ASH 2023: Treatment options for patients with high-risk R/R MCL

The treatment landscape for mantle cell lymphoma (MCL) is rapidly advancing; however, patients with relapsed/refractory (R/R) MCL and high-risk features, such as TP53 mutations/deletions or elevated Ki-67 proliferation index (PI), have historically had limited treatment options and poor outcomes. Below, we summarize three key presentations on the treatment of high-risk R/R MCL, presented during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition. Goy presented outcomes of brexucabtagene autoleucel (brexu-cel) from the ZUMA-2 (NCT02601313) and ZUMA-18 (NCT04162756) studies,¹ Kambhampati presented real-world outcomes of brexu-cel from a CIBMTR high-risk subgroup analysis,² and Cohen presented safety and efficacy outcomes of pirtobrutinib with prior covalent Bruton’s tyrosine kinase inhibitor (cBTKi) exposure, including high-risk subgroup analyses from the phase 1/2 BRUIN study.³

Brexu-cel: ZUMA-2 and ZUMA-18 study outcomes¹

This analysis provides insight into overall survival (OS) outcomes of brexu-cel after 4 years in ZUMA-2 and the primary analysis of ZUMA-18.

Study design

ZUMA-2 enrolled adults (aged ≥18 years) with R/R MCL and ≤5 prior regimens, including a BTKi. The Lymphoma Hub has previously reported on the study design and phase II results of the ZUMA-2 trial.

ZUMA-18 is an ongoing open-label, expanded-access study including two cohorts of adult (aged ≥18 years) patients with R/R MCL. In Cohort 1, patients with ≥1 prior regimen underwent leukapheresis and conditioning chemotherapy; they received a single infusion of brexu-cel at a target dose of 2 × 10⁶ cells/kg (or a fixed dose of 2 × 10⁸ anti-CD19 chimeric antigen receptor T cells for patients ≥ 100 kg). In Cohort 2, patients received the same treatment without leukapheresis (utilizing the initial leukapheresis product). Key endpoints for both ZUMA-2 and ZUMA-18 included overall response rate (ORR), overall survival (OS), and safety.

Results

ZUMA-2

As of July 23, 2022, 68 patients were treated, with a median follow-up for all treated patients of 47.5 months and a median OS of 58.7 months for patients with complete response (CR). After 4 years of median follow-up, 30 patients were still alive and 27 had achieved a CR.

ZUMA-18

As of February 3, 2023, 23 patients enrolled in ZUMA-18 exhibited an investigator-assessed ORR of 87%, CR rate of 57%, partial response rate of 30%, and 9% had progressive disease (PD). The median DOR was 15.1 months in responders and 20 months in patients with CR. The median PFS was 16.1 months in all treated patients and 21 months in the patients with CR. In all patients, the median OS was not reached at data cutoff, with a 24-month OS rate of 58%. At data cutoff, 14 patients were alive and nine patients died due to an adverse event (AE; n = 5), PD (n = 2), and other causes (n = 2).

Brexu-cel-related Grade ≥3 AEs occurred in 18 patients, with common events including anemia, neutropenia, leukopenia, febrile neutropenia, and thrombocytopenia. Any grade cytokine release syndrome occurred in 87% and neurological events were reported 70% of patients. There were five Grade 5 AEs, including one brexu-cel-related AE (multiorgan dysfunction syndrome) and four deemed unrelated to treatment (sepsis, n = 2; aspiration, n = 1; encephalopathy, n = 1).

Brexu-cel: CIBMTR subgroup analysis of high-risk subgroups²

Study design

Patients with high-risk features (del TP53/17p and ≥Ki-67 50%) receiving brexu-cel for R/R MCL from 84 US centers between July 2020 and December 2022 were enrolled in the CIBMTR observational database for a post-authorization safety study. Efficacy endpoints were ORR, CR, DOR, PFS, OS, and relapse/PD. Safety endpoints included cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, prolonged cytopenias, infections requiring treatment, subsequent neoplasms, and non-relapse mortality.

Results

Of the 456 patients included in the analysis, 42% had a TP53/17p deletion and/or Ki-67 PI ≥50%, and 67% did not met ZUMA-2 eligibility criteria at diagnosis. Median follow-up was 12.2 months and DOR, PFS, and OS were evaluated at 12 months. There was no statistically significant difference in OS and PFS at any time between all high-risk subgroups in univariate analysis.

• For patients with TP53/17p deletion vs without deletion, CR was 84% (ORR, 95%; PFS, 53%; OS, 57%) vs 81% (ORR, 90%; PFS, 60%; OS, 76%).
• For patients with Ki-67 PI ≥50% vs <50%, CR was 83% (ORR, 92%; PFS, 63%; OS, 74%) vs 84% (ORR, 93%; PFS, 57%; OS, 76%).
• For patients eligible vs ineligible to ZUMA-2, CR was 84% (ORR, 93%; PFS, 66%; OS, 75%) vs 79% (ORR, 90%; PFS, 58%; OS, 75%).

Response rates were consistent across high-risk subgroups, with a 6- and 12-month DOR of 83% and 69% in patients in CR, respectively. PFS and OS rates at 12 months were 75% and 61%, respectively; these results were comparable with the ZUMA-2 primary analysis (61% and 83%, respectively).

Safety endpoints were largely consistent among all subgroups. Prolonged neutropenia and thrombocytopenia occurred more frequently in patients with vs without TP53/17p deletion (25% vs 13% and 28% vs 16%, respectively). Grade ≥3 CRS occurred more frequently in ZUMA-2-ineligible vs eligible patients (11% vs 10%) and Grade ≥3 immune effector cell-associated neurotoxicity syndrome occurred less frequently in ZUMA-2-ineligible vs eligible patients (27% vs 31%). Non-relapse mortality was consistent across the subgroups.

Pirtobrutinib in patients with prior cBTKi: BRUIN subgroup analysis³

Study design

BRUIN (NCT03740529) is an ongoing phase I/II study including patients with B-cell malignancies. This subgroup analysis included previously treated adult patients with R/R MCL, including patients who received prior BTKi therapy, high-risk molecular features such as Ki-67 and TP53, and BTKi naïve patients. Key endpoints were ORR, DOR, PFS, OS, and safety.

Results

Overall, 166 patients with R/R MCL were enrolled, including cBTKi naïve patients (n = 14) and those previously exposed to a cBTKi (n = 152). Patients were enrolled across a dose escalation range and expansion (25–300 mg/day). The median age was 70 years, 52% and 28% had intermediate- and high-risk sMIPI (simplified prognostic index for advanced stage mantle cell lymphoma) scores. About half of patients had TP53 mutations, and two thirds had a Ki-67 index of ≥30%.

• cBTKi pretreated patients had an ORR of 49.3% (CR, 15.8%; PR, 33.6%). Median DOR was 21.6 months, with 18- and 24-month rates of 51.9% and 38.9%, respectively. The median PFS was 5.6 months and OS was 23.5 months.
• cBTKi naïve patients had a higher ORR of 85.7% (CR and PR, 42.9%). The 18- and 24-month DOR was 90.0%.
• Discontinued cBTKi patients had ORRs of 43.0% (PD) and 90.5% (toxicity/other reasons).

In the MCL cohort (n = 166), the median time on treatment was 5.5 months and common AEs included fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). Grade ≥3 treatment-emergent AEs included fatigue (2.4%), anemia (2.4%), and platelet count decreased (3%). Treatment-related AEs led to dose reductions in eight patients and discontinuation in five patients.