Αρχική World News BRAF Inhibitor and Rituximab for the Management of Refractory or Relapsed HCL

BRAF Inhibitor and Rituximab for the Management of Refractory or Relapsed HCL

In a phase II, single-centre, academic study involving patients with hairy-cell leukaemia (HCL), a chemotherapy-free regimen of BRAF inhibitor, vemurafenib and the anti-CD20 monoclonal antibody, rituximab was active in patients in whom treatment with purine analogues had failed. Italian researchers from the Ospedale S. Maria della Misericordia in Perugia, who published their findings on 13 May 2021 in The New England Journal of Medicine, wrote that addition of rituximab to vemurafenib led to a complete response (CR) in 87% of the patients and 78% were progression-free at 3 years. Owing to the absence of myelotoxic effects, this combination may also be helpful as a definitive treatment in the context in which highly immunosuppressive chemotherapy is contraindicated, such as in patients who have active infections or are at risk for COVID-19.

The authors wrote in the study background that HCL is a CD20-positive, indolent, mature B-cell neoplasm that is highly responsive to the purine analogues cladribine and pentostatin. However, up to 58% of the patients with HCL have a relapse, with the disease becoming progressively less sensitive to purine analogues, which also cause cumulative haematologic and immunologic side effects. Therefore, for patients with refractory or relapsed HCL, non-myelosuppressive therapies that provide a durable CR, including the eradication of minimal residual disease (MRD), are needed.

In HCL, a BRAF V600E kinase–activating mutation plays a pathogenetic role. In clinical studies involving patients with refractory or relapsed HCL, BRAF V600E targeting with vemurafenib led to a response in 91% of the patients, of whom 35% had CR. However, the median relapse-free survival (RFS) was only 9 months after treatment was stopped.

Vemurafenib-resistant leukaemic cells retain strong CD20 expression, which is a potential target for rituximab. Rituximab frequently induces responses, but induces few complete remissions in patients with refractory or relapsed HCL. Because rituximab is non-myelotoxic and may complement intracellular BRAF inhibition in killing leukaemic cells, the study team performed this phase II clinical study of adding rituximab to vemurafenib in an effort to improve the depth and duration of response in patients with refractory or relapsed HCL. The primary endpoint was CR at the end of planned treatment.

Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A CR was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5 patients) and all those who had previously been treated with BRAF inhibitors (7 patients) had CR.

Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks.

Of the 26 patients with a CR, 17 (65%) were cleared of MRD. Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months. The RFS among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer RFS.

Side effects, mostly of grade 1 or 2, were those that had previously been observed for these agents.

The authors concluded that in their small study, a chemotherapy-free, non-myelotoxic regimen of vemurafenib and rituximab was associated with a durable CR in most patients with refractory or relapsed HCL. Randomised comparison of combination of vemurafenib and rituximab is warranted against the chemotherapy-based standard of care in the context of first-line treatment to assess whether similar efficacy can be obtained with less side effects.

The grants were reported from the European Research Council, Associazione Italiana per la Ricerca sul Cancro, Leukemia and Lymphoma Society, Hairy Cell Leukemia Foundation, Ministero della Salute, and the Fondation ARC pour la Recherche sur le Cancer.

Reference

Tiacci E, De Carolis L, Simonetti E, et al. Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia. N Engl J Med 2021;384:1810-1823. DOI: 10.1056/NEJMoa2031298.

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