Hairy Cell Leukemias (HCL) with Unmutated V-Genes Have a Poorer Response to Single Agent 2CdA Than HCL with Mutated V-Genes.
Authors: Forconi Francesco , Sozzi Elisa , Raspadori Donatella , Toraldo Francesca , Defina Marzia , Zaja Francesco , Rigacci Luigi , Stelitano Caterina , Gallamini Andrea , Galieni Piero , Intermesoli Tamara , Stefani P.M. , Zaccaria Alfonso , Lenoci Mariapia , Bocchia Monica , Lauria Francesco 
Published: October 2019

Abstract
Hairy cell leukemia (HCL) is a rare B-cell neoplasm highly responsive to purine analogues 2Chlorodeossiadenosine (2CdA) or Desossicoformicin or Interferons as single agents, and only a minority are refractory. Patients who obtain any response (either complete or partial) tend to have survivals as normal healthy subjects and/or will benefit from repeating the treatments in case of relapse. Conversely, the minority of patients who do not respond to one of the drugs often do not respond to the others and have a poor prognosis. We have recently observed that the majority of HCL have mutated VH genes, while a minority have unmutated VH genes. In the most common B-cell neoplasm chronic lymphocytic leukemia (CLL), VH gene status has prognostic impact and correlates with progression, treatment-response and surivival. In the process of identifying prognostic parameters of responsiveness to 2CdA, we prospectively investigated the VH and VL genes expressed by the tumor cells and response to treatment in patients receiving subcutaneous 2CdA. In newly diagnosed HCL requiring treatment, enrolled in an Italian multicenter trial (ICGHCL2004), peripheral blood mononuclear cells were obtained prior to treatment, and the expressed tumor VH and VL transcripts were identified by RT-PCR and cloning. Tumor sequences with > 98% homology to germline VH and VL genes were defined as “unmutated”. Patients received 0.1 mg/kg subcutaneous 2CdA (Litak) for 5 or 7 consecutive days and responses were evaluated by immunohistochemistry of trephine bone marrow biopsies 2 and/or 6 months after the end of treatment. Of 56 patients recruited, 22 patients were evaluable for response. Definition of response was according to consensus resolution criteria. We observed that 19/22 patients responded to subcutaneous 2CdA (15 CR, 4 PR), while 3/22 patients demonstrated refractory or progressive disease, indicating similar efficacy of subcutaneous to intravenous administration. Leukocytosis was observed in 2/3 refractory, but also in 2/21 responsive patients. In one of one patient in CR, molecular remission was also documented in the bone marrow by PCR and capillary electrophoresis. Most remarkably, the 3/3 refractory HCL shared the common feature of expressing unmutated VH and VL genes, in contrast to the responsive patients that all carried mutated VH and/or VL genes. From our series, there are indications that mutational status may relate with tumor burden (leukocytosis) and, more importantly, with response to 2CdA. Overall, the interim data suggest that HCL patients with unmutated VH genes may not benefit from single agent subcutaneous 2CdA and provide elements to build new clinical trials with combined strategies in cases of refractory/non responsive HCL where the immunogenenetic tumor profile is provided.