Targeted next generation sequencing and identification of risk factors in World Health Organization defined atypical chronic myeloid leukemia

Abstract

Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8% and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (p=0.02), low hemoglobin (p=0.01), red blood cell transfusion dependence (p=0.03), high white blood cell count (p=0.02), TET2 (p=0.03), NRAS (p=0.04), PTPN11 (p=0.02) mutations and the presence of ≥3 gene mutations (p=0.006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (p=0.003) [age >67: HR 10.1, 95% CI 1.3–119], low hemoglobin (p=0.008) [HB< 10gm/dl: HR 8.2, 95% CI 1.6–23.2] and TET2 mutations (p=0.01) [HR 8.8, 95% CI 1.6–47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dl and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0–1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months respectively.

Atypical chronic myeloid leukaemia: A case of an orphan disease—A multicenter report by the Polish Adult Leukemia Group

“…They can be also found in cases of systemic mastocystosis with eosinophilia while they are not present in other tumors . Mutations of other genes have also been reported in aCML, among them ASXL1 , SRSF2 , EZH2 , TET2 , SF3B1 , CEBPA , RAS , RUNX1 , and FLT3 …”

“…At present, although the pathognomonic mutations are lacking, the diagnosis of aCML may be aided by both SETBP1 ( SET‐binding protein 1 ) and ETNK1 ( ethanolamine kinase 1 ) mutations. Mutations of SETBP1 are encountered in 12 to 33% aCML patients . SETBP1 localizes on chromosome 18q21.1 and codes for protein with a predominantly nuclear localization that is expressed in hematopoietic stem/progenitor cells and also in committed progenitors.…”

“…Mutations of ETNK1 lead to loss of catalytic activity of ethanolamine kinase responsible for biosynthesis of phosphatidylethanolamine necessary for, ie, maintenance of cell‐membrane architecture and topology of transmembrane proteins, synthesis of diacylglycerols, fatty acids and phosphatidic acid, cytokinesis, and many other processes . The mutations are encountered in approximately 8% of aCML and 2.6 to 14% CMML patients . They can be also found in cases of systemic mastocystosis with eosinophilia while they are not present in other tumors .…”

Molecular profiling and targeted inhibitor therapy in atypical chronic myeloid leukaemia in blast crisis

“…Allogeneic stem cell transplantation is the only potentially curative option but in those patients ineligible, treatment has largely relied on agents used for MDS and MPN with varying degrees of success 3. Mutations in genes associated with other myeloid malignancies are detected in all patients with 60% of cases harbouring more than one mutation 4. This underlying molecular complexity allied to heterogeneous clinical features means that no current standard of care exists for patients with aCML.…”

“…Targeted NGS has been recently shown to identify prognostically relevant mutations4; however, this case clearly demonstrates that this approach also has the capacity to characterise clinically actionable mutations such as FLT3 -ITD mutations that are infrequent in aCML 5. Given previous reports of hypomethylating agents in MPN blast crisis6 and their combination with an FLT3 inhibitor in salvaging relapsed FLT3 -ITD-positive acute myeloid leukaemia,7 8 a sorafenib and azacytidine regimen was initiated that has resulted in an extended response in a patient with high-risk, chemotherapy-refractory aCML who had previously failed multiple lines of therapy.…”