MRD-driven treatment with venetoclax-R2 in mantle cell lymphoma: the Nordic Lymphoma Group MCL7 VALERIA trial.

"Conflict-of-interest disclosure: M.J. has received grants, personal fees and nonfinancial support from AbbVie; grants and nonfinancial support from Celgene, during the conduct of the study; grants and nonfinancial support from Janssen; and has received grants, personal fees, and nonfinancial support from Kite/Gilead, BeiGene, AstraZeneca, Roche, and Pierre Fabre, outside the submitted work. C.U.N. has received research funding and/or consultancy fees outside the current work from AbbVie, AstraZeneca, Janssen, Octapharma, Takeda, CSL Behring, BeiGene, and Genmab. S.L. has received grants and personal fees from Genmab; personal fees from Incyte; grants from Nordic Nanovector; grants and personal fees from Novartis; grants and personal fees from Roche; personal fees from Merck; grants from Bayer; grants and personal fees from Celgene; and personal fees from Orion, outside the submitted work. I.G. has received institutional support from Takeda, Janssen Cilag, and Lokon Pharma. A.P. has received consultation and personal fees outside the current work from Gilead, BeiGene, Roche, and Incyte. The remaining authors declare no competing financial interests."

"Sequencing was funded by grants from the Research Council of Finland and Finnish Cancer Organization (S.L.). The study was supported by a research grant from 10.13039/100006483AbbVie to the Nordic Lymphoma Group. Study drug was supported by 10.13039/100006483AbbVie and 10.13039/100002491Bristol Myers Squibb. The companies were not involved in the protocol writing, in collection, analysis, or interpretation of the data, or in writing of the report but were able to review the manuscript before submission."

"Key eligibility criteria included age of ≥18 years; confirmed MCL diagnosis; ≥1 previous treatments including at least 1 rituximab-containing regimen; Eastern Cooperative Oncology Group performance status score of 0 to 3; measurable disease (long axis of >1.5 cm); absolute neutrophil count of ≥1000/mm3; platelets of ≥100 000/mm3 or ≥50 000/mm3 if bone marrow involvement; alanine amino transferase and aspartate amino transferase lower than 3-times the upper limit of normal; and serum creatinine no higher than 2-times the upper limit of normal. Key exclusion criteria included known central nervous system involvement, and active hepatitis B or C infection. The study was approved by the respective national ethics committees in the 4 countries and conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation guidelines for Good Clinical Practice. All patients provided written informed consent. The trial was registered at www.ClinicalTrials.gov as #NCT03505944. Despite improvements in treatment of mantle cell lymphoma (MCL), most patients eventually relapse. In this multicenter phase 1b/2 trial, we evaluated safety and efficacy of minimal residual disease (MRD)–driven venetoclax, lenalidomide, and rituximab (venetoclax-R2) in relapsed/refractory (R/R) MCL and explored the feasibility of stopping treatment in molecular remission. The primary end point was overall response rate (ORR) at 6 months. After dose escalation, the recommended phase 2 dose was lenalidomide 20 mg daily, days 1 to 21; venetoclax 600 mg daily after ramp-up; and rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks. MRD monitoring by RQ-PCR was performed every 3 months. When MRD-negativity in the blood was reached, treatment was continued for another 3 months; if MRD-negativity was then confirmed, treatment was stopped. In total, 59 patients were enrolled, with a median age of 73 years. At 6 months, the ORR was 63% (29 complete remission [CR], 8 partial remission [PR]), and 40% (4 CR, 2 PR) for patients previously failing a Bruton tyrosine kinase (BTK) inhibitor. Median progression-free survival (PFS) was 21 months, with median overall survival of 31 months. TP53 mutation was associated with inferior PFS (P < .01). Overall, 28 patients (48%) discontinued treatment in molecular remission, and 25 remain MRD negative after a median of 17.4 months. Hematological toxicity was frequent, with 52 of 59 (88%) patients with G3-4 neutropenia and 21 of 59 (36%) patients with G3-4 thrombocytopenia. To conclude, MRD-driven venetoclax-R2 is feasible and tolerable and shows efficacy in R/R MCL, also after BTK inhibitor failure. This trial was registered at www.ClinicalTrials.gov as #NCT03505944."