Abstract
Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival. Until now, the diagnosis has been based on morphological grounds only, possibly making the real frequency of the disease underestimated. Only recently, new insights in the molecular biology of MDS/MPN syndromes have deepened our knowledge of aCML, enabling us to have a better molecular profile of the disease. The knowledge gleaned from next generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing aCML from alternative MDS/MPN or MPNs. The most commonly mutated genes (>20%) in aCML are SETBP1, ASXL1, N/K-RAS, SRSF2, and TET2, and less frequently (< 10%) CBL, CSFR3, JAK2, EZH2, and ETNK1. Several of these mutations affect the JAK-STAT, MAPK, and ROCK signaling pathways, which are targetable by inhibitors that are already in clinical use and may lead to a personalized treatment of aCML patients unfit for allogeneic transplant, which is currently the only curative option for fit patients. In this review, we present two emblematic clinical cases and address the new molecular findings in aCML and the available treatment options.
Highlights
Atypical chronic myeloid leukemia, BCR-ABL1 negative is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia, and poor survival
The knowledge gleaned from generation sequencing has complemented morphologic and laboratory WHO criteria for myeloid neoplasms and can provide greater specificity in distinguishing Atypical chronic myeloid leukemia (aCML) from alternative MDS/MPN or MPNs
The presence of a CSF3R mutation is uncommon in aCML and, if detected, should prompt a careful morphologic review to exclude an alternative diagnosis of chronic neutrophilic leukemia or other myeloid neoplasm
Summary
Atypical chronic myeloid leukemia (aCML) is a rare BCR-ABL1 negative myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) with a high rate of transformation to acute myeloid leukemia (AML), and is historically characterized by poor survival. The challenges of aCML management affect both diagnosis, due to the heterogeneity of the disease clinical features and the absence of unique biomarkers, and treatment choices, since no current standards of care exist. We describe two representative aCML clinical cases presenting in two different age groups and review the clinicopathologic features and management of the disease. Hb Plts BM blasts Screening for mutations in JAK2, CALR and MPL BCR/ABL Gene mutations identified by NGS panel Screening for ETNK1 mutations Karyotype Treatment Follow-up time (months after diagnosis) Status at last follow up. 41 32.12 × 109/L hypogranulated neutrophils 46% band-cells 12% eosinophils 2% basophils monocytes 6%. Eosinophils basophils monocytes 15% lymphocytes 9% myeloblasts 1% promyelocytes 14% metamyelocytes 6% myelocites 8% 14.9 g/dL 239 × 109/L. negative negative SETBP1 p.D868N (VAF 47.1%) SRSF2 p.P95H (VAF 52.34%) TET2 p.Y1245Lfs*22 (VAF 52.8%). WBC, white blood cells; Hb, hemoglobin; PLTS, platelets; PB, peripheral blood; BM, bone marrow; NGS, generation sequencing; CR, complete response; PR, partial response
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