Continued Response Off Treatment After BRAF Inhibition in Refractory Hairy Cell Leukemia

Case ReportWe treated a 51-year-old white man with classic hairy cell leukemia (HCL) who was-in contrast to most patients with HCL-refractory to multiple lines of conventional therapy. 1 In February 2009, the patient with HCL presented with splenomegaly, massive bone marrow infiltration, and worsening pancytopenia.He was treated with a 5-day course of cladribine (0.14 mg/kg), which neither improved cytopenia nor reduced the degree of bone marrow infiltration.In December 2010 with disease progression, second-line therapy with pentostatin (7 ϫ 4 mg/m 2 every 2 weeks) was initiated but no response was observed.Salvage treatment combining rituximab (8 ϫ 375 mg/m2) and cladribine (0.14 mg/kg for 5 days) was given starting in May 2011.Again the patient failed to respond showing progressive and severe thrombocytopenia (Ͻ 30,000/L).We demonstrated the presence of the BRAFV600E mutation with a mutation-specific antibody and 454 sequencing. 1 In order to investigate if recurrent mutations may have contributed to refractoriness to purine analogs (PAs), a panel of genes commonly mutated across lymphoid malignancies were analyzed (EZH2, KRAS, MYD88, NOTCH1, NRAS, PIK3CA, SF3B1, or TP53).No mutations were demonstrated.Potential therapeutic options including splenectomy, interferon (plus rituximab) as well as experimental treatment with vemurafenib were discussed with the patient.After intensive counseling the patient provided written informed consent to vemurafenib treatment.Before vemurafenib treatment the patient had splenomegaly (24.8 cm x 8.3 cm) and massive bone marrow infiltration with consequent severe cytopenias (leukocytes 680/L; hemoglobin 10.0 g/dL; platelets 36,000/L).The serum CD25 (sCD25) level, which is considered a reliable marker of HCL load, was 24,800U/mL (normal range, Ͻ 900U/ mL) (Fig 1). 2 Treatment with vemurafenib was started with 240 mg twice per day after a single loading dose of 960 mg.Within a couple of days the spleen softened and decreased in size.After 6 and 16 days of 240 mg twice per day the spleen size had shrunk to 18.8 ϫ 5.8 and 14 ϫ 5 cm, respectively.There was no evidence of tumor lysis, but sCD25 fell rapidly and platelets, hemoglobin, and leukocyte counts rose (Fig 1).The dose of vemurafenib was increased to 720 mg/d on day 16 as there was still evidence of a minute but measurable HCL clone on fluorescence-activated cell sorting examination of the peripheral blood.On day 20 of treatment, the patient developed fever and upper airway infection and was treated with oral antibiotics.The infection resolved, but the patient developed painful skin lesions which were interpreted as erythema nodosum.No biopsy was obtained.Antibiotics were discontinued after 7 days and the skin lesions disappeared.At the same time bilirubin levels slightly rose (max: 1.4 mg/dL) without