Search

The combination of venetoclax and hypomethylating agent (HMA/venetoclax) has emerged as a treatment option for patients with de novo acute myeloid leukemia (AML) who are unfit to receive intensive chemotherapy. In this single-center retrospective study, we evaluated clinical outcomes following treatment with HMA/venetoclax in 35 patients with advanced myeloproliferative neoplasms, myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes or AML with extramedullary disease. The composite complete remission (CR) rate (including confirmed/presumed complete cytogenetic response, acute leukemia response-complete, CR and CR with incomplete hematologic recovery) was 42.9% with median overall survival (OS) of 9.7 months. Complex karyotype was associated with inferior median OS (3.7 versus 12.2 months; p = 0.0002) and composite CR rate (22% versus 50.0%; p = 0.2444). Although SRSF2 mutations were associated with higher composite CR rate (80.0% versus 28.0%; p = 0.0082), this was not associated with longer median OS (10.9 versus 8.0 months; p = 0.2269). Future studies should include these patient subgroups. [ABSTRACT FROM AUTHOR]

There are currently no known predictors of myelodysplastic syndrome (MDS)/myeloproliferative overlap neoplasm (MPN) patients' response to hypomethylating agents (HMA). Forty-three patients with MDS/MPN who were treated with HMA during chronic phase and had next-generation sequencing using the established 63-genes panel were identified. Complete and partial remission and marrow response were assessed based on the MDS/MPN International Working Group response criteria. On univariate analysis, younger age, higher number of mutations, and mutations in SETBP1, RUNX1, or EZH2 were associated with no response. Multivariable analysis for modeling response were conducted via least absolute shrinkage and selection operator logistic regression approach, and showed that mutations in SETBP1, RUNX1, or EZH2 predict lack of HMA response. While limited by sample size, our findings suggest that genomic landscape can potentially identify MDS/MPN patients with lower likelihood of response to HMA. [ABSTRACT FROM AUTHOR]

Abstract: Cytogenetic aberrations identified by metaphase cytogenetics (MC) have important diagnostic, prognostic and therapeutic roles in myelodysplastic syndromes (MDS). Fluorescence in situ hybridization (FISH) complements MC by the ability to evaluate large numbers of both interphase and metaphase nuclei. However, clinically practical FISH strategies are limited to detection of known lesions. Single nucleotide polymorphism array (SNP-A)-based karyotyping can reveal unbalanced defects with superior resolution over MC and FISH and identify segmental uniparental disomy (UPD) undetectable by either method. Using a standardized approach, we focused our investigation on detection of −5/del(5q), −7/del(7q), trisomy 8 and del(20q) in patients with MDS (N =52), MDS/myeloproliferative overlap syndromes (N =7) and acute myeloid leukemia (N =15) using MC, FISH and SNP-A karyotyping. The detection rate for del(5q) was 30, 32 and 32% by MC, FISH, and SNP-A, respectively. No single method detected all defects, and detection rates improved when all methods were used. The rate for detection of del(5q) increased incrementally to 35% (MC+FISH), 38% (MC+SNP-A), 38% (FISH+SNP-A) and 39% (all three methods). Similar findings were observed for −7/del(7q), trisomy 8 and −20/del(20q). We conclude that MC, FISH and SNP-A are complementary techniques that, when applied and interpreted together, can improve the diagnostic yield for identifying genetic lesions in MDS and contribute to the better description of abnormal karyotypes. [Copyright &y& Elsevier]

Identification of genomic signatures with consistent clinicopathological features in myelodysplastic/myeloproliferative neoplasm (MDS/MPN) is critical for improved diagnosis, elucidation of biology, inclusion in clinical trials, and development of therapies. We describe clinical and pathological features with co-existence of mutations in ASXL1 (missense or nonsense), SRSF2 , and SKI homologous region of SETBP1 , in 18 patients. Median age was 68 years with a male predominance (83%). Leukocytosis and neutrophilia were common at presentation. Marrow features included hypercellularity, granulocytic hyperplasia with megakaryocytic atypia, while the majority had myeloid hyperplasia and/or erythroid hypoplasia, myeloid dysplasia, and aberrant CD7 expression on blasts. Mutations in growth signaling pathways (RAS or JAK2) were noted at diagnosis or acquired during the disease course in 83% of patients. Two patients progressed upon acquisition of FLT3-TKD (acute myeloid leukemia) or KIT (aggressive systemic mastocytosis) mutations. The prognosis is poor with only two long-term survivors, thus far, who underwent blood or marrow transplantation. We propose that the presence of co-occurring ASXL1, SRSF2, and SETBP1 mutations can be diagnostic of a subtype of MDS/MPN with neutrophilia if clinical and morphological findings align. Our report underscores the association between genotype and phenotype within MDS/MPN and that genomic signatures should guide categorization of these entities. • Co-occurring ASXL1, SRSF2, and SETBP1 mutations suggest MDS/MPN with neutrophilia. • Prognosis is poor and timely intervention with BMT should be considered. • Acquisition of signal transduction mutations (such as RAS or JAK2) is common. [ABSTRACT FROM AUTHOR]