Novel combinations for R/R MCL: Key updates from ASH 2022

The treatment landscape for mantle cell lymphoma (MCL) is rapidly advancing; however, there remains an unmet need for effective novel therapies in patients with relapsed/refractory (R/R) MCL. Here, we summarize three key studies on novel combinations for the treatment of R/R MCL presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition; Minson presented a time-limited combination of ibrutinib and tisagenlecleucel (tisa-cel) in R/R MCL;¹ Jerkeman presented treatment outcomes for a venetoclax, lenalidomide, and rituximab combination therapy in R/R MCL;² and Soumerai presented safety and efficacy data for zandelisib plus zanubrutinib in R/R FL and MCL.³

Time-limited combination of ibrutinib and tisa-cel in R/R MCL¹

TARMAC (NCT04234061) is an ongoing, multicenter, single-arm phase II trial assessing the efficacy and safety of a time-limited combination of ibrutinib (560 mg daily) and tisa-cel (3.0 × 10⁸) infusion (range, 1.3–4.6) in patients with R/R MCL. The primary endpoint was complete response (CR) rate at Month 4 after tisa-cel infusion, with key secondary endpoints including safety, objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and subgroup analysis based TP53 mutation status.

• Overall, 20 patients received treatment, the median age was 66 years and 75% of patients were male; the median number of prior therapies was two, with 55% and 50% of patients having received prior autologous stem cell transplant and Bruton’s tyrosine kinase inhibitors (BTKis), respectively.
• High-risk molecular profiles included TP53 mutation (n = 8) and SWI/SNF chromatin domain (n = 8).
• At Month 4 post-tisa-cel infusion, ORR was 80% (comprising 80% CR and 20% progressive disease). Subgroup analysis also showed a high rate of CR at Month 4 in BTKi-naïve (90%), BTKi-exposed (70%), TP53-mutated (88%), TP53-wildtype (80%), and SWI-SNF aberrant populations (88%).
• Most patients in CR were also MRD-negative, 14 patients (70%) demonstrated MRD-negativity in peripheral blood and bone marrow by flow cytometry; eight patients were also negative by retrospective high-throughput immunoglobulin sequencing.
• At a median follow-up of 13 months, median PFS was not reached; 6- and 12-month event free survival rates were 85% and 75%, respectively.
• Subgroup analyses demonstrated durable responses in BTKi-exposed, TP53-mutated and SWI-SNF aberrant subgroups. Response rates and durability of responses were similar between TP53 wildtype and TP53 mutated patients.
• Patients in MRD-negative CR at Month 4 (deep responders) demonstrated higher peak chimeric antigen receptor (CAR)-T (p = 0.033) and CAR-T area under the curve to Day 28 (p = 0.041) compared with others or MRD-positive patients.
• In total, 15 patients experienced CRS (Grade 1–2 [n = 11], Grade 3 [n = 4], and no Grade 4 events). One episode of immune effector cell-associated neurotoxicity syndrome (Grade 2) was observed with complete resolution.
• Atrial fibrillation, associated with infection due to bridging therapy, was observed in one patient. Overall Grade 3–4 adverse events (AEs) were seen in 75% of patients and serious AEs were reported in 70% of the patients. There were no deaths.

Presenter’s conclusions

The time-limited combination of ibrutinib and tisa-cel, regardless of prior BTKi exposure and/or TP53 status, was found to be a promising treatment option in R/R MCL, leading to a high rate of durable responses. Deep responses were associated with less depleted baseline T-cell states and more robust CAR T-cell expansion; treatment also had a good safety profile. These findings support additional research into the combination of BTKis and T-cell redirecting immunotherapies for the treatment of patients with MCL.

Venetoclax, lenalidomide and rituximab combination in R/R MCL²

VALERIA (NCT03505944) is an ongoing multi-center, open-label, phase Ib-II trial assessing the efficacy and safety of combination venetoclax (600 mg daily), lenalidomide (50 mg daily), and rituximab in BTKi-failed and BTKi-naïve patients with R/R MCL. The primary endpoint was ORR at 6 months compared to Regimen 2 (lenalidomide + rituximab),⁴ to explore the feasibility of an MRD-driven strategy and to investigate the role of ctDNA in R/R MCL.

• Overall, 59 patients received treatment with a median age of 72 years, 81% were male and 36% were MIPI high-risk. The median number of previous treatment lines was two and 44% of patients had previously received autologous stem cell transplant.
• Hematological toxicity was the most frequent AE; including Grade 3–4 neutropenia (88%) (all required granulocyte colony stimulating factor support) and Grade 3–4 thrombocytopenia (36%). Eight events of Grade 3-4 infection were recorded.
• Non-hematological AEs included gastrointestinal, infections, rash, respiratory, muscular, and cardiovascular disorders. Serious AEs were reported in 55 patients and were primarily infections. Two deaths were recorded due to progressive multifocal leukoencephalopathy  (n = 1) and aspergillus (n = 1).
• At 6 months, ORR was 63% (CR, 49%; partial response [PR], 14%). Among the 15 patients previously exposed to a BTKi, ORR was 40% (CR, 27%; PR, 13%). Seventeen patients stopped treatment early due to toxicity or other reasons; at 24 months, PFS was 46% and OS was 57%.
• Molecular remission at 3 and 6-months was 97% and 94%, respectively; evaluable patients were MRD negative.
• Overall, 21 patients (36%) stopped treatment in molecular remission (three patients restarted after 9–12 months and all reversed to MRD-negativity) and seven patients (12%) stopped the treatment in metabolic CR.
• Genotyping analysis showed ATP as the most common mutation (32%) followed by TP53 mutation (25%); ctDNA analysis is ongoing.

Presenter’s conclusions

Irrespective of prior BTKi exposure and/or TP53 status, the combination of venetoclax, lenalidomide and rituximab was found to be effective and well-tolerated in patients with R/R MCL. Neutropenia frequently occurred and needed granulocyte colony stimulating factor support. It was possible to stop treatment in molecular remission. It was also shown that this combination can be potentially clinically useful as a bridge to allo-SCT or CAR-T.

Zandelisib plus zanubrutinib in R/R FL and MCL³

This is an ongoing, multi-arm phase Ib trial investigating the combination of zandelisib and zanubrutinib in patients with R/R MCL (NCT02914938). The primary objective was the safety and tolerability of combination zandelisib (60 mg once daily) and zanubrutinib (80 mg twice daily) in patients with R/R follicular lymphoma (FL) or MCL. Efficacy endpoints included investigator-assessed ORR, DOR, and PFS.

• Overall, 50 patients received treatment, 31 with FL and 19 with MCL. The median age was 67 years and median number of prior therapies was two (53% had received ≥2 prior therapies).
• As of October 17, 2022, the ORR in patients with FL was 86.7% (CR, 23.3%; PR, 63%). With a median follow-up of 9.2 months, the median DOR was 20.6 and with a median follow-up of 11.1 months, the median PFS was 22.4 months. Tumor reduction was observed in 97% of the patients.
• As of October 17, 2022, the ORR in patients with MCL was 72.2% (CR, 8%; PR, 64%). At a median follow-up of 9.4 months, median DOR was not estimated and at a median follow-up of 11.1 months, the median PFS was 10.1 months. Tumor reduction was observed in 94% of the patients.
• Treatment-emergent AEs reported in ≥15% of patients are summarized in Table 1. Two patients discontinued the treatment due to decreased neutrophil count and drug rash with eosinophilia and systemic symptoms (one patient each). The only death in the study was a 68 year old patient with MCL who died of complications related to COVID-19.

Table 1. Treatment-emergent adverse events in patients with R/R FL or MCL

ALT, alanine aminotransferase; AST, aspartate aminotransferase; FL, follicular lymphoma; MCL, mantle cell lymphoma; R/R, relapsed/refractory; TEAE, treatment-emergent adverse event, WBC, white blood cells. *Adapted from Soumerai et al.3 †Occurring in ≥15% of patients (N = 50)
TEAEs, %†	Grade 3	Grade 4
Diarrhea	2	—
Neutrophil count decreased	8	12
Platelet count decreased	4	2
Anemia	6	—
AST increased	6	—
ALT increased	8	—
WBC count decreased	2	—
Headache	2	—
Arthralgia	2	—
Nausea	2	—
Rash maculo-papular	4	—

Presenter’s conclusions

In comparison to either agent alone, zanubrutinib and zandelisib were well tolerated and did not increas the frequency or severity of class-related adverse events. Patients with R/R FL and MCL both had high response rates; furthermore, the depth of response seemed to increase with time. These findings encourage further research to fully elucidate the potential of this combination for the treatment of B-cell malignancies.