First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

Autor: Jae H Park, Eric S. Winer, Scott F. Huntington, Gottfried von Keudell, Shreya Vemuri, Madhulika Shukla, Julie C Kinoshita, Victoria Falco, Steven D. Gore, Richard M. Stone, Omar Abdel-Wahab, Martin S. Tallman
Rok vydání: 2021
Předmět:
Zdroj: Blood. 138:43-43
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood-2021-151074
Popis: Background: We have previously reported >90% overall response rates of the BRAF inhibitor, vemurafenib, in patients (pts) with relapsed or refractory (R/R) hairy cell leukemia (HCL) (Tiacci and Park et al. NEJM 2015). However, complete response (CR) rate was observed in 35-40% of the pts and 50% relapsed with vemurafenib monotherapy (Park JH et al. Blood 2018, 132;392). Anti-CD20 antibodies such as rituximab and obinutuzumab have demonstrated efficacy in HCL, and the recent data reported improved CR rate when rituximab was added to vemurafenib in R/R HCL (Tiacci et al. NEJM 2021). We therefore initiated a phase II multi-center clinical trial to investigate the efficacy of vemurafenib and obinutuzumab in pts with newly diagnosed HCL (NCT03410875). Methods: Adult pts with previously untreated HCL who met criteria for initiation of treatment (i.e., ANC Results: A total of 30 pts was enrolled to the study. The median age of the pts was 54 years old (range, 28-82). 27 pts were male. The median pretreatment ANC, Hgb and PLT were 0.8k/ul (range, 0.0-2.6), 12.3g/dL (range, 7.0-15.0), and 83k/ul (range, 21-153), respectively. Sixteen of 28 pts had baseline splenomegaly as assessed by CT. Three pts discontinued the study due to adverse events (verrucous hyperplasia, pneumonia and rash) at a median of 50 days from treatment initiation (range, 29-56). Twenty-seven pts completed all 4 months of study treatments. Of those 27 patients, 26 pts achieved CR (96%) and 1 pt achieved PR (4%) at month 4. With no further treatment, all 27 patients achieved CR by month 10. MRD was assessed in 26 of 27 CR pts and was undetectable in 25 pts (96%). After 1 month of vemurafenib and before the first dose of obinutuzumab, 20 (74%), 25 (93%) and 24 pts (89%) had ANC recovery to >1.0K/ul, Hgb >10 g/dL and PLT 100k/uL, respectively. With the median follow-up of 16.7 months (range, 4.9 - 36), all pts remain in continuous remission without relapse. The most common vemurafenib-related AEs were rash (61%; Gr1/2-14%, Gr3- 46%), arthralgia (46%; Gr1/2-36%, Gr3-11%), fatigue (29%, all Gr1), alopecia (25%, all Gr1), and pruritis (21%, Gr1-2) (Table). There was no reported case of febrile neutropenia but grade 1 fever was observed in 14%. Two pts experienced grade 2 obinutuzumab infusion reaction, all occurring with the first infusion, but were able to complete all intended doses of obinutuzumab without subsequent infusion reactions. Five pts had vemurafenib dose reductions and 12 pts had vemurafenib dose interruptions due to AE, most commonly due to rash and arthralgia. T cell subsets were obtained at month 5-8 and 12; all pts showed CD4 counts >200 with the median absolute CD4 count of 540 (range, 214-1231) and 639 cells/ul (range, 402-1446), respectively. Conclusion: Vemurafenib and obinutuzumab combination therapy induced 100% CR rate with high MRD negativity (96%) in pts with HCL in the frontline setting, and is a promising chemotherapy-free targeted therapeutic approach for HCL. Most pts had normalization of cytopenia after a 4-week lead-in of vemurafenib with no case of febrile neutropenia and no evidence of significant T cell immunosuppression on therapy. While we have not observed any relapse to date, a longer follow-up is needed to assess durability of remission compared to purine nucleoside-treated cohorts. Figure 1 Figure 1. Disclosures Park: Amgen: Consultancy; Autolus: Consultancy; BMS: Consultancy; PrecisionBio: Consultancy; Affyimmune: Consultancy; Kura Oncology: Consultancy; Innate Pharma: Consultancy; Intellia: Consultancy; Minerva: Consultancy; Servier: Consultancy; Kite Pharma: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Novartis: Consultancy. Winer: Novartis: Consultancy; Takeda: Consultancy; Abbvie: Consultancy. Huntington: Novartis: Consultancy; Bayer: Honoraria; SeaGen: Consultancy; Thyme Inc: Consultancy; Pharmacyclics: Consultancy, Honoraria; Servier: Consultancy; Genentech: Consultancy; Flatiron Health Inc.: Consultancy; DTRM Biopharm: Research Funding; AbbVie: Consultancy; TG Therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Research Funding. von Keudell: AbbVie: Research Funding; BMS: Research Funding; Janssen: Research Funding; Merck: Research Funding; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Stone: Macrogenics: Consultancy; Jazz: Consultancy; Janssen: Consultancy; Innate: Consultancy; Glaxo Smith Kline: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bristol Meyers Squibb: Consultancy; Boston Pharmaceuticals: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Consultancy, Research Funding; OncoNova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Abdel-Wahab: Merck: Consultancy; Prelude Therapeutics: Consultancy; Foundation Medicine Inc: Consultancy; H3B Biomedicine: Consultancy, Research Funding; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; NYU Grand Rounds: Honoraria; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. OffLabel Disclosure: vemurafenib and obinutuzumab for treatment of HCL
Databáze: OpenAIRE
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