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Philadelphia (Ph) chromosome is a cytogenetic hallmark of chronic myeloid leukemia (CML). Most patients with CML harbor either the e13a2 or e14a2 BCR-ABL fusion product, while a small subset of the cases expresses e1a2 or e19a2 transcripts. We report a patient with chronic myelomonocytic leukemia (CMML), initially Ph chromosome negative at presentation, with rapid disease progression to acute myeloid leukemia (AML) and appearance of Ph chromosome and BCR-ABL e6a2, a very uncommon fusion transcript. The AML was refractory to treatment with subsequent emergence and dominance of a Ph negative leukemic clone. The patient expired shortly after disease progression.
Philadelphia (Ph) chromosome results from the reciprocal translocation t(9;22)(q34.1;q11.2), and is a diagnostic feature for chronic myeloid leukemia (CML). In most cases, the breakpoint in BCR occurs in M-bcr region, leading to production of e13a2 and/or e14a2 fusion transcripts. The breakpoints infrequently occur in either m-bcr or μ-bcr, producing e1a2 or long e19a2 fusion transcripts. Several other variant transcripts, such as e8a2, e13a3, e14a3, and e6a2 have also been identified and account for <1% of CML cases. Late appearing Ph chromosome may be acquired over the course of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) or MDS, representing disease progression and often signifying poor prognosis. In this report we describe a patient with chronic myelomonocytic leukemia (CMML), a subtype of MDS/MPN, which progressed to AML with gain of the rare BCR-ABL1 fusion transcript e6a2 and died shortly of tumor lysis syndrome.
This report illustrates an unusual case of CMML which transformed to AML rapidly with emergence of the rare BCR-ABL1 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.
CML with BCR-ABL1 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 (Table 1). 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+ clone 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.
In summary, our case illustrates the importance of combining conventional karyotype/FISH and appropriate molecular studies to detect rare BCR-ABL fusion transcripts such as e6a2. As a late appearing secondary Ph chromosome is usually considered a poor prognostic factor in hematopoietic malignancies, individualized therapeutic strategies such as newer TKIs and allogeneic stem cell transplantation may be warranted.