Al‐Kali, Aref

AbstractWe retrospectively reviewed 72 anemic patients with myelofibrosis (MF; median age 68 years), who were JAK2 inhibitor‐naïve at the time of study entry to a phase‐1/2 momelotinib clinical trial. Driver mutation profile included JAK2 69%, CALR 17%, MPL 8%, and triple‐negative 6%; other mutations included ASXL1 39% and SRSF2 17%. Momelotinib was administered at a median dose of 300 mg daily. Anemia response was assessed by formal criteria and documented in 44% of all patients with hemoglobin levels below the sex‐adjusted reference range (n = 72), 48% of those with hemoglobin <10 g/dl (n = 54), and 46% of those who were transfusion‐dependent at the time of study entry (n = 28). Anemia response was more likely with post‐essential thrombocythemia MF (83% vs 37%; p = .001), lower serum ferritin (p = .003), and shorter time from diagnosis to momelotinib therapy (p = .001); the first two variables were also predictive in transfusion‐dependent patients. Post‐momelotinib median survival was 3.2 years; in univariate analysis, survival was superior in anemia responders (median 3.8 vs. 2.8 years; p = .14) and in the presence of type 1/like CALR mutation and inferior in the presence of age > 65 years, ASXL1/SRSF2 mutation, unfavorable karyotype, DIPSS‐plus high risk, red cell transfusion need and higher serum ferritin. Multivariable analysis confirmed the favorable impact of anemia response on survival (p = .02; HR 0.5, 3/5/10‐year survival; 69%/38%/25%). This survival advantage was also noted in transfusion‐dependent patients (3.7 vs. 1.9 years; p = .01; HR 0.3) and appeared to be restricted to patients with an unfavorable genetic profile. The current study suggests a short‐term survival benefit associated with anemia response in momelotinib‐treated patients with MF.

Abstract Objectives Patients with clonal cytopenia of undetermined significance (CCUS) are at increased risk of developing myeloid neoplasia (MN). We evaluated whether a simple flow cytometry immunophenotyping (FCIP) assay could differentiate the risk of development of MN in patients with CCUS. Methods Bone marrow aspirates were assessed by FCIP panel in a cohort of 80 patients identified as having CCUS based on next-generation sequencing or cytogenetics from March 2015 to May 2020, with available samples. Flow cytometric assay included CD13/HLA-DR expression pattern on CD34-positive myeloblasts; CD13/CD16 pattern on maturing granulocytic precursors; and aberrant expression of CD2, CD7, or CD56 on CD34-positive myeloblasts. Relevant demographic, comorbidity, and clinical and laboratory data, including the type and extent of genetic abnormalities, were extracted from the electronic health record. Results In total, 17 (21%) patients with CCUS developed MN over the follow-up period (median survival follow-up, 28 months [95% confidence interval, 19-31]). Flow cytometry immunophenotyping abnormalities, including the aberrant pattern of CD13/HLA-DR expression, as detected at the time of the diagnosis of CCUS, were significantly associated with risk of developing MN (hazard ratio, 2.97; P = .006). Additional FCIP parameters associated with the development of MN included abnormal expression of CD7 on myeloblasts and the presence vs absence of any FCIP abnormality. Conclusions A simple FCIP approach that includes assessment of CD13/HLA-DR pattern on CD34-positive myeloblasts can be useful in identifying patients with CCUS at higher risk of developing MN.

AbstractThe current study was approached with the assumption that response to induction chemotherapy, in acute myeloid leukemia (AML), overshadows pre‐treatment risk variables in predicting survival and therefore be used as an anchor for a simplified risk model. We considered 759 intensively‐treated patients with AML, not promyelocytic: median age 60 years; primary 66%, secondary 25%, and therapy‐related 9%; European LeukemiaNet cytogenetic risk category favorable 8%, intermediate 61%, and adverse 31%. Complete remission with (CR) or without (CRi) count recovery was achieved in 608 (80%) patients. After a median follow‐up of 22 months, 503 deaths, 272 relapses, and 257 allogeneic hematopoietic stem cell transplants (AHSCTs) were recorded. Multivariable analysis identified failure to achieve CR/CRi (HR 3.8, 95% CI 3.1–4.8), adverse karyotype (2.2, 1.8–2.8), and age >55 years (2.1, 1.6–2.7) as main risk factors for survival. HR‐weighted scoring resulted in four‐tiered risk stratification: low (0 points; N = 183), intermediate‐1 (1 point; N = 331), intermediate‐2 (2 points; N = 117), and high (≥3 points; N = 128), with respective median survival (5‐year rate) not reached (68%), 34 (37%), 13 (20%), and 5 (5%) months (p < .001). FLT3‐ITD mutation was associated with inferior survival in intermediate‐1 (p = .004) and TP53 in intermediate‐2 (p = .06) and high (p = .02) risk disease; the latter was fully accounted for by the close association between TP53 mutation and complex/monosomal karyotype while the observations regarding FLT3‐ITD were not affected by treatment with midostaurin. AHSCT had a favorable impact on survival, most apparent in intermediate‐1 (p < .001), intermediate‐2 (p = .03), and high (p = .01) risk disease. The proposed 3‐factor survival model offers a novel prototype that is amenable to further enhancement by molecular information and was validated in an external cohort of 1032 intensively‐treated AML patients.