TY - JOUR
T1 - Clinicopathologic correlates and natural history of atypical chronic myeloid leukemia
AU - Montalban-Bravo, Guillermo
AU - Kanagal-Shamanna, Rashmi
AU - Sasaki, Koji
AU - Masarova, Lucia
AU - Naqvi, Kiran
AU - Jabbour, Elias
AU - DiNardo, Courtney D.
AU - Takahashi, Koichi
AU - Konopleva, Marina
AU - Pemmaraju, Naveen
AU - Kadia, Tapan M.
AU - Ravandi, Farhad
AU - Daver, Naval
AU - Borthakur, Gautam
AU - Estrov, Zeev
AU - Khoury, Joseph D.
AU - Loghavi, Sanam
AU - Soltysiak, Kelly A.
AU - Pierce, Sherry
AU - Bueso-Ramos, Carlos
AU - Patel, Keyur P.
AU - Verstovsek, Srdan
AU - Kantarjian, Hagop M.
AU - Bose, Prithviraj
AU - Garcia-Manero, Guillermo
N1 - Publisher Copyright:
© 2021 American Cancer Society
PY - 2021/9/1
Y1 - 2021/9/1
N2 - 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.
AB - 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.
KW - chronic myeloid leukemia
KW - clinical outcomes
KW - mutational codominance
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UR - http://www.scopus.com/inward/citedby.url?scp=85105157187&partnerID=8YFLogxK
U2 - 10.1002/cncr.33622
DO - 10.1002/cncr.33622
M3 - Article
C2 - 33914911
AN - SCOPUS:85105157187
SN - 0008-543X
VL - 127
SP - 3113
EP - 3124
JO - Cancer
JF - Cancer
IS - 17
ER -