Biclonal <i>IGHV</i>‐4‐34 hairy cell leukemia variant and CLL ‐ successful treatment with ibrutinib and venetoclax
Authors: Preetesh Jain, Rashmi Kanagal‐Shamanna, Sergej Konoplev, Zhuang Zuo, Zeev Estrov
Journal: American Journal of Hematology (2018)

IGHV-4-34 hairy cell leukemia variant (HCLv) is uncommon and exhibits distinct immunophenotypic and molecular features.1 These patients are generally refractory to purine analogue based therapies which are the current standard of care in the treatment of HCL. Ibrutinib and venetoclax are very potent novel therapies which are approved as single agent in patients with chronic lymphocytic leukemia (CLL),2 however the relevance of these agents in HCLv is not well studied. In this report, we present a unique patient with concurrent biclonal IGHV-4-34 HCL variant (VH4-34 HCL-v) and CLL which responded very well after treatment with a combination of ibrutinib and venetoclax. A 79 year old gentleman presented with a significant past oncologic history. He was diagnosed with Rai stage 0 CLL and concurrent HCL-v in 2014. Initial evaluation showed leukocytosis of 14.6 K/uL with an absolute lymphocyte count of 12.1 K/uL (Figure 1A). A peripheral blood smear showed small and medium-size lymphocytes. Flow cytometry analysis revealed that 25% of the small lymphocytes were typical CLL cells and 17% were medium-size monotypic B lymphocytes, which were negative for CD5 and CD10. Both lymphocytes expressed lambda light chain restriction. Bone marrow (BM) aspiration (Figure 1B–J) demonstrated concurrent involvement by CLL and HCLv. Immunophenotype studies using BM aspirate material detected two neoplastic B-cell populations with distinct immunophenotypic characteristics. One population, HCLv (highlighted blue) demonstrated CD19 (G), bright CD20 (H), bright CD22 (J), FMC-7, and bright monotypic immunoglobulin lambda light chain and was negative for CD5 (G), CD43 (J), CD200, and immunoglobulin kappa light chain (H). Another population of CLL cells (highlighted pink) demonstrates aberrant coexpression of CD5 and CD19 (G), dim CD20 (H), dim CD22 (J), CD43 (J), CD200, and dim monotypic immunoglobulin lambda light chain (I) and was negative for FMC-7 and immunoglobulin kappa light chain (H). Multiplex PCR amplification of IGH (immunoglobulin heavy chain) was performed using a single multiplex master mix targeting the leader sequences for variable (V) segments and the joining (J) gene regions of IGH. Sequencing of the PCR products was performed using the Illumina MiSeq platform and compared to germ line IGHV sequences. Somatic hypermutation testing demonstrated two clones utilizing VH4 gene (VH4-34 clone for HCLv, unmutated and VH4-30 for CLL, mutated; Figure 1K). Cytogenetic studies showed a normal karyotype, while FISH was positive for del(11q), del(13q) and trisomy 12. TP53 gene mutation was detected (p.H179D) while BRAF (V600E) and MAP2K mutations were not detected. The patient was under observation and later lost to follow-up. In January 2017, he was treated at an outside facility with seven cycles of bendamustine and rituximab due to disease progression. The patient responded well to this treatment but he had multiple episodes of febrile neutropenia. In February 2018, the patient presented with significant B-symptoms and massive (18 cm) splenomegaly. BM exam showed involvement by IGHV-4-34 HCLv (~15%) with complex karyotype, TP53 mutation and minimal residual CLL (0.01%) (Figure 1L). CT scan showed minimal lymphadenopathy and massive splenomegaly (spleen 24 cm craniocaudally; Figure 1M). Considering the clinical progression, he was started on single agent ibrutinib 420 mg orally daily for 3 months and at 3 months we initiated dose escalation with venetoclax (20 mg as starting dose to 400 mg PO daily). After 5 months of therapy, the patient had significant improvement in clinical symptoms and remarkable reduction in spleen size (Figure 1N). Repeat BM exam after 3 months of therapy demonstrated findings similar to those prior to starting ibrutinib. To the best of our knowledge, this is the first reported case demonstrating an excellent clinical response with a combination of nonchemotherapeutic agents, ibrutinib–venetoclax in IGHV-4-34 HCLv. HCL variant is generally refractory to chemo-therapies,3 however response to single agent ibrutinib was shown in one case report.4 In our opinion, development of chemotherapy free combination of ibrutinib–venetoclax should be further explored in patients with HCL and its variant forms.