The risk of progression from smoldering multiple myeloma to symptomatic disease is related to the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis.

We evaluated the prognostic relevance of several clinical and laboratory parameters in 226 Mayo Clinic patients with chronic myelomonocytic leukemia (CMML): 152 (67%) males and median age 71 years. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included anemia, thrombocytopenia, increased levels of white blood cells, absolute neutrophils, absolute monocyte count (AMC), absolute lymphocytes, peripheral blood and bone marrow blasts, and presence of circulating immature myeloid cells (IMCs). Spliceosome component (P=0.4) and ASXL1 mutations (P=0.37) had no impact survival. On multivariable analysis, increased AMC (>10 × 10(9)/l, relative risk (RR) 2.5, 95% confidence interval (CI) 1.7-3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4-2.7), decreased hemoglobin (<10 g/dl, RR 1.6, 99% CI 1.2-2.2) and decreased platelet count (<100 × 10(9)/l, RR 1.4, 99% CI 1.0-1.9) remained significant. Using these four risk factors, a new prognostic model for overall (high risk, RR 4.4, 95% CI 2.9-6.7; intermediate risk, RR 2.0, 95% CI 1.4-2.9) and leukemia-free survival (high risk, RR 4.9, 95% CI 1.9-12.8; intermediate risk, RR 2.6, 95% CI 1.1-5.9) performed better than other conventional risk models and was validated in an independent cohort of 268 CMML patients.

Unlike the case with acute myeloid leukemia, there is limited information on the prognostic impact of isocitrate dehydrogenase (IDH) mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (6 R132S and 2 R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts, 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1 and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (P ¼ 0.0004; hazard ration 4.0, 95% confidence interval 1.9 -8.8), revised International Prognostic Scoring System risk category (Po0.0001), and red cell transfusion need (P ¼ 0.002) as independent predictors of inferior survival. In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (P ¼ 0.001; hazard ration 7.0, 95% confidence interval 2.3 -20.8). The presence of IDH2R140Q did not affect the overall (P ¼ 0.54) or leukemia-free (P ¼ 0.81) survival. The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS.

SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)-RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (ϳ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instances, significance was completely accounted for by World Health Organization morphologic risk categorization. In other words, when RARS and RCMD-RS were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations. (Blood. 2012; 119(2):569-572)

SRSF2, SF3B1, and U2AF35 (U2AF1) are the three most frequent genes involved with spliceosome mutations in myeloid malignancies. SF3B1 mutations are most frequent (~80%) in myelodysplastic syndromes (MDS) with ring sideroblasts (RS) but lack prognostic relevance. SRSF2 mutations are associated with shortened overall (OS) and leukemia-free survival (LFS) in both MDS and myelofibrosis. In this study of 226 patients with chronic myelomonocytic leukemia (CMML), mutational frequencies were 40% for SRSF2 (all affecting P95), 6% for SF3B1 (primarily K700E) and 9% for U2AF35 (mostly S34F and Q157P/R). These mutations were mutually exclusive and 54% of the patients displayed at least one mutation. The three mutation groups were phenotypically similar, with the exception of higher RS% (P < 0.0001) in patients with SF3B1 mutations. At a median follow-up of 15 months, 176 (78%) deaths and 32 (14%) leukemic transformations were documented. OS (median survivals of 17, 16, 17, and 20 months; P 5 0.48) and LFS (leukemic transformation rates of 17, 13, 15, and 5%; P 5 0.63) were similar among patients with none of the three mutations, SRSF2, SF3B1, or U2AF35 mutations, respectively. We conclude that SRSF2 is the most frequently mutated spliceosome gene in CMML but neither it nor SF3B1 or U2AF35 mutations are prognostically relevant. Am. J. Hematol. 88:201-206, 2013. V C 2012 Wiley Periodicals, Inc. IntroductionChronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by features overlapping between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). The 2008 World Health Organization (WHO) criteria for diagnosis of CMML include; persistent peripheral blood monocytosis >1 3 10(9)/L, absence of the BCR-ABL1 fusion, absence of rearrangements of the PDGFRA or PDGFRB genes, absence of 20% myeloblasts or promonocytes in the blood and bone marrow (BM), and presence of dysplasia in one or more myeloid lineages [1]. CMML is further subclassified into CMML-1 (<5% circulating blasts and <10% BM blasts) and CMML-2 (5-19% circulating blasts, 10-19% BM blasts, or when Auer rods are present irrespective of the blast count), with the median over-all survival (OS) being 20 and 15 months respectively [1,2].Genetic aberrations are common in CMML and tend to involve different cellular targets and epigenetic regulatory pathways. These include mutations involving; RUNX1 . Thus far, in CMML, loss-of-function mutations involving EZH2 and ASXL1 have been associated with poor outcomes [10,11]. The data with regard to the other mutations needs further elucidation.Mutations in genes of the splicing machinery, such as SF3B1 (splicing factor 3B, subunit 1), SRSF2 (serine/arginine-rich splicing factor 2) and U2AF35, also known as U2AF1 (U2 small nuclear RNA auxiliary factor) are common in patients with myeloid malignancies [12][13][14]. SF3B1 mutations have a high prevalence ( 80%) in MDS and ring sideroblasts (RS) and do not influence either OS or leukemiafree survival (LFS) [15,16]. Similarly, these...