Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management

Abstract

Disease Overview Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow. Diagnosis aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN‐NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN‐ring sideroblasts‐thrombocytosis (MDS/MPN‐RS‐T), and aCML. Mutations and Karyotype Cytogenetic abnormalities are seen in 40–50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN‐NOS can be further stratified by mutational profiles into CMML‐like, MDS/MPN‐RS‐T‐like, aCML‐like, TP35‐mutated, and “others”, respectively. Risk Stratification The Mayo Clinic aCML model stratifies patients based on age >67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low‐risk (0–1 points) and high‐risk (>2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN‐NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS‐R. Treatment Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality.

A case report of atypical chronic myeloid leukemia with complete hematological and major molecular response to Venetoclax/Azacitidine treatment

“…aCML is a rare disease, and standard treatment approaches are lacking both domestically and internationally. Patients should be treated promptly when they manifest progressive leukocytosis, anemia, thrombocytopenia, spleen enlargement, or other disease-associated symptoms ( 2 , 5 ). Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is recommended as a preferred option for younger patients with a suitable donor; however, the optimal timing of transplantation remains controversial ( 6 ).…”

“…This can involve the use of agents like hydroxyurea or interferon to mitigate tumor burden and alleviate splenomegaly-related symptoms. Regrettably, these interventions tend to yield suboptimal results, particularly in advanced stages of the disease ( 2 ). Based on the good efficacy of demethylated drugs such as decitabine or azacitidine in Chronic Myelomonocytic Leukemia (CMML), some studies have tried to use these drugs in aCML treatment ( 7 ).…”

“…It was reclassified as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the WHO 2022 classification. aCML is characterized by marked leukocytosis/granulocytosis like CML, yet it lacks discernible evidence of the classic t(9;22) BCR-ABL1 translocation as determined through cytogenetic studies, polymerase chain reaction (PCR), or fluorescence situ hybridization (FISH) ( 2 , 3 ). Due to the heterogeneity of its clinical features and the lack of unique biomarkers, as well as limited treatment options, aCML currently lacks a standardized treatment protocol ( 4 ).…”

Application of Newly Customized Myeloid NGS Panel in the Diagnosis of Myeloid Malignancies

“…Myeloid malignancies are a group of diseases that includes acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), chronic myeloid leukemia (CML), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and other rare diseases. 8 These malignancies have different phenotypes owing to their genetic, epigenetic, and cytogenetic abnormalities. Mutational characterization is used in the diagnostic and prognostic stratification of myeloid neoplasia, and may further inform personalized treatment strategies using targeted and selective therapies.…”

Should we move to a genomic classification of neutrophilic myeloid neoplasms?

“… 4 Importantly, we would like to highlight that our molecular-risk classification was able to differentiate patients with a median OS of 42.8 months from those with a median survival of 13.0 months, which is clearly superior to the comparison of CNL and aCML thus supporting molecular-based risk scores. 2 , 5 …”