Nature Reviews Clinical Oncology | 2021
HCL — vemurafenib plus rituximab holds promise
Abstract
0123456789();: Nature reviews | CliniCal OnCOlOgy Original article Tiacci, E. et al. Vemurafenib plus rituximab in refractory or relapsed hairycell leukemia. N. Engl. J. Med. 384, 1810–1823 (2021) Hairy cell leukaemia (HCL), an indolent malignancy involving mature CD20+ B cells, is typically highly responsive to purineanalogue chemotherapy. Nevertheless, disease relapse typically occurs in >50% of patients, with progressively worsening responses to chemotherapy. HCL is caused by BRAF mutations, and the BraF inhibitor vemurafenib has demonstrated activity in the relapsed and/or refractory (r/r) disease setting. Now, data from a singlecentre phase ii trial suggest that combining vemurafenib with the antiCD20 antibody rituximab greatly improves the efficacy of treatment. in this trial, 30 cytopenic patients with r/r HCL were assigned to receive two 28day cycles of vemurafenib twice daily plus rituximab on days 1 and 15, followed by four additional doses of rituximab. the patients had received a median of three prior therapies, including a purine analogue in all patients, rituximab in 14 patients and a BraF inhibitor in 7. a complete response (Cr) at the end of treatment, the primary end point of the study, occurred in 26 patients (87%), including all of those with prior exposure to a BraF inhibitor. Minimal residual disease (MrD) negativity in the blood and bone marrow was achieved in 17 (65%) of the 26 patients with a Cr. these responses were rapid, mostly occurring within the first two cycles of treatment. Moreover, cytopenias typically resolved by 4 weeks. Progressionfree survival among all 30 patients was 78% at 37 months; in those with a Cr, relapsefree survival (rFs) was 85% at 34 months. Of note, the four patients without a sustained Cr had persistence of MrD, and three of these patients had previously received BraF inhibitor monotherapy. indeed, failure to clear MrD and prior treatment with a BraF inhibitor were both associated with inferior rFs (56% versus 100% and 57% versus 95%, respectively), whereas prior receipt of rituximab was not (89% versus 82%). these findings compare favourably with the outcomes of vemurafenib monotherapy in two multicentre phase ii trials involving a total of 54 patients with r/r HCL. in this combined cohort, the Cr rate was 35%, with a median rFs of 9 months overall and 19 months in patients with a Cr. the toxicity prolife of the combination was consistent with that observed with vemurafenib monotherapy, with additional rituximabrelated infusion reactions and neutropenia. adverse events were transient and mostly of grade 1 or 2, although 14 patients required vemurafenib dose reductions for ≥2 weeks. these data underscore the potential of the vemurafenib and rituximab regimen as a short, safe, chemotherapyfree, nonmyelotoxic therapy capable of inducing rapid, deep and durable responses. Notably, the efficacy of this combination compares favourably with that of the antiCD22 immunotoxin moxetumomab pasudotox in patients with r/r HCL after ≥2 prior therapies (Cr rate 43%, MrDnegative rate 35%), a treatment approved by the FDa in 2018.