Effect of vemurafenib in HCL. (A) Cumulative incidence of blood count improvement. Upper row and lower left image: cumulative incidence of patients achieving hemoglobin >12 g/dL, neutrophils >1000 μL, and platelets >100/nL on vemurafenib treatment. Nineteen of 21 patients had thrombocytopenia <100 000/μL, and platelet counts improved above this threshold on vemurafenib treatment in all 19 patients. Hemoglobin levels were <10 g/dL in 15 of 21 patients and <12 g/dL in 20 of 21 patients. Hemoglobin levels improved in 19 of 20 patients with vemurafenib, but 1 patient developed AML-M6 and did not improve above this threshold. Eighteen of 21 patients had neutropenia <1000/μL and improved with vemurafenib treatment above this threshold. There was no difference in recovery of blood counts of patients who received low (≤240 mg twice daily) or high doses of vemurafenib (>240 mg twice daily) (hemoglobin, P = .38; platelets, P = .25; neutrophils, P = .24). Lower right panel (Response): cumulative vemurafenib doses of patients who achieved a CR and partial remission (P = .67; OR, 0.99; 95% CI, 0.98-1.03; effect 1000 mg). Patients who achieved a CR did not receive higher cumulative doses of vemurafenib. (B) Bone marrow findings during vemurafenib treatment: PAX5 (nuclear stain, red) and p-ERK (cytoplasmatic stain, green) of trephine biopsy material before (upper left picture) and during (upper right picture) vemurafenib treatment (Heidelberg 01, day 6). P-ERK was undetectable upon vemurafenib treatment in hairy cells (n = 4). Hairy cell infiltration (BRAF V600E immunohistochemistry) decreased with diverse kinetics. The complete abrogation of p-ERK in PAX5-positive cells with 240 mg of vemurafenib suggests sufficient on-target activity. (C) Disease course summarized by sCD25 and platelet dynamics: sCD25 levels (U/L) and platelet counts during and after vemurafenib treatment are shown (n = 6; top to bottom: Heidelberg 01-06). Gray boxes show the vemurafenib treatment interval. Four patients received low-dose vemurafenib (240 mg twice daily). Patient Heidelberg 01 had escalated dosing from day 17 (days 17-36, 480 mg twice daily; days 37-56, 720 mg twice daily; days 57-58, 960 mg twice daily) and patient Heidelberg 02 received 480 mg twice daily (days 23-43) and 720 mg twice daily (days 44-51). sCD25 decreased to normal levels upon vemurafenib treatment in all patients. After cessation of vemurafenib, sCD25 levels rose, exhibiting individual progression patterns (yellow box indicates rituximab and pentostatin treatment).