Vemurafenib with rituximab induces complete response in advanced hairy-cell leukemia
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Vemurafenib plus rituximab induced durable complete responses in the majority of a small cohort of patients with relapsed or refractory hairy-cell leukemia, according to a phase 2 study published in The New England Journal of Medicine.
“Because hairy-cell leukemia cells that are resistant to vemurafenib [Zelboraf, Genentech] strongly retain expression of the B-cell antigen CD20, we hypothesized that these cells could be cleared using the anti-CD20 monoclonal antibody rituximab [Rituxan; Genentech, Biogen], which has some single-agent activity in relapsed or refractory hairy-cell leukemia, producing frequent responses but few complete ones,” Enrico Tiacci, MD, associate professor of hematology at University and Hospital of Perugia in Italy, told Healio. “This served as rationale for designing the currently published study that is based on the combination of vemurafenib plus rituximab, two nonmyelotoxic agents that kill leukemic cells through different mechanisms, with the aim to improve the response depth and duration in refractory or relapsed hairy-cell leukemia.”
The single-center, academic trial included 30 patients (median age, 61 years; men, n = 28) with relapsed or refractory BRAF V600E-mutated hairy-cell leukemia who received a median three (range, 1-14) previous therapies. Researchers assessed the safety and efficacy of the oral BRAF inhibitor vemurafenib, dosed at 960 mg twice daily for 8 weeks, plus concurrent and sequential rituximab, administered in eight IV infusions of 375 mg/m2 over 18 weeks.
Patients received two induction cycles, each consisting of 4 weeks of vemurafenib and two infusions of rituximab on days 1 and 15. After a 2-week break and an evaluation that included bone marrow biopsy, researchers administered four additional doses of rituximab 2 weeks apart as consolidation therapy, followed by an end-of-treatment evaluation 4 weeks after the final rituximab dose and monitoring of response every 6 months thereafter.
Complete response at the end of planned treatment served as the primary endpoint. Secondary endpoints included time to response, minimal residual disease (MRD) status, PFS, RFS, MRD-free survival and safety.
Results showed 26 patients (87%; P = .005) in the intention-to-treat population achieved complete response, which included all 10 patients with chemotherapy-refractory disease, all five patients with rituximab-refractory disease, and all seven patients previously treated with BRAF inhibitors.
Of the patients who achieved complete response, 17 (65%) also achieved MRD negativity. All patients who achieved MRD negativity after treatment remained free of MRD in bone marrow and peripheral blood at a median 28.5 months after first negative MRD status.
Thrombocytopenia cleared after a median 2 weeks and neutropenia after a median 4 weeks, researchers noted.
Researchers reported a PFS rate of 78% at median follow-up of 37 months among all patients and an RFS rate of 85% at median follow-up of 34 months among the 26 patients who achieved response.
Results of a post-hoc analysis showed correlations of MRD negativity and lack of prior BRAF inhibitor treatment with longer RFS.
Grade 1 or grade 2 adverse events appeared similar to those previously observed for vemurafenib and rituximab.
“During the COVID-19 pandemic, BRAF inhibitors should be considered instead of purine analogs [because] the latter agents are profoundly myelotoxic and immunosuppressive,” Brunangelo Falini, MD, head of the Institute of Hematology at the Medical School of Perugia University in Italy and a co-author of the study, told Healio. “Although adding rituximab to the BRAF inhibitor will reduce the antibody response to SARS-CoV-2 vaccines, the combination may still be considered [for patients with hairy-cell leukemia] who for some reason do not have a clear vaccination schedule in place and cannot defer antileukemic treatment because of severe infections or transfusion dependency, as this drug combination induces very rapid responses.”
Moreover, the COVID-19 mRNA vaccines also elicit a potent T-cell-mediated response that is not affected by rituximab, Falini added.
“Currently, vemurafenib plus rituximab represents the best chemotherapy-free therapeutic option for refractory or relapsed hairy-cell leukemia [because] it compares favorably, both in terms of complete response and achievement of MRD negativity, with the anti-CD22 immunotoxin moxetumomab pasudotox [Lumoxiti, Innate Pharma], which is the only targeted agent approved by regulatory agencies in this clinical setting. Moreover, unlike moxetumomab, the activity of vemurafenib plus rituximab does not seem to be negatively affected by previous splenectomy or substantial splenomegaly.”
The researchers now plan to conduct a randomized trial in the front-line setting.
“Given the excellent results achieved with vemurafenib plus rituximab in [patients with refractory or relapsed hairy-cell leukemia], we are planning a randomized comparison of vemurafenib plus rituximab against the chemotherapy-based standard of care, cladribine plus rituximab, in the front-line setting to assess whether similar efficacy can be obtained with lower toxicity,” Tiacci said.
For more information:
Enrico Tiacci, MD, and Brunangelo Falini, MD, can be reached at Centro di Riceerche Emato-Oncologiche, Ospedale S. Maria della Misericordia, Blocco R, Piano 2, Piazzale Menghini 8, 06132 Perugia, Italy. Email Enrico Tiacci: enrico.tiacci@unipg.it; email: Brunangelo Falini: brunangelo.falini@unipg.it.
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