Novel and Emerging Therapeutic Interventions in Relapsed and Refractory Diffuse Large B-Cell Lymphoma

Brad S. Kahl, MD

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy and the most common subtype of non-Hodgkin lymphoma (NHL) in adults.^1,2 Roughly 30% to 40% of patients develop relapsed/refractory DLBCL (RR-DLBCL), which, in addition to being associated with a significantly increased risk of morbidity and mortality, presents unique treatment challenges.³

Earlier this year, a select group of clinician stakeholders in hematology and oncology convened in Miami, Florida, to discuss the current and emerging treatment landscape of RR-DLBCL. Presented by OncLive^®, the case-based discussion was moderated by Brad Kahl, MD, of the Washington University School of Medicine in St. Louis, Missouri. Stakeholders shared clinical perspectives on treatment approaches for RR-DLBCL, with an emphasis on emerging and novel therapies beyond the first line for patients who are ineligible or have undergone transplant or chimeric antigen receptor (CAR) T-cell therapy without success. This article summarizes the stakeholder discussion, including treatment challenges, key data, and real-world insights into the potential impact of emerging treatment options.

Case Presentation

The case presented involved a 74-year-old white woman with stage IIIB diffuse DLBCL. Findings included fatigue, recurring night sweats, and a left neck mass. Investigations revealed multiple sites of lymphadenopathy (bilateral cervical area, mediastinum, abdomen, and retroperitoneum) with the largest nodal mass measuring 8 cm. Laboratory results showed elevated lactate dehydrogenase levels (330 U/L) and an International Prognostic Score of 2. The cervical lymph node biopsy revealed DLBCL, with an immunohistochemical profile exhibiting a nongerminal center B-cell subtype and negative bone marrow biopsy results. The patient was first treated with 6 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and achieved complete response (CR), seen by positron emission tomography/computed tomography scan, after therapy. Ten months later, however, the patient developed a new right neck mass and recurring night sweats. Laboratory examinations revealed mild anemia (hemoglobin, 10.5 g/dL) and elevated lactate dehydrogenase levels (280 U/L). Restaging investigations revealed adenopathy in the neck and abdomen (largest mass, 7.5 cm) on positron emission tomography/computed tomography scan. The right cervical lymph node biopsy confirmed the presence of nongerminal center B-cell DLBCL, and bone marrow biopsy results were positive with a score of 2 on the ECOG performance status scale. The patient was deemed ineligible for CAR T-cell therapy because of advanced age.

Emerging Treatment Options

This real-world case illustrates the challenges clinicians face when treating patients with DLBCL who have needs beyond first-line treatment options. It also highlights the need for more evidence-based therapies to be explored, such as mechanistic (cell-based) or immune-based treatments, for example. Several novel therapeutic agents to address these unmet needs are currently undergoing clinical evaluation, with 1 antibody-drug conjugate (ADC) having been approved by the FDA in 2019.

Polatuzumab Vedotin

An ADC comprising a monoclonal antibody against CD79b, polatuzumab vedotin (PV) is covalently conjugated through a cleavable linker to the microtubule-disrupting antimitotic agent monomethyl auristatin to induce apoptosis.⁴ PV was approved by the FDA for use in adults with RR-DLBCL after at least 2 prior therapies.⁵ The approval was based on the results of a multicenter, open-label phase Ib/II study comparing the use of polatuzumab plus bendamustine and rituximab (PVBR), BR alone, or PV plus bendamustine and obinutuzumab in patients with RR-DLBCL.⁵ In the primary analysis, the PVBR cohort showed a 40% CR at the end of treatment, whereas the BR group showed a significantly lower rate of 18%, respectively.⁶ Median overall survival (OS) with PVBR was 12.4 months compared with 4.7 months with BR alone.⁶

Stakeholder insights. PV may have a limited duration of response (DOR) in clinical practice because of biological differences between the study patient population and patients seen in the clinic. Nevertheless, PV can address and benefit a patient’s symptom response rate as a shortterm solution or bridge therapy to prepare patients for CAR T-cell therapy or stem cell therapy.

Selinexor

Another emerging medication for the treatment of RR-DLBCL is selinexor. In February 2020, it was granted priority review designation by the FDA for the treatment of patients who have received at least 2 prior therapies and are not eligible for high-dose chemotherapy with stem cell rescue or CAR T-cell therapy.⁷ The FDA accepted a supplemental new drug application for selinexor in February 2020. Selinexor functions by inhibiting XPO1, which is 1 of 7 nuclear export proteins and is also the primary mediator of nuclear export for various key tumor suppressor and cell-cycle regulatory proteins.⁸

In a phase IIb, single-agent study consisting of 127 patients with 2 or more prior lines of therapy, investigators assessed the drug’s overall response rate (ORR), DOR, and safety. Patients were given 60 mg of selinexor twice weekly per 28-day cycle.⁹ The median time to response was 57 days, and the median DOR was 9.2 months. The median OS was 9.1 months, and the median progression-free survival (PFS) was 3.6 months, respectively. Fourteen patients achieved CR with a DOR of 13.5 months, whereas 21 patients had a partial response (PR). The most commonly reported treatment-related adverse effects (TRAEs; grades 3, 4) included thrombocytopenia (24%, 13%, respectively), neutropenia (13.4%, 7.1%), nausea (6%, 0%), anemia (13%, 1%), fatigue (9%, 0%), and anorexia (3%, 0%).⁹

Stakeholder insights. The OS data suggest that selinexor may address some of the current unmet needs in RR-DLBCL and could be considered a viable option as a bridge therapy in appropriate patients. Stakeholders discussed their experiences and concerns with toxicity when using selinexor 80 mg and dexamethasone 20 mg in multiple myeloma, an approved indication. If selinexor is approved in DLBCL, it will likely be at the studied dose of 60 mg twice per week, which may potentially help to limit toxicities.

Tafasitamab

Immunological-based therapies are also gaining traction, as they target T-cell and natural killer cell expansion and activation, direct cell apoptosis, and can be used to treat multiple lymphomatic diseases. Tafasitamab is a monoclonal antibody that targets CD19 on tumor cells, leading to natural killer cell—mediated cytotoxicity.¹⁰ In 2014, tafasitamab was granted orphan drug, medicinal product, and fast track designation by the FDA for DLBCL, chronic lymphocytic leukemia, and small lymphocytic lymphoma. This decision was based on the results of the L-MIND trial (NCT02399085), a phase IIb, single-arm study that assessed the safety and efficacy of tafasitamab plus lenalidomide in patients with RR-DLBCL. The ORR was 52% with 19 (83%) of 23 responders still in remission.¹⁰ Treatment-related serious AEs occurred in 8 (16%) patients.

Stakeholder insights. Although the patient population studied was selective, the phase II safety and efficacy results are promising.

Mosunetuzumab

Niche populations could potentially benefit from the emergence of investigational immune targeted therapies. Mosunetuzumab is a full-length bispecific CD20/CD3 bispecific antibody directing T cells to engage and eliminate CD20+ B cells.¹¹ Currently, an ongoing and actively recruiting phase I/Ib dose-escalation and expansion study using mosunetuzumab is investigating indication-specific cohorts (patients who have not undergone prior allogeneic stem cell therapy or recent CAR T-cell therapy). Group A was administered mosunetuzumab on day 1 of each 21-day cycle, and group B was given ascending doses of mosunetuzumab administered on days 1, 8, and 15 of cycle 1, followed by a fixed dose on day 1 of every 21-day cycle (maximum of 17 cycles).^11,12 Expansion phases are ongoing, but preliminary results from group B showed that 43.8% of patients achieved ORR and 25.0% achieved CR.¹² Among patients who achieved CR, 92.6% of patients with indolent NHL and 68.2% of patients with aggressive NHL remained in remission, with median time from the first CR at 5.8 months (range, 0.0-25.4) and 8.8 months (range, 0.2-28.9), respectively.¹²

Stakeholder insights. Mosunetuzumab is an immunotherapy that relies on T-cell immunity that could potentially address a high-risk niche population. In particular, the AE profile is comparable to that of CAR T-cell therapy, and the finite duration of treatment may also represent a clinical benefit.

Hu5F9-G4

Another immunotherapy in development is Hu5F9-G4 (5F9), a first-in-class humanized immunoglobulin G4 isotype monoclonal antibody targeting CD47.¹³ 5F9 synergizes with rituximab, an anti-CD20 tumor-targeting antibody, to eliminate B-cell NHL cells by enhancing F9 receptor-mediated antibody-dependent cellular phagocytosis.¹⁴ 5F9 plus rituximab was investigated in a phase Ib/II dose-escalation study in patients with RR B-cell NHL to examine dose-limiting toxicities. Results showed an objective response rate of 40% among patients with DLBCL; 33% of the patients achieved CR and 7% of patients experienced PR. The median DOR was not reached among patients with DLBCL at a median follow-up of 6.2 months.

Stakeholder insights. Although the PR rates are not encouraging, the ORR was notable. Moreover, the novel immune modulating mechanism of action may translate to clinical utility in practice for 5F9.

Loncastuximab Tesirine

Loncastuximab tesirine (ADCT-402) is a novel anti-CD19 ADC that binds to the CD19 antigen on the tumor cell surface, releasing pyrrolobenzodiazepine dimers.¹⁵ In 2019, a single-arm, multicenter, open-label, 2-stage, phase II trial of patients with RR-DLBCL took place, undergoing 2 or more multiagent treatments, without bulky disease (tumor ≥10 cm).¹⁶ The primary end point of the study was ORR, with efficacy, DOR, PFS, and OS as secondary objectives to evaluate health-related quality of life.⁶ Results showed an ORR of 44.2%, meeting futility requirements. Ten (19.2%) patients achieved CR, and 13 (25.0%) patients attained PR, respectively. In addition, 11 patients (21.2%) had stable disease following the interim analysis. Treatment discontinuation due to TRAEs occurred in 19.2% of patients.¹⁶

Stakeholder insights. The accumulating toxicity in the short study follow-up is a concern for ADCT-402. More durability data are needed before assessing the potential of this agent as anything more than a bridge therapy.

Conclusions and Future Directions

Table. Emerging Therapies for the Treatment of Relapsed/Refractory DLBCL^{6,9,10,12,13,16} (Click to Enlarge)

References

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14. Advani R, Flinn I, Popplewell L, et al. Activity and tolerability of the first-inclass anti-CD47 antibody Hu5F9-G4 with rituximab tolerated in relapsed/ refractory non-Hodgkin lymphoma: initial phase 1b/2 results. J Clin Oncol. 2018;36:15(suppl):7504. doi: 10.1200/JCO.2018.36.15_suppl.7504.
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16. Carlo-Stella C, Zinzani PLL, Kahl, BS, et al. Interim futility analysis of a phase 2 study of loncastuximab tesirine, a novel pyrrolobenzodiazepine-based antibody- drug conjugate, in patients with relapsed or refractory diffuse large B cell lymphoma. Blood. 2019;134(suppl):757. doi: 10.1182/blood-2019-128401.

Challenges exist in the treatment of patients with RR-DLBCL, especially in those who are ineligible or have not had success with transplant or CAR T-cell therapy. Emerging therapies could fill a void for patients who relapse after previous therapies, specifically CAR T-cell therapy, specifically as bridge treatments or supplements to first-line treatments (Table).^{6,9,10,12,13,16} As the therapeutic spectrum continues to develop, further data regarding toxicity and DORs will continue to shape treatment approaches.