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Recently, the BRAF V600E mutation was reported in all cases of hairy cell leukemia (HCL) but not in other peripheral B-cell neoplasms. We wished to confirm these results and assess BRAF status in well-characterized cases of HCL associated with poor prognosis, including the immunophenotypically defined HCL vari-

Hairy cell leukemia variant (HCLv) presents with high disease burden, lack of typical antigens like CD25, and poor response to standard treatments like cladribine. Occasionally, patients with classic HCL respond poorly. Clinical and molecular features of HCL and HCLv has not been compared. Rearrangements expressing immunoglobulin VH chain were sequenced, including 22 from 20 patients with HCLv and 63 from 62 patients with classic HCL. Most patients were seeking relapsed/refractory trials, representing a poor-prognosis population. VH4-34, a gene commonly used in autoimmune disorders, was observed in 8 (40%) HCLv and 6 (10%) classic (P ‫؍‬ .004) HCL patients. Compared with 71 VH4-34 ؊ rearrangements, 14 VH4-34 ؉ rearrangements were more frequently (P < .001) unmutated, defined as greater than 98% homologous to germline sequence. VH4-34 ؉ patients had greater white blood cell counts at diagnosis (P ‫؍‬ .002), lower response rate (P < .001) and progressionfree survival (P ‫؍‬ .007) after initial cladribine, and shorter overall survival from diagnosis (P < .001). Response and survival were more closely related to VH4-34 status than to whether or not patients had HCLv. VH4-34 ؉ HCL is an important disorder that only partly overlaps with the previously described HCLv. Response to initial single-agent cladribine therapy is suboptimal; these patients should be considered for alternative approaches, including antibody-related therapy. IntroductionHairy cell leukemia variant (HCLv) is a B-cell disorder, recognized for nearly 30 years, which accounts for 10% of hairy-cell leukemia (HCL) cases. Morphology of variant cells was reported to be intermediate between that of classic HCL and prolymphocytic leukemias. [1][2][3] Patients typically present with leukocytosis rather than leukopenia and often lack the neutropenia, anemia, and/or thrombocytopenia with which classic HCL patients present. 1,2,4 By flow cytometry, B-cell antigens FMC7, CD11c, CD20, CD22, and surface immunoglobulin are strongly positive in both classic HCL and HCLv, whereas HCLv differs from classic HCL by lack of CD25, HC-2, and CD123 and by expression of CD27. [3][4][5][6][7] CD103 is usually positive in both but can be negative in HCLv. 2 HCLv lacking both CD25 and CD103 may be difficult to differentiate from splenic marginal zone lymphoma (SMZL)/splenic lymphoma with villous lymphocytes without also relying on morphologic differences between HCL and SMZL. 2,6,7 In contrast to the high complete remission and overall response rates of classic HCL to the administration of purine analogs pentostatin and cladribine, [8][9][10] response in patients with HCLv is limited to partial responses in approximately 50% of patients. [2][3][4]11,12 Several complete responses of HCLv to monoclonal antibody-based therapy with and without chemotherapy have been reported. [13][14][15][16][17] Like other mature B lymphocytes, the malignant cells in HCL patients have 1 or sometimes 2 different rearrangements for immunoglobulin heavy chain. Significant variability can be observ...

PURPOSE Single-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal residual disease (MRD), leading to relapse and repeated treatments. Rituximab can clear MRD, but long-term results are unknown and optimal timing of rituximab undefined. PATIENTS AND METHODS Patients were randomly assigned to first-line cladribine 0.15 mg/kg intravenously days 1-5 with 8 weekly doses of rituximab 375 mg/m2 begun either day 1 (concurrent, CDAR) or ≥ 6 months later (delayed) after detection of MRD in blood. MRD tests included blood and bone marrow (BM) flow cytometry, and BM immunohistochemistry. RESULTS Sixty-eight patients with purine analog-naïve classic HCL were randomly assigned 1:1 to concurrent versus delayed arms. At 6 months after CDAR versus cladribine monotherapy, CR rates were 100% versus 88% ( P = .11), MRD-free CR rates 97% versus 24% ( P < .0001, primary end point), and blood MRD-free rates 100% versus 50% ( P < .0001), respectively. At 96 months median follow-up, 94% versus 12% remained MRD free. Compared with CDAR, delayed rituximab after cladribine achieved lower rate (67% of 21 evaluable patients; P = .0034) and durability ( P = .0081, hazard radio favoring CDAR, 0.094) of MRD-free CR. Nevertheless, 12 patients in the delayed arm remained MRD free when restaged 6-104 (median, 78) months after last delayed rituximab treatment. Compared with cladribine monotherapy, CDAR led to brief grade 3/4 thrombocytopenia (59% v 9%; P < .0001) and platelet transfusions without bleeding (35% v 0%; P = .0002), but higher neutrophil ( P = .017) and platelet ( P = .0015) counts at 4 weeks. CONCLUSION Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed rituximab. Longer follow-up will determine if MRD-free survival leads to less need for additional therapy or cure of HCL.