Leukemia & Lymphoma, June 2011; 52(S2): 99–102
Molecular variant of hairy cell leukemia with poor prognosis
EVGENY ARONS & ROBERT J. KREITMAN Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Abstract Hairy cell leukemia variant (HCLv), described 30 years ago, was reported to present with high disease burden and less often leukopenia, and later was reported to be resistant to purine analogs. Patients with HCLv were overrepresented among patients with HCL seeking relapsed/refractory trials. To compare clinical and molecular features of classic HCL (HCLc) and HCLv, 85 rearrangements expressing immunoglobulin variable heavy chain were sequenced, taken from 20 patients with HCLv and 62 with HCLc. The gene VH4-34, commonly used in autoimmune disorders, was found in eight patients (40%) withHCLv versus
six (10%) with HCLc (p¼0.004). Ninety-three percent of the VH4-34 rearrangements were unmutated, defined as 498% homologous to the germline sequence. Clinical features of VH4-34þ patients that were similar to those with HCLv included higher white blood cell counts at diagnosis (p¼0.002) and lower response (p¼0.00001) and progression-free survival (p¼0.007) after first-line cladribine, and shorter overall survival from diagnosis (p50.0001). It was found that VH4-34 was independent from HCLv and a stronger predictor than HCLv in associating with poor prognosis.We conclude that VH4-34þ hairy cell leukemia, which only partly overlaps with HCLv, is associated with poor prognosis after single-agent cladribine.
However, cases are observed which respond well to antibody therapy either alone or in combination with purine analog. Keywords: Immunoglobulin rearrangement, HCL, HCLv, VH4-34, IGHV4-34
Diagnosis of hairy cell leukemia variant
Cawley et al. in 1980 reported a B-cell disorder similar to classic hairy cell leukemia (HCLc) which stained for tartrate resistant acid phosphatase (TRAP) and had ‘hairy’ cytoplasmic projection, but less neutropenia andmore circulating malignant cells [1]. In contrast to the excellent outlook for patients with HCLc, particularly after purine analog therapy, patients with hairy cell leukemia variant (HCLv) have a relatively poor response to treatment and also shorter overall survival [2]. In fact, the World Health Organization (WHO) has recognized HCLv as a disease distinct from HCLc. HCLv is defined by: cytohematologic features (leukocytosis, monocytes, prominent nucleoli, blastic/convoluted nuclei, and/or absence of circumferential shaggy contours), variant immunophenotype (absence of CD25, annexin A1, or TRAP), and resistance to conventional HCL therapy [3]. Other HCLc-related markers usually absent in HCLv include CD123, CD24, and HC2. CD103 is usually positive in HCLc and HCLv but can be negative in HCLv [4], although CD103- negative HCL should suggest splenic marginal zone lymphoma/splenic lymphoma with villous lympho-
cytes (SMZL or SLVL), particularly if CD11c is negative or dim.
Molecular characterization of classic hairy cell leukemia and hairy cell leukemia variant
As in other B-cell malignancies as well as in normal B- cells, the malignant cells have one or occasionally two rearrangements expressing immunoglobulin heavy chain, taken from one each of several variable (IGHV), diversity (IGHD), and junctional (IGHJ) genes. For evenmore diversity inIGHsequence, and to bind more avidly to antigen, the IGH sequence may undergo somatic hypermutation. The resulting IGH sequences are monoclonal and unique for each patient. We previously took advantage of this specificity by designing a real-time quantitative polmerase chain reaction (RQ-PCR) assay that used sequence-specific primers and probe [5].Compared to conventionalPCR used to detect minimal residual disease(MRD)inHCL using consensus primers, the RQ-PCR assay was far more sensitive, able to detect a hairy cell diluted in 106 normal cells [5].We previously reported a study of 24 IGH rearrangements in 20 patients with HCLc and three with HCLv [6], and compared results to 70
Correspondence: Robert J. Kreitman, Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, 37/5124b, 37 Convent Drive, MSC 4255, Bethesda, MD 20892, USA. Tel: (301)496-4797. E-mail:
kreitmar@mail.nih.gov
ISSN 1042-8194 print/ISSN 1029-2403 online 2011 Informa UK, Ltd. DOI: 10.3109/10428194.2011.565841
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