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  • This report illustrates an unusual case of CMML which transf


    This report illustrates an unusual case of CMML which transformed to AML rapidly with emergence of the rare e6a2 fusion transcript. The possibility CML in blasts crisis was excluded as the CMML biopsy showed dysgranulopoiesis and lacked Ph chromosome and BCR-ABL1 fusion transcript. We further reviewed the previous reports of e6a2 fusion transcript, the vast majority of which were CML with male predominance () . Two of these cases also co-expressed e1a2 transcript, likely representing low level alternative exon splicing . The other reported CMML case harboring e6a2 fusion transcript, similar to our case, acquired the Ph chromosome later in the disease course . CML with e6a2 fusion transcript appears to be associated with more aggressive clinical features, including accelerated/blastic phase on presentation , rapid disease progression , and imatinib treatment failure . Their response to TKI treatment is variable (). Briefly, 3 of 7 patients who received a TKI (#5, #6, #10) responded to imatinib, nilotinib, or dasatinib; with disease stabilization or hematologic/molecular remission. Three patients (#7–9) showed persistent/progressive disease, while one died early from infection (#3). The other reported CMML case (#11) showed molecular response to imatinib after 3 months, although long term followup is not available. Our patient is unique since although his Ph+ (R)-baclofen of drastically diminished in response to nilotinib (95% to 3.4%), his blast burden remained high (80%) with dominance of the Ph negative clone. Although it is tempting to speculate that the Ph negative clone may have been selected from suppression of the Ph+ clone by nilotinib, the patient’s rapidly progressive disease may be due to an inherently aggressive biological behavior of his antecedent CMML and unrelated to TKI therapy, a notion that appears to be supported by the presence of RUNX1 and TP53 mutations in the CMML specimen. It was hypothesized that shorter BCR-ABL transcripts are associated with a more aggressive clinical course due to lack of important regulatory bcr sequences within the fusion proteins . Specifically in e6a2 transcript, the breakpoint in bcr intron 6 may result in partial loss of GEF/dbl-like domain that mediates interaction with several Ras-like G proteins involved in cell proliferation and signal transduction, which leads to enhanced tyrosine kinase activity of the BCR-ABL1 fusion protein.
    Introduction Classical hairy cell leukemia is a rare, chronic mature B-cell lymphoproliferative disorder that exhibits specific morphologic, immunohistochemical and immunophenotypic features – expressing CD20, CD22, CD25, CD11c, CD103, CD123 and annexin A1. In 2011, Tiacci et al. proposed a genetic lesion that accounted for all studied cases of classical hairy cell leukemia—the V600E BRAF mutation, which serves in the RAS signaling cascade to propagate cell survival and division [1]. This mutation has been heralded as a key mutation in the pathogenesis of classical hairy cell leukemia, with BRAF-inhibitors being investigated in clinical trials for relapsed c-HCL [2]. Here we present a rare case of wild type BRAF c-HCL in a newly diagnosed woman of childbearing age.
    Discussion The differential diagnosis for pancytopenia and splenomegaly in the context of a hypercellular bone marrow and marrow fibrosis, as indicated by the moderate to marked diffuse increase in reticulin fibers (grade 2–3 on a scale of 0–3) includes hairy cell leukemia, myeloid disorders such as myelodysplastic syndromes, myeloproliferative neoplasms, primary myelofibrosis, acute myeloid leukemia and systemic mast cell disease [3]. Based on the morphology of the cells, classical hairy cell leukemia (c-HCL), hairy cell leukemia variant (vHCL) and splenic marginal zone lymphoma (SMZL) should be the main diagnostic considerations. The morphology of the atypical lymphocyte in the bone marrow touch imprint (Fig. 1, A), diffuse infiltrate of the CD20 positive atypical B-cells (Fig. 1, B&C) in the bone marrow and Annexin-1 (Fig. 1, D) positivity of these atypical B-cells confirms the diagnosis of classical hairy cell leukemia. The BRAF V600E mutation is considered key to the pathophysiology and diagnosis of c-HCL. In (R)-baclofen of an attempt to confirm Tiacci, Xi et al. found that 11% of the tested population with c-HCL, without IgHV4-34, expressed wild-type BRAF, alluding to an alternate mechanism of action behind the pathophysiology of c-HCL in these patients. However, patients in this study were seeking treatment for relapsed HCL and had completed at least one cycle of cladribine, unlike our patient. While related wild-type BRAF processes like variant Hairy Cell Leukemia (vHCL) and IgHV4-34+ hairy cell leukemia confer poorer prognoses, the prognosis of wild-type BRAF in c-HCL is unknown; nonetheless, with 85–90% rates of CR after one cycle of cladribine, our patient has responded similarly [4,5]. While BRAF inhibitors, like vemurafenib, have exhibited 30–40% CR and 60% partial response rate in refractory c-HCL, in BRAF wild-type cells, vemurafenib paradoxically increases gene transcription by stimulating the kinase activity of BRAF dimers [6]. Therefore, with case reports documenting BRAF V600 negative c-HCL, we may recommend BRAF screening in exon 15 (v600) and 11 [7]. In addition to this, this case highlights the dilemma surrounding cladribine exposure in a woman of childbearing age attempting to conceive, for which minimal data exists. Cladribine is a purine analog that inhibits the enzyme adenosine deaminase, interfering with the cell\'s ability to transcribe DNA. It is characterized as a FDA pregnancy category D where safety and efficacy in children has not been established. The median age of onset at 52 years and c-HCL shares a 4.2 to 1 male to female predilection, indicating the low prevalence of c-HCL in women of childbearing age [6]. In a PubMed literature search for “cladribine, pregnancy”, there is only one case report of successful pregnancy POST cladribine exposure [8]. Further literature search has shown successful splenectomy in a pregnant patient with c-HCL followed by one cycle of cladribine post 6 months breastfeeding, resulting in CR [9].