Vemurafenib + rituximab safe, effective for refractory/relapsed HCL

In the majority of patients with refractory/relapsed hairy cell leukemia (HCL) included in this small phase II study, short, chemotherapy free treatment with vemurafenib plus rituximab was safe and quickly brought about deep, durable complete responses, according to results published in The New England Journal of Medicine. Researchers recorded complete responses in 87% of patients, minimal residual disease-negative status in 60%, and relapse-free survival of 85% at a median of 34 months.

“Hairy-cell leukemia (HCL) is an indolent, mature B-cell neoplasm that is highly responsive to the purine analogues cladribine and pentostatin. However, up to 58% of patients with HCL have a relapse, with the disease becoming progressively less sensitive to purine analogues, which also cause cumulative hematologic and immunologic toxic effects. Therefore, for patients with refractory or relapsed HCL, non-myelosuppressive therapies that provide a durable complete response, including the eradication of minimal residual disease (MRD), are needed,” wrote Enrico Tiacci, MD, of the Institute of Hematology, Ospedale S. Maria della Misericordia, and the Department of Medicine, University of Perugia, Perugia, Italy, and colleagues.

They conducted the single-center academic study in patients with refractory/relapsed HCL to determine the efficacy and safety of vemurafenib plus concurrent, sequential rituximab. The primary end point of the study was complete response at conclusion of treatment. The standard vemurafenib dose (960 mg twice daily) was chosen because it had been previously approved for the treatment of BRAF V600E-positive solid cancers and had proven efficacy for relapsed or refractory HCL.

In all, they assigned 30 patients (median age 61 years; 28 men) with HCL who had had a median of three previous therapies, to treatment with vemurafenib (960 mg twice daily for eight weeks) plus concurrent and sequential rituximab (375 mg/m2 of body surface area, eight doses over 18 weeks).

Patients received two induction cycles comprised of four weeks of vemurafenib and two rituximab infusions on days 1 and 15. This was followed by two weeks of rest and evaluation of response, which included bone marrow biopsy. After they completed the second cycle, patients received four additional doses of rituximab as consolidation therapy, spaced two weeks apart. Researchers conducted the final evaluation four weeks after patients received the last dose of rituximab.

Tiacci et al defined complete response as the resolution of cytopenias, with hemoglobin counts of greater than or equal to 11 g/dL, neutrophil counts of greater than or equal to 1,5000/mm3, and platelet counts of greater than or equal to 100,000/mm3BRAF V600E.

In the intention-to-treat population, 87% of patients (n=26; P=0.005) demonstrated a complete response, as did 100% of the 10 patients with disease refractory to chemotherapy, five who were refractory to rituximab, and all seven patients previously treated with BRAF inhibitors. Among the 26 patients with a complete response, 65% were cleared of MRD.

At a median follow-up of 37 months, progression-free survival was 78%, and at 34 months, relapse-free survival was 85% in the 26 patients exhibiting a complete response. Seventeen patients (65%) were MRD-negative after the end of treatment, and at a median of 28.5 months after MRD-negative status was first seen, survival free from MRD in bone marrow and peripheral blood was 100%.

Upon post-hoc analysis, Tiacci and colleagues found a correlation between MRD negativity and no previous treatment with a BRAF inhibitor with longer relapse-free survival. Upon exploratory analysis, they also observed that patients previously treated with BRAF inhibitor monotherapy had deeper and longer responses with subsequent treatment with vemurafenib plus rituximab.

But, they noted, these patients “seemed to benefit from these two successive treatments for a shorter cumulative time than did patients who had not received a BRAF inhibitor previously and who received vemurafenib directly with rituximab in a single treatment. These findings suggest that, although such a regimen remains a valuable option for patients whose disease progresses after receipt of a BRAF inhibitor, vemurafenib plus rituximab can be offered instead of vemurafenib alone as soon as patients are considered to be eligible for a BRAF inhibitor.”

Thrombocytopenia and neutropenia were both transient and resolved after a median of two and four weeks, respectively. Toxic effects were similar to those previously reported, were mostly of grade 1 or 2, and most commonly include infusion-relation reactions (29%) and transient neutropenia (16%). Grade 4 drug-related adverse events included transient neutropenia (n=1), hyperbilirubinemia (n=1), increase in pancreatic enzyme level (n=2), and an increase in ƴ-glutamyltransferase or alkaline phosphatase level (n=1).

Tiacci and colleagues wrote: “In a comparison with historical data on vemurafenib alone, the addition of rituximab to vemurafenib led to more than double the percentage of patients with a complete response (35% vs ≥87%) and also halved the median time to a complete response (eight weeks vs four weeks). The median exposure to vemurafenib and to its potential side effects was also halved, from a period of 16 to 18 weeks to eight weeks, so that patients were able to receive this drug safely at a high dose intensity (median, 92%).

“A randomized comparison of vemurafenib plus rituximab is warranted against the chemotherapy-based standard of care in the context of first-line therapy to assess whether similar efficacy can be obtained with lower toxicity,” they concluded.

  1. In a small, phase II study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL.

  2. Adding rituximab to vemurafenib led to more than double the percentage of patients with a complete response compared with historical data (35% vs ≥87%), and also halved the median time to a complete response from eight to four weeks.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

This study was funded by the European Research Council, Associazione Italiana per la Ricerca sul Cancro, the Leukemia and Lymphoma Society, the Hairy Cell Leukemia Foundation, the Ministero della Salute, and the Fondation ARC pour la Recherche sur le Cancer.

Tiacci disclosed financial support from Innate Pharma and Shire. He holds a patent for discovery of BRAF mutations as HCL biomarker, licensed to Trovagene.

Cat ID: 118

Topic ID: 78,118,730,118,466,935,192,925