Abstract 2710: Molecular and clinical characteristics of IGHV4-34 expressing classic and variant HCL
Authors: Arons Evgeny , Potocka Katherine , Stetler-Stevenson Maryalice , Zhou Hong , Raffeld Mark , Sokolsky Mark , Davies Sarah , Kreitman Robert J. 
Published: July 2017

Abstract
Classic hairy cell leukemia (HCLc) is a B-cell malignancy with distinctive immunophenotype, typically expressing CD20, CD22, CD25, CD11c, CD103, CD123, annexin A1, tartrate-resistant acid phosphatase (TRAP), and BRAF V600E mutation. Purine analog therapy is highly effective with complete remission rates of approximately 85% in first line. HCL variant (HCLv) is recognized as a distinct entity, lacking CD25 and usually lacking annexin A1, tartrate-resistant acid phosphatase expression, CD123, and also lacks the BRAF V600E mutation. Patients respond poorly to purine analogs, with partial response in less than 50% and relatively poor overall survival from diagnosis. HCLc expressing B-cell receptor (BCR) with the IGHV4-34 immunoglobulin rearrangement has a poor prognosis like HCLv, whether immunophenotypically consistent with HCLv or HCLc, and also lacks BRAF V600E. We previously reported a series of 17 patients expressing IGHV4-34, immunophenotypically resembling HCLc in 7 and HCLv in 10 cases. Using routine deep sequencing of patient samples for immunoglobulin rearrangements, we have been able to accumulate 42 IGHV4-34 expressing cases including 23 classic HCL and 19 HCLv. Six (26%) of 23 HCLc vs 12 (63%) of 19 HCLv were truly unmutated, with VH gene germline identity (GI) 100%. Eleven (48%) of 23 HCLc and 7 (37%) of 19 HCLv were borderline-mutated (97≤GI&lt;100), and 6 (26%) of 23 HCLc were significantly mutated (97&lt;GI). There was no significant difference between the 5 groups with respect to either IGHD or IGHJ genes usage, or CDR3 length. However, we found a significant restriction of IGHD genes between 12 HCLv truly unmutated and 6 HCLc truly unmutated cases, in that there was no overlap of any IGHD genes between these 2 groups (p&lt;0.0001). Of 28 cases test for BRAF V600E, only 5 were positive, all HCLc with GI 93.18-97.49%. The 23 BRAF wild-type (WT) cases included one with only one with GI=93.64%, but GI was &gt;98.7% for the remaining 22 cases (p&lt;0.0001). Of the 23 BRAF WT cases, 9 patients died of disease, 9 have active disease, and only 2 are in remission. Patients commonly had highly aggressive courses, with infiltration of HCLc/HCLv into spinal cord and cranial nerves, cardiac muscle, lungs, and cervical lymph nodes. Complete remission was achieved only through either recombinant immunotoxin therapy of combination purine analog and rituximab, but not by purine analogs alone. Additional clinical and genetic studies are ongoing to better characterize this poor-prognosis syndrome and determine if therapy can be optimized.
Citation Format: Evgeny Arons, Katherine Potocka, Maryalice Stetler-Stevenson, Hong Zhou, Mark Raffeld, Mark Sokolsky, Sarah Davies, Robert J. Kreitman. Molecular and clinical characteristics of IGHV4-34 expressing classic and variant HCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2710. doi:10.1158/1538-7445.AM2017-2710