TY - JOUR
T1 - Phenotypic subtypes of leukaemic transformation in chronic myelomonocytic leukaemia
AU - Montalban-Bravo, Guillermo
AU - Kanagal-Shamanna, Rashmi
AU - Li, Ziyi
AU - Hammond, Danielle
AU - Chien, Kelly
AU - Rodriguez-Sevilla, Juan Jose
AU - Sasaki, Koji
AU - Jabbour, Elias
AU - DiNardo, Courtney
AU - Takahashi, Koichi
AU - Short, Nicholas
AU - Issa, Ghayas C.
AU - Pemmaraju, Naveen
AU - Kadia, Tapan
AU - Ravandi, Farhad
AU - Daver, Naval
AU - Borthakur, Gautam
AU - Loghavi, Sanam
AU - Pierce, Sherry
AU - Bueso-Ramos, Carlos
AU - Kantarjian, Hagop
AU - Garcia-Manero, Guillermo
N1 - Publisher Copyright:
© 2023 British Society for Haematology and John Wiley & Sons Ltd.
PY - 2023/11
Y1 - 2023/11
N2 - Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics.
AB - Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics.
KW - CMML
KW - genotype
KW - monocytic
KW - myeloid
KW - phenotype
KW - transformation
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U2 - 10.1111/bjh.19060
DO - 10.1111/bjh.19060
M3 - Article
C2 - 37608562
AN - SCOPUS:85168674760
SN - 0007-1048
VL - 203
SP - 581
EP - 592
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 4
ER -