Refractory hairy cell leukemia‐variant
Authors: Zhihong Hu, Yi Sun, Wei Wang, L. Jeffrey Medeiros, Rashmi Kanagal‐Shamanna
Journal: American Journal of Hematology (2016)

A 67-year-old woman, with a history of hairy cell leukemia-variant (HCL-v), diagnosed 3 years earlier and treated with single-agent rituximab with complete remission, presented with relapsed disease unresponsive to rituximab. A computerized tomography scan showed moderate splenomegaly without lymphadenopathy. Complete blood count and differential: Hgb 13 g/dL, platelets 202 K/μL, WBC 41.7 K/μL (88% lymphocytes, 2% monocytes, and 9% neutrophils). Peripheral blood smear showed numerous lymphocytes with abundant cytoplasm, prominent circumferential cytoplasmic hairy projections, mild nuclear contour irregularities, condensed chromatin; a subset of cells had small nucleoli (Image 1, panels A, B, C). The bone marrow (BM) biopsy showed an interstitial and sinusoidal lymphocytic infiltrate (Image 1, panel D), highlighted by PAX-5 (Image 1, inset, panel D). Aspirate smears demonstrated numerous lymphocytes with morphological features as described in the blood (Image 1, panels E, F, G). The neoplastic cells were also positive for CD20, and DBA.44; and negative for annexin A1, and BRAF. Flow cytometry immunophenotyping revealed a B-cell population positive for monotypic kappa, CD11c, CD19, CD20bright, CD22bright, CD79bbright, and CD103 (Image 1, panel H). Molecular studies showed monoclonal IgH gene rearrangement, germline IGHV, and absent BRAF V600E mutation. Karyotype was diploid. The diagnosis of recurrent HCL-v was confirmed. Cladribine followed by rituximab was recommended. Histopathologic and immunophenotypic findings of HCL-v. A–C: Peripheral blood (PB) smear shows lymphocytosis with hairy cytoplasmic projections (Wright–Giemsa; 1,000×). D: Bone marrow (BM) biopsy shows sinusoidal and interstitial lymphoid infiltrate (H&E; 400×) highlighted by PAX-5 (inset, 400×). E–G: BM aspirate smear shows lymphocytes with similar morphology seen in PB smear (Wright–Giemsa; 1,000×). H: Flow cytometry analysis of BM aspirate reveals a clonal B-cell population positive for CD103, CD11c, and negative for CD25. HCL-v is currently regarded as a provisional entity in the WHO classification 1. The clinical presentation and immunophenotype of HCL-v are distinct from classical HCL (HCL-c), although HCL-v also shows "hairy" cytoplasmic projections. HCL-v patients often lack pancytopenia and monocytopenia which are characteristic for HCL-c. The leukemic cells of HCL-v are positive for pan-B cell antigens, CD11c, CD103, and DBA.44; unlike HCL-c, generally do not express CD25, CD123, CD200 and annexin A1 2. In the era of precision medicine, distinguishing between HCL-c and HCL-v is important biologically and for clinical management. Patients with HCL-c usually respond well to purine analog therapy and have a median overall survival (OS) of 20 years. BRAF V600E mutation is present in most cases of HCL-c except those with IGHV4-34; patients who fail purine analog often respond to BRAF inhibitors. In contrast, HCL-v patients respond poorly to single agent purine analogs and have a median OS of 9 years. Recommended therapy for HCL-v is cladribine followed by rituximab, which has a 65% 5-year failure-free survival rate 3, 4. BRAF V600E mutation is usually absent in HCL-v and patients do not respond to BRAF inhibitors. Instead, MAP2K1 (MEK) mutations have been reported in about half of HCL-v cases 5. Overall, more effective treatments are needed for patients with HCL-v. ZH and RK-S collected data. ZH, LJM, and RK-S wrote the manuscript. All authors have reviewed and approved the manuscript.