Durable Responses with Vemurafenib plus Rituximab in Hairy-Cell Leukemia

Hairy-cell leukemia (HCL) often initially responds to the chemotherapeutic purine analogues cladribine and pentostatin, but up to about half of patients relapse. In patients with multiple prior lines of therapy, treatment with either the BRAF^V600E inhibitor vemurafenib or the CD20 antibody rituximab—used because BRAF^V600E is the key HCL driver and because HCL expresses CD20, respectively—has shown some promise, but neither has produced high rates of durable complete responses. To attempt to address the shortcomings of vemurafenib and rituximab as monotherapies, Tiacci, Falini, and colleagues conducted a phase II clinical trial investigating the use of vemurafenib plus rituximab in 30 patients with relapsed or refractory HCL. An intention-to-treat analysis including all 30 patients revealed that 87% (26 patients) had complete responses, including all 10 patients whose disease was refractory to purine analogues, all seven patients who had previously received a BRAF^V600E inhibitor, and all five evaluable patients whose disease was refractory to rituximab; importantly, 60% had minimal residual disease (MRD) negativity. Among the 26 patients whose disease could be evaluated for relapse at a median follow-up time of 36 months, the relapse-free survival rate was 85% (22 patients), and all four patients (15%) who experienced disease relapse had MRD positivity at the time of initial response. Although cross-trial comparisons should be interpreted with caution, the complete response rate and relapse-free survival rate compare favorably with previously determined values for vemurafenib or rituximab alone, as well as with those of standard therapeutic options available in the relapsed/refractory setting (e.g., the anti-CD22 immunotoxin moxetumomab pasudotox or chemoimmunotherapy with a purine analogue plus rituximab). The safety profile of this combination treatment was as expected based on the adverse events observed with each agent alone, and the most common treatment-emergent adverse events were of grade 1 or 2, including infusion-related reactions (from rituximab) along with hyperbilirubinemia, pancreatic enzyme level increases, arthralgia or arthritis, rash or erythema, skin papilloma or warts, liver enzyme increases, and hypophosphatemia (from vemurafenib). In summary, the promising rate of durable responses along with the lack of unexpected toxicities in patients with relapsed or refractory HCL treated with vemurafenib plus rituximab indicate that this combination treatment should be investigated in further trials, including in the first-line setting.

Tiacci E, De Carolis L, Simonetti E, Capponi M, Ambrosetti A, Lucia E, et al. Vemurafenib plus rituximab in refractory or relapsed hairy-cell leukemia. N Engl J Med 2021;384:1810–23.

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