Citations

AbstractTherapy related myeloid neoplasms (t‐MN) including therapy related myelodysplastic syndromes (t‐MDS) and acute myeloid leukemia (t‐AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t‐CMML. T‐CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t‐CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t‐MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t‐CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t‐CMML in comparison to d‐CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t‐CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4‐3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5‐3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5‐3.7). In summary, we highlight the unique genetics and independent prognostic impact of t‐CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t‐MN.

AbstractA 27‐gene panel was used for next‐generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS‐R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2‐2.5), SETBP1 (HR 4.1, 95% CI 1.6‐10.2) and TP53 (HR 2.2, 95% CI 1.3‐3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5‐10.2), IDH2 (HR 3.7, 95% CI 1.2‐11.4), and CSF3R (HR 6.0, 95% CI 1.6‐22.6) for leukemia‐free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS‐R weakened the significance of TP53 mutations/variants (P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS‐R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia‐free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS‐R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision‐making in lower risk MDS.

Abstract Based on suggestive information from recent epidemiologic data and earlier retrospective studies, we revisited the effect of gender on survival in 1,494 patients with essential thrombocythemia (ET). The primary study population included 904 patients from the Mayo Clinic (median age 58 years; 65% females); risk distribution, according to the international prognostic score for ET (IPSET), was 23% high, 42% intermediate and 35% low. Multivariable analysis that included IPSET‐relevant risk factors identified male sex (HR 1.6, 95% CI 1.3‐2.0), age ≥60 years (HR 4.3, 95% CI 3.4‐5.4) and leukocyte count ≥11 × 10(9)/L (HR 1.5, 95% CI 1.3‐1.9) as independent predictors of shortened survival. These findings were confirmed by analysis of a separate cohort of 590 ET patients (65% females) from the University of Florence, Italy, with corresponding HRs (95% CI) of 1.6 (1.1‐2.5), 4.6 (2.2‐9.5) and 1.8 (1.1‐2.8). The independent prognostic effect of gender was further corroborated by a separate multivariable analysis against IPSET risk categories; HR (95% CI) for the Mayo Clinic/Florence cohorts were 1.5/1.6 (1.2/1.1‐1.8/2.5) for male sex, 6.8/7.5 (5.0/3.1‐9.3/18.3) for IPSET high risk and 2.8/4.1 (2.1/1.8‐3.8/9.5) for IPSET intermediate risk. Furthermore, the survival disadvantage in men was most apparent in IPSET high risk category and in patients older than 60 years. In both patient cohorts, thrombosis history garnered significance in univariate, but not in multivariable analysis. The observations from the current study suggest that women with ET live longer than their male counterparts and that gender might supersede thrombosis history as a risk variable for overall survival.

AbstractPalliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. To assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for postsplenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 × 10(9)/L, 25% leukocyte count >25 × 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate‐2, 21% intermediate‐1 and 3% low. Among informative cases, karyotype was abnormal in 60% and driver mutational status was JAK2 75%, CALR 15%, MPL 4% and triple‐negative 6%. At median follow‐up of 1.3 years, from time of splenectomy, 95 (79%) deaths and 30 (25%) leukemic transformations were recorded. Median postsplenectomy survival was 1.5 years; in multivariable analysis, survival was adversely affected by age >65 years, transfusion need, leukocyte count >25 × 10(9)/L and circulating blasts ≥5%; these variables were subsequently used to devise an HR‐weighted scoring system with high (3‐4 risk factors), intermediate (2 risk factors) and low (0‐1 risk factors) risk categories; the corresponding postsplenectomy median survivals were 0.3 (HR 5.9, 95% CI 3.2‐11.0), 1.3 (HR 2.9, 95% CI 1.8‐4.6) and 2.9 years. Postsplenectomy survival was not affected by driver mutational status or occurrence of leukemic transformation. Leukemia‐free survival was predicted by very high risk karyotype. The observations from the current study might help identify appropriate candidates for splenectomy in MF.

Objective We observed that pediatric patients with B lymphoblastic leukemia which expressed CD36 at diagnosis seemed to have worse outcome than patients whose blasts did not. Here, we describe the patient, disease characteristics, pathological, molecular, and genetic features and outcomes of patients with CD36+ B-LL compared to patients with CD36− B-LL. Methods We retrospectively reviewed all flow cytometry reports from September 2008 to December 2015 to identify patients diagnosed at our institution with CD36 expression on B lymphoblasts. CD36− control patients were chosen from our leukemia database and matched 2:1 to CD36+ patients for National Cancer Institute (NCI) risk group at diagnosis. We reviewed diagnostic marrow slides for cytoplasmic granules and abstracted clinical data from patient charts. To identify underlying genetic abnormalities, clinical FISH testing and RNA sequencing was performed on 5 of our CD36+ patients, and RNA-seq data from the NIH Therapeutically Applicable Research to Generate Effective Treatments (TARGET) ALL Expansion Phase 2 data set were examined. Results Twenty-five of 366 (6.83%) patients diagnosed at our institution in the study period had CD36+ blasts. With a median follow-up of 5.32 years, 5-year event-free survival (EFS) and overall survival (OS) were significantly worse for CD36+ patients compared to CD36− patients who were NCI Standard Risk at diagnosis (EFS: 60% ± 15.49 vs 95% ± 4.87, P = .016; OS: 90% ± 9.5 vs 100%, P = .019). NCI Standard Risk patients whose blasts were both CD36+ and had granules had the worst survival compared to CD36− patients without granules (EFS 25% ± 21.65 vs 95% ± 4.87, P = .0004). From our CD36+ patients and the TARGET database, we found 2 ABL2 mutations, 1 PDGFRB mutation, and 2 NRAS mutations. Conclusions For NCI Standard Risk patients, CD36 expression on B-lymphoblasts identifies patients with B-LL who have especially poor outcome. This may be due to underlying genetic abnormalities that may be amenable to targeted therapy.

SummaryThe definition of the myelodysplastic syndrome (MDS) subtype ‘MDS with isolated del(5q)’ was expanded to include cases with one additional non‐chromosome 7 based cytogenetic abnormality in the 2016 revised World Health Organization classification. This study applied the revised definition to a large primary MDS cohort, and evaluated the prognostic impact of the additional cytogenetic abnormality. Seventy‐two of 1067 patients (7%) met the ‘MDS with isolated del(5q)’ criteria, 11 (1%) of whom had an additional cytogenetic abnormality. There was no survival difference between patients in whom del(5q) occurred alone, compared to those with one additional cytogenetic abnormality (P = 0·52).