Citations

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.

AbstractMonocytosis (absolute monocyte count, AMC ≥ 1 × 109/L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the current study, we examined the prevalence, laboratory and molecular correlates, and prognostic relevance of monocytosis in polycythemia vera (PV). Among 267 consecutive patients with World Health Organization (WHO)‐defined PV, 55 (21%) patients displayed an AMC of ≥1 × 109/L and 18 (7%) an AMC of ≥1.5 × 109/L. In general, PV patients with monocytosis were significantly older and displayed higher frequencies of leukocytosis (81% vs. 50% at AMC ≥1 × 109/L) and TET2/SRSF2 mutations (57%/29% vs. 19%/1% at AMC ≥ 1.5 × 109/L). In univariate analysis, AMC ≥1.5 × 109/L adversely affected overall (OS; P = .004; HR 2.6, 95% CI 1.4‐4.8) and myelofibrosis‐free (MFFS; P = .02; HR 4.4, 95% CI 1.3‐15.1) survival; during multivariable analysis, significance was borderline sustained for OS (P = .05) and MFFS (P = .06). Other independent risk factors for OS included unfavorable karyotype (P = .02, HR 3.39, 95% CI 1.17‐9.79), older age (P < .0001, HR 3.34 95% CI 1.97‐5.65), and leukocytosis ≥15 × 109/L (P = .004, HR 2.04, 95% CI 1.26‐3.29). In conclusion, in the current study, we encountered a higher than expected prevalence of monocytosis in patients with PV and the mutation profile and age distribution of PV patients with monocytosis is akin to those of patients with CMML and might partly contribute to their worse prognosis.

AbstractThe 2016 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (MPN) underscore the prognostically‐relevant distinction between essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre‐PMF). In addition, leukocytosis has been identified as an important prognostic marker in otherwise WHO‐defined ET. However, controversy remains regarding the objectivity of morphologic criteria in distinguishing ET from pre‐PMF and the precise prognostic cutoff values for leukocytosis. Serum lactate dehydrogenase (LDH) level might be a biologically more accurate measure of leukocyte turnover and a more sensitive marker of pre‐PMF, in otherwise WHO‐defined ET. In the current study of 183 consecutive patients with WHO‐defined ET, the presence of grade 1 bone marrow (BM) fibrosis did not affect presenting clinical or laboratory features; in contrast, increased serum LDH at diagnosis was associated with leukocytosis (p = .002), thrombocytosis (p < .001), palpable splenomegaly (p = .03) and higher international prognostic score (IPSET) (p = .002); serum LDH did not correlate with BM fibrosis, JAK2/CALR/MPL or TET2/ASXL1 mutations. In univariate analysis, risk factors for survival included age ≥60 years (p = .002; HR 10.2, 95% CI 2.3‐44.6), male sex (p = .02; HR 3.2, 95% CI 1.2‐8.2), leukocyte count ≥15 × 109/L (p = .007; HR 4.7, 95% CI 1.5‐14.6), and increased serum LDH (p = .002; HR 3.7, 95% CI 1.5‐9.1), but not BM fibrosis (p = .17). In multivariable analysis, age, sex and serum LDH remained significant; serum LDH also remained significant, in the context of IPSET (p = .003) and in patients with leukocytosis (p = .003). We conclude that serum LDH level carries an independent prognostic value for survival in ET and might represent a biologically more accurate surrogate for leukocytosis.

Key Points More than half of patients with PV or ET harbor DNA mutations/variants other than JAK2/CALR/MPL. The presence of some of these mutations adversely affects overall, leukemia-free, or myelofibrosis-free survival.

Key Points More than 80% of patients with PMF harbor DNA variants/mutations other than JAK2/CALR/MPL. Some of these variants/mutations adversely affect overall or leukemia-free survival independent of conventional risk stratification.

Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra‐cutaneous organs.Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V.Risk stratification: The 2008 World Health Organization (WHO) classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent (SM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD) and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis.Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (±corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases.Investigational drugs: Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 91:1147–1159, 2016. © 2016 Wiley Periodicals, Inc.