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Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma
Perspective
Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma Mendel Goldfinger,1 Mina Xu,2 Joseph R. Bertino,1 Dennis L. Cooper1 Abstract Lenalidomide has modest single-agent activity comparable with other newer drugs in recurrent diffuse large B cell lymphoma with response rates between 19% and 28%. Retrospective series and 1 prospective study suggest that clinically significant responses were predominantly limited to patients with activated B cell (ABC) lymphoma, a finding in agreement with lenalidomide’s potent inhibition of nuclear factor kB, the key driver of ABC lymphomas. Recently completed trials will determine whether the additional use of lenalidomide with R/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) enhances survival compared with R/CHOP alone and whether this activity is limited to ABC lymphomas. Lenalidomide also appears to have activity in the maintenance setting regardless of cell of origin and might play an important role in patients with recurrent disease who are not transplantation candidates. Similarly, because of the ability of lenalidomide to cross the bloodebrain barrier, it needs to be further explored in patients with high risk for central nervous system spread. The results of lenalidomide combination studies with chemotherapy and with checkpoint inhibitors are eagerly awaited. Clinical Lymphoma, Myeloma & Leukemia, Vol. 19, No. 6, e307-11 ª 2019 Elsevier Inc. All rights reserved. Keywords: Activated B-cell, Cell of origin, Germinal center, PDL-1, Revlimid
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately one-third of non-Hodgkin lymphoma1 and is projected to be the seventh most common malignancy diagnosed in the United States in 2019.2 Although the prognosis of DLBCL significantly improved 15 years ago with the additional use of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone),3 up to 40% of patients are not cured and it is disappointing that R/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care for newly treated patients today. Thus, recent strategies incorporating higher dose intensity afforded by growth factors and stem cells have not resulted in superior cure rates4-6 and the preliminary report of a long-awaited study that compared continuous infusion dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab with R/CHOP was also negative.7 The results of treatment for recurrent disease remain poor, particularly for patients who have primary resistance or relapse 1 Department of Hematology and Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ 2 Department of Pathology, Yale School of Medicine, New Haven, CT
Submitted: Oct 8, 2018; Revised: Jan 27, 2019; Accepted: Feb 15, 2019; Epub: Feb 27, 2019 Address for correspondence: Mendel Goldfinger, MD, Department of Hematology and Medical Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany St, New Brunswick, NJ 08901 E-mail contact: mendelgoldfi[email protected]
2152-2650/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2019.02.012
within 1 year of completing rituximab-containing treatment.8 In addition, there have been no US Food and Drug Administration (FDA)-approved second-line therapies for DLBCL and it seems that for now, strategies such as chimeric antigen receptor T cells, which are FDA-approved as a third-line treatment, offers the greatest hope for patients in whom R/CHOP treatment has failed.9,10 In contrast to the lack of progress in primary treatment, there has been a dramatic increase in the understanding of the heterogeneous biology of DLBCL and the hope that this knowledge can be leveraged into better treatments in the near future. For example, gene expression profiling (GEP) has divided most cases of DLBCL into lymphomas arising from germinal center B (GCB) or activated B cells with a small fraction remaining unclassified.11 GCB lymphomas have different biologic features than activated B cell (ABC) lymphomas, which are thought to arise from cells in the post germinal center and are blocked at the stage of plasmacytic differentiation. The ABC, GCB, and unclassified groups have been imperfectly compressed into GCB and non-GCB cell of origin (COO) using more widely available immunohistochemistry (IHC) techniques but with a 10% to 20% lack of fidelity compared with GEP, not including the cases in the GEP unclassified category.12-14 The COO has had prognostic significance in most11,13,15,16 but not all studies14 with response and overall survival after R/CHOP worse in non-GCB compared with GCB lymphoma. The poorer response in the ABC lymphomas is believed to be due to multiple factors, especially constitutive activation of the antiapoptotic nuclear factor
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Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma Table 1 Studies Using Single-Agent Lenalidomide in DLBCL Reference
Patient n
Dose
Trial Design
Response Rate (%)
Wiernik et al26
26
25 mg days 1-25
Prospective; median 4 previous Rx
19; only 1/26 had CR
Witzig et al28
108
25 mg days 1-25
Prospective; median 3 previous Rx
40
25 mg days 1-21
123
15 or 25 mg days 1-21
Retrospective; median 4 previous Rx Retrospective; median 1 previous Rx
Hernandez-Ilizaliturri et al29 Mondello et al30
Comment
Response rate similar to that with other effective single agents, lower response than in MCL, follicular grade III, and transformed follicular lymphoma 28; 7/30 had CR Response rate similar to that with other effective single agents, lower response than in MCL, follicular grade III, and transformed follicular lymphoma 53 (ABC) vs. 9 (GCB) No increase in OS in ABC vs. GCB 65 (ABC) vs. 3 (GCB)
No increase in OS in ABC vs. GCB
Abbreviations: ABC ¼ activated B-cell; DLBCL ¼ diffuse large B-cell lymphoma; GCB ¼ germinal center B; MCL ¼ mantle-cell lymphoma; OS ¼ overall survival; Rx ¼ treatment.
kB (NF-kB) signaling pathway. Accordingly, the latter was a major target of recent negative studies in which R/CHOP was not inferior to R/CHOP regimens in which bortezomib was either substituted for vincristine17 or given in addition to vincristine.18 Interestingly, there appears to be geographic differences in the proportion of ABC lymphomas because a recent preliminary study suggests that ABC lymphomas are nearly twice as common in East Asian populations than North America/Australia/New Zealand populations.19 In addition to ABC COO, recurrent genomic translocations involving MYC and either BCL2 and/or BCL6 detected using fluorescence in situ hybridization analysis, so-called “double and triple hit lymphoma” have been associated with an especially dismal prognosis and a high incidence of central nervous system (CNS) spread.20,21 Although most double/triple hit lymphomas also show IHC overexpression of MYC and BCL2 (“double-expressors”), it is important to recognize that double-expressor lymphomas are much more common than double-hit lymphomas.20,21 In addition, although double-expressor lymphomas are more common in ABC than GCB COO, double- and triple-hit lymphomas are almost entirely confined to lymphomas of GCB origin.22 At present, other than being associated with a worse prognosis, there is no treatment implication for the diagnosis of double-expressor lymphoma whereas double- and triple-hit lymphomas have been recommended to receive dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab and CNS prophylaxis.20,21 Lenalidomide (Revlimid; Celgene Corp, Summit, NJ) is a second-generation immunomodulatory drug, which has direct antineoplastic activity mediated by inhibition of tumor cell proliferation and angiogenesis. It also potentiates the activity of rituximab and has pleiotropic effects on the immune microenvironment that in aggregate, strengthen the immune synapse.23 Although in multiple myeloma it is known that a major part of the mechanism of action of lenalidomide is mediated by cereblon,24 a central role for the latter in lymphoma is not established and the primary mode of action of lenalidomide in lymphoma and chronic lymphocytic leukemia remains unclear. However, after studies showed that lenalidomide had particularly cytotoxic activity in ABC cell lines that was mediated via strong inhibition of NF-kB,25 it has become an attractive agent for inclusion in the treatment of ABC DLBCL. Early trials that evaluated single-agent lenalidomide in heavily pretreated patients with recurrent/refractory DLBCL yielded
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response rates of 19% to 28% (Table 1).26-30 Retrospective analyses showed that responses were tightly associated with an ABC COO, an observation that fit with the potent inhibition of NF-kB signaling by lenalidomide.29,30 More recently, Czuczman et al reported the results from a prospective phase II/III trial in which 111 patients with relapsed or refractory DLBCL were randomized to single-agent lenalidomide versus investigator’s choice (IC; gemcitabine, rituximab, etoposide, or oxaliplatin).12 Compared with IC, lenalidomide showed an improved overall response rate (27.5% vs. 11.8%) and progression-free survival (PFS; 13.6 weeks vs. 7.9 weeks). In contrast to the retrospective analyses that showed lenalidomide responses were nearly entirely limited to ABC lymphomas, this study showed a similar response rate in ABC and GCB COO (determined using IHC) but there was a trend for prolonged PFS in the ABC group. Interestingly, in a subgroup of patients in whom GEP was also performed, 5 of 11 patients with ABC lymphoma responded to lenalidomide and had a PFS of 82 weeks compared with only 3 of 21 patients with GCB type with a PFS of only 13.2 weeks. In view of the small number of patients who had GEP, the finding of more and frequent and durable responses in the ABC group should be considered preliminary especially because there was not a survival advantage for lenalidomide in any group of patients. Similarly, retrospective series that identified COO according to Hans IHC criteria have not shown a survival advantage after lenalidomide in ABC compared with GCB patients despite lopsided response rates favoring ABC versus GCB.29,30 An important observation in the study by Czuczman et al as well as others12-14 is the relatively poor agreement between IHC and GEP with only an 82% concordance rate. Accordingly, current studies generally use a validated nanostring technology that can be performed on formalinfixed paraffin-embedded tissue.22 A notable advantage of the latter platform is that in addition to more accurate assignment to ABC and GCB COO, it preserves the 10% to 15% unclassifiable rate of GEP, an important distinction from the binary IHC classifications. A recent study has highlighted the ability of lenalidomide to enhance the activity of accessory immune cells including natural killer (NK) cells and macrophages.31 MOR208 is a humanized monoclonal anti-CD19 antibody that has been Fc-engineered to increase NK-mediated antibody-dependent cytotoxicity and macrophage-mediated antibody-dependent phagocytosis. In a population of 81 relapsed/refractory patients with a median age of
Mendel Goldfinger et al Table 2 Expression of PD-L1 in DLBCL Non-GCB Trial Andorsky et al Kiyasu et al49 Xing et al50
PD-L1 47
3/6 6/13 110/792 10/31
D
(50%) (32%) (14%) (32%)
GCB PD-L1D 0/6 0/11 22/451 4/52
(0%) (0%) (5%) (8%)
Specimens Cell lines Lymphoma tissue Lymphoma tissue Lymphoma tissue
Abbreviations: DLBCL ¼ diffuse large B-cell lymphoma; GCB ¼ germinal center B; PD-L1 ¼ programmed death ligand 1.
72 years who had been treated with 1 to 3 regimens and who were not candidates for autologous stem cell transplantation, MOR208 administered weekly and then every other week with a standard schedule of lenalidomide 25 mg/d for 21 days, resulted in an overall response rate of 58%, including 33% complete responses (CRs). Responses were durable with the median duration of response not reached and with 70% of responding patients remaining progression-free after 12 months. A breakdown of ABC versus GCB type was not presented. Nevertheless, the high overall response rate suggests that this combination was active in both types of lymphoma and supports the idea that lenalidomide used in combination might enhance lymphoma cell-killing through mechanisms apart from direct cytotoxicity. MOR208 has been awarded breakthrough status on the basis of these result. Because the approved chimeric antigen receptor T-cell products also target CD19, it will be important to determine whether previous MOR208 treatment reduces the response rate with subsequent chimeric antigen receptor T-cell therapy. Lenalidomide is also one of several agents that are being used in combination with R/CHOP in a strategy called R(X)/CHOP (X has also included everolimus,32 epratuzumab,33 bortezomib,17,18 and ibrutinib34) to improve the outcome of DLBCL in the front-line setting. In a pilot study of R2/CHOP (lenalidomide with R/ CHOP), Nowakowski et al35 showed that in contrast to an earlier control group treated with R/CHOP, the PFS and overall survival of ABC lymphoma patients treated with R2/CHOP approximated that of GCB patients in the current and retrospective cohorts, suggesting that the additional use of lenalidomide abolished the adverse effect of ABC COO but also implied a lack of activity in GCB lymphoma. A recently published longer follow-up with a larger population of patients confirmed these findings.36 Nevertheless, these observations must be considered tentative on the basis of the comparison with a retrospective cohort, the relatively small number of patients treated with R2/CHOP, and the inherent error rate in assigning COO according to IHC. Moreover, a recent retrospective analysis of the prospectively conducted RICHOVER-60 and R-MegaCHOEP studies14 did not show a decreased survival in ABC patients, thereby challenging what has become a fundamental tenet since the earliest study of COO in DLBCL.37 Two completely accrued trials including an Eastern Cooperative Oncology Group trial (NCT01856192), in which R2/CHOP is compared with R/CHOP, and the ROBUST trial (NCT02285062), in which the study population is restricted to patients with ABC DLBCL should provide a more definitive answer regarding the differential effect of lenalidomide in ABC versus GCB lymphomas.
Apart from the eagerly anticipated results of ongoing studies that are comparing R2/CHOP versus R/CHOP, an additional situation in which R2/CHOP requires further exploration is the patient with a high risk of secondary CNS disease. Although intrathecal methotrexate and Cytarabine have been traditionally used for CNS prophylaxis, their benefit is questionable,38,39 possibly in part because spread of lymphoma to the (inaccessible) brain parenchyma is more common than to the leptomeninges.39 Conversely, prophylactic systemic high dose (3 g/m2) methotrexate, although theoretically sound and clinically effective,40 is not an ideal option because of the potential for renal toxicity and the need for hospitalization in most centers.41 In the latter regard, Castellino et al reported that there were only 2 CNS relapses in 112 patients treated with R2/CHOP, despite a significant number of patients with high-risk disease.36 Rubenstein et al have provided the pharmacokinetic rationale for the potential effectiveness of lenalidomide because the cerebrospinal fluid/plasma partition coefficient is 20% at 15- and 20-mg dose levels and 9/14 patients with CNS lymphoma achieved response to lenalidomide monotherapy.42 Although identifying a population at high risk for CNS disease is controversial, Klanova et al showed that in a population of 1418 DLBCL patients randomized to R/CHOP versus obinutuzumab with CHOP, ABC and unclassifiable COO were independently associated with an increased risk for CNS disease such that patients who had a high CNS-IPI score and ABC/unclassifiable COO, the risk of CNS disease was 15.8%.39 Because lenalidomide is reputed to be particularly active in ABC COO, the additional use of lenalidomide for CNS prophylaxis should be further studied in these high-risk patients. Another niche area that requires further evaluation is the use of R2/CHOP in MYC-rearranged patients. Chamuleau et al recently reported the results of a phase II HOVON trial in which 58 patients with MYC-rearranged DLBCL were treated with R2/CHOP of whom 41 (78%) had double-hit lymphoma. In this group that also received intrathecal methotrexate, 62% achieved a positron emission tomography-computed tomography CR and a 1-year overall survival of 79%.43 Because nearly all double-/triple-hit lymphomas are of GCB origin and therefore theoretically unlikely to benefit from the additional use of lenalidomide, it is not clear why this combination was studied. Nevertheless, the results were excellent and require confirmation. A weakness of these data is that a single hit with MYC rearrangement was shown in a much larger study to be of minor prognostic importance and even double-/ triple-hit lymphomas in which the MYC translocation partner was not an immunoglobulin gene, was also found to be minimally disadvantageous.44 Because 21% of the patients in the lenalidomide with R/CHOP study had a single hit and the translocation partner of the double-/triple-hit patients was not described, it is difficult to place this study in context. It should also be noted that in more recent trials in which MYC rearrangement and double-/ triple-hit pathology were found retrospectively in patients prospectively enrolled in clinical trials for DLBCL, the outcome has not been nearly as dismal as expected. For example, in the large study by Rosenwald et al, the overall survival was worst for double-/triple-hit and MYC translocated to an immunoglobulin gene at 51% at 2 years compared with 76.4% for the remaining MYCrearranged patients.44
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Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma Two recent studies have suggested a potentially important role for lenalidomide in the maintenance setting. Thieblemont et al showed that lenalidomide was associated with a statistically significant increase in PFS in older (60-80 years of age) patients who achieved a partial response or CR after first-line R/CHOP treatment.45 In subset analysis this advantage was limited to patients with GCB type according to IHC but was not apparent in patients analyzed with the more accurate nanostring technology. Similarly, Ferreri et al showed promising results with maintenance lenalidomide in patients with relapsed DLBCL who had achieved remission but were transplantation-ineligible because of age or comorbidities. They also did not find a difference in response in GCB versus ABC COO.46 The apparent lack of effect of COO in the maintenance studies has been considered as evidence that the mechanism of action might be immunologic rather than directly tumoricidal, a hypothesis consistent with the immunomodulatory activity of lenalidomide but for which direct evidence is lacking. With respect to the immune microenvironment in DLBCL, it has recently been shown that approximately 10% to 17% of patients with DLBCL have evidence of programmed death ligand 1 (PD-L1) expression on tumor cells47-50 but with a much higher incidence and percentage of positive tumor cells in patients with Epstein-Barr Virus-associated DLBCL.48 Several studies have shown that the presence of PD-L1 in DLBCL has been seen predominantly in patients with ABC lymphoma (Table 2)47-50 and in some studies, has been associated with a poorer prognosis.49,50 Although programmed death 1/PD-L1 inhibitors have been shown to have good activity in patients with high expression of PD-L1 such as classic Hodgkin lymphoma,51-54 NK T-cell lymphoma55 and a small series of CNS lymphomas,56 the activity of checkpoint inhibitors in lymphomas with a lower expression of PD-L1 is uncertain.57 Interestingly, lenalidomide has been shown to downregulate PDL1 in myeloma58 and lymphoma cells, thereby providing another potential mechanism of action in the latter diseases.59 Future studies should also focus on the minimum dose of lenalidomide required for immunomodulatory/maintenance therapy, which might be lower than the dose being tested in combination with R/CHOP. For example, in the recent lenalidomide maintenance study by Thieblemont et al, in which a dose of 25 mg/d was used, 61% of patients terminated treatment prematurely suggesting that the impressive results of lenalidomide on PFS might have been even greater with a better tolerated dose.45 The relatively benign side effect profile of low-dose lenalidomide (10 mg) should also facilitate combination immunomodulatory protocols as are already being explored in multiple myeloma.60 For example, Chan et al described a patient with primary refractory double-hit lymphoma with a remarkable response to the combination treatment with pembrolizumab and lenalidomide.61 Clearly, other poor-prognosis lymphomas such as Richter syndrome that have recently been shown to have some responsiveness to checkpoint inhibition, would also be candidates for combination therapy.62
Conclusion Completed but not yet reported studies will determine whether the additional use of lenalidomide increases the cure rate of R/CHOP in DLBCL and whether this effect is limited to lymphomas with an ABC COO as predicted by GEP. Lenalidomide
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should be further evaluated in patients with a high risk for CNS spread as well as in the maintenance setting for high risk patients who are not transplantation candidates. Thus far, the available evidence does not suggest that when used in the maintenance setting that the COO is important. The results of combination immunomodulatory treatments in which lenalidomide is combined with checkpoint inhibitors are eagerly awaited.
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Mendel Goldfinger et al 23. Gribben JG, Fowler N, Morschhauser F. Mechanisms of action of lenalidomide in B-cell non-Hodgkin lymphoma. J Clin Oncol 2015; 33:2803-11. 24. Kronke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014; 343:301-5. 25. Yang Y, Shaffer AL 3rd, Emre NC, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell 2012; 21:723-37. 26. Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin lymphoma. J Clin Oncol 2008; 26:4952-7. 27. Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin lymphoma. J Clin Oncol 2009; 27:5404-9. 28. Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of singleagent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Ann Oncol 2011; 22:1622-7. 29. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer 2011; 117: 5058-66. 30. Mondello P, Steiner N, Willenbacher W, et al. Lenalidomide in relapsed or refractory diffuse large B-cell lymphoma: is it a valid treatment option? Oncologist 2016; 21:1107-12. 31. Salles GA, Duell J, Gonzalez-Barca E, et al. Single-arm phase II study of MOR208 combined with lenalidomide in patients with relapsed or refractory diffuse large Bcell lymphoma: L-Mind. Blood 2017; 130:4123. 32. Johnston PB, LaPlant B, McPhail E, et al. Everolimus combined with R-CHOP21 for new, untreated, diffuse large B-cell lymphoma (NCCTG 1085 [Alliance]): safety and efficacy results of a phase 1 and feasibility trial. Lancet Haematol 2016; 3: e309-16. 33. Micallef IN, Maurer MJ, Wiseman GA, et al. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma. Blood 2011; 118: 4053-61. 34. Younes A, Sehn LH, Johnson P, et al. A global, randomized, placebo-controlled, phase 3 study of ibrutinib plus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP) in patients with previously untreated nongerminal center B-cell-like diffuse large B-cell lymphoma. Blood 2018; 132:784. 35. Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with RCHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J Clin Oncol 2015; 33:251-7. 36. Castellino A, Chiappella A, LaPlant BR, et al. Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials. Blood Cancer J 2018; 8:108. 37. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503-11. 38. Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood 2009; 113:3896-902. 39. Klanova M, Sehn LH, Bence-Bruckler I, et al. Integration of COO into the clinical CNS International Prognostic Index could improve CNS relapse prediction in DLBCL. Blood 2019; 133:919-26. 40. Ferreri AJ, Bruno-Ventre M, Donadoni G, et al. Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era. Br J Haematol 2015; 168:654-62. 41. Chin CK, Cheah CY. How I treat patients with aggressive lymphoma at high risk of CNS relapse. Blood 2017; 130:867-74. 42. Rubenstein JL, Geng H, Fraser EJ, et al. Phase 1 investigation of lenalidomide/ rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv 2018; 2:1595-607.
43. Chamuleau ME, Nijland M, Zijlstra JM, et al. Successful treatment of MYC rearrangement positive large B cell lymphoma patients with R-CHOP 21 plus lenalidomide: results of a multicenter phase II HOVON trial. Blood 2018; 132:786. 44. Rosenwald A, Sehn LH, Maucort-Boulch D. Prognostic significance of MYC single, double, triple hit and MYC-translocation partner status in diffuse large Bcell lymphoma - a study by the Lunenburg lymphoma biomarker consortium. Blood 2018; 132:627. 45. Thieblemont C, Tilly H, Gomes da Silva M, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 2017; 35:2473-81. 46. Ferreri AJ, Sassone M, Zaja F, et al. Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial. Lancet Haematol 2017; 4:e137-46. 47. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res 2011; 17:4232-44. 48. Chen BJ, Chapuy B, Ouyang J, et al. PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 2013; 19:3462-73. 49. Kiyasu J, Miyoshi H, Hirata A, et al. Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood 2015; 126:2193-201. 50. Xing W, Dresser K, Zhang R, et al. PD-L1 expression in EBV-negative diffuse large B-cell lymphoma: clinicopathologic features and prognostic implications. Oncotarget 2016; 7:59976-86. 51. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin lymphoma. N Engl J Med 2015; 372:311-9. 52. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol 2016; 34:3733-9. 53. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol 2017; 35:2125-32. 54. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 2016; 17:1283-94. 55. Kwong YL, Chan TS, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood 2017; 129:2437-42. 56. Nayak L, Iwamoto FM, LaCasce A, et al. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 2017; 129:3071-3. 57. Galanina N, Kline J, Bishop MR. Emerging role of checkpoint blockade therapy in lymphoma. Ther Adv Hematol 2017; 8:81-90. 58. Giuliani M, Janji B, Berchem G. Activation of NK cells and disruption of PD-L1/ PD-1 axis: two different ways for lenalidomide to block myeloma progression. Oncotarget 2017; 8:24031-44. 59. Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood 2012; 120:1412-21. 60. Badros A, Hyjek E, Ma N, et al. Pembrolizumab, pomalidomide and low dose dexamethasone for relapsed/refractory multiple myeloma. Blood 2017; 130: 1189-97. 61. Chan TS, Khong PL, Kwong YL. Pembrolizumab and lenalidomide induced remission in refractory double-hit lymphoma. Ann Hematol 2016; 95:1917-8. 62. Ding W, LaPlant BR, Call TG, et al. Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL. Blood 2017; 129:3419-27.
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Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma Mendel Goldfinger,1 Mina Xu,2 Joseph R. Bertino,1 Dennis L. Cooper1 Abstract Lenalidomide has modest single-agent activity comparable with other newer drugs in recurrent diffuse large B cell lymphoma with response rates between 19% and 28%. Retrospective series and 1 prospective study suggest that clinically significant responses were predominantly limited to patients with activated B cell (ABC) lymphoma, a finding in agreement with lenalidomide’s potent inhibition of nuclear factor kB, the key driver of ABC lymphomas. Recently completed trials will determine whether the additional use of lenalidomide with R/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) enhances survival compared with R/CHOP alone and whether this activity is limited to ABC lymphomas. Lenalidomide also appears to have activity in the maintenance setting regardless of cell of origin and might play an important role in patients with recurrent disease who are not transplantation candidates. Similarly, because of the ability of lenalidomide to cross the bloodebrain barrier, it needs to be further explored in patients with high risk for central nervous system spread. The results of lenalidomide combination studies with chemotherapy and with checkpoint inhibitors are eagerly awaited. Clinical Lymphoma, Myeloma & Leukemia, Vol. 19, No. 6, e307-11 ª 2019 Elsevier Inc. All rights reserved. Keywords: Activated B-cell, Cell of origin, Germinal center, PDL-1, Revlimid
Diffuse large B-cell lymphoma (DLBCL) accounts for approximately one-third of non-Hodgkin lymphoma1 and is projected to be the seventh most common malignancy diagnosed in the United States in 2019.2 Although the prognosis of DLBCL significantly improved 15 years ago with the additional use of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone),3 up to 40% of patients are not cured and it is disappointing that R/CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard of care for newly treated patients today. Thus, recent strategies incorporating higher dose intensity afforded by growth factors and stem cells have not resulted in superior cure rates4-6 and the preliminary report of a long-awaited study that compared continuous infusion dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab with R/CHOP was also negative.7 The results of treatment for recurrent disease remain poor, particularly for patients who have primary resistance or relapse 1 Department of Hematology and Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, Robert Wood Johnson Medical School, New Brunswick, NJ 2 Department of Pathology, Yale School of Medicine, New Haven, CT
Submitted: Oct 8, 2018; Revised: Jan 27, 2019; Accepted: Feb 15, 2019; Epub: Feb 27, 2019 Address for correspondence: Mendel Goldfinger, MD, Department of Hematology and Medical Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, 195 Little Albany St, New Brunswick, NJ 08901 E-mail contact: mendelgoldfi[email protected]
2152-2650/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.clml.2019.02.012
within 1 year of completing rituximab-containing treatment.8 In addition, there have been no US Food and Drug Administration (FDA)-approved second-line therapies for DLBCL and it seems that for now, strategies such as chimeric antigen receptor T cells, which are FDA-approved as a third-line treatment, offers the greatest hope for patients in whom R/CHOP treatment has failed.9,10 In contrast to the lack of progress in primary treatment, there has been a dramatic increase in the understanding of the heterogeneous biology of DLBCL and the hope that this knowledge can be leveraged into better treatments in the near future. For example, gene expression profiling (GEP) has divided most cases of DLBCL into lymphomas arising from germinal center B (GCB) or activated B cells with a small fraction remaining unclassified.11 GCB lymphomas have different biologic features than activated B cell (ABC) lymphomas, which are thought to arise from cells in the post germinal center and are blocked at the stage of plasmacytic differentiation. The ABC, GCB, and unclassified groups have been imperfectly compressed into GCB and non-GCB cell of origin (COO) using more widely available immunohistochemistry (IHC) techniques but with a 10% to 20% lack of fidelity compared with GEP, not including the cases in the GEP unclassified category.12-14 The COO has had prognostic significance in most11,13,15,16 but not all studies14 with response and overall survival after R/CHOP worse in non-GCB compared with GCB lymphoma. The poorer response in the ABC lymphomas is believed to be due to multiple factors, especially constitutive activation of the antiapoptotic nuclear factor
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Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma Table 1 Studies Using Single-Agent Lenalidomide in DLBCL Reference
Patient n
Dose
Trial Design
Response Rate (%)
Wiernik et al26
26
25 mg days 1-25
Prospective; median 4 previous Rx
19; only 1/26 had CR
Witzig et al28
108
25 mg days 1-25
Prospective; median 3 previous Rx
40
25 mg days 1-21
123
15 or 25 mg days 1-21
Retrospective; median 4 previous Rx Retrospective; median 1 previous Rx
Hernandez-Ilizaliturri et al29 Mondello et al30
Comment
Response rate similar to that with other effective single agents, lower response than in MCL, follicular grade III, and transformed follicular lymphoma 28; 7/30 had CR Response rate similar to that with other effective single agents, lower response than in MCL, follicular grade III, and transformed follicular lymphoma 53 (ABC) vs. 9 (GCB) No increase in OS in ABC vs. GCB 65 (ABC) vs. 3 (GCB)
No increase in OS in ABC vs. GCB
Abbreviations: ABC ¼ activated B-cell; DLBCL ¼ diffuse large B-cell lymphoma; GCB ¼ germinal center B; MCL ¼ mantle-cell lymphoma; OS ¼ overall survival; Rx ¼ treatment.
kB (NF-kB) signaling pathway. Accordingly, the latter was a major target of recent negative studies in which R/CHOP was not inferior to R/CHOP regimens in which bortezomib was either substituted for vincristine17 or given in addition to vincristine.18 Interestingly, there appears to be geographic differences in the proportion of ABC lymphomas because a recent preliminary study suggests that ABC lymphomas are nearly twice as common in East Asian populations than North America/Australia/New Zealand populations.19 In addition to ABC COO, recurrent genomic translocations involving MYC and either BCL2 and/or BCL6 detected using fluorescence in situ hybridization analysis, so-called “double and triple hit lymphoma” have been associated with an especially dismal prognosis and a high incidence of central nervous system (CNS) spread.20,21 Although most double/triple hit lymphomas also show IHC overexpression of MYC and BCL2 (“double-expressors”), it is important to recognize that double-expressor lymphomas are much more common than double-hit lymphomas.20,21 In addition, although double-expressor lymphomas are more common in ABC than GCB COO, double- and triple-hit lymphomas are almost entirely confined to lymphomas of GCB origin.22 At present, other than being associated with a worse prognosis, there is no treatment implication for the diagnosis of double-expressor lymphoma whereas double- and triple-hit lymphomas have been recommended to receive dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab and CNS prophylaxis.20,21 Lenalidomide (Revlimid; Celgene Corp, Summit, NJ) is a second-generation immunomodulatory drug, which has direct antineoplastic activity mediated by inhibition of tumor cell proliferation and angiogenesis. It also potentiates the activity of rituximab and has pleiotropic effects on the immune microenvironment that in aggregate, strengthen the immune synapse.23 Although in multiple myeloma it is known that a major part of the mechanism of action of lenalidomide is mediated by cereblon,24 a central role for the latter in lymphoma is not established and the primary mode of action of lenalidomide in lymphoma and chronic lymphocytic leukemia remains unclear. However, after studies showed that lenalidomide had particularly cytotoxic activity in ABC cell lines that was mediated via strong inhibition of NF-kB,25 it has become an attractive agent for inclusion in the treatment of ABC DLBCL. Early trials that evaluated single-agent lenalidomide in heavily pretreated patients with recurrent/refractory DLBCL yielded
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response rates of 19% to 28% (Table 1).26-30 Retrospective analyses showed that responses were tightly associated with an ABC COO, an observation that fit with the potent inhibition of NF-kB signaling by lenalidomide.29,30 More recently, Czuczman et al reported the results from a prospective phase II/III trial in which 111 patients with relapsed or refractory DLBCL were randomized to single-agent lenalidomide versus investigator’s choice (IC; gemcitabine, rituximab, etoposide, or oxaliplatin).12 Compared with IC, lenalidomide showed an improved overall response rate (27.5% vs. 11.8%) and progression-free survival (PFS; 13.6 weeks vs. 7.9 weeks). In contrast to the retrospective analyses that showed lenalidomide responses were nearly entirely limited to ABC lymphomas, this study showed a similar response rate in ABC and GCB COO (determined using IHC) but there was a trend for prolonged PFS in the ABC group. Interestingly, in a subgroup of patients in whom GEP was also performed, 5 of 11 patients with ABC lymphoma responded to lenalidomide and had a PFS of 82 weeks compared with only 3 of 21 patients with GCB type with a PFS of only 13.2 weeks. In view of the small number of patients who had GEP, the finding of more and frequent and durable responses in the ABC group should be considered preliminary especially because there was not a survival advantage for lenalidomide in any group of patients. Similarly, retrospective series that identified COO according to Hans IHC criteria have not shown a survival advantage after lenalidomide in ABC compared with GCB patients despite lopsided response rates favoring ABC versus GCB.29,30 An important observation in the study by Czuczman et al as well as others12-14 is the relatively poor agreement between IHC and GEP with only an 82% concordance rate. Accordingly, current studies generally use a validated nanostring technology that can be performed on formalinfixed paraffin-embedded tissue.22 A notable advantage of the latter platform is that in addition to more accurate assignment to ABC and GCB COO, it preserves the 10% to 15% unclassifiable rate of GEP, an important distinction from the binary IHC classifications. A recent study has highlighted the ability of lenalidomide to enhance the activity of accessory immune cells including natural killer (NK) cells and macrophages.31 MOR208 is a humanized monoclonal anti-CD19 antibody that has been Fc-engineered to increase NK-mediated antibody-dependent cytotoxicity and macrophage-mediated antibody-dependent phagocytosis. In a population of 81 relapsed/refractory patients with a median age of
Mendel Goldfinger et al Table 2 Expression of PD-L1 in DLBCL Non-GCB Trial Andorsky et al Kiyasu et al49 Xing et al50
PD-L1 47
3/6 6/13 110/792 10/31
D
(50%) (32%) (14%) (32%)
GCB PD-L1D 0/6 0/11 22/451 4/52
(0%) (0%) (5%) (8%)
Specimens Cell lines Lymphoma tissue Lymphoma tissue Lymphoma tissue
Abbreviations: DLBCL ¼ diffuse large B-cell lymphoma; GCB ¼ germinal center B; PD-L1 ¼ programmed death ligand 1.
72 years who had been treated with 1 to 3 regimens and who were not candidates for autologous stem cell transplantation, MOR208 administered weekly and then every other week with a standard schedule of lenalidomide 25 mg/d for 21 days, resulted in an overall response rate of 58%, including 33% complete responses (CRs). Responses were durable with the median duration of response not reached and with 70% of responding patients remaining progression-free after 12 months. A breakdown of ABC versus GCB type was not presented. Nevertheless, the high overall response rate suggests that this combination was active in both types of lymphoma and supports the idea that lenalidomide used in combination might enhance lymphoma cell-killing through mechanisms apart from direct cytotoxicity. MOR208 has been awarded breakthrough status on the basis of these result. Because the approved chimeric antigen receptor T-cell products also target CD19, it will be important to determine whether previous MOR208 treatment reduces the response rate with subsequent chimeric antigen receptor T-cell therapy. Lenalidomide is also one of several agents that are being used in combination with R/CHOP in a strategy called R(X)/CHOP (X has also included everolimus,32 epratuzumab,33 bortezomib,17,18 and ibrutinib34) to improve the outcome of DLBCL in the front-line setting. In a pilot study of R2/CHOP (lenalidomide with R/ CHOP), Nowakowski et al35 showed that in contrast to an earlier control group treated with R/CHOP, the PFS and overall survival of ABC lymphoma patients treated with R2/CHOP approximated that of GCB patients in the current and retrospective cohorts, suggesting that the additional use of lenalidomide abolished the adverse effect of ABC COO but also implied a lack of activity in GCB lymphoma. A recently published longer follow-up with a larger population of patients confirmed these findings.36 Nevertheless, these observations must be considered tentative on the basis of the comparison with a retrospective cohort, the relatively small number of patients treated with R2/CHOP, and the inherent error rate in assigning COO according to IHC. Moreover, a recent retrospective analysis of the prospectively conducted RICHOVER-60 and R-MegaCHOEP studies14 did not show a decreased survival in ABC patients, thereby challenging what has become a fundamental tenet since the earliest study of COO in DLBCL.37 Two completely accrued trials including an Eastern Cooperative Oncology Group trial (NCT01856192), in which R2/CHOP is compared with R/CHOP, and the ROBUST trial (NCT02285062), in which the study population is restricted to patients with ABC DLBCL should provide a more definitive answer regarding the differential effect of lenalidomide in ABC versus GCB lymphomas.
Apart from the eagerly anticipated results of ongoing studies that are comparing R2/CHOP versus R/CHOP, an additional situation in which R2/CHOP requires further exploration is the patient with a high risk of secondary CNS disease. Although intrathecal methotrexate and Cytarabine have been traditionally used for CNS prophylaxis, their benefit is questionable,38,39 possibly in part because spread of lymphoma to the (inaccessible) brain parenchyma is more common than to the leptomeninges.39 Conversely, prophylactic systemic high dose (3 g/m2) methotrexate, although theoretically sound and clinically effective,40 is not an ideal option because of the potential for renal toxicity and the need for hospitalization in most centers.41 In the latter regard, Castellino et al reported that there were only 2 CNS relapses in 112 patients treated with R2/CHOP, despite a significant number of patients with high-risk disease.36 Rubenstein et al have provided the pharmacokinetic rationale for the potential effectiveness of lenalidomide because the cerebrospinal fluid/plasma partition coefficient is 20% at 15- and 20-mg dose levels and 9/14 patients with CNS lymphoma achieved response to lenalidomide monotherapy.42 Although identifying a population at high risk for CNS disease is controversial, Klanova et al showed that in a population of 1418 DLBCL patients randomized to R/CHOP versus obinutuzumab with CHOP, ABC and unclassifiable COO were independently associated with an increased risk for CNS disease such that patients who had a high CNS-IPI score and ABC/unclassifiable COO, the risk of CNS disease was 15.8%.39 Because lenalidomide is reputed to be particularly active in ABC COO, the additional use of lenalidomide for CNS prophylaxis should be further studied in these high-risk patients. Another niche area that requires further evaluation is the use of R2/CHOP in MYC-rearranged patients. Chamuleau et al recently reported the results of a phase II HOVON trial in which 58 patients with MYC-rearranged DLBCL were treated with R2/CHOP of whom 41 (78%) had double-hit lymphoma. In this group that also received intrathecal methotrexate, 62% achieved a positron emission tomography-computed tomography CR and a 1-year overall survival of 79%.43 Because nearly all double-/triple-hit lymphomas are of GCB origin and therefore theoretically unlikely to benefit from the additional use of lenalidomide, it is not clear why this combination was studied. Nevertheless, the results were excellent and require confirmation. A weakness of these data is that a single hit with MYC rearrangement was shown in a much larger study to be of minor prognostic importance and even double-/ triple-hit lymphomas in which the MYC translocation partner was not an immunoglobulin gene, was also found to be minimally disadvantageous.44 Because 21% of the patients in the lenalidomide with R/CHOP study had a single hit and the translocation partner of the double-/triple-hit patients was not described, it is difficult to place this study in context. It should also be noted that in more recent trials in which MYC rearrangement and double-/ triple-hit pathology were found retrospectively in patients prospectively enrolled in clinical trials for DLBCL, the outcome has not been nearly as dismal as expected. For example, in the large study by Rosenwald et al, the overall survival was worst for double-/triple-hit and MYC translocated to an immunoglobulin gene at 51% at 2 years compared with 76.4% for the remaining MYCrearranged patients.44
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Checking in on Lenalidomide in Diffuse Large B Cell Lymphoma Two recent studies have suggested a potentially important role for lenalidomide in the maintenance setting. Thieblemont et al showed that lenalidomide was associated with a statistically significant increase in PFS in older (60-80 years of age) patients who achieved a partial response or CR after first-line R/CHOP treatment.45 In subset analysis this advantage was limited to patients with GCB type according to IHC but was not apparent in patients analyzed with the more accurate nanostring technology. Similarly, Ferreri et al showed promising results with maintenance lenalidomide in patients with relapsed DLBCL who had achieved remission but were transplantation-ineligible because of age or comorbidities. They also did not find a difference in response in GCB versus ABC COO.46 The apparent lack of effect of COO in the maintenance studies has been considered as evidence that the mechanism of action might be immunologic rather than directly tumoricidal, a hypothesis consistent with the immunomodulatory activity of lenalidomide but for which direct evidence is lacking. With respect to the immune microenvironment in DLBCL, it has recently been shown that approximately 10% to 17% of patients with DLBCL have evidence of programmed death ligand 1 (PD-L1) expression on tumor cells47-50 but with a much higher incidence and percentage of positive tumor cells in patients with Epstein-Barr Virus-associated DLBCL.48 Several studies have shown that the presence of PD-L1 in DLBCL has been seen predominantly in patients with ABC lymphoma (Table 2)47-50 and in some studies, has been associated with a poorer prognosis.49,50 Although programmed death 1/PD-L1 inhibitors have been shown to have good activity in patients with high expression of PD-L1 such as classic Hodgkin lymphoma,51-54 NK T-cell lymphoma55 and a small series of CNS lymphomas,56 the activity of checkpoint inhibitors in lymphomas with a lower expression of PD-L1 is uncertain.57 Interestingly, lenalidomide has been shown to downregulate PDL1 in myeloma58 and lymphoma cells, thereby providing another potential mechanism of action in the latter diseases.59 Future studies should also focus on the minimum dose of lenalidomide required for immunomodulatory/maintenance therapy, which might be lower than the dose being tested in combination with R/CHOP. For example, in the recent lenalidomide maintenance study by Thieblemont et al, in which a dose of 25 mg/d was used, 61% of patients terminated treatment prematurely suggesting that the impressive results of lenalidomide on PFS might have been even greater with a better tolerated dose.45 The relatively benign side effect profile of low-dose lenalidomide (10 mg) should also facilitate combination immunomodulatory protocols as are already being explored in multiple myeloma.60 For example, Chan et al described a patient with primary refractory double-hit lymphoma with a remarkable response to the combination treatment with pembrolizumab and lenalidomide.61 Clearly, other poor-prognosis lymphomas such as Richter syndrome that have recently been shown to have some responsiveness to checkpoint inhibition, would also be candidates for combination therapy.62
Conclusion Completed but not yet reported studies will determine whether the additional use of lenalidomide increases the cure rate of R/CHOP in DLBCL and whether this effect is limited to lymphomas with an ABC COO as predicted by GEP. Lenalidomide
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should be further evaluated in patients with a high risk for CNS spread as well as in the maintenance setting for high risk patients who are not transplantation candidates. Thus far, the available evidence does not suggest that when used in the maintenance setting that the COO is important. The results of combination immunomodulatory treatments in which lenalidomide is combined with checkpoint inhibitors are eagerly awaited.
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