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