FAQs: Optimal Selection and Sequencing of Treatment for Patients With Aggressive B-Cell Lymphomas

Key Takeaways

• Identifying patients with double-hit diffuse large B-cell lymphoma upfront is important for optimal treatment of the disease.
• Bispecific antibodies are being investigated in relapsed or refractory mantle-cell lymphoma and diffuse large B-cell lymphoma, with promising efficacy in these settings.
• CAR T-cell therapy is an important treatment option in the management of patients with relapsed/refractory diffuse large B-cell lymphoma.

In this commentary adapted from a discussion among John P. Leonard, MD; John N. Allan, MD; and Laurie H. Sehn, MD, MPH, during a live symposium titled “Aggressive B-Cell Lymphomas: Experts Discuss New Care Standards and Evolving Treatment Strategies,” held on December 9, 2022, the experts address important clinical questions about how to select and sequence treatments for patients with aggressive B-cell lymphomas.

How do you test for MYC and BCL2 alterations in your clinical practice, and how would you manage a patient with double-hit diffuse large B-cell lymphoma (DLBCL) and central nervous system (CNS) involvement?

Laurie H. Sehn, MD, MPH:
I think it is important to identify patients with double-hit DLBCL upfront for the optimal treatment of the disease. The presence of MYC and BCL2 rearrangements portends poor prognosis. Of importance, there are several ways in which MYC and BCL2 can be expressed, with a mixed bag of varying biology. At my institution, we uniformly test for the MYC status initially, more recently using next-generation sequencing. So, if a patient’s disease does not harbor MYC rearrangements, we do not perform testing for BCL2 rearrangements. In my opinion, if the disease is positive for MYC rearrangements, follow-up testing is needed to determine the presence or absence of BCL2 rearrangements, most especially to determine whether the patient has double-hit DLBCL.

Treating a patient with double-hit DLBCL and CNS involvement can be very challenging. In my practice, I would treat such a patient with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) by default and integrate high-dose methotrexate in between treatment cycles. If the patient responds well to therapy, I will consider proceeding with autologous stem cell transplant. Compared with R-CHOP, dose-adjusted etoposide/prednisone/vincristine/cyclophosphamide/doxorubicin plus rituximab (DA-EPOCH-R) with systemic methotrexate is associated with more toxicities; hence, I tend not to use it without data justifying that it is more effective. At present, I do not think there are enough data in support of the use of DA-EPOCH-R in this scenario.

How do you approach the treatment of patients with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL)? 

Laurie H. Sehn, MD, MPH:
Of note, patients with PMBCL were excluded from the phase III POLARIX trial of polatuzumab vedotin plus rituximab and cyclophosphamide/doxorubicin/prednisone (R-CHP) vs placebo plus R-CHOP. The trial included only previously untreated patients with DLBCL. So, it is unknown whether polatuzumab vedotin plus R-CHP will be effective in patients with PMBCL. At my institution, we preferentially use DA-EPOCH-R for these patients, particularly if they have bulky disease, although we still use R-CHOP in patients with PMBCL with low-risk, small-volume disease or those with favorable prognostic features. These patients may benefit from the use of targeted and novel agents. 

John P. Leonard, MD:
I agree with Dr. Sehn. In fact, there is an ongoing phase III trial evaluating the efficacy and safety of adding nivolumab to chemoimmunotherapy (DA-EPOCH-R or R-CHOP) for newly diagnosed patients with PMBCL (NCT04759586).

What are your thoughts on using another antibody–drug conjugate (ADC) following disease progression on polatuzumab vedotin in DLBCL?

John N. Allan, MD:
Loncastuximab tesirine is a CD19-directed antibody and alkylating agent conjugate that is approved by the FDA for relapsed or refractory large B-cell lymphoma after ≥2 lines of systemic therapy, including DLBCL not otherwise specified (NOS), DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. Polatuzumab vedotin is a CD79b-directed ADC that is approved by the FDA in combination with bendamustine and rituximab for patients with relapsed or refractory DLBCL NOS after ≥2 previous therapies. These 2 approved ADCs have different payloads with different toxicity profiles. For instance, polatuzumab vedotin is associated with peripheral neuropathy and cytopenias, whereas loncastuximab tesirine is associated with cytopenias, edema, and effusions. So, due to the fact that these agents have different targets and because the toxicity profiles are different but manageable, it is possible to sequence these 2 agents in any order as the patient experiences disease progression on one. 

Is there sufficient evidence in support of the use of a CD19-directed therapy for a patient with relapsed/refractory DLBCL following disease progression on CAR T-cell therapy? 

John N. Allan, MD:
The answer to this question is unknown, as there is insufficient evidence informing us of the efficacy of a CD19-targeted agent following relapse on a CAR T-cell therapy (axicabtagene ciloleucel or lisocabtagene maraleucel) in DLBCL. As a rule of thumb, if a patient experiences relapse post CAR T-cell therapy, I generally perform a rebiopsy to ensure that CD19 is still in fact expressed on the lymphoma cells, particularly if I am considering another CD19-targeted agent. For CD19-directed ADCs to be effective, evidence suggests that CD19 does not need to be highly expressed on the lymphoma cells. The same seems to apply to anti-CD79b and anti-CD30 ADCs. With that said, we have very limited data available regarding the effectiveness of a CD19-directed therapy following progression on a CAR T-cell therapy. Despite the lack of evidence, these agents should be considered. However, CD20-directed bispecific antibodies such as glofitamab, epcoritamab, and odronextamab are effective in this setting as salvage therapy. These 3 bispecific antibodies have already demonstrated complete response rates of approximately 30% or higher in patients with relapsed or refractory DLBCL after previous exposure to a CAR T-cell therapy. Of note, other effective treatment options in patients with relapsed or refractory DLBCL NOS following disease progression on ≥2 lines of therapy, including CAR T-cell therapy, include selinexor, a selective inhibitor of nuclear export, and the CD19-directed antibody, tafasitamab, in combination with lenalidomide. 

What are your thoughts on the use of a bispecific antibody before CAR T-cell therapy in mantle cell lymphoma (MCL)? 

John P. Leonard, MD:
I can argue for the use of bispecific antibodies such as epcoritamab, odronextamab, and glofitamab either before or after CAR T-cell therapy, and there are ongoing clinical studies that will shed more light on the efficacy of these bispecific antibodies before CAR T-cell treatment. On the one hand, the phase II ELM-2 trial is investigating odronextamab among patients with B-cell non-Hodgkin lymphoma, including MCL, who have not received any previous treatment with any CAR T-cell therapy (NCT03888105). The phase I/II EPCORE-NHL-1 trial is investigating epcoritamab in patients with relapsed or refractory B-cell lymphomas, including MCL, who have not received a CAR T-cell therapy within 30 days before the first epcoritamab administration (NCT03625037). On the other hand, the phase II BiCAR trial is investigating glofitamab after CAR T-cell therapy in relapsed or refractory lymphomas (NCT04703686). In a phase I/II trial, glofitamab demonstrated a complete metabolic response rate of 67% in patients with relapsed or refractory MCL. At the moment, however, there are no randomized trial data suggesting increased benefit either way. 

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