Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia

Abstract

Background There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). Methods The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46‐89 years). Results The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035‐0.593; P = .007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1‐ and 3‐year survival. Conclusions aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients.

Allogeneic Hematopoietic Stem Cell Transplantation for Mixed or Overlap Myelodysplastic/Myeloproliferative Disorders

“…Recently, in a new multivariate analysis on 65 patients, older age, thrombocytopenia, increased BM blasts, and abnormal serum lactate dehydrogenase (LDH) were parameters independently associated with decreased OS. Based on these parameters, a new scoring system was generated for a more accurate prediction of survival (67). The mutational landscape of aCML mainly involves SETBP1 and ETNK1 genes, while other commonly identified mutations include ASXL1, N/K-RAS, SRSF2, and TET2 and less frequently (<10%) CBL, CSFR3, and EZH2.…”

Chronic neutrophilic leukemia and atypical chronic myeloid leukemia: 2024 update on diagnosis, genetics, risk stratification, and management

“…170,171 A 2023 analysis of 347 adult patients with aCML registered in the Netherlands Cancer Registry from 2001 to 2019 disclosed a median age of 72 years (71% aged >65 years), 65% being male. 172 The clinical profile includes frequent splenomegaly (range 40-67%), symptoms associated with anemia and/or thrombocytopenia, including mucocutaneous bleeding (up to 15%), constitutional symptoms, manifestations related to extramedullary disease, 7,173 and more rarely, disseminated intravascular coagulation, 174 signs of spontaneous tumor lysis, or acute renal dysfunction. 173 Up to a third of patients may be transfusion-dependent at presentation.…”

“…172 The clinical profile includes frequent splenomegaly (range 40-67%), symptoms associated with anemia and/or thrombocytopenia, including mucocutaneous bleeding (up to 15%), constitutional symptoms, manifestations related to extramedullary disease, 7,173 and more rarely, disseminated intravascular coagulation, 174 signs of spontaneous tumor lysis, or acute renal dysfunction. 173 Up to a third of patients may be transfusion-dependent at presentation. 173 Overall prognosis is poor with median survival times recorded in the 10-29 month range and high rates of leukemic transformation (up to 30-40% within 12-18 months of diagnosis).…”

“…173 Up to a third of patients may be transfusion-dependent at presentation. 173 Overall prognosis is poor with median survival times recorded in the 10-29 month range and high rates of leukemic transformation (up to 30-40% within 12-18 months of diagnosis). 7,114,170,172,175,176 7.1 | Laboratory findings and 31.8 Â 10 9 /L.…”

The impact of SETBP1 mutations in neurological diseases and cancer

“…T A B L E 1 SETBP1 mutation and diseases. -Hidalgo et al, 2017;Carvalho et al, 2015) p.D868A ND SGS (Hoischen et al, 2010) p.D868N PS SGS, aCML, sAML, RAEB, CMML1, CMML2, CNL, JMML, PT, MDS (Carvalho et al, 2015;Cui et al, 2014;Elliott et al, 2015;Gao et al, 2020;Hirao et al, 2022;Hoischen et al, 2010;Kwon et al, 2022;Li et al, 2019;Makishima et al, 2013;Montalban-Bravo et al, 2021;Mori et al, 2022;Piazza et al, 2013;Polprasert et al, 2022;Volk et al, 2015;Wakamatsu et al, 2021;Yin et al, 2019) p.D868Y ND CMML2 (Makishima et al, 2013) p.S869C ND SGS (Landim et al, 2015) p.S869G ND aCML (Piazza et al, 2013) p (Acuna-Hidalgo et al, 2017;Elliott et al, 2015;Hoischen et al, 2010;Mori et al, 2022) p.G870N ND CNL (Cui et al, 2014) p.G870S PS SGS, aCML, CMML, CNL, sAML, JMML PMF, PNH, MDS (Fontana et al, 2020;Herenger et al, 2015;Hirao et al, 2022;Hoischen et al, 2010;Kim et al, 2021;Ko et al, 2013;Kwon et al, 2022;Leone et al, 2020;Makishima et al, 2013;Montalban-Bravo et al, 2021;Park et al, 2021;Piazza et al, 2013;…”