Lasho, Terra L.

The primary objective of treatment in essential thrombocythemia (ET) is to prevent thromboembolic complications. In this regard, advanced age and thrombosis history have long distinguished “low” from “high” risk patients. More recently, JAK2V617F and cardiovascular (CV) risk factors were identified as additional modifiers, leading to the development of a 3‐tiered International Prognostic Score of Thrombosis for ET (IPSET‐thrombosis): “low,” “intermediate,” and “high”. The international data set used to develop IPSET‐thrombosis was recently re‐analyzed in order to quantify the additional pro‐thrombotic effect of JAK2V617F and CV risk factors in specific risk subcategories. The revised IPSET‐thrombosis identified four risk categories based on three adverse variables (thrombosis history, age >60 years and JAK2V617F): very low (no adverse features), low (presence of JAK2V617F), intermediate (age >60 years) and high (presence of thrombosis history or presence of both advanced age and JAK2V617F). In this study of 585 patients with ET (median age 68 years; 61% female), we validated the revised IPSET‐thrombosis by confirming significant differences in thrombosis risk between “very low” and “low” (HR 2.4, 95% CI 1.1 − 5.3) and between “intermediate” and “high” (HR 2.3, 95% CI 1.1 − 5.2) risk patients. Furthermore, in multivariable analysis, only JAK2V617F (HR=1.8, CI= 1.07 − 2.94) and history of thrombosis (HR=2.1, CI= 1.20 − 3.58) were independently predictive of future thrombotic events. The revised IPSET‐thrombosis needs confirmation in prospective studies, especially in terms of risk‐adapted therapy that includes the need for aspirin therapy in very low risk, twice‐daily aspirin therapy for low risk and cytoreductive therapy for low or intermediate risk patients. Am. J. Hematol. 91:390–394, 2016. © 2016 Wiley Periodicals, Inc.

Colony stimulating factor 3 receptor gene (CSF3R) mutations have recently been associated with chronic neutrophilic leukemia (CNL). Fourteen patients with CSF3R‐mutated CNL (median age 67 years; 57% males) were screened for additional mutations; 8 (57%) and 5 (38%) harbored an ASXL1 and/or SETBP1 mutation (two patients expressed both), respectively. Two patients developed blastic transformation, both SETBP1‐mutated and ASXL1‐unmutated, whereas two other cases evolved into chronic myelomonocytic leukemia (CMML), both ASXL1‐mutated and SETBP1‐unmutated. Median survival was 23.2 months (10 deaths documented). On multivariable analysis mutated ASXL1 (P = 0.009; HR 19.6, 95% CI 2.1–184.1) and thrombocytopenia (P = 0.005; HR 28.8, 95% CI 2.8–298.2) were independently predictive of shortened survival. This study provides information on the natural history of CSF3R‐mutated CNL and identifies mutant ASXL1 and thrombocytopenia as risk factors for survival. The study also suggests pathogenetic roles for SETBP1 and ASXL1 mutations in disease evolution into blast phase disease and CMML, respectively. Am. J. Hematol. 90:653–656, 2015. © 2015 Wiley Periodicals, Inc.

Among 274 patients with chronic myelomonocytic leukemia (CMML) and followed for a median of 17.1 months, blast transformation (BT) occurred in 36 (13%). On multivariable analysis, risk factors for BT were presence of circulating blasts (HR 5.7; 95% CI 2.8–11.9) and female gender (HR 2.6; 95% CI 1.3–5.1); the results remained unchanged when analysis was restricted to CMML‐1. ASXL1/SRSF2/SF3B1/U2AF1/SETBP1 mutational frequencies were not significantly different between time of CMML diagnosis and BT. Median survival post‐BT was 4.7 months (5‐year survival 6%) and better with allogeneic stem cell transplant (SCT) (14.3 months vs. 4.3 months for chemotherapy vs. 0.9 months for supportive care; P = 0.03). Neither karyotype nor mutational status was independently associated with risk of BT or post‐BT survival. We conclude that female patients with CMML and those with circulating blasts are at a higher risk of BT. Post‐BT survival is dismal and our observations suggest consideration of allogeneic SCT prior to BT.Am. J. Hematol. 90:411–416, 2015. © 2015 Wiley Periodicals, Inc.

SummaryAmong 826 patients with primary myelofibrosis (PMF) and analysable metaphases on cytogenetic studies, 352 (42·6%) had abnormal karyotype, of which 240 (68·2%) were sole aberrations and 48 (13·6%) were complex; the most frequent abnormalities were 20q− (23·3%), 13q− (18·2%), +8 (11·1%), +9 (9·9%), chromosome 1q+ (9·7%) and −7/7q− (7·1%). Phenotypic correlates included: abnormal karyotype with anaemia (P = 0·02), leucopenia (P < 0·01) and thrombocytopenia (P < 0·01); complex karyotype with younger age (P = 0·04) and thrombocytopenia (P < 0·01); leucopenia with 20q−, +8 and −7/7q− and thrombocytopenia with 20q− and −7/7q−. Cytopenias were less likely to occur with 13q−. 476 patients were annotated for JAK2/CALR/MPL mutations; abnormal karyotype frequencies were 43% in JAK2, 42% CALR, 33% MPL mutated and 34% triple‐negative cases (P = 0·3). A proportion of patients were also screened for ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1 and SF3B1 mutations; in all instances, mutational frequencies were higher in patients with normal karyotype, reaching significance for ASXL1 (P = 0·02) and U2AF1 (P = 0·01). 13q− was associated with mutant CALR (P = 0·03), +9 with mutant JAK2 (P = 0·02) and 20q− with mutant SRSF2 (P = 0·02). The current PMF study provides detailed cytogenetic information and correlations with mutations and clinical phenotype.

Four hundred and nine patients with chronic myelomonocytic leukemia (CMML) were included in the international collaborative study (268 (66%) and 141 (34%) from Mayo clinic and French consortium respectively). Thirty percent displayed an abnormal karyotype, including; 72% sole, 16% two, and 11% complex abnormalities. The most common abnormalities included; +8 (23%), ‐Y (20%), ‐7/7q‐(14%), 20q‐ (8%), +21 (8%), and der(3q) (8%). Patients with an abnormal karyotype were more likely to be elderly (P = 0.03), be anemic (P = 0.0009), have leukocytosis (P = 0.02) with neutrophilia (P = 0.03), demonstrate increased circulating immature myeloid cells (P = 0.0003), peripheral blood blasts (P < 0.0001), and bone marrow blasts (P < 0.0001). ASXL1 (P = 0.04) and SF3B1 (P = 0.03) mutations clustered with an abnormal karyotype, whereas SRSF2 (P = 0.02) mutations occurred more commonly with a normal karyotype. A step‐wise survival analysis resulted in three distinct cytogenetic risk categories: high (complex and monosomal karyotypes), intermediate (all abnormalities not in the high or low risk groups) and low [normal, sole ‐Y and sole der (3q)] with median survivals of 3 [hazard ratio (HR) = 8.1, 95% confidence interval (CI) = 4.6–14.2], 20 (HR = 1.7, 95% CI = 1.2–2.3) and 41 months, respectively. In multivariable analysis, this particular cytogenetic risk stratification remained significant in the context of the Molecular Mayo Model (P < 0.0001), MD Anderson prognostic model (P < 0.0001), the GFM CMML model (P < 0.0001) and was effective in predicting leukemic transformation (P = 0.004). Am. J. Hematol. 89:1111–1115, 2014. © 2014 Wiley Periodicals, Inc.