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Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma
Christopher Melani1, Rahul Lakhotia1, Stefania Pittaluga1
1From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management Section (S.M.S.), Center for Cancer Research, the Laboratory of Pathology, Clinical Center (S.P., T.D.-H., S.D.P., E.S.J.), and the Biometric Research Program, Division of Cancer Treatment and Diagnosis (G.W.), National Cancer Institute, the Division of Pre-Clinical Innovation Chemistry Technologies, National Center for Advancing Translational Sciences (C.J.T., M.C., F.A.T.), and the Clinical Center Pharmacy Department (C.L.), National Institutes of Health, Bethesda, and Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore (S.T.L.) - all in Maryland; the Division of Hematology and Oncology, University of Virginia, Charlottesville (C.A.P.); Mario Lemieux Center for Blood Cancers, University of Pittsburgh School of Medicine, Pittsburgh (R.J.F.); and Adaptive Biotechnologies, Seattle (A.J., H.S.).
Background:
The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.
Methods:
We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.
Results:
In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 or BCL6 (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.
Conclusions:
Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
Insights
The ViPOR regimen showed durable remissions in specific diffuse large B-cell lymphoma (DLBCL) subtypes. This combination therapy, including venetoclax, demonstrated manageable adverse events in relapsed or refractory DLBCL patients.
Area of Science:
- Oncology
- Hematology
- Clinical Pharmacology
Background:
- Targeting oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to pathway-specific drugs.
- The potential for curative treatment by targeting multiple survival pathways in DLBCL remains unknown.
Purpose of the Study:
- To evaluate the safety and efficacy of a novel combination regimen, ViPOR, in patients with relapsed or refractory DLBCL.
- To determine the recommended phase 2 dose of venetoclax within the ViPOR regimen.
Main Methods:
- A single-center, phase 1b-2 study of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) was conducted.
- Phase 1b determined the recommended dose of venetoclax (800 mg), with phase 2 evaluating efficacy in DLBCL patients.
- ViPOR was administered every 21 days for six cycles.
Main Results:
- A dose-limiting toxicity of grade 3 intracranial hemorrhage established the phase 2 dose of venetoclax.
- Among 48 evaluable DLBCL patients, objective response was 54% and complete response was 38%.
- Complete responses were observed in non-GCB DLBCL and high-grade B-cell lymphoma with specific gene rearrangements; 2-year progression-free survival was 34% and overall survival was 36%.
Conclusions:
- The ViPOR regimen achieved durable remissions in patients with specific molecular DLBCL subtypes.
- Adverse events associated with ViPOR were primarily reversible.
- The study was funded by the National Cancer Institute and others (ClinicalTrials.gov NCT03223610).
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