Treatment and Sequencing Options Continue to Evolve in Relapsed/Refractory DLBCL

The emergence of novel agents, including CAR T-cell therapies and antibody-drug conjugates, plus existing options such as chemoimmunotherapy and bone-marrow transplant, have combined to raise questions about the sequencing of these treatments in patients with diffuse large B-cell lymphoma.

The emergence of novel agents, including CAR T-cell therapies and antibody-drug conjugates, plus existing options such as chemoimmunotherapy and bone-marrow transplant, have combined to raise questions about the sequencing of these treatments in patients with diffuse large B-cell lymphoma (DLBCL), according to Greg Nowakowski, MD.

“We have now multiple agents that are approved, and if you imagine possible permutations and combinations of those, the number gets quite high,” Nowakowski, a professor of medicine and oncology in the Lymphoma Program at the Mayo Clinic in Rochester, Minnesota, said in a presentation delivered during the 26th Annual International Congress on Hematologic Malignancies®, an event hosted by Physicians’ Education Resource, LLC.1 “[We] clearly won’t be able to study those [permutations] in randomized settings. We will see more and more real-world data on sequencing of therapy [and] how to best choose therapy in the future. And this field is likely to evolve even more in the near future with bispecifics coming to this space.”

In his presentation, Nowakowski touched on the current standard of care in DLBCL, clinical trials investigating recently approved therapeutic agents in the space, and options for patients who relapse following CAR T-cell therapy.

Emerging Agents Disrupting the Current Standard of Care

The current frontline standard of care for DLBCL consists of rituximab (Rituxan) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP), or R-CHOP–like regimens. This method leads to cure in 50% to 60% of patients.2 Patients who progress to the second-line setting and are transplant eligible will receive high-dose chemotherapy. Approximately half of patients will be eligible for autologous stem cell transplant (ASCT), while the other half will progress and require third-line treatment. However, only 10% to 15% of patients will be cured in the second-line setting with ASCT.3

Patients who are ineligible for ASCT in the second-line setting are typically given tafasitamab-cxix (Monjuvi) plus lenalidomide (Revlimid), or chemotherapy. In the third-line setting, several options exist, including tafasitamab plus lenalidomide, CAR T-cell therapy, polatuzumab vedotin-piiq (Polivy) plus bendamustine and rituximab (BR), selinexor (Xpovio), loncastuximab tesirine-lpyl (Zynlonta), or chemotherapy.

In June 2019, the FDA granted an accelerated approval to polatuzumab vedotin in combination with BR for patients with relapsed/refractory DLBCL who received at least 2 prior therapies.4 A phase 2 study (NCT02257567) tested the efficacy of polatuzumab vedotin plus BR in patients with relapsed/refractory DLBCL and follicular lymphoma who received at least 1 line of prior treatment, and who were transplant ineligible or progressed after ASCT.5 The DLBCL arm achieved an overall response rate (ORR) of 45% with polatuzumab vedotin vs an ORR of 17.5% with BR alone.

Additionally, in June 2020, selinexor was approved by the FDA for adult patients with relapsed/refractory DLBCL who received at least 2 lines of prior therapy. The phase 2b SADAL trial (NCT02227251) explored selinexor in patients with relapsed/refractory DLBCL who received 2 to 5 lines of prior treatment.6 The single-arm study elicited a 28% ORR (95% CI, 20.7%-37.0%), a median duration of response of 9.3 months (95% CI, 4.8-23.0), and a median overall survival (OS) of 9.1 months (95% CI, 6.6-15.1).

In July 2020, the combination of tafasitamab and lenalidomide was approved by the FDA for patients with DLBCL who were ineligible for ASCT. This combination produced an ORR of 60% in the phase 2 L-MIND trial (NCT02399085), including a complete response (CR) rate of 43%.7

“What was really encouraging about this study was [the median] progression-free survival [(PFS) of 16.2 months] and [the median] OS [of 31.6 months, which was] very significant” Nowakowski said. “[These] two standard end points looked extremely favorable in this study, and [the] responses appeared to be quite durable.”

Furthermore, the RE-MIND trial (NCT04150328) compared combination data from the L-MIND trial with real-world data of lenalidomide monotherapy in transplant-ineligible patients with relapsed/refractory DLBCL.8 The combination arm had a significantly better ORR at 67.1% vs the lenalidomide arm at 34.2% (odds ratio, 3.89; 95% CI, 1.90-8.14; P < .0001).

In April 2021, the FDA approved loncastuximab tesirine for patients with relapsed/refractory DLBCL who received at least 2 prior lines of systemic therapy. This humanized anti-CD19 antibody is stochastically conjugated through a cathepsin-cleavage valine-alanine linker to a pyrrolobenzodiazepine dimer toxin, causing DNA crosslinking. This agent was explored in the phase 2 LOTIS-2 trial (NCT03589469), where it elicited an ORR of 48.3% (95% CI, 39.9%-56.7%).9

The advent of these new agents has presented a potential shift in the treatment paradigm for DLBCL. “The future pattern of care can change in DLBCL. The first line may change with the inclusion of polatuzumab [vedotin],” Nowakowski said. “CAR T cells could be moving to the second-line space, and there are additional agents, particularly bispecific antibodies, which likely will get approved in the third- or second-line setting.”

Treatment Options for Post–CAR T Relapse

If CAR T-cell therapy is moved to the second-line setting in DLBCL, Nowakowski noted patients and clinicians will need to prepare for more post–CAR T-cell therapy relapses. A long-term follow-up of patients with relapsed/refractory DLBCL who were administered tisagenlecleucel (Kymriah) showed that at 5 years approximately 60% of patients experienced disease relapse.10

“Those patients can be quite challenging [to treat],” Nowakowski said. “We know the outcome of patients post–CAR T-cell relapse is extremely poor. Median OS is only [5.3] months, and patients who relapse early, by day 30 post–CAR T-cell therapy have particularly poor outcomes, with [an OS] of 3.75 months.”

However, Nowakowski explained that prolonged cytopenias represented a major barrier to enrollment in clinical trials for patients with aggressive B-cell lymphoma who progress after CD19-directed CAR T-cell therapy. Across 4 clinical trials exploring selinexor, polatuzumab plus BR, tafasitamab plus lenalidomide, and loncastuximab tesirine, 47% of patients were excluded.2,6,7,9 Additionally, time from CD19-directed CAR T-cell therapy to disease progression was shorter in patients who were ineligible for enrollment (median 1.1 months [range, 0.5-4.7]) vs those who were eligible for enrollment (median 3.0 months [range, 0.9-2.7]; P = .004).

“Unless we change the inclusion criteria and change our clinical trials, [these agents are] not a viable option for many patients post–CAR T-cell relapse,” said Nowakowski, who added that using cytopenias as exclusion criteria serves as a hindrance to enrollment. Nowakowski also pointed to nonmyelosuppressive strategies, including immunotherapy and targeted therapy, as preferred options post–CAR T-cell relapse.

For example, a study examined the use of lenalidomide in patients following CAR T-cell therapy relapse. A total of 33 patients progressed after tisagenlecleucel and 26 progressed following axicabtagene ciloleucel (Yescarta).11 Patients were administered lenalidomide plus rituximab (n = 30), lenalidomide alone (n = 10), or obinutuzumab (Gazyva) alone (n = 1). Data showed an ORR of 27.1%, including a CR in 9 patients. Notably, 11 patients who started treatment before day 15 post–CAR T-cell infusion experienced a higher ORR at 63.6% and a higher CR rate at 36.4%. The median PFS was 101 days, and the median OS was 225 days.

Notably, Nowakowski also said an older treatment option, radiation therapy, could represent another route for patients following relapse on CAR T-cell therapy.12

“All of us who see patients post–CAR T cells know that relapses could be [found in] somewhat unusual [places]. Sometimes they are localized, sometimes they are in unusual spaces,” Nowakowski said. “If you do have a localized relapse, radiation can provide durable stable disease, during which a patient can recover hematologically and become a candidate for other therapy,” Nowakowski concluded.


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  6. 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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  8. Nowakowski GS, Rodgers TD, Marino D, et al. RE-MIND study: a propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). J Clin Oncol. 2020:38(suppl 15):8020. doi:10.1200/JCO.2020.38.15_suppl.8020
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  12. Imber BS, Sadelain M, DeSelm C, et al. Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy. Br J Haematol. 2020;190(1):45-51. doi:10.1111/bjh.16541