Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

Abstract

BACKGROUND BRAF-V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia who relapsed after or were refractory to purine analogues. METHODS We conducted in Italy and USA two phase-2 single-arm multicenter studies of vemurafenib (960 mg twice daily) given for a median of 16 and 18 weeks, respectively. Primary endpoints were complete remission rate and overall response rate. Patient enrollment was completed (n=28) in the Italian trial in April 2013 and is still open (n=26/36) in the American trial. RESULTS Drug-related adverse events were usually of grade 1-2, and those most frequently requiring dose reductions were rash and arthralgia/arthritis; secondary cutaneous tumors (treated with simple excision) developed in 6/50 patients. Overall response rates were 96% (25/26 evaluable Italian patients) and 100% (24/24 evaluable American patients), obtained after a median of 8 weeks and 12 weeks, respectively. Complete response rates were 34.6% (9/26) and 41.7% (10/24), respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free and treatment-free survivals were respectively 19 and 25 months in complete responders, and 6 and 18 months in partial responders. In the American trial, 1-year progression-free and overall survival were 73% and 91%, respectively. Frequent persistence of phospho-ERK+ bone marrow leukemic cells at the end of treatment suggests bypass MEK-ERK reactivation as a resistance mechanism. CONCLUSIONS A short oral course of vemurafenib proved safe and highly effective in relapsed/refractory hairy cell leukemia patients (Funded by AIRC, ERC, Roche/Genentech and others; EudractCT number: 2011-005487-13, ClinicalTrials.gov number NCT01711632).

Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer

“…73e75 Two recently published multicenter phase 2 clinical trials, in addition to multiple smaller studies, demonstrate that BRAF inhibitor vemurafenib is highly effective (96% response rate) in patients with relapsed or refractory hairy-cell leukemia. 76 Another example, multiple recent studies demonstrate strong evidence that mutations of RAS genes or amplification of mutated BRAF gene reactivates the mitogen-activated protein kinase pathway, resulting in acquired resistance to BRAF inhibitor therapy in melanoma. 77e81 It is foreseeable that certain level B evidence may lead to new FDA-approved therapeutic application and/ or be adopted into professional guidelines in the near future and become level A evidence.…”

Hairy cell leukemia 2018: Update on diagnosis, risk‐stratification, and treatment

“…This leads to a loss in the HCL‐specific gene expression profile signature and reverses the morphology of hairy cells to smooth cells and eventually apoptosis. The role of B‐actin and leucocyte‐specific transcript 1 (LST1) in determining the hairy cell morphology remains to be established 16, 17…”

“…In all cases, novel therapeutic agents will depend on the BRAF mutational status. In case of mutated BRAF , specific inhibitors of the BRAF pathway should represent the best option (see below) 16, 40. In unmutated BRAF cases, depending on the accessibility of the drug and of clinical trials, immunotoxins, BCR inhibitors or a combination of bendamustine with rituximab should be considered.…”

“…Vemurafenib (Zelboraf) is a low‐molecular‐weight orally available BRAF serine‐threonine kinase inhibitor and has demonstrated significant activity in patients with melanoma and subsequently in BRAF ‐V600E positive cancers,15 including patients with HCL 16, 41. The vemurafenib dose and the duration of treatment remain to be determined.…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…Richard Rosenquist, 1 Andreas Rosenwald, 2 Ming-Qing Du, 3 Gianluca Gaidano, 4 Patricia Groenen, 5 Andrew Wotherspoon, 6 Paolo Ghia, 7 Philippe Gaulard, 8 Elias Campo, 9 Kostas Stamatopoulos, 10 on behalf of the European Research Initiative on CLL (ERIC) and the European Association for Haematopathology (EAHP) become possible to appreciate the panorama of recurrently affected genes that contribute to disease pathogenesis and/or evolution, at least in major lymphoma subtypes. Mounting evidence suggests that certain gene mutations have diagnostic, prognostic and/or predictive impact.…”