Tefferi, Ayalew

About 85% of patients with essential thrombocythemia (ET) harbor one of three driver mutations: JAK2, calreticulin (CALR), and MPL; the remaining ( ∼15%) are wild type for all three mutations and are referred to as being “triple negative.” Furthermore, CALR mutations in ET are structurally classified as type 1/type 1‐like or type 2/type 2‐like variants. The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis‐free (MFFS), thrombosis‐free, and leukemia‐free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple‐negative. Among the 109 CALR‐mutated cases, 52% were classified as type 1/type 1‐like and 48% as type 2/type 2‐like. In univariate analysis, triple‐negative patients displayed the best and MPL mutated the worst OS (P = 0.007); however, the difference in OS was no longer apparent on multivariable analysis that included age and sex as covariates (P = 0.5). LFS was also similar among the different mutational groups (P = 0.6) whereas MFFS was significantly shorter in MPL‐mutated patients on both univariate and multivariable analyses (age‐adjusted P = 0.02; HR 7.9, 95% CI 2.0–31.5). Also in multivariable analysis that included thrombosis history, age, and cardiovascular risk factors, the presence of JAK2 or MPL mutations was independently associated with higher risk of thrombosis (P = 0.02; HR 1.9, 95% CI 1.1–3.4). In conclusion, driver mutational status in ET does not appear to influence overall or LFS, even after CALR variant stratification. However, the presence of MPL mutations might be associated with a higher risk of fibrotic transformation and the presence of JAK2/MPL mutations with higher risk of thrombosis. Am. J. Hematol. 91:503–506, 2016. © 2016 Wiley Periodicals, Inc.

Refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS‐T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS‐T. We analyzed clinical and laboratory variables in 82 patients and applied a 27‐gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2 V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis ( n = 82), anemia ( P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2–4.6] and abnormal karyotype ( P =.01) [HR 6.1, 95% CI 2.7‐13.8] were independently prognostic for inferior survival. In patients with NGS information ( n = 48), univariate analysis showed association between poor survival and presence of SETBP1 ( P = 0.04) or ASXL1 ( P = 0.08) mutations whereas the absence of these mutations ( ASXL1 wt/ SETBP1 wt) was favorable ( P = 0.04); the number of concurrent mutations did not provide additional prognostication ( P = 0.3). We developed a HR‐weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively ( P = 0.01). In summary, we confirm the unique mutational landscape in RARS‐T and provide a novel mutation‐enhanced prognostic model. Am. J. Hematol. 91:492–498, 2016. © 2016 Wiley Periodicals, Inc.

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.

In myeloproliferative neoplasms (MPNs), controversy persists regarding the usefulness and reproducibility of bone marrow (BM) features. Disagreements concerning the WHO classification are mainly focused on the discrimination between essential thrombocythemia (ET) and prefibrotic/early primary myelofibrosis (prePMF) and prodromal polycythemia vera (PV). Criticism mostly refers to lack of standardization of distinctive BM features precluding correct morphological pattern recognition. The distinction between WHO‐defined ET and prePMF is not trivial because outcome is significantly worse in prePMF. Morphology was generally considered to be non‐specific for the diagnosis of PV. Recent studies have revealed under‐diagnosis of morphologically and biologically consistent PV. Am. J. Hematol. 91:430–433, 2016. © 2015 Wiley Periodicals, Inc.

Chronic neutrophilic leukemia (CNL) is a potentially aggressive myeloproliferative neoplasm, for which current WHO diagnostic criteria include leukocytosis of ≥25 × 109/L (of which >80% are neutrophils) and with <10 and <1% circulating immature granulocytes and blasts, respectively without dysplasia, clinical, or molecular criteria for other myeloproliferative disorders, nor an identifiable cause for physiologic neutrophilia in the absence of markers of myeloid clonality. Such a pathogenic clonal marker has now been identified as a somatic activating mutation of CSF3R, most commonly CSF3R T618I, thus demanding revision of the current WHO diagnostic classification to include the molecular criterion of mutated CSF3R. The clinical presentation, disease course and prognosis of CSF‐R mutated CNL have been recently outlined. Co‐operative mutations in SETBP1 and ASXL1 appear to be of prognostic significance and correlate with disease progression. Advances in the understanding of the molecular pathogenesis of CNL, have not yet fully translated into satisfactory therapeutic strategies, but the foundations for these are strengthening. Am. J. Hematol. 91:342–349, 2016. © 2015 Wiley Periodicals, Inc.