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

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 <1.0k/ul, Hgb <10.0g/dL or PLT <100k/ul) were enrolled. Patients received a 28-day lead in cycle of vemurafenib 960 mg bid, followed by concurrent obinutuzumab-vemurafenib from months 2-4, for total duration of 4 months. Obinutuzumab was administered at 1000mg IV on days 1, 8, and 15 of month 2, and day 1 of month 3 and 4. Vemurafenib dose reductions were allowed for drug-related adverse events (AEs). Response was assessed at the end of month 4 with bone marrow (BM) biopsy and CT scans. The primary objective was to determine the efficacy of vemurafenib and obinutuzumab combination as assessed by CR rates. Secondary objectives included assessment of safety, MRD negativity rate, and BRAF allele burden by digital PCR. MRD was assessed from month 4 BM by multiparameter flow cytometry and/or IgH clonality by PCR. The study adopted a Simon's minimax 2-stage design and required ≥7 CR in the first 9 pts in the first stage to continue accrual for a total of 28 pts. The study began enrollment March 2018 and completed accrual in February 2021.

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.

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