Newer Agents on the Horizon for Refractory or Relapsed DLBCL

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Although treating patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains challenging, some newer therapies on the horizon offer promise, including bispecific antibodies, anti-CD47 antibodies, antibody-drug conjugates, and chimeric antigen receptor (CAR) T-cell therapy, explained Matthew J. Matasar, MD, Section Head for Aggressive B-Cell Lymphoma at Memorial Sloan Kettering Cancer Center (MSK), New York. During the 2021 National Comprehensive Cancer Network (NCCN) Annual Congress: Hematologic Malignancies, Dr. Matasar reviewed the current unmet needs for patients with relapsed or refractory DLBCL, second-line and third-line (and beyond) strategies, and emerging therapies.1

Matthew J. Matasar, MD

Matthew J. Matasar, MD

“Relapsed or refractory DLBCL is a significant unmet need,” Dr. Matasar explained. “Only half of these patients can go on to curative autologous stem cell transplantation [ASCT]. Of those who can get to transplant, only half go on to be cured. There are few effective treatment options for patients who are ineligible for transplant, and the prognosis remains poor.”

Dr. Matasar continued: “Pooled phase III studies and observational studies have shown low response rates for current therapies for relapsed or refractory DLBCL. Overall response rates are around 26%, and complete response rates are around 7%. For patients with primary refractory disease, rates are even lower, and those who relapse 12 months after ASCT have a similarly poor prognosis.”

Second-Line Therapy for Resistant DLBCL

Although practice patterns are heterogeneous in the United States, several options are used to treat relapsed or refractory DLBCL.

Second-line treatment for relapsed or refractory DLBCL is based on stratification for transplant eligibility/ineligibility. Transplant-eligible patients are treated with platinum-based therapy; if they have an adequate response, they go on to high-dose chemotherapy and ASCT. If not, they are managed with third-line therapy.

Transplant-ineligible patients are further categorized as potential candidates for CAR T-cell therapy or not eligible for such therapy. “If they are candidates for CAR-T, we use regimens that do not interfere with CAR-T [ie, anti-DC19 therapy]. Rituximab plus gemcitabine/oxaliplatin, bendamustine/rituximab plus polatuzumab vedotin-piiq, and ibrutinib can be considered,” Dr. Matasar said. “The choices are more liberalized for patients who will never go on to CAR-T. We can use anti-CD19 therapy and polatuzumab vedotin in this group.”

For transplant-eligible patients, no one individual platinum-based chemotherapy stands out as better than any other. “Regardless of the choice, overall response rates are similar,” he explained “Unfortunately, outcomes for patients who receive R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone] in the first-line setting have very low response rates to platinum-based chemotherapy.”

CAR T-cell therapies have been studied in relapsed or refractory DLBCL in the second line: axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel. Dr. Matasar said that two studies—ZUMA-7 and TRANSFORM—showed greater event-free survival with the respective CAR T-cell products, but this is based on press releases, and the full studies have not been presented.

Other Second-Line Options

Bendamustine/rituximab and gemcitabine/oxaliplatin are both used to treat relapsed or refractory DLBCL, with similar outcomes. Dr. Matasar said that median overall survival is poor with both regimens—around 1 year.

“At MSK, gemcitabine/oxaliplatin is our preferred regimen for second-line treatment of ineligible patients, and survival is measured in weeks—not months,” he noted.

The antibody-drug conjugate polatuzumab vedotin combined with bendamustine/rituximab may become a new standard of care in the second-line setting. The GO29635 trial found superior outcomes with polatuzumab vedotin plus bendamustine/rituximab compared with bendamustine/rituximab alone in 80 randomly assigned patients; more than 50% had primary refractory disease. No new safety signals emerged with longer follow-up in the randomized arms and 106 additional patients in the extension cohort. Median progression-free survival in randomly assigned patients was 9.2 months with polatuzumab vedotin plus bendamustine/rituximab vs 3.7 months with bendamustine/rituximab. Median overall survival was 12.4 months vs 4.7 months, respectively. A total of 11 patients from the randomly assigned cohort of polatuzumab vedotin plus bendamustine/rituximab are long-term survivors, with overall survival of more than 24 months.

“The addition of polatuzumab vedotin improves outcome regardless of patient cohort. Median progression-free and overall survival improvements were seen across all subsets when polatuzumab vedotin was added,” he stated. “We are building on the success of the regimen of polatuzumab vedotin plus bendamustine/rituximab.”

Ongoing studies include the phase III randomized, controlled POLARGO trial. It will compare rituximab plus gemcitabine/oxaliplatin with or without polatuzumab vedotin in 206 patients with transplant-ineligible DLBCL. The trial should be up and running this year or next, Dr. Matasar said.

A separate study, the PolaR-ICE program, will explore the combination of polatuzumab vedotin plus rituximab, etoposide, carboplatin, and ifosfamide in transplant-eligible patients with DLBCL in the hope of improving response rates and successfully delivering ASCT.

Other New Additions

“Polatuzumab vedotin is not the only new addition to the armamentarium,” Dr. Matasar continued. The combination of the anti-CD19 antibody tafasitamab-cxix plus lenalidomide was evaluated in the phase II L-MIND trial in 80 patients, with a maximum of 3 lines of prior therapy.2 Myelosuppression was the main treatment-emergent adverse event. The objective response rate was 60%, and the complete response rate was 43%. At a median follow-up of 17+ months, median progression-free survival was 12.1 months, and the median duration of response was 21.7 months. A total of 28 patients are still in ongoing treatment.

“Overall survival is excellent. Median overall survival has not been reached, and the 12-month overall survival is 74%,” reported Dr. Matasar.

Third-Line Therapy and Beyond

“Third-line therapy and beyond becomes more challenging, as these patients have different characteristics. The first question we ask is whether the patient is potentially eligible for CAR-T therapy. Then, we ask whether they are immediately eligible,” Dr. Matasar explained.

“For patients who can go directly to CAR-T, we proceed to leukapheresis when possible. If bridging therapy is possible, we do not use anti-CD19 therapy, because it could interfere with CAR-T,” he cautioned.

For patients who achieve a complete response on bridging therapy, it is an open question whether they will benefit from consolidative CAR T-cell therapy. “This situation is best handled case by case,” Dr. Matasar suggested.

For patients who may be eligible for CAR T-cell therapy in the future, after debulking they become eligible for leukapheresis. If they fail to respond to debulking therapy, then other therapeutic options should be considered.

The next decision is whether patients who will never be eligible for CAR T-cell therapy are candidates for a clinical trial. For those who are ineligible or do not have access to clinical trials, U.S. Food and Drug Administration (FDA)-approved regimens include polatuzumab vedotin plus bendamustine/rituximab, tafasitamab plus lenalidomide, and loncastuximab tesirine-lpyl. 

CAR T-Cell Therapy in Multiply Relapsed Patients With DLBCL

Three different CAR T-cell products have been approved by the FDA for multiply relapsed patients with DLBCL: axicabtagene ciloleucel, lisocabtagene maraleucel, and tisagenlecleucel. Each agent has yielded high overall response rates, but there are differences in toxicity and eligibility criteria. The most important adverse events associated with CAR T-cell therapy include cytokine-release syndrome and neurotoxicity. Treatment selection is individualized based on patient characteristics, efficacy, and toxicity.

Dr. Matasar said that experience at MSK with CAR T-cell therapy compared with other agents used historically in the third line and beyond showed superior responses for CAR T-cell therapy, with improved progression-free and overall survival.3 After investigators adjusted for unfavorable pretreatment characteristics, response rates with CAR T-cell therapy remained significantly superior, with similar survival between cohorts.

The antibody-drug conjugate loncastuximab tesirine is now FDA-approved in the third line and beyond in relapsed or refractory DLBCL.4 The single-arm, open-label phase II LOTIS-2 trial evaluated loncastuximab tesirine in 145 patients with relapsed or refractory DLBCL. The mean number of treatment cycles was 4.3. Among all patients, the overall response rate was 48.3%, with a complete response in 24.1% and a partial response in 24.2%. An additional 15.2% had stable disease. The median duration of response was about 10 months. The most common grade 3 or higher treatment-emergent adverse events were myelosuppression, gamma-glutamyl transferase level increase, and anemia.

“The toxicity of loncastuximab tesirine is different from that of polatuzumab vedotin, because these antibody-drug conjugates have different chemotherapy ‘payloads,’” he said.

We are very encouraged by anti-CD47 antibodies, and there will be ongoing development of bispecific antibodies in this disease state [B-cell lymphoma].
— Matthew J. Matasar, MD

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Emerging Therapies for Resistant DLBCL

“Bispecific antibodies are the most exciting of the emerging therapies. These agents are directed against a B-cell antigen as well as CD3, to activate T cells directed against B cells. A number of these drugs are under clinical development,” Dr. Matasar noted, including mosunetuzumab, glofitamab, epcoritamab, and IGM-2323.

The bispecific antibody study furthest along is GO29781, which is a phase I/IIb trial of mosunetuzumab in relapsed or refractory B-cell non-Hodgkin lymphoma. To date, the study has enrolled about 200 patients with aggressive B-cell lymphoma. Patients have had a median of three prior lines of therapy (a minority being CAR T-cell therapy).

“Despite these patients being at high risk, the response rates are relatively encouraging: an overall response rate of about 35% and a complete response rate of 20% to 25%,” he reported. “Toxicity is relatively modest [compared with CAR-T]. This drug is being developed in parallel with intravenous and subcutaneous administration. This may ameliorate toxicity without sacrificing efficacy.”

Anti-CD47 antibodies such as magrolimab and TTI-621/TTI-622 are also under study. “We are very encouraged by anti-CD47 antibodies, and there will be ongoing development of bispecific antibodies in this disease state,” Dr. Matasar continued. 

DISCLOSURE: Dr. Matasar reported relationships and financial interests with Bayer, Daiichi Sankyo, Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen Pharmaceuticals, and Merck.


1. Matasar MJ: Diffuse large B-cell lymphoma: Optimizing therapy for relapsed/refractory disease. 2021 NCCN Virtual Congress: Hematologic Malignancies. Presented October 16, 2021.

2. Duell J, Maddocks KJ, González-Barca E, et al: Long-term outcomes from the phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica 106:9, 2021.

3. Sermer D, Batlevi C, Palombo ML, et al: Outcomes in patients with DLBCL treated with commercial CAR-T cells compared with alternate therapies. Blood Adv 4:4669-4678, 2020.

4. Caimi PF, Weiyun A, Alderuccio JP, et al: Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): A multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 22:790-800, 2021.