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

Langabeer, Stephen E.; Comerford, Claire; Quinn, John; Murphy, Philip

doi:10.1136/jclinpath-2017-204621

Cited by 5 publications

(5 citation statements)

References 8 publications

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“…upfront transplantation versus transplantation after initial treatment to reduce the disease burden), the intensity of the conditioning regimen, the impact of previously administered treatments, and the possible impact of the molecular profile of the patients still remain unanswered. Nevertheless, the advanced age of most patients with aCML probably dictates the use of reduced intensity conditioning regimens while the molecular profile of the patients may be useful for the monitoring of minimal residual disease ( 49 ) and as a guide for post-transplant maintenance in cases with targetable mutations.…”

Section: Treatment Approaches For Acmlmentioning

confidence: 99%

Atypical Chronic Myelogenous Leukemia, BCR-ABL1 Negative: Diagnostic Criteria and Treatment Approaches

Diamantopoulos

Viniou

2021

Front. Oncol.

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Atypical chronic myelogenous leukemia (aCML), BCR/ABL1 negative is a rare myelodysplastic/myeloproliferative neoplasm, usually manifested with hyperleukocytosis without monocytosis or basophilia, organomegaly, and marked dysgranulopoiesis. In this review, we will discuss the classification and diagnostic criteria of aCML, as these have been formulated during the past 30 years, with a focus on the recent advances in the molecular characterization of the disease. Although this entity does not have a definitive molecular profile, its molecular characterization has contributed to a better understanding and more accurate classification and diagnosis of aCML. At the same time, it has facilitated the identification of adverse prognostic factors and the stratification of patients according to their risk for leukemic transformation. What is more, the molecular characterization of the disease has expanded our therapeutic choices, thoroughly presented and analyzed in this review article.

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Section: Treatment Approaches For Acmlmentioning

confidence: 99%

Atypical Chronic Myelogenous Leukemia, BCR-ABL1 Negative: Diagnostic Criteria and Treatment Approaches

Diamantopoulos

Viniou

2021

Front. Oncol.

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“…BCR‐ABL–negative atypical chronic myeloid leukemia (aCML) is a rare clonal, hematopoietic stem cell disorder characterized by the presence of hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia along with peripheral blood (PB) leukocytosis, with increased numbers of neutrophils and immature granulocytic precursors composing ≥10% of leukocytes, in the absence of absolute basophilia and monocytosis and BCR‐ABL1 rearrangement or other features of myeloproliferative neoplasms 1 . Next‐generation sequencing (NGS) has identified recurrent mutations in ASXL1 , SETBP1 , ETNK1 , TET2 , and other RAS pathway mutations, as well as CSF3R mutations, in aCML 2‐10 . In addition, recent data suggest that comutation patterns may be associated with distinct myelodysplastic/myeloproliferative neoplasm (MDS/MPN) subtypes, with ASXL1 and SETBP1 comutations frequently observed in aCML 7 .…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia

Bravo

Kanagal‐Shamanna

Sasaki

et al. 2021

Cancer

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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.

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“…Atypical CML is characterized by the presence of hypercellular bone marrow (BM) with granulocytic proliferation and granulocytic dysplasia along with peripheral blood (PB) leukocytosis with increased numbers of neutrophils and immature granulocytic precursors comprising ≥10% of leukocytes, in the absence of absolute basophilia and monocytosis and BCR-ABL1 rearrangement or other features of MPN (1). Nextgeneration sequencing (NGS) identified recurrent mutations in ASXL1, SETBP1, ETNK1, TET2, and other RAS pathway mutations, as well as CSF3R mutations, in aCML (2)(3)(4)(5)(6)(7)(8)(9)(10). In addition, recent data suggests that co-mutation patterns may be associated with distinct MDS/MPN subtypes, with ASXL1 and SETBP1 co-mutations frequently observed in aCML (7).…”

Section: Introductionmentioning

confidence: 99%

Clinicopathologic Correlates and Natural History of Atypical Chronic Myeloid Leukemia

Montalban‐Bravo

Kanagal‐Shamanna

Sasaki

et al. 2020

Preprint

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There is limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML). We evaluated the clinicopathological features, outcomes, and responses to therapy of 65 patients with aCML. Median age was 67 years (range 46-89). The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 tended to appear within dominant clones, with frequent SRSF2 and SETBP1 codominance, while other RAS pathway mutations were more likely to appear as minor clones. Acquisition of new, previously undetectable mutations at transformation was observed in 63% of evaluable patients, the most common involving signaling pathway mutations. Hypomethylating agents were associated with the highest response rates and duration. With a median overall survival of 25 months (95% CI 20-30), intensive chemotherapy was associated with worse OS than other treatment modalities, and allogeneic stem cell transplantation was the only therapy associated with improved outcomes (HR 0.044, 95% CI 0.035-0.593, p=0.007). Age, platelet count, BM blast percentage, and serum LDH levels were independent predictors of survival and were integrated in a multivariable model which allowed to predict 1-year and 3-year survival.

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

Cited by 5 publications

References 8 publications

Atypical Chronic Myelogenous Leukemia, BCR-ABL1 Negative: Diagnostic Criteria and Treatment Approaches

Atypical Chronic Myelogenous Leukemia, BCR-ABL1 Negative: Diagnostic Criteria and Treatment Approaches

Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia

Clinicopathologic Correlates and Natural History of Atypical Chronic Myeloid Leukemia

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