Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), and accounts for about a quarter of cases in the United States, with more than 27,000 new cases identified each year.1 Depending on factors including race and gender, 5-year survival ranges from approximately 55% to 62%, although patients treated with first-line immunochemotherapy can achieve cure rates of 60% to 70%.1,2
First-line therapy has been established with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), although dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) has shown efficacy for patients with MYC-rearranged aggressive B-cell lymphomas.3 However, 30% to 40% of patients will experience a relapse following first-line treatment and an additional 10% of patients will have primary refractory disease.4
According to revised guidelines issued in 2007 by the International Harmonization Project, relapsed DLBCL is defined by the appearance of any new lesion following a complete response, with refractory DLBCL being the failure to reduce more than 50% of lesions in size after initial therapy.5 The prognosis for relapsed patients has traditionally been poor, with survival largely dependent on the type of therapy administered and response post relapse, although a wide range of regimens are available for second-line and subsequent treatments.6 Salvage combination cytotoxic chemotherapy followed by high-dose myeloablative therapy and autologous stem cell transplantation (ASCT) or in select cases, allogeneic hematopoietic cell transplantation (alloHCT), has been the standard care for eligible relapsed/refractory patients and can be curative in some cases. However, eligibility for this approach depends largely on response to salvage chemotherapy, performance status, age, and the presence of comorbidities, and only half of patients with relapsed or refractory disease are candidates for transplant.4
Several combination chemotherapy regimens are currently used for patients who are not transplant candidates, and, in addition, the landscape of treatment for relapsed/refractory DLBCL continues to evolve. Several new agents have recently entered the marketplace that may provide options for at least some patients. These include polatuzumab vedotin-piiq, an antibody drug conjugate used in combination with bendamustine and rituximab; tafasitamab-cxix, a CD19-directed cytolytic antibody used with lenalidomide; and selinexor, for use after at least 2 lines of systemic therapy.
Among patients who are not eligible for transplantation, radiation therapy can also be an option, as it may provide effective palliation and in select cases, may be administered with curative intent if the relapsed/refractory disease is localized.7
One of the major breakthroughs in treatment for relapsed/refractory DLBCL has been the development of chimeric antigen receptor (CAR) T-cell therapy. Two products, axicabtagene ciloleucel and tisagenlecleucel, have been approved for this indication, and both have demonstrated high rates of durable responses. Guidelines from the National Comprehensive Cancer Network (NCCN) recommend the use of CAR T-cell therapy for patients who achieve a partial response after receiving second-line therapy, whether or not they are eligible for a transplant, as well as for those who relapse after a complete response to second-line therapy or with progressive disease.8
Second-Line Therapy With Goal of ASCT
Second-line therapy followed by high-dose therapy with ASCT is the backbone of treatment for relapsed/refractory DLBCL that is chemotherapy-sensitive at the time of relapse. Currently, undergoing ASCT represents the best option for remission. Some data show that across all therapies, the 4-year rate of overall survival after relapse is 28%, but significantly improves to 51% for patients who undergo ASCT.9 A systematic review of observational and interventional studies reported a median survival of 10 months after relapse, in patient populations that include a mix of those who received second-line treatment and those who did not.6 The proportion of patients who were alive at 1 year was 41% post relapse, and 27% at 5 years. For those who received second-line therapy, those proportions were 60% and 30%, respectively. The median survival was 40 months from the time of ASCT postrelapse; 73% were alive at 1 year and 45% at 5 years.
NCCN guidelines recommend several regimens that can be used with intention to proceed to transplant. Their preferred regimens are as followed (in alphabetical order)8:
- Dexamethasone, cisplatin, cytarabine (DHAP) ± rituximab
- Dexamethasone, cytarabine, oxaliplatin (DHAX) ± rituximab
- Gemcitabine, dexamethasone, cisplatin (GDP) ± rituximab or gemcitabine, dexamethasone, carboplatin ± rituximab
- Ifosfamide, carboplatin, etoposide (ICE) ± rituximab
Other recommended regimens (in alphabetical order) include:
- Etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) ± rituximab
- Gemcitabine, oxaliplatin (GemOx) ± rituximab
- Mesna, ifosfamide, mitoxantrone, etoposide (MINE) ± rituximab
The most optimal chemotherapy regimens are those that provide the highest response rates with the most tolerable toxicity, but thus far, there is no clear evidence from randomized trials that shows one regimen to be superior over another.4 The NCCN recommends that rituximab should be included in the regimen if relapse occurs after a “reasonable” period of remission, such as more than 6 months, and continued C20 expression is shown on biopsy. The addition of rituximab to these protocols significantly improves progression‐free survival in patients who had not been previously exposed to it as part of their first-line treatment, but the use of rituximab in those who experienced an early relapse and prior exposure was associated with a worse outcome. One study found that the 3-year event-free survival was affected by prior rituximab treatment compared with no rituximab (21% vs 47%, respectively); however, the progression-free survival among responding patients (68 participants) who received ASCT was better than participants who did not undergo ASCT (39% vs 14%, respectively; P <.001).10 Given that many patients do develop disease that is refractory to rituximab, available evidence suggests reconsideration of its role in salvage therapy. The goal of second-line therapy is to proceed to ASCT, and patients who achieve a complete response can be treated with high dose consolidation therapy and radiotherapy in preparation for transplantation. Patients who achieve a partial response can also proceed to ASCT, while other options include CAR T-cell therapy or a clinical trial. Another alternative is alloHCT, which can be considered in patients with persistent bone marrow involvement or who had an inadequate response to second-line therapy.
Second-Line Without Transplant/Subsequent Therapy
A substantial proportion of patients are not eligible for high dose therapy followed by ASCT either because they were not initial candidates for this therapeutic sequence or did not achieve a satisfactory response from salvage therapy. Treatment options for this population include various chemotherapy regimens, enrollment into a clinical trial, radiotherapy to localized lesions, rituximab therapy, optimal supportive care, and palliative treatment.8
The NCCN guidelines also recommend second-line and subsequent regimens for patients who are not candidates for ASCT. These include:
- GemOx ± rituximab
- Polatuzumab vedotin ± bendamustine ± rituximab (given after ≥2 prior therapies and for patients with translocations of MYC and BCL2 and/or BCL6)
- Cyclophosphamide, etoposide, prednisone, procarbazine (CEPP) ± rituximab; orally and intravenously
- Cyclophosphamide, etoposide, vincristine, prednisone (CEOP) ± rituximab
- DA-EPOCH ± rituximab
- GDP ± rituximab or gemcitabine, dexamethasone, carboplatin ± rituximab
- Gemcitabine, vinorelbine ± rituximab (category 3)
Patients with CD30-positive disease may benefit from treatment with brentuximab vedotin and regimens of lenalidomide (with or without rituximab) and ibrutinib.11-13 These are all appropriate options to consider at relapse, particularly for those with nongerminal center B-cell–like (GCB) DLBCL.
Patients with refractory DLBCL, defined as no response to the last chemotherapy or relapse ≤12 months post-ASCT, have poor overall survival rates. Results from the SCHOLAR-1 study, a patient-level analysis of outcomes of refractory DLBCL from 2 large randomized trials and 2 academic databases, showed that response rates to treatment were consistently low (range 20%-39%) across all subgroups (primary refractory, refractory to second-line or later-line therapy, and relapsed ≤12 months after ASCT), with the lowest response rates observed in primary refractory and high-risk International Prognostic Score (IPI) cohorts.14
Options after second-line treatment, for those who are refractory to salvage therapy as well as relapsed disease following high dose therapy or alloHCT, include third-line systemic therapy, palliative involved site radiation therapy (ISRT), or best supportive care. The NCCN recommends that a biopsy should be repeated in patients who are ineligible for transplant after achieving a PET positive partial response to second-line therapy before initiating third-line treatment.8 The reasoning is that posttreatment inflammation can result in false positivity with resultant reduction in the specificity.
However, outcomes have been consistently poor for patients with progressive disease after 2 or more prior lines of systemic therapy, without the likelihood of gaining any additional benefits from further treatment.14 That said, several new therapies are now available which may offer options for at least some patients who have already received multiple lines of therapy and/or remain resistant to standard treatment.
CAR T-Cell Therapy
CAR T-cell therapy is an emerging modality in which a patient’s autologous T-cells are genetically modified to express a CAR specific for a tumor antigen, expanded in vitro, and then re-infused back to the patient. The first clinical report of CAR T-cells was published in 2010, in which a patient with advanced follicular lymphoma experienced a dramatic disease regression after receiving an infusion of CAR T-cells that were engineered to target CD19.15 The initial studies of CAR T-cell therapies selected CD19 as the target antigen since it is expressed on the surface of almost all B-cell malignancies, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and many types of non-Hodgkin lymphoma (NHL), as well as normal B-cell precursors. Two anti-CD19 CAR T-cell therapies, axicabtagene ciloleucel and tisagenlecleuce, have received regulatory approval for the treatment of adult patients with relapsed/refractory DLBCL.
A multicenter phase 2 JULIET study ( ClinicalTrials.gov Identifier: NCT02445248) evaluated tisagenlecleucel in patients with relapsed/refractory DLBCL who had received 2 or more lines of therapy and who were ineligible for or had disease progression after ASCT.16 The best overall response rate was 52%, with 40% of the cohort achieving a complete response and 12% of the cohort achieving a partial response. Response rates were consistent across all subgroups, and at 12 months following the initial response, the rate of relapse-free survival was estimated to be 65%; it was even higher (79%) among patients who had achieved a complete response.
Axicabtagene ciloleucel was also evaluated in a multicenter phase 2 ZUMA-1 study (ClinicalTrials.gov Identifier: NCT02348216) in a cohort of patients with refractory DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma, which was defined as progressive or stable disease as the best response to the most recent chemotherapy regimen or disease progression/relapse within 12 months of ASCT.17 The objective response rate was 82%, and the complete response rate was 54%. At a median follow-up of 15.4 months, 42% of the cohort continued to have a response, with 40% maintaining a complete response. At 18 months, the overall rate of survival was 52%.
Novel New Therapies
Three new drugs designated for second-line/subsequent therapy have recently entered the marketplace, providing another option for some patients with relapsed/refractory disease.
Polatuzumab vedotin-piiq (Polivy, Genentech/Roche), was granted accelerated approval in June 2019, to be used in combination with bendamustine and a rituximab product for adult patients with relapsed/refractory DLBCL who have already received at least 2 prior therapies.18
A first-in-class antibody-drug conjugate, polatuzumab targets CD79b received its approval based on results of the GO29365 study (DCDS4501A; ClinicalTrials.gov Identifier: NCT02257567), an open-label phase 1b/2 clinical trial that randomized patients with relapsed or refractory DLBCL to receive either polatuzumab vedotin-piiq in combination with bendamustine and a rituximab product or bendamustine/rituximab alone for up to six 21-day cycles.19 All patients had received 1 or more prior line of therapy and were considered transplant ineligible.
Combination therapy with polatuzumab vedotin-piiq resulted in a significantly higher complete response rate, and reduced the risk of death by 58% compared with patients in the control group. The complete response rate was 40% vs 17.5%, favoring the polatuzumab vedotin group. Among the patients who achieved partial or complete response with the experimental therapy, 16 (64%) patients had response durations of at least 6 months and 12 (48%) patients achieved durable responses of at least 12 months.
The NCCN guidelines note that bendamustine, rituximab, and polatuzumab vedotin-piiq is indicated for patients with translocations of MYC and BCL2 and/or BCL6 who have received 2 or more prior therapies.8
Another new therapeutic option, indicated specifically for third line/subsequent treatment, received accelerated approval in June 2020.20 Selinexor (XPOVIO, Karyopharm Therapeutics), an orally available, small molecule inhibitor of CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1), is indicated for adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, who have received at least 2 lines of systemic therapy.
The approval was based on results from the SADAL trial (KCP-330; ClinicalTrials.gov Identifier: NCT02227251), a multicenter, single-arm, open-label phase 2b study trial in patients with DLBCL who had been previously treated with 2 to 5 lines of systemic regimens.21 Patients in the final outcome and safety analysis achieved an overall response rate of 28%. Of this group, 12% achieved a complete response and 17% a partial response.
The NCCN guidelines recommend selinexor for third-line and subsequent therapy, and to be given only after at least 2 lines of systemic therapy.8
The most recent addition to the armamentarium is novel agent tafasitamab-cxix (Monjuvi, MorphoSys US Inc), which received regulatory approval on July 31, 2020.22 A humanized Fc-modified cytolytic CD19 targeting monoclonal antibody, it is indicated for use in combination with lenalidomide for adult patients with relapsed/refractory DLBCL that is not otherwise specified, including DLBCL arising from low grade lymphoma, and in patients who are not eligible for ASCT.
The efficacy of tafasitamab-cxix with lenalidomide was evaluated in an open label, multicenter single-arm trial (L-MIND; ClinicalTrials.gov Identifier: NCT02399085) and was conducted in 81 patients who were not candidates for high-dose chemotherapy and subsequent ASCT.23 Patients received tafasitamab-cxix 12 mg/kg intravenously with lenalidomide (25 mg orally on days 1 to 21 of each 28-day cycle) for maximum of 12 cycles, which was followed by tafasitamab-cxix as monotherapy.
Within this cohort, 48 (60%) achieved an objective response, with 34 (43%) having a complete response and 14 (18%) had a partial response. The median response duration was 21.7 months.
Although clinical studies in recent years suggest that patients with relapsed or refractory disease have poor overall survival rates, the scarcity of data reporting outcomes in this patient population has led to the development of several promising treatments. In turn, these developments increase the need to understand expected and overall responses to help investigators and clinicians determine benchmarks for patient response rates in the future.
Disclosures: Some authors of referenced materials have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to each referenced study for a full list of author disclosures.
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- National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts:NHL – Diffuse Large B-Cell Lymphoma (DLBCL). https://seer.cancer.gov/statfacts/html/dlbcl.html. Updated July 24, 2020. Accessed August 28, 2020.
- Dunleavy K, Fanale MA, Abramson JS, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet Haematol. 2018;5(12):e609-e617. doi:10.1016/S2352-3026(18)30177-7
- Gisselbrecht C, Van Den Neste E. How I manage patients with relapsed/refractory diffuse large B cell lymphoma. Br J Haematol. 2018;182(5):633-643. doi:10.1111/bjh.15412
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- Ng AK, Yahalom J, Goda JS, et al. Role of radiation therapy in patients with relapsed/refractory diffuse large B-cell lymphoma: guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2018;100(3):652-669. doi:10.1016/j.ijrobp.2017.12.005
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) B-Cell Lymphomas Version 4.2020 — August 13, 2020. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed September 10, 2020.
- Farooq U, Maurer MJ, Thompson CA, et al. Clinical heterogeneity of diffuse large B cell lymphoma following failure of front-line immunochemotherapy. Br J Haematol. 2017;179(1):50-60. doi:10.1111/bjh.14813
- Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28:4184-4190. doi:10.1200/JCO.2010.28.1618
- Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood 2015;125(9):1394-1402. doi:10.1182/blood-2014-09-598763
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- Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study [published correction appears in Blood. 2018 Feb 1;131(5):587-588]. Blood. 2017;130(16):1800-1808. doi:10.1182/blood-2017-11-817775
- Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood. 2010;116(20):4099-4102. doi:10.1182/blood-2010-04-281931
- Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. doi:10.1056/NEJMoa1804980
- Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447
- US Food and Drug Administration. FDA approves polatuzumab vedotin-piiq for diffuse large B-cell lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-polatuzumab-vedotin-piiq-diffuse-large-b-cell-lymphoma. Published June 10, 2019. Accessed August 28, 2020.
- Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-Cell lymphoma. J Clin Oncol. 2020;38(2):155-165. doi:10.1200/JCO.19.00172.
- US Food and Drug Administration. FDA approves selinexor for relapsed/refractory diffuse large B-cell lymphoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selinexor-relapsedrefractory-diffuse-large-b-cell-lymphoma. Published June 22, 2020. Accessed August 28, 2020.
- Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4
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- Monjuvi [package insert]. Boston, MA: MorphosysSys AG; 2020.
- KymriahTM [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 2018.
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Reviewed September 2020