Low-dose vemurafenib induces complete remission in a case of hairy-cell leukemia with a V600E mutation.

Hairy-cell leukemia (HCL) is a lymphoproliferative disorder characterized by the presence of CD103-positive circulating B cells, pancytopenia and splenomegaly. HCL cases were recently shown to harbor a mutation at codon 600 of BRAF (V600E), suggesting that this genetic event represents a key driver of the disease. Recently, Dietrich et al. reported a case of refractory HCL treated with escalating doses of vemurafenib. Vemurafenib exhibited remarkable activity, with rapidly decreased splenomegaly, increased platelets, and normalization of hemoglobin and granulocyte counts. In consideration of these data, we used vemurafenib to treat a 72-year old patient who presented with a relapse of HCL and the BRAF V600E mutation. In 1989, our then 49-year old male patient was diagnosed with HCL, treated with a splenectomy and follow-up interferon, and demonstrated a complete hematologic response. However, in 2003 and 2009, the patient presented with relapses and was treated with cladribine. Tolerance was very poor with grade IV infectious toxicities after both treatments. In June 2012, the patient presented with a new progression, as revealed by the presence of dyspnea and bicytopenia (platelet count 24x10/L, hemoglobin 6.9 g/dl), a normal neutrophil count, and a circulating HCL level of 4x10/L (morphological examination). A bone marrow aspiration was performed but was not conclusive. The V600E mutation was detected in blood leukemic cells. Considering the patient's medical history, and after obtaining informed consent, we initiated vemurafenib at a dose of 240 mg twice daily (Day 0). The kinetics of the hemogram and hairy-cell leukemia are detailed in (Table 1). Our patient experienced grade III anemia and grade II neutropenia without infection or other complications. At Day 19, the CD19/CD103 cell fraction had decreased from 86% to 5%, and the patient remained cytopenic (Figure 1) and required one final red blood cell transfusion. Due to the satisfactory treatment efficiency and the persistent cytopenia, we maintained the treatment with vemurafenib at a constant dose (240 mg x 2), which is in contrast to the management of previously published case of HCL. The percentage of cells harboring the V600E mutation was monitored using a pyrosequencing assay, and this method has recently been described as rapid, sensitive and quantitative. At Day 56, the immunophenotyping and percentage of mutated cells were comparable to those of a healthy volunteer donor (Figure 2). The blood cell counts at Day 56 had improved, with a hemoglobin level of 9.2 g/dL without transfusion, leukocytes 3.200x10/L and platelets 253x10/L. A bone marrow aspiration showed a CD19/CD103 cell frequency of 5%. At this point, the vemurafenib was stopped. One month after completion of the treatment (Day 90), the patient showed complete remission, as defined by Grever (hematologic blood count was normal and blood morphological examination showed no evidence of HCL cells). However, close follow up was maintained. Our observations suggest that the inhibition of mutated BRAF by vemurafenib may represent an important therapeutic advancement for the treatment of HCL. Vemurafenib is used as a targeted therapy against mutated BRAF in HCL, as imatinib is used against BCR-ABL tyrosine kinase mutations in chronic myelogenous leukemia. According to these data, the detection of the BRAF V600Emutation is intriguing in cases of HCL. In contrast with the previously reported case of HCL, our data suggest that 240 mg of vemurafenib twice a day is sufficient to obtain hematologic, cytological and molecular responses. However, we did not use a loading dose or