Tefferi, Ayalew

Disease overview:Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell‐derived clonal myeloproliferation that is often but not always accompanied byJAK2,CALRorMPLmutation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression and shortened survival.Diagnosis:Diagnosis is based on bone marrow morphology. The presence ofJAK2,CALRorMPLmutation is supportive but not essential for diagnosis; approximately 90% of patients carry one of these mutations and 10% are “triple‐negative.” None of these mutations are specific to PMF and are also seen in essential thrombocythemia (ET). According to the revised 2016 World Health Organization (WHO) classification and diagnostic criteria, “prefibrotic” PMF (pre‐PMF) is distinguished from “overtly fibrotic” PMF; the former might mimic ET in its presentation and it is prognostically relevant to distinguish the two.Risk stratification:The Dynamic International Prognostic Scoring System‐plus (DIPSS‐plus)uses eight predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 109/L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 109/L and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, −7/7q‐, i(17q), inv(3), 5/5q‐, 12p‐, or 11q23 rearrangement). The presence of 0, 1, “2 or 3” and ≥4 adverse factors defines low, intermediate‐1, intermediate‐2 and high‐risk disease with median survivals of approximately 15.4, 6.5, 2.9 and 1.3 years, respectively. Most recently, DIPSS‐plus‐independent adverse prognostic relevance has been demonstrated for certain mutations includingASXL1andSRSF2whereas patients with type 1/likeCALRmutations, compared to their counterparts with other driver mutations, displayed significantly better survival.Risk‐adapted therapy:Observation alone is a reasonable treatment strategy for asymptomaticloworintermediate‐1DIPSS‐plus risk disease, especially in the absence of high‐risk mutations. All other patients withhighorintermediate‐2 riskdisease, or those harboring high‐risk mutations such asASXL1orSRSF2, should be considered for stem cell transplant, which is currently the only treatment modality with the potential to favorably modify the natural history of the disease. Non‐transplant candidates should be encouraged to participate in clinical trials, since the value of conventional drug therapy, including the use of JAK2 inhibitors, is limited to symptoms palliation and reduction in spleen size. Specifically, JAK2 inhibitors have not been shown to induce complete clinical or cytogenetic remissions or significantly affectJAK2/CALR/MPLmutant allele burden. Splenectomy is considered for drug‐refractory splenomegaly. Involved field radiotherapy is most useful for post‐splenectomy hepatomegaly, non‐hepatosplenic EMH, PMF‐associated pulmonary hypertension and extremity bone pain. Am. J. Hematol. 91:1262–1271, 2016. © 2016 Wiley Periodicals, Inc.

DNMT3A mutations are seen in ∼5% of patients with chronic myelomonocytic leukemia (CMML) and thus far, have had an indeterminate prognostic impact on survival. We carried out this study to assess the prognostic impact of DNMT3A mutations on a larger informative cohort of CMML patients (n = 261). DNMT3A mutations were seen in 6% (n = 16); 56% (n = 9) male, with a median age of 64 years. Eighty‐one % of DNMT3A mutations were missense, with the Arg882 mutational hot spot accounting for 63% of all changes. Five (31%) patients had an abnormal karyotype whereas concurrent gene mutations (SF3B1/SRSF2/U2AF1−56%, TET2−50%, and ASXL1−25%) were seen in all patients. Apart from a higher frequency of SF3B1 (P = 0.0001) and PTPN11 (P = 0.005) mutations and a lower frequency of SRSF2 (P = 0.004) mutations, there were no significant differences between DNMT3A mutated patients and their wildtype counterparts. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wildtype (median 27 months) patients (P = 0.0007; HR 2.9, 95% CI 1.5–5.7); with other variables of significance including lower hemoglobin (P = 0.002), higher leukocyte count (P = 0.0009), higher monocyte count (P = 0.0012), circulating blast % (P = 0.001), circulating immature myeloid cells (P = 0.01), bone marrow blast % (P = 0.045), abnormal karyotype (P = 0.02), and ASXL1 (P = 0.01) mutations. In a multivariable model that included the aforementioned variables, when both DNMT3A and ASXL1 mutations were added, only DNMT3A (P < 0.0001) and ASXL1 (P = 0.004) mutations remained significant. DNMT3A mutations were also predictive of a shortened leukemia‐free survival. These findings warrant inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models. Am. J. Hematol. 92:56–61, 2017. © 2016 Wiley Periodicals, Inc.

Myelofibrosis is a myeloproliferative neoplasm with cardinal features of extramedullary hematopoiesis, hepatosplenomegaly, cytopenias, and constitutional symptoms that result in shortened survival and leukemic transformation. It is a disease predominantly of the elderly, and currently available therapies only offer symptom control without curative benefit or ability to alter disease progression. Allogeneic hematopoietic stem-cell transplant (HSCT) is the only potentially curative intervention; however, this is only feasible in younger and medically fit patients and selectively offered to those with high-risk disease. Despite ongoing advancements, HSCT is associated with substantial morbidity and mortality, and the determination of which patients with myelofibrosis are ideal candidates and the selection of the opportune moment to proceed with transplantation remains challenging. This review summarizes our current recommendations for the role of and indications for HSCT in myelofibrosis.

In routine practice, the World Health Organization classification of systemic mastocytosis (SM) is also the de facto prognostic system; a core value is distinguishing indolent (ISM) from advanced SM (includes aggressive SM [ASM], SM with associated hematological neoplasm [SM‐AHN] and mast cell leukemia [MCL]). We sequenced 27 genes in 150 SM patients to identify mutations that could be integrated into a clinical‐molecular prognostic model for survival. Forty four patients (29%) had ISM, 25 (17%) ASM, 80 (53%) SM‐AHN and 1 (0.7%) MCL; overall KITD816V prevalence was 75%. In 87 patients, 148 non‐KIT mutations were detected; the most frequently mutated genes were TET2 (29%), ASXL1 (17%), and CBL (11%), with significantly higher mutation frequency in SM‐AHN > ASM > ISM (P < 0.0001). In advanced SM, ASXL1 and RUNX1 mutations were associated with inferior survival. In multivariate analysis, age > 60 years (HR = 2.4), hemoglobin < 10 g/dL or transfusion‐dependence (HR = 1.7), platelet count < 150 × 109/L (HR = 3.2), serum albumin < 3.5 g/dL (HR = 2.6), and ASXL1 mutation (HR = 2.3) were associated with inferior survival. A mutation‐augmented prognostic scoring system (MAPSS) based on these parameters stratified advanced SM patients into high‐, intermediate‐, and low‐risk groups with median survival of 5, 21 and 86 months, respectively (P < 0.0001). These data should optimize risk‐stratification and treatment selection for advanced SM patients. Am. J. Hematol. 91:888–893, 2016. © 2016 Wiley Periodicals, Inc.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms. Diagnosis is based on the presence of persistent (>3 months) peripheral blood monocytosis (>1 × 109/L), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼20–30% of patients, while >90% have gene mutations. Mutations involving TET2 (∼60%), SRSF2 (∼50%), ASXL1 (∼40%), and RAS (∼30%) are frequent; with only ASXL1 mutations negatively impacting overall survival. Two molecularly integrated, CMML‐specific prognostic models include; the Groupe Français des Myélodysplasies (GFM) and the Molecular Mayo Model (MMM). The GFM model segregates patients into 3 groups based on: age >65 years, WBC >15 × 109/L, anemia, platelets <100 × 109/L, and ASXL1 mutation status, with respective median survivals of 56 (low), 27.4 (intermediate), and 9.2 (high) months. The MMM is based on ASXL1 mutational status, absolute monocyte count >10 × 109/L, hemoglobin <10 g/dL, platelets <100 × 109/L and circulating immature myeloid cells. This model stratifies patients into four groups; high (≥3 risk factors), intermediate‐2 (2 risk factors), intermediate‐1 (1 risk factor) and low (no risk factors), with median survivals of 16, 31, 59, and 97 months, respectively. Hypomethylating agents such as 5‐azacitidine and decitabine are commonly used, with overall response rates of ∼30–40% and complete remission rates of ∼7–17%. Allogeneic stem cell transplant is the only potentially curative option, but is associated with significant morbidity and mortality. Individualized therapy, including epigenetic modifiers and small molecule inhibitors, are exciting prospects. Am. J. Hematol. 91:632–642, 2016. © 2016 Wiley Periodicals, Inc.