be needed to evaluate this risk.
In the R2 arm of this study, 55% patients experienced grades 3 and 4 neutropenia. With a median age of presentation for both follicular lymphoma and MZL of over 60 years, oncologists should remain aware of this potentially fatal complication, especially in the frail, the elderly, and previously treated individuals who may have a high risk of myelosuppression. Clinicians should be prepared to rapidly adopt strategies of dose interruption, dose reduction, and growth factor use, as implemented in the trial. Of note, despite the high rates of severe neutropenia, only 3% of the participants experienced febrile neutropenia, and 71% patients in R2 group and 61% in rituximab group completed planned protocol therapy. Growth factor use was high at 36% in the R2 group, which may have been responsible for a lower incidence of febrile neutropenia.
Increased toxicities of tumor flare, rash, and constipation were observed in the R2 arm. Patients with greater than grade 1 neuropathy were excluded. For those at risk of thromboembolism, prophylactic anticoagulation or antiplatelet therapy was recommended in the trial. Lenalidomide dose was reduced to 10 mg for those with creatinine clearance of 30 to 59 mL/min.
The cost-effectiveness of lenalidomide/rituximab combination has not been fully studied against a sequential approach of using rituximab and lenalidomide for a limited number of cycles. The cost of a Revlimid 10-mg pill may be over $700.10 Costs associated with supportive care due to additional toxicities have not been quantified. For those with cost concerns or lack of insurance coverage, the R2 regimen may be cost prohibitive without financial assistance from charities.
Indolent NHL remains mostly incurable. The R2 approach is still not a curative one, and resources should be directed to investigate a cure for this population. Whenever feasible, participation in a clinical trial should be encouraged. Parameters have not been reported based on prognostic groups, and the study did not identify any biomarkers that may correlate with improved outcome. Perhaps a biomarker-based trial design may be most suitable in explaining the heterogeneity in follicular and marginal zone lymphomas.
—Rakesh Gaur, MD, MPH, FACP, Cancer and Blood Center at Kansas Institute of Medicine, Lenexa, KS
1. Perry AM, Diebold J, Nathwani BN, et al. Classification of non-Hodgkin lymphoma in seven geographic regions around the world: review of 4539 cases from the International Non-Hodgkin Lymphoma Classification Project. Haematologica. 2016;101:1244-1250.
2. Armitage JO, Longo DL. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood. 2016;127:2804-2808.
3. Tan D, Horning SJ, Hoppe RT, et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: The Stanford University experience. Blood. 2013;122:981-987.
4. Olszewski AJ, Castillo JJ. Survival of patients with marginal zone lymphoma: Analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2013;119:629-638.
5. Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164:811-821.
6. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33:3635-3640.
7. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379:934-947.
8. Andorsky DJ, Coleman M, Yacoubeman A, et al. MAGNIFY: Phase IIIb interim analysis of induction R2 followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37 (suppl; abstr 7513).
9. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279-3289.
10. Revlimid prices, coupons and patient assistance programs. www.drugs.com/price-guide/revlimid. Accessed August 27, 2019.
1. Perry AM, Diebold J, Nathwani BN, et al. Classification of non-Hodgkin lymphoma in seven geographic regions around the world: review of 4539 cases from the International Non-Hodgkin Lymphoma Classification Project. Haematologica. 2016;101:1244-1250.
2. Armitage JO, Longo DL. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood. 2016;127:2804-2808.
3. Tan D, Horning SJ, Hoppe RT, et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: The Stanford University experience. Blood. 2013;122:981-987.
4. Olszewski AJ, Castillo JJ. Survival of patients with marginal zone lymphoma: Analysis of the Surveillance, Epidemiology, and End Results database. Cancer. 2013;119:629-638.
5. Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164:811-821.
6. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33:3635-3640.
7. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379:934-947.
8. Andorsky DJ, Coleman M, Yacoubeman A, et al. MAGNIFY: Phase IIIb interim analysis of induction R2 followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2019;37 (suppl; abstr 7513).
9. McCarthy PL, Holstein SA, Petrucci MT, et al. Lenalidomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis. J Clin Oncol. 2017;35:3279-3289.
10. Revlimid prices, coupons and patient assistance programs. www.drugs.com/price-guide/revlimid. Accessed August 27, 2019.