Efficacy of Chemo-Free Combination Therapy with BRAF Inhibitor and Rituximab in Classic Hairy Cell Leukemia: Insights from the French Experience

Background: Hairy cell leukemia (HCL) is a rare form of leukemia. The introduction of purine analogs has revolutionized its prognosis, leading to a life expectancy closer to that of the general population. However, patients experience relapses and require other treatment options. The BRAF V600E mutation is present in 80-100% of patients with HCL, which has prompted the use of BRAF inhibitors (vemurafenib or dabrafenib) in this condition. Recently, the combination of vemurafenib with rituximab has shown efficacy with durable responses in relapsed patients.

Here, we present, for the first time, real-life data on the combination of a BRAF inhibitor with rituximab through a retrospective study involving 9 French centers. Data collection was completed by July 1, 2023.

Results: We collected data from 17 patients with a male-to-female ratio of 13:4; the median age was 69 years (38-90), and 6 patients were aged over 75. The median number of previous treatments was 4 (0-7), and 3 patients were treatment-naive because they were deemed ineligible for purine analogs based on age or performance status. All 14 relapsed patients had previously received purine analogs once or multiple times (1-3). The median progression-free survival (PFS) after purine analogs was 48 months, and the median PFS after the last line of therapy was 24 months. Five patients were exposed to moxetumumab pasudotox, and 3 patients received single-agent vemurafenib previously. The BRAF V600E mutation was tested and positive for 16 patients.

In our cohort, 13 patients received a combination of vemurafenib with rituximab (V+R), and 4 patients received a combination of dabrafenib with rituximab (D+R). All patients received the same regimen (Tiacci, NEMJ 2021), which included an induction phase (V+R or D+R for 8 weeks) followed by rituximab consolidation (4 injections every 15 days), except for one patient who received a rituximab sequence followed by vemurafenib.

At the time of analysis, 15 out of 17 patients had completed the treatment, and the remaining 2 had completed the induction phase. Fourteen patients initiated treatment at the standard dose (960 mg bid for vemurafenib and 150 mg bid for dabrafenib), and 3 patients at a reduced dose (240-480 mg bid for vemurafenib). Toxicity of any grade was reported in 15 out of 17 patients, with 3 of them experiencing grade 3-4 toxicity. Skin toxicity was the most frequent, recorded in 12 patients (grade 1-2), leading to temporary treatment interruption in 2 patients and dose reduction in 6 patients. Other toxicities included musculoskeletal, hepatic, hematological, and cardiac, with only one patient experiencing a grade 2 infection during treatment. No secondary cancers were reported during or after treatment. Treatment was discontinued due to toxicity in 5 patients, with 4 of them resuming treatment later. Eight patients required a dosage reduction, with a median final vemurafenib dosage of 480 mg bid. At the end of treatment, 14 patients achieved a complete hematological response, and 1 patient achieved a partial response. Among the 9 patients with early response data, the median time for platelet recovery was 15 days, and for neutrophil recovery, it was 14 days. End-of-treatment bone marrow aspiration and/or biopsy was performed for 8 patients, showing a complete response in 7 patients. With a median follow-up of 12 months (4-56), only 2 patients had progressed, and as of the last update, no patients had died, and the 2 relapsed patients achieved a complete response after a new line of therapy.

Conclusion: Despite a limited median follow-up of 12 months, the combination of a BRAF inhibitor with rituximab proves to be an effective regimen in heavily treated patients with HCL, achieving a 100% overall response rate. Our study confirms a rapid hematological response and an acceptable toxicity profile, even in elderly patients. The most frequent toxicity observed was cutaneous toxicity, mainly grade 1-2, and it never led to a definitive treatment discontinuation. A comparison of the two BRAF inhibitors in terms of efficacy or toxicity cannot be established due to the small sample size of patients treated with dabrafenib. Lastly, the combination of rituximab with vemurafenib or dabrafenib appears to be an interesting option in frontline treatment for patients ineligible for purine analogs.