1. Fuerst, Mark L.

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New novel agents to treat relapsed/refractory diffuse large B-cell lymphoma (DLBCL) may be used as a bridge to other therapies, including chimeric antigen receptor (CAR) T-cell therapy and stem cell transplantation, and may eventually replace other therapies.

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A high unmet medical need exists in relapsed/refractory DLBCL patients who are not eligible for stem cell transplantation. From 30-40 percent of DLBCL patients fail to respond or relapse from initial therapy. Patients who fail first-line therapy and are not eligible for high-dose chemotherapy and autologous stem cell transplantation have a poor outcome and require more therapeutic options.


"Few efficacious and safe treatment options are available for the more than 11,000 DLBCL patents who need therapy," said Leo I. Gordon, MD, the Abby and John Friend Professor of Oncology Research and Professor of Medicine (Hematology and Oncology) at Northwestern University Feinberg School of Medicine, at the 2021 Great Debates & Updates in Hematologic Malignancies virtual symposium.


Investigators are examining new treatment ideas in upfront and relapsed/refractory DLBCL. These include, in first-line DLBCL, the immunomodulating agent avadomide, the CAVALLI study of a combination of venetoclax and R-CHOP, and the ALLIANCE trial of venetoclax and dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab). In refractory/relapsed DLBCL, new concepts include off-the-shelf CAR T-cell therapy, dual CARs, and autologous CARs plus novel agents, such as polatuzumab, tafasitamab, selinexor, and mosenetuzumab.


Several novel agents have recently received FDA approval: polatuzumab in 2019; selinexor in July 2020; tazemetostat in July 2020; and tafasitamab plus lenalidomide in August 2020.


Polatuzumab Vedotin

Polatuzumab vedotin is a CD79b targeted agent and antibody-drug conjugate. CD79b is a signaling component of the B-cell receptor that is present in more than 95 percent of DLBCLs.


In a single-arm trial, polatuzumab vedotin combined with bendamustine + rituximab (BR) was compared with BR in a randomly assigned cohort of patients with transplantation-ineligible relapsed/refractory DLBCL (J Clin Oncol 2020; doi: 10.1200/JCO.19.00172). Results showed polatuzumab vedotin combined with BR resulted in a significantly higher complete response (CR) rate and reduced the risk of death by 58 percent compared with BR alone.


"A better progression-free survival (PFS) suggests a flattening of the curve in 25 percent of patients, and overall survival was a little better with polatuzumab," said Gordon.



Tafasitamab is an Fc-enhanced monoclonal antibody targeting CD19, a B cell-specific target. It is thought to enhance the immune response to malignant B cells through antibody-dependent cellular cytotoxicity and ADCP3 Mutational Fc enhancement. CD19 is an ideal B cell-specific target since it enhances BCR signaling and tumor proliferation, Gordon noted.


This investigational anti-CD19 antibody is under development in key trials for relapsed/refractory DLBCL. "Tafasitamab monotherapy use until progression has resulted in durable responses and was well-tolerated in patients with non-Hodgkin Lymphoma," he said. "We also see activity by combining tafasitamab with other agents."


Lenalidomide has been well-studied as an anti-lymphoma agent, alone or in combination, and it may have synergistic effects with tafasitamab. "Tafasitamab plus lenalidomide shows enough preclinical rationale to combine the two agents," he said.


The Phase II L-MIND study examined a combination of tafasitamab and lenalidomide in relapsed/refractory DLBCL. These patients, who were not eligible for high-dose therapy and transplant, had 1-3 prior regimens. The primary endpoint, overall response rate (ORR), after two lines of therapy was 67 percent and for more than two lines of therapy was 57 percent. CR was seen in about half the patients. The median PFS was 23.5 months, and for those with PFS more than 24 months, 45 percent remain in remission. Non-hematologic toxicity was not prominent, he noted.


A new study, First-MIND, is an open-label, prospective, randomized, Phase Ib study designed to evaluate the safety and preliminary efficacy of tafasitamab plus lenalidomide in addition to R-CHOP in patients with newly diagnosed DLBCL.


"Tafasitamab combination trials include transplant-ineligible relapsed/refractory DLBCL patients. Tafasitamab therapy until progression, as monotherapy, and in combination with lenalidomide has achieved enduring responses. PFS seems to be independent of refractoriness to prior rituximab containing treatments," said Gordon.


In terms of safety, tafasitamab in combination with lenalidomide showed mainly hematological adverse events. "The treatment schedule allows for outpatient treatment," he noted.



The multicenter, multinational, open-label, Phase IIb SADAL trial in relapsed/refractory DLBCL assessed the response to single-agent selinexor, an oral selective inhibitor of nuclear export (Lancet Haematol 2020; Selinexor led to an ORR of 28 percent and CR rate of 12 percent, with no difference in GCB versus non-GCB tumors, noted Gordon. The researchers concluded that selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed/refractory DLBCL who received at least two lines of previous chemoimmunotherapy.



Mosunetuzumab is a full-length, fully humanized IgG1 CD20/CD3 bispecific T-cell engager (BiTE). It redirects T cells to engage and eliminate malignant B cells, and has been tested in clinical trials in indolent and aggressive lymphoma.


An open-label, multicenter, Phase I/Ib, dose-escalation, and expansion study of mosunetuzumab in relapsed/refractory non-Hodgkin lymphoma found the drug induced CR in poor prognosis patients, including those who are resistant to or relapsing after CAR T-cell therapies (Blood 2019; The drug was active in treatment through multiple lines of therapy. "This BiTE antibody led to an ORR of about 46 percent and CR of about 24 percent, including a CR of 20 percent in DLBCL. The duration of response appears durable," said Gordon.


In comparing novel agents to transplantation or CAR T-cell therapy, Gordon said that "most CARs are in early treatment. We don't know how many patients will remain alive." He admitted that follow-up of novel agents is relatively short, and there are no long-term trials of novel agents and the longest follow-up is for transplant.


"Whether novel agents will be used as a replacement for transplant and CARs or a bridge to other therapies remains to be seen," he stated.


Mark L. Fuerst is a contributing writer.