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Early Relapse in Lymphoma: What are the Implications, and What Are the Options?

Presentation by Amanda Cashen, MD, Washington University, St. Louis at ESMO22 Pennsylvania.

When patients with lymphoma experience what is considered an ‘early’ relapse, or a poor response to their initial treatment (primary refractory disease), it is generally considered a harbinger of poor outcome and/or an indicator of more advanced disease. At this year’s third ESMO US review session, held in Philadelphia PA, Dr Amanda Cashen from Washington University, St. Louis, reviewed the implications of early relapse for the three most common types of non-Hodgkin’s Lymphoma (NHL), and relevant updates in treatment as reported at the ESMO 2022 Congress.

Diffuse Large B-Cell Lymphoma (DLBCL)

For DLBCL, an early relapse to first line (1L) therapy is generally considered as a relapse occurring within the first 12 months of therapy. Treatment for these early-relapsing patients consists of salvage chemotherapy followed by an autologous stem cell transplant (ASCT), however, only a small proportion of patients will be eligible for ASCT and the outcome for these patients, as Dr Cashen noted, has generally been very poor, based on prospective data from the CORAL and ORCHAARD studies. For these patients experiencing relapsing/resistant (R/R) DLBCL, some of the recently approved treatments include antibody-drug conjugate (ADC) therapies such as polatuzumab vedotin (anti-CD79b) and loncastuximab tesirine (anti-CD19), and a monoclonal antibody treatment, tafasitamab (anti-CD19). The overall response rate (ORR) for these therapies ranges from 45% to 58%, however, Dr Cashen noted these are unlikely to provide long term remission for patients. More recently, chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (Axi-Cel) has emerged as an option for 2nd line therapy for DLBCL, with a significant improvement (P<0.0001) in event-free survival (EFS) of 40.5% versus 16.3% with standard of care (SOC). The ORR was 83% with Axi-Cel vs. 50% for SOC, with a complete response (CR) rate of 65% vs. 32%, and a 2-year overall survival (OS) rate of 61% vs. 52%. Another smaller study has established the efficacy of the CAR T-cell therapy lisocabtagene maraleucel (Liso-Cel) with a significant improvement in OS (P<0.0001), improved ORR and CR, and 1-year OS with Liso-Cel versus SOC. Another promising investigational modality for R/R DLBCL which Dr Cashen noted are bi-specific antibodies targeting CD20 and CD3, epcoritamab and glofitamab, for which ORRs of 63% and 80%, respectively, were reported at ESMO 2022.

Follicular Lymphoma (FL)

For FL, progression within 2 years (24 months) of the 1L therapy, also known as a POD24, is known to be a significant poor prognostic factor, with a 5-year survival of 87% for patients without a POD24, as compared to 62% for those with a POD24. Dr Cashen noted that POD24 is seen in about 20% of patients with FL, and if it should occur, a biopsy is indicated to rule out transformation of the lymphoma into DLBCL (which would necessitate a different treatment modality). For these early relapsing patients whose disease remains as FL, Dr Cashen notes that clinicians should consider clinical trials, 2nd-line chemo-immunotherapy followed by ASCT, chemotherapy-free approaches, and CAR T-cell therapies. Chemotherapy free options in the R/R FL setting include lenalidomide/rituximab, lenalidomide/obinutuzumab, and the PI3 kinase inhibitors idelalisib and copanlisib. She noted that these chemo-free regimens can be an attractive option, with reported response rates ranging from 57% to 80% in patients with a POD24, with good PFS and duration of responses.

More recently, the Phase II ELARA trial (N=97 patients) showed that treatment with the CAR T-cell therapy tisagenlecleucel (Tisa-Cel) was associated with an 86% ORR, a CR rate of 69% (including 59% and 88% for those with and without a POD24, respectively), and the EFS was durable for many patients. The ZUMA-5 trial of Axi-Cel in R/R FL showed ORR of 92% (with 92% ORR for patients with a POD24) and a CR rate of 77%. Dr Cashen also noted that Bi-specific T-cell engagers (BiTE) therapies, which target the cell surface molecules CD19 or CD20 in addition to CD3, have also shown promise in R/R FL, with ORRs ranging between 68% (mosunetuzumab) and 90% (epcoritamab), with durable remissions observed. While only available in clinical trials at present, she expects that BiTE therapies will likely be another option for FL treatment in the future.

Mantle-Cell Lymphoma (MCL)

For patients with MCL, relapses occurring within the first 24 months of treatment have also been associated with poor overall survival. In addition, Dr Cashen noted it is important to consider several established high-risk features of MCL at diagnosis, including a blastoid variant subtype, a high proliferation or Ki67 index (>30%), a high-risk mantle cell international prognostic index (MIPI) score, mutations in p53, and a complex karyotype. Dr Cashen noted that, following a first relapse in MCL, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib is favored over the use of rituximab-chemotherapy for both PFS and OS in patients who have an early relapse. Other options for patients with early relapse in MCL include next-generation BTK inhibitors. She noted, however that response rates to all of the BTK inhibitors can be lower in patients with MCL risk factors as noted earlier. Additional options are ASCT (although only a small number of patients would be candidates), CAR T-cell therapy, and enrollment in clinical trials such as those utilizing combinations of targeted agents, ADCs, and BiTEs. Recent results from the ZUMA-2 trial of R/R MCL patients after 1 to 5 prior therapies showed that KTE-X19 (brexucabtagene autoleucel) was associated with a 91% ORR (with 94% ORR for those with a POD24) and a CR rate of 68%. As such, Dr Cashen suggests CAR-T cells at present would be the most effective approach for R/R MCL after failure of a BTK inhibitor, and the Brexu-Cel CAR-T preparation is now approved in this setting following 1 or more prior lines of therapy.

See more from the 2022 ESMO Pennsylvania Conference here.

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