DNTM3A Mutations and Prognosis in Chronic Myelomonocytic Leukemia

Abstract Background : DNMT3A mutations result in epigenetic dysregulation and impart a negative prognostic impact in acute myeloid leukemia and myelodysplastic syndromes. In chronic myelomonocytic leukemia (CMML), DNMT3A mutations are seen in 2-5% of patients. In a large Groupe Français des Myélodysplasies (GFM) study (n=312), DNMT3A mutations were seen in 2% and were not included in further survival analyses (Itzykson JCO 2013). In a prior Mayo Clinic study (n=175), DNMT3A mutations were seen in 5% (n=9) and on univariate, but not multivariate analysis (Patnaik Blood C J 2016), were associated with shortened over-all survival (OS). We carried out this study on a larger CMML cohort (n=261), with more (n=15) informative cases to assess the impact of DNMT3A mutations. Methods : 261 patients with World Health Organization (WHO)-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. The 2016 WHO diagnostic criteria were used. Results: Among the 261 study patients, 65% were males and median age was 70 years (range, 28-91). 154 (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations (LT) were documented. Mutational frequencies ≥4% were encountered in; TET2 45%, ASXL1 45%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, DNMT3A 6%, U2AF1 6%, SF3B1 5%, ZRSR2 4%, Tp53 4%, and IDH2 4%. i) DNTM3A mutated CMML: phenotypic and molecular correlates DNMT3A mutations were seen in 15 (6%) patients; 64% male with a median age of 64 years. DNMT3A amino acid substitutions included; R882H 50%, R882C 29%, R910P 7%, R598* 7% and R320* 7%. The median variant allele frequency burden was 45%. Concurrent gene mutations were detected in; TET2 43%, ASXL1 21%, SF3B1 21%, U2AF1 14%, RUNX1 14%, SETBP1 14%, NRAS 14%, SRSF2 7%, JAK2 7% and Tp53 7%. There was no difference between DNMT3A mutated and wild-type patients in terms of age and gender distribution, hemoglobin level, leukocyte, monocyte (AMC), and platelet counts, peripheral blood (PB) or BM blast content. Concurrent gene mutations were equally distributed with the exception for a higher prevalence of SF3B1 (p=0.003) and a lower prevalence of SRSF2 (p=0.004) mutations in DNMT3A mutated CMML. Four (29%) patients underwent leukemic transformation. ii) Impact on OS and leukemia-free survival (LFS): Median survival for the entire cohort (n=261) was 24 months. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wild-type (median 27 months) patients (p=0.0007; HR 2.9, 95% CI 1.5-5.7; Figure 1A). Other variables of significance, in univariate analysis, included lower hemoglobin (p=0.002), higher leukocyte count (p=0.0009), higher AMC (p=0.0012), PB blast % (p=0.001), circulating immature myeloid cells (IMC, p=0.01), BM blast % (p=0.045), abnormal karyotype (p=0.02), and ASXL1 (p=0.01) mutations. Survival was also adversely affected by the presence of either (n=133) or both (n=3) ASXL1/DNMT3A mutations (0=0.007, Figure 1B). In multivariable analysis (MVA) excluding ASXL1 and DNMT3A mutations, hemoglobin (p=0.03), IMC (p=0.013) and AMC (p=0.02) retained significance. When ASXL1 mutations were added to the MVA, ASXL1 (p=0.01) mutations, AMC (p=0.012) and IMC (p=0.03) retained significance. Similarly, when only DNMT3A mutations were added to the MVA, DNMT3A (p=0.003) mutations, IMC (p=0.01) and AMC (p=0.02) retained significance. When both DNMT3A and ASXL1 mutations were added to the MVA, only DNMT3A (p<0.0001) and ASXL1 (p=0.004) mutations remained significant. DNMT3A mutations predicted shortened OS, independent of the ASXL1 inclusive GFM model (p<0.0001) and Mayo Molecular Model (p=0.002). DNMT3A mutations (p=0.0018), along with low hemoglobin levels (p=0.003) independently predicted for a shorter LFS. Conclusions: DNMT3A mutations are seen in ~5% of patients with CMML and impart a negative prognostic impact on both OS and LFS. This finding warrants inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models. Disclosures No relevant conflicts of interest to declare.

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Prognostic Interaction Between ASXL1 and TET2 Mutations in Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood.v126.23.2864.2864 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2864-2864

Author(s):

Mrinal M Patnaik ◽

Terra L. Lasho ◽

Pooja Vijayvargiya ◽

Christy Finke ◽

Curtis A. Hanson ◽

...

Keyword(s):

Survival Data ◽

Prognostic Model ◽

Conflicts Of Interest ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Chronic Myelomonocytic Leukemia ◽

Signal Pathways ◽

Prognostic Impact ◽

Significant Difference ◽

Myelomonocytic Leukemia

Abstract Background : Gene mutations are common (~90%) in patients with chronic myelomonocytic leukemia (CMML) and involve epigenetic regulators (TET2 ~ 60%, ASXL1 ~40%), spliceosome components (SRSF2 ~40%) and signal pathways (RAS ~30%). Of these, thus far, only ASXL1 mutations have been shown to adversely impact overall survival (OS). In the current study, we used a 27-gene panel assay to identify additional prognostically-relevant mutations in CMML and to also determine if number of mutations carries prognostic relevance. Methods : 175 patients with WHO-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP1. Paired-end indexed libraries were prepared from individual patient DNA using the NEBNext Ultra Library prep protocol on the Agilent Bravo liquid handler. Capture libraries were assembled according to Nimblegen standard library protocol. Base-calling was performed using Illumina's RTA version 1.17.21.3. Genesifter software was utilized to analyze targeted sequence data. Specific variants were deemed as mutations if they were associated with a hematological malignancy (as identified by COSMIC database), or if they were not associated with a dbSNP Results: Among the 175 study patients, 66% were males and median age was 70 years. 146 (83%) patients were subclassified as CMML-1. At a median follow-up of 23 months, 146 (83%) deaths and 25 (14%) leukemic transformations were documented. Median survivals were 24 months for CMML-1 and 16 months for CMML-2 (p=0.38). Mutational frequencies were; TET2 46%, ASXL1 45%, SRSF2 45%, SETBP1 19%, CBL 14%, RUNX1 14%, NRAS 12%, U2AF1 8%, SF3B1 6%, ZRSR2 6%, Tp53 5%, DNMT3A 5%, IDH2 5%, PTPN11 5%, SH2B3 5%, JAK2 4%, NPM1 3%, CSF3R 2%, IDH1 2%, EZH2 1%, SUZ12 1%, KIT 1%, FLT3 1%, CALR 1%. 172 patients (98%) had at least one mutation, 21 (12%) had 2, 24 (14%) had 3, 20 (11%) had 4, 9 (5%) had 5, while one (1%) patient had 6 concurrent mutations. Risk stratification was based on Mayo prognostic model: 25% high, 32% intermediate and 43 % low risk. In univariate analysis, presence of ASXL1 mutations (p=0.01), absence of TET2 mutations (p=0.005) and presence of DNMT3A mutations (p=0.02) were associated with inferior survival; in multivariable analysis, ASXL1 (p=0.01) and TET2 (p=0.03) mutations remained significant. In order to determine prognostic interaction between these two mutations, patients were stratified into four mutational categories: ASXL1wt/TET2wt (n =56), ASXL1mut/TET2wt (n =31), ASXL1mut/TET2mut (n =50) and ASXL1wt/TET2mut (n =38). Survival data in these four groups showed significant difference in favor of ASXL1wt/TET2mut (median survival 38 months; p=0.016), compared to those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (31 months)and ASXL1mut/TET2mut (16 months); there was no significant difference in survival among the latter three groups (p=0.3) (Figure). The number of mutations per patient did not affect outcome (p=0.3). In multivariable analysis, presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (p=0.003) remained significant when risk factors used in the Mayo prognostic model (HB <10 gm/dl, AMC >10 x 10(9)/L, platelets <100 x 10(9)/L, circulating IMC) were added to the model; the same was true for ASXL1wt/TET2mut (p=0.036). In a separate multivariable analysis that included the Mayo prognostic model as a single variable along with presence of ASXL1 and absence of TET2 mutations; or absence of ASXL1wt/TET2mut mutational status, the respective hazard ratios were 1.4 (95% CI 1.07-2.1; p=0.012), 1.5 (95% CI 1.07-2.1; p=0.03) and 1.8 (95% CI 1.2-2.7; p=0.001). Leukemia-free survival was worse in ZRSR2 -mutated cases (p=0.03). Conclusions: Almost 100% of patients with CMML express one or more myeloid neoplasm-relevant mutations. The current study suggests a favorable prognostic impact from TET2 mutations, unless accompanied by ASXL1 mutations. Disclosures No relevant conflicts of interest to declare.

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ASXL1 and SETBP1 Mutations and Their Prognostic Contribution In Chronic Myelomonocytic Leukemia: An International Study Of 431 Patients

Blood ◽

10.1182/blood.v122.21.1510.1510 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1510-1510

Author(s):

Mrinal M Patnaik ◽

Raphael Itzykson ◽

Terra L Lasho ◽

Olivier Kosmider ◽

Christy Finke ◽

...

Keyword(s):

Platelet Count ◽

Risk Stratification ◽

Prognostic Model ◽

Univariate Analysis ◽

Multivariable Analysis ◽

International Study ◽

Chronic Myelomonocytic Leukemia ◽

Prognostic Impact ◽

Missense Mutations ◽

Myelomonocytic Leukemia

Abstract Background Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder with overlapping features between myelodysplastic syndromes and myeloproliferative neoplasms. Numerous models exist for CMML prognostication, with more recent studies suggesting (JCO 201; 31:2428) or refuting (Leukemia 2013; 27:1504) the prognostic contribution of ASXL1 mutations. Furthermore, SETBP1 mutations were recently shown to be associated with shortened overall survival (OS) in CMML (Leukemia 2013; 10:1038). In the current international study, we examine these issues in a larger cohort of 431 patients. Methods 431 patients with WHO-defined CMML were included in the study. 235 (55%) were seen at the Mayo Clinic from 1997 through 2012. The remainders were from the French CMML registry (JCO 201; 31:2428). All patients underwent bone marrow (BM) examination and cytogenetic evaluation at diagnosis. DNA analysis for spliceosome component mutations (SRSF2, SF3B1 and U2AF1), ASXL1 and SETBP1 mutations were carried out on BM specimens obtained at diagnosis. In order to address the aforementioned discrepancy regarding the prognostic impact of ASXL1 mutations, relevant analyses in the Mayo cohort were first performed with and without inclusion of missense ASXL1 mutations. ASXL1 mutations from the French cohort did not include missense mutations. We evaluated the prognostic relevance of ASXL1 and SETBPI mutations, as well as several other clinical and laboratory parameters including those previously identified by the MDAPS (Blood 2002;99:840) the Spanish cytogenetic risk stratification (Haematologica 2011;96:375), and the Mayo prognostic model (Leukemia 2013;27;1504). Results Among the 431 study patients, 286 (66%) were males and median age was 73 years (range, 17-93 years). There were 368 (85%) patients with CMML-1 and the remainder had CMML-2. At a median follow-up of 23 months, 260 (60%) deaths and 70 (16%) leukemic transformations were documented. Median survivals were 38 months for CMML-1 and 24 months for CMML-2 (p=0.11). Mutational frequencies were 44% (173/390) for SRSF2, 6% (23/379) for SF3B1, 7% (27/387) for U2AF1, 38% (164/411) for ASXL1 (excluding missense mutations), and 5% (21/431) for SETBP1. Risk stratification was, based on i) Mayo prognostic model: 172 (40%) high, 151 (35%) intermediate and 94 (25 %) low risk, ii) MDAPS: 15 (3%) high, 73 (17%) intermediate-2, 125 (29%) intermediate-1 and 218 (50%) low risk and iii) Spanish cytogenetic stratification system: 316 (73%) low, 43 (10%) intermediate and 50 (12%) high risk. In the Mayo cohort, univariate analysis revealed that the exclusion of missense mutations changed the prognostic impact of ASXL1 mutations from non-significant (p=0.08) to significant (p=0.001). Accordingly, all subsequent analyses excluded missense ASXL1 mutations. In univariate analysis, lower hemoglobin (p<0.0001), lower platelet count (p=0.0027), higher absolute monocyte count (AMC) (p<0.0001), higher absolute lymphocyte count (ALC) (p=0.0002), circulating immature myeloid cells (IMC) (P<0.0001), cytogenetic risk stratification (p<0.0001) and ASXL1 mutations (p<0.0001) were significant for OS. In multivariable analysis, lower hemoglobin (p=0.0001; RR 2, 99% CI 1.6-2.6), lower platelet count (p=0.002; RR 1.5, 99% CI 1.2-1.9), higher AMC (p=0.0002; RR 2.2, 99% CI 1.6-3.1) and ASXL1mutations (p=0.0009; RR 1.9, 99% CI 1.5-2.4) retained their independent negative prognostic impact. Similarly, in univariate analysis, leukemia-free survival (LFS) was negatively affected by age (p=0.0015), lower hemoglobin (p=0.0002), lower platelet count (p=0.0002), higher AMC (p<0.0001), higher ALC (p=0.0001), circulating IMC (p<0.0001), BM blasts (p<0.0001), and cytogenetic risk stratification (p=.0002). ASXL1 (p=0.17) and SETBP1(p=0.87) mutations were not found to be significant. In multivariable analysis, lower platelet count (p=0.0005), higher AMC (P=0.0042), circulating IMC (P=0.008) and cytogenetic risk stratification (p=0.009) retained their independent negative prognostic impact. Conclusions In the current international study of a large cohort of patients with CMML, we confirm and clarify the independent prognostic relevance of ASXL1 mutations. The relatively high frequency of ASXL1 mutations in CMML warrants its inclusion in contemporary prognostic models. Disclosures: No relevant conflicts of interest to declare.

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"Proliferative" Versus "Dysplastic" Chronic Myelomonocytic Leukemia: Molecular and Prognostic Correlates

Blood ◽

10.1182/blood.v128.22.1987.1987 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1987-1987

Author(s):

Mrinal M Patnaik ◽

Terra L. Lasho ◽

Christy Finke ◽

Matthew T Howard ◽

Curtis A. Hanson ◽

...

Keyword(s):

Leukocyte Count ◽

Univariate Analysis ◽

Hemoglobin Level ◽

Chronic Myelomonocytic Leukemia ◽

World Health ◽

Prognostic Impact ◽

Apparent Difference ◽

Myelomonocytic Leukemia ◽

Proliferative Cmml

Abstract Background : The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms has recommended distinction between "proliferative" (WBC ≥ 13 x 10(9)/L) and "dysplastic" (WBC < 13 X 10(9)/L) subtypes of chronic myelomonocytic leukemia (CMML). In the current study of 261 molecularly-annotated cases, we sought to clarify the prognostic relevance of distinguishing proliferative from dysplastic CMML and also describe differences in the distribution of disease-associated mutations. Methods : 261 patients with WHO-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, and SETBP. The 2016 WHO criteria were used to sub-classify CMML into proliferative and dysplastic subtypes. Results :Among the 261 study patients, 65% were males and median age was 70 years. 154 (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations were documented. Mutational frequencies were; TET2 45%, ASXL1 45%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%, U2AF1 6%, DNMT3A 6%, SF3B1 5%, ZRSR2 4%, Tp53 4%, IDH2 4%, KRAS 3%, PTPN11 2%, SH2B3 1%, CSF3R 1%, IDH1 1%, EZH2 1%, SUZ12 1%, KIT 1%, FLT3 1%, and CALR 1%. Risk stratification was based on the Mayo Molecular Model: 31% high, 30% intermediate-1, 28% intermediate-2 and 11 % low risk. i) Dysplastic versus proliferative CMML: phenotypic and molecular differences 139 (53%) patients had proliferative and 122 (47%) dysplastic subtypes. There was no difference between the CMML subtypes in terms of age and gender distribution, hemoglobin level, platelet count or BM blast content. Patients with proliferative CMML had higher absolute monocyte counts (AMC) (p<0.0001), circulating immature myeloid cells (IMC, p<0.001), circulating blasts (p<0.001) and serum LDH levels (p=0.01). The following gene mutations were more common in proliferative vs dysplastic CMML: ASXL1 (54% vs 37%, p=0.009), JAK2 (11% vs 3%, p=0.01) and CBL (11% vs 8%, p=0.047); SF3B1 mutations were more common in dysplastic CMML (8% vs 1%, p=0.02). There was no difference in the incidence of TET2, DNMT3A and SRSF2 mutations whereas there was a trend towards a higher prevalence of NRAS (p=0.06) and CSF3R (p=0.06) mutations in proliferative CMML. Cytogenetic abnormalities (p=0.03), including higher risk categories by the Spanish (p=0.03) and the Mayo-French (p=0.01) systems were more common in proliferative CMML. ii) Impact on overall and leukemia-free survival: Median survival for the entire cohort (n=261) was 24 months. In univariate analysis, survival was shorter in patients with proliferative (median 20 months) versus dysplastic (median 29 months) CMML (p=0.008; HR1.5, 95% CI 1.1-2.1; Figure 1A). Other variables of significance, in univariate analysis, included hemoglobin (p=0.001), leukocyte count (p=0.001), AMC (p=0.003), PB blast % (p=0.003), IMC (p=0.01), BM blast % (p=0.045), abnormal karyotype (p=0.02), ASXL1 (p=0.01) and DNMT3A (p=0.0003) mutations. In multivariable analysis, the difference in survival between proliferative and dysplastic subtypes remained significant with the addition of hemoglobin level (p=0.01), PB blast % (p=0.02), IMC (p=0.04), BM blast % (p=0.01) or DNMT3A mutations (p=0.01). This was, however, not the case with addition of leukocyte count (p=0.32), AMC (p=0.18) or ASXL1 mutational status (p=0.14); whereas the adverse impact on survival from the latter three parameters remained significant. The prognostic impact of ASXL1 mutations was most apparent in dysplastic CMML (Figure 1B). There was no difference in leukemic transformation rates (p=0.4). Conclusions: In the context of current prognostic models, sub-classification of CMML into proliferative and dysplastic subtypes might not provide additional prognostic value. The apparent difference in survival between the two subtypes of CMML is probably accounted for by the higher prevalence of leukocytosis/monocytosis and of ASXL1 mutations in proliferative CMML. Disclosures No relevant conflicts of interest to declare.

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Concomitant Analysis of EZH2 and ASXL1 Mutations In Myelofibrosis, Chronic Myelomonocytic Leukemia and Blast-Phase Myeloproliferative Neoplasms

Blood ◽

10.1182/blood.v116.21.3070.3070 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3070-3070 ◽

Cited By ~ 4

Author(s):

Omar Abdel-Wahab ◽

Animesh Pardanani ◽

Jay Patel ◽

Terra Lasho ◽

Adriana Heguy ◽

...

Keyword(s):

Mutation Analysis ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Normal Karyotype ◽

Chronic Myelomonocytic Leukemia ◽

Blast Phase ◽

Idh Mutations ◽

Myelomonocytic Leukemia

Abstract Abstract 3070 Background: EZH2 and ASXL1 mutations were recently described in a spectrum of myeloid malignancies; mutational analysis of small patient cohorts has suggested the highest mutational frequency in myelofibrosis (MF) and chronic myelomonocytic leukemia (CMML). The current study seeks to determine i) EZH2 and ASXL1 mutational frequencies in WHO-defined subcategories of MF, CMML and blast-phase myeloproliferative neoplasm (MPN), ii) if these mutations are mutually exclusive of TET2, IDH, JAK2 and MPL mutations and iii) clinical correlates of ASXL1 and EZH2 mutations in primary MF (PMF) and CMML. Methods: The study population included 94 patients: 46 PMF, 22 post-polycythemia vera/essential thrombocythemia MF (post-PV/ET MF), 11 blast-phase MPN and 15 CMML (10 CMML-1 and 5 CMML-2). High throughput DNA resequencing was used to screen archived bone marrow for EZH2, ASXL1, TET2, IDH, JAK2 and MPL mutations. Results: ASXL1 mutations were identified in all disease categories, including PMF (13%), post-PV/ET MF (23%), blast phase MPN (18%), and CMML (20%). We identified somatic mutations in TET2 in 15%, 14%, 18%, and 13% of PMF, post-PV/ET MF, blast phase MPN, and CMML, respectively. By contrast, mutations in EZH2 and IDH1/2 were less frequent. EZH2 mutations were seen in 3 out of 46 PMF patients (7%) and were not observed in patients with post-PV/ET MF or blast phase MPN. Mutations in IDH1/2 were restricted to blast-phase MPN (36%) and PMF (7%). No mutations in EZH2 or IDH1/2 were seen in CMML. Although we identified frequent TET2 and ASXL1 mutations, we only identified one patient with concurrent mutations in both genes. Three ASXL1 mutation-positive patients also had mutations in EZH2 or IDH and one patient had concurrent ASXL1, TET2 and IDH mutations. In addition, 7 ASXL1, 7 TET2, and 1 IDH mutated patients were JAK2V617F-positive. MPL mutations were also documented in all three mutation categories. All EZH2- and ASXL1-mutated PMF patients displayed normal karyotype and none underwent leukemic transformation during follow-up. Furthermore, mutated versus unmutated patients, in both instances, were not significantly different in age and sex distribution or clinical characteristics. The 3 EZH2-mutated PMF patients died after 29, 48 and 67 months from the time of mutation analysis. In univariate analysis, the presence of mutant ASXL1 in PMF was associated with worse survival (p=0.06) but the borderline significance was lost during multivariable analysis that included risk stratification according to DIPSS (Passamonti et al. Blood 2010; 115: 1703–1708). The 3 ASXL1 mutated CMML cases were alive after 40, 34 and 12 months from time of mutation analysis and none of them had progressed to acute leukemia; karyotype was normal in two of the patients and showed isolated trisomy 8 in one. Conclusions: ASXL1 mutations are as frequent as TET2 mutations in MF and CMML. In contrast, EZH2 mutations are infrequent and cluster with PMF. ASXL1 and EZH2 mutations are not mutually exclusive events, seem to be associated with normal karyotype and do not appear to be leukemogenic or prognostically detrimental in PMF or CMML. Disclosures: No relevant conflicts of interest to declare.

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Phenotypic and Prognostic Correlates of Spliceosome Mutations (SRSF2, SF3B1, U2AF35) in Chronic Myelomonocytic Leukemia with ≥ 1% Ring Sideroblasts.

Blood ◽

10.1182/blood.v120.21.2803.2803 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2803-2803

Author(s):

Mrinal M. Patnaik ◽

Terra L Lasho ◽

Curtis A Hanson ◽

Janice M Hodnefield ◽

Ryan A Knudson ◽

...

Keyword(s):

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Significant Risk ◽

Chronic Myelomonocytic Leukemia ◽

Prognostic Impact ◽

Hematopoietic Stem ◽

Mutational Hotspots ◽

Ring Sideroblasts ◽

Myelomonocytic Leukemia

Abstract Abstract 2803 Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms. Ring sideroblasts (RS) represent abnormal mitochondrial iron accumulation in MDS; with ≥15% RS necessary for the conventional diagnosis of MDS-RS. Somatic spliceosome mutations are recurrent in MDS, with SF3B1 mutations being the most frequent in MDS-RS (∼75%) and SRSF2 in CMML (∼28%). The distribution of these mutations in the presence of both RS and monocytosis is unknown and their prognostic relevance, in the particular setting, undetermined. Methods: Using the Mayo Clinic database for myeloid malignancies (1997–2007), we identified patients who met the 2008 WHO criteria for CMML, and who also displayed at least 1% RS in their bone marrow (BM). All patients underwent BM examination and cytogenetic evaluation at diagnosis and the pathology slides, including iron stains, were centrally re-reviewed to accurately quantify BM RS. DNA was interrogated in the three most frequent spliceosome genes with somatic mutations; SF3B1, SRSF2 and U2AF35. Results: Sixty four patients met the above stipulated criteria for CMML with ≥1% RS; 46 (72%) were males and median age was 71 years (range, 17–90 years). Fifty three (83%) had CMML-1 and the remainder CMML-2. The percentage of patients with ≥15% RS was 41%: 30% had 15–49% RS and 11% had >50% RS. Thirty patients (47%) displayed SRSF2 mutations (mutational frequencies were 58% in the presence of <15% RS, 42% with 15–49% RS and 0% with >50% RS), 9 (14%) SF3B1 mutations (3% with <15% RS, 26% with 15–49% RS and 43% with >50% RS), and 5 (8%) U2AF35 mutations (8% with <15% RS, 11% with 15–49% RS and 0% with >50% RS). Mutational hotspots were P95 for SRSF2 (93%), K700 for SF3B1 (67%) and Q157 for U2AF35 (60%). The three spliceosome mutations were mutually exclusive. At a median follow-up of 26 months, 49 (77%) deaths and 11 (17%) leukemic transformations were documented. In univariate analysis, significant risk factors for survival included increased levels of white blood cell (WBC), absolute neutrophil (ANC), absolute monocyte (AMC), absolute lymphocyte (ALC) counts, the Spanish cytogenetics risk stratification system (Haematologica 2011;96:375), and the presence of circulating blasts. Neither the presence of spliceosome mutations (SF3B1/SRSF2/U2AF35) nor the percentage of RS (considered both as a continuous and a categorical variable), had an impact on either overall or leukemia-free survival. Conclusions: Among spliceosome mutations in CMML, those involving SRSF2 are by far the most frequent, even in the presence of ring sideroblasts. However, in patients with >50% RS, only SF3B1 mutations were seen whereas in those with 15–49% RS, SRSF2 mutations were more common. These observations suggest that SF3B1 mutations play a dominant but not exclusive role in the pathogenesis of RS. Regardless, the current study did not suggest prognostic impact from either the presence of the spliceosome mutations studied or the percentage of RS. Disclosures: No relevant conflicts of interest to declare.

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Spliceosome GENE MUTATIONS ARE Also PRESENT In the Diverse Mutational Spectrum of CHRONIC Myelomonocytic LEUKEMIA

Blood ◽

10.1182/blood.v118.21.1402.1402 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1402-1402

Author(s):

Hideki Makishima ◽

Anna M Jankowska ◽

Valeria Visconte ◽

Ramon V. Tiu ◽

Kathryn M Guinta ◽

...

Keyword(s):

Somatic Mutations ◽

Chromosomal Abnormalities ◽

Conflicts Of Interest ◽

Snp Array ◽

Uniparental Disomy ◽

Gene Mutations ◽

P53 Mutation ◽

Chronic Myelomonocytic Leukemia ◽

Homozygous Mutation ◽

Myelomonocytic Leukemia

Abstract Abstract 1402 Chronic myelomonocytic leukemia (CMML) is characterized by monocytic proliferation, cytomorphologic dysplasia and frequent progression to acute myelogeneous leukemia (AML). The molecular basis of CMML is poorly defined, although somatic mutations in a number of genes have recently been identified in a proportion of patients (epigenetic regulatory genes, spliceosomal genes, apoptosis genes, growth signal transducers and others). We performed a comprehensive analysis of molecular lesions, including somatic mutations detected by sequencing and chromosomal abnormalities investigated by metaphase and SNP-array karyotyping. We have selected a cohort of 72 patients (36 CMML1, 16 CMML2 and 20 sAML evolved from CMML). Our mutational screen performed in stages (as new mutations were discovered by our and other groups) and currently reveals mutations in UTX in 8%, DNMT3A in 9%, CBL in 14%, IDH1/2 in 4%, KRAS in 2.7%, NRAS in 4.1%, JAK2 in 1%, TET2 in 48%, ASXL1 in 43%, EZH2 in 5.5%, RUNX1 37%. Based on the discovery of various spliceosomal mutations in myeloid malignancies, novel mutations were also found in CMML, in U2AF1 in 12%, SF3B1 in 14%, SFRS19 in 6 % of cases tested. Chromosomal defects were detected in 60% of patients. In particular, a high frequency of somatic uniparental disomy (sUPD) were identified 71% of patients with abnormal cytogenetics, including UPD1p (N=3), UPD7q (N=8), UPD4q (N=6), UPD2p (N=2), UPD17q (N=2), UPD11q (N=5), UPDX (N=1), UPD21q (N=2). Some of the detected mutations were homozygous through their association with sUPD as for example for 3 EZH2, 1 UTX, 6 TET2, 2 DNMT3A, 5 CBL, 1 NRAS, 1 U2AF1 mutations. Furthermore, UPD17p implies that a P53 mutation is also present in this case as previously LOH17p was shown to be invariably associated with P53 mutations. Similarly, 2 cases of UPD17q imply that homozygous mutation of SRSF2, which is one of the Serine/arginine-rich splicing factor, may be present in this location and the mutation analysis is ongoing. In over 90% of >1 mutation was found but many patients harbored multiple mutations with frequent combinations of TET2/CBL or TET2/ASXL1 as well as RUNX1 and U2AF1 serving as examples. There was an accumulation of mutations from sAML, CMML2 and CMML1 suggesting stepwise accumulation of lesions. In serial studies, some of the mutations were present at the inception (e.g., TET2, ASXL1 and DNMT3A) in some cases originally heterozygous mutations were also while other can occur in the course of disease (e.g. CBL). RAS and DNMT3A mutations were associated with a higher blasts count. In sum, combined analysis of molecular lesions in CMML reveals that similar phenotype may be a result of diverse mutations associated with seemingly unrelated pathways and that clinical phenotype may be a result of a combination of mutations which accumulate as the disease progresses. Survival analyses will require large cohorts to account for various confounding factors including the presence of multiple chromosomal abnormalities and mutations in one patient, however currently EZH2, DNMT3 and CBL mutations appear to convey less favorable prognosis. Disclosures: No relevant conflicts of interest to declare.

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Spliceosome Mutations Involving SRSF2, SF3B1 and U2AF35 in World Health Organization Defined Chronic Myelomonocytic Leukemia; Prevalence, Clinical Correlates and Prognosis

Blood ◽

10.1182/blood.v120.21.1711.1711 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1711-1711

Author(s):

Mrinal M. Patnaik ◽

Terra L Lasho ◽

Christy Finke ◽

Curtis A Hanson ◽

Janice M Hodnefield ◽

...

Keyword(s):

High Risk ◽

Chronic Myelomonocytic Leukemia ◽

Low Risk ◽

World Health ◽

Prognostic Impact ◽

Intermediate Risk ◽

Free Survival ◽

Clinical Correlates ◽

Significant Difference ◽

Myelomonocytic Leukemia

Abstract Abstract 1711 Background: Mutations in genes of the splicing machinery, such as SF3B1, SRSF2 and U2AF35 are common in patients with myelodysplastic syndromes [MDS] (Nature 2011;478:64) and chronic myelomonocytic leukemia [CMML] (Haematologica 2012;Epub). In MDS, SRSF2 gene mutations are an independent risk factor for shortened over-all (OS) and leukemia-free survival (LFS) (Blood 2012;119:3578). In MDS with ring sideroblasts (RS), SF3B1 mutations have a high prevalence (∼50%), but do not influence either, the OS or the LFS (Blood 2012;119:569). We carried out this study to evaluate the prevalence, clinical correlates and prognosis of the aforementioned spliceosome mutations in CMML. Methods: The study included 227 patients with WHO defined CMML who were seen at the Mayo Clinic from 1997 through 2007. All patients underwent bone marrow (BM) examination and cytogenetic evaluation at diagnosis. DNA was interrogated in the three most frequent spliceosome genes with somatic mutations; SRSF2, SF3B1 and U2AF35. Results I: Prevalence and clinical correlates Among the 227 study patients, 153 (67%) were male, median age was 71 years (range, 17–90 years) and 192 (85%) met the WHO criteria for CMML-1. Ninety (40%) patients had SRSF2 mutations (86% CMML-1), 13 (6%) had SF3B1 mutations (75% CMML-1) and 20 (9%) had U2AF35 mutations (95% CMML-1). One-hundred and twenty three (54%) patients had at least one of three spliceosome mutations (86% CMML-1). Mutational hot spots were P95 for SRSF2 (P95L-n=36/H-n=32/R-n=13/A-n=1), K700E (n=7) and H662Q (n=2) for SF3B1, and Q157 (Q157R-n=5/P-n=5/G-n=1) and S34F (n=7) for U2AF35. Seven patients (54%) with SF3B1 mutations had ≥1% RS, with 5 (38%) showing ≥15% RS. Mutations involving all three spliceosome genes were mutually exclusive. The cytogenetic distribution based on the Spanish risk stratification system (Haematologica 2011;96:375) was; SRSF2 mutations: 69 (77%) low risk, 11 (12%) intermediate risk, and 10 (11%) high risk (+8-n=3, del/monosomy 7-n=2, monosomal karyotype-n=5); SF3B1 mutations: 8 (62%) low risk and 5 (38%) intermediate risk; U2AF35 mutations: 15 (75%) low risk, 3 (15%) intermediate risk and 2 (10%) high risk (p=0.89). The distribution of mutations according to the MD Anderson prognostic scoring system [MDAPS] (Blood 2002;99:840) was; SRSF2 - low-n=41, intermediate-1-n=26, intermediate-2-n=18, high-n=5, SF3B1- low-n=7, intermediate-1-n=3, intermediate-2-n=2, high-n=1, and U2AF35- low-n=11, intermediate-1-n=5, intermediate-2-n=3, high-n=1 (p=0.73). There was no statistically significant difference, among the three mutation groups, in prognostically relevant parameters, including gender distribution, median age, hemoglobin values, platelet counts, peripheral blood (PB) and BM blast counts, absolute neutrophil counts (ANC) and absolute monocyte counts (AMC). The only notable difference was that patients with the SF3B1 mutation had a lower median white blood cell count (p=0.04) and a lower absolute lymphocyte count (p=0.045). Results II: Prognostic impact of spliceosome mutations At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. Median survivals for patients with mutations involving SRSF2, SF3B1 and U2AF35 were 24, 17 and 12 months, respectively. In univariate analysis, the presence of SRSF2 (p=0.67), SF3B1 (p=0.96) or U2AF35 (p=0.49) mutations had no prognostic impact on OS. Similarly, none of the three spliceosome mutations affected LFS; corresponding p values were 0.55 for SRSF2, 0.9 for SF3B1 and 0.38 for U2AF35 mutations respectively. We then examined possible prognostic value of having none of these mutations (n=104) vs otherwise (n=123) and the results were once again negative (p=0.87). Conclusions: SRSF2 is the most frequently mutated spliceosome gene in CMML, but neither it nor SF3B1 or U2AF35 mutations affect overall or leukemia-free survival in CMML. Furthermore, the current study suggests limited genotype-phenotype association, save for the already established association between SF3B1 mutations and RS. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Impact of Hematopoietic Recovery After Fludarabine, IV Busulfan and Antithymocyte Globulins (FB2 regimen) Reduced-Intensity Conditioning Regimen (RIC) Allogeneic Stem Cell Transplantation (allo-SCT)

Blood ◽

10.1182/blood.v120.21.4483.4483 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4483-4483

Author(s):

Amandine Lebourgeois ◽

Marion Loirat ◽

Benoit Tessoulin ◽

Elsa Lestang ◽

Pierre Peterlin ◽

...

Keyword(s):

Conflicts Of Interest ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Prognostic Impact ◽

Immune Recovery ◽

Post Transplant ◽

Factors Associated ◽

Before And After ◽

Circulating Lymphocytes ◽

The Impact

Abstract Abstract 4483 Introduction: RIC regimens are increasingly used prior to allo-SCT. The FB2 regimen (Fludarabine 120–150 mg/m2 + IV Busulfan 6.4 mg/Kg + ATG Thymoglobuline 5mg/Kg) is currently the most widely used RIC regimen in many European centres. This retrospective analysis aimed to assess the hematopoietic and immune recovery in a homogeneously treated cohort of 53 patients (males: n=33; median age: 59 years (range: 22–70)) who received the FB2 regimen between January 2007 and October 2010 in our department. Patients and Methods: Diagnoses were as follow: AML n=23; ALL n=1; biphenotypic leukemia n=1; lymphoma n=16; myelodysplastic syndrome n=9; multiple myeloma n=3. Nineteen patients (36%) had received a prior autologous SCT. The majority of patients (n=40, 75.5%) were transplanted in complete remission. Thirty patients received a graft from a matched sibling donor (56.5%). All patients, but one (who received unmanipulated bone marrow) received G-CSF-mobilized PBSCs. GVHD prophylaxis consisted of cyclosporine (CsA) alone in patients transplanted with an HLA-identical sibling, and CsA+ mycophenolate mofetyl in other cases. None of the patients received G-CSF during aplasia following transplant while nine patients received erythropoietin before day+100. Results: Engraftment was achieved in 96% of patients (n=51). Median times for neutrophils (n=51) and platelets (n=22) recovery were 17 days (range: 0–39) and 10 days (range: 4–186), respectively. The majority of patients (n=31, 58%) did not receive platelet support during aplasia. The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 30% and 15%, respectively, while overall incidence of chronic extensive GVHD was 33%. With a median follow-up of 19 months (range: 2–53), the 2-year OS, DFS, relapse incidence, and NRM were 63%, 59.5%, 35% and 6%, respectively. In univariate analysis, when regarding pre-transplant factors associated with outcome, the only factor correlated with a significantly higher 2-year OS and DFS was a higher total circulating lymphocytes count at transplant (> 730/mm3) (OS: 81.5% vs 43.2%, p=0.01; DFS: 73.2% vs 45.5%, p=0.03). Regarding post-transplant factors, we found that higher recovery of leukocytes (>5000/mm3) (2-year OS: 78% vs 46%, p=0.007; 2-year DFS: 70% vs 48%, p=0.08), neutrophils (>3230/mm3) (2-year OS: 76% vs 50%, p=0.02; 2-year DFS: 67.5% vs 52.0%, p=0.09), and monocytes (>590/mm3) (2-year OS: 80% vs 47%, p=0.004; 2-year DFS: 75% vs 42%, p=0.007) at day+30 post-transplant were the most significant factors associated with outcome. In multivariate analysis, the only independent factors associated with a significantly higher OS and DFS were a better immune status at transplant (lymphocytes count >730/mm3; HR 0.22; 95%CI: 0.08–0.63, p=0.005; and HR: 0.29; 95%CI: 0.12–0.71, p=0.006, respectively) and a higher monocytes count at day+30 post-transplant (>590/mm3) (HR: 0.24; 95%CI: 0.08–0.66, p=0.006; and HR: 0.28; 95%CI: 0.11– 0.68, p=0.005; respectively). Conclusion: These results suggest that hematopoietic status and recovery before and after FB2 RIC allo-SCT can be significant predictors of outcome. This paves the way for future studies aiming to closely monitor the kinetics of immune recovery after RIC allo-SCT and to evaluate the impact of growth factors and other immunostimulatory cytokines in the setting of RIC allo-SCT. Disclosures: No relevant conflicts of interest to declare.

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Impact of M1a and M1b staging in patients (pts) with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3590 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3590-3590 ◽

Cited By ~ 1

Author(s):

Hagen F. Kennecke ◽

Jason Yu ◽

Sharlene Gill ◽

Winson Y. Cheung ◽

Charles Davic Blanke ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Primary Tumor ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

Primary Tumors ◽

7Th Edition ◽

The Impact

3590 Background: In 2009, pts with M1 colorectal cancer were divided into two subsets for the American Joint Committee on Cancer (AJCC) 7th edition. Pts with metastases (mets) confined to one organ or site at initial diagnosis became stage M1a while multiple sites or peritoneal mets became M1b. The objectives of the study are to evaluate the impact of site of mets and M1a/b staging among pts with M1 colorectal cancer. Methods: All pts referred to the BC Cancer Agency from 1999-2007 with newly diagnosed M1 colon or rectal cancer were included. Demographic, treatment, and outcome data were prospectively collected. The prognostic impact of individual sites of mets was assessed by hazard ratio estimates from univariate Cox models. Multivariable Cox proportional-hazards models were used to determine variables associated with overall survival in the entire cohort and in those undergoing resection of their primary tumor. Results: 2,049 pts with M1 disease were included. Median age was 66 years; 71% had colonic origin; 70% had their primary tumor resected; and 69% received chemotherapy. In univariate analysis, solitary mets were associated with improved survival. In multivariable analysis, M1a/b status still had significant prognostic effect. The effect remained significant in the subgroup analysis of pts with resected primary tumors when histology, T and N stage were included. Conclusions: Pts with solitary mets, including peritoneum, have superior overall survival as compared to those with multiple sites of mets. AJCC 7th edition staging that includes M1a/b provides significant prognostic information and should be considered in clinical practice and trials of pts with M1 disease who otherwise have few prognostic factors. [Table: see text]

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ASXL1 Mutations in Myelodysplastic Syndromes with 1% or More Ring Sideroblasts: Prevalence, Clinical Correlates and Prognostic Relevance

Blood ◽

10.1182/blood.v126.23.2882.2882 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2882-2882

Author(s):

Naseema Gangat ◽

Terra L. Lasho ◽

Mrinal M Patnaik ◽

Christy Finke ◽

Mark R Litzow ◽

...

Keyword(s):

Median Survival ◽

Myelodysplastic Syndromes ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Refractory Anemia ◽

Prognostic Impact ◽

Wild Type ◽

Monosomy 7 ◽

Clinical Correlates ◽

Ring Sideroblasts

Abstract Background: Addition of sex combs-like 1 (ASXL1) is frequently mutated (mutational frequency 14-29%) and is prognostically relevant in myelodysplastic syndromes (MDS) (Bejar, NEJM 2011, Thol, JCO 2011). The prevalence and prognostic impact of ASXL1 mutation in MDS with ring sideroblasts (MDS-RS) is not known. MDS-RS is defined by the presence of ≥15% RS in bone marrow (BM), with refractory anemia with ring sideroblasts (RARS) being the prototype but may also be seen in other categories. Methods : Our institutional database was reviewed to identify patients with WHO-defined primary MDS with ≥1% BM RS. Pathology slides, including iron stains, were reviewed to accurately quantify BM RS percentage and confirm WHO morphologic categories. All patients were annotated for their mutational status including ASXL1, JAK2, MPL and IDH with a subset for SF3B1 by PCR sequencing performed on BM specimens obtained at diagnosis. Results : i) Patient characteristics: A total of 76 MDS patients displayed ≥1% BM RS (median age 72 years; 76% males); 51 (67%) patients had ≥15% BM RS. IPSS-R risk categories for the entire 76 study patients were 30% very low, 37% low, 14% intermediate, 11% high and 8% very high; IPSS-R karyotype was normal in 63%, very good/good risk 17%, intermediate risk 12%, and poor/very poor in 8%; 3% had monosomal karyotype. ii) Prevalence of ASXL1 mutations: Twenty-one (28%) of the 76 study patients were ASXL1 mutated; ASXL1 mutational frequencies were 25% (16/63 patients) in the absence and 38% (5/13 patients) in the presence of excess blasts (P =0.34). When considering only those patients with ≥15% BM RS (n =51), ASXL1 mutations were detected in 12 (24%) patients with mutational frequencies of 24% (11/46 patients) in the absence and 20% (1/5 patients) in the presence of excess blasts (P =0.84); ASXL1 mutational frequencies were 13% (3/23 patients) in RARS and 37% (7/19 patients) in RCMD-RS (P=0.07). In terms of other mutations, all 76 study patients were wild-type for JAK2 and MPL, whereas IDH2 R140Q mutations were present in 4 (5%) patients, including 3 with concomitant ASXL1 and IDH2 mutations. IDH1 mutation was seen in only 1 patient. 25 of 43 (58%) patients screened were mutated for SF3B1, including 4 (9%) who were mutated for both ASXL1 and SF3B1. Significant associations were evident between ASXL1 and IDH2 mutations (P =0.02) but not between ASXL1 and SF3B1 mutations (P =0.61). iii) Clinical correlates of ASXL1 mutations: Among all 76 study patients, presence of ASXL1 mutation did not correlate with age (P =0.30), hemoglobin level (P =0.17), platelet count (P =0.53), BM blast percentage (P =0.17), WHO morphologic category (P =0.34), transfusion dependence (P =0.84), IPSS-R cytogenetic categories (P =0.93), or IPSS-R risk group (P =0.33). The results were unchanged when analyzing the 51 patients with MDS-RS (i.e. ≥15% BM RS). Amongst the ASXL1 mutated patients (n =21) IPSS-R cytogenetic categories were as follows: 13 patients with normal karyotype (62%), 2 patients with trisomy 8 (10%), 1 patient each with -Y, del(11q), del(5q), del(20q), isochromosome 17 and monosomy 7 (5% each). iv) Prognostic impact of ASXL1 mutations: Median follow-up was 42.5 months, during which time 69 (91%) deaths and 8 (11%) leukemic transformations were documented. ASXL1 mutated patients had a median survival of 29 months, compared to 45 months in ASXL1 wild-type patients (P =0.04). However, the difference in median survival was no longer significant during multivariable analysis, which instead identified only IPSS-R and transfusion need as being independent predictors of inferior survival. Amongst those patients without excess blasts (n =63), presence of ASXL1 mutation predicted inferior survival in univariate analysis (P =.04) and significance was sustained during multivariable analysis that included IPSS-R cytogenetic categories (P =.04) but became borderline when WHO morphologic category was included (P =0.06); ASXL1 mutated patients had a shortened median survival of 43 months compared to 66 months in ASXL1 wild-type patients (P =.04). In the presence of ≥15% BM RS, ASXL1 mutations did not affect survival (P =0.48); the results were the same for RARS (P =0.9) and RCMD-RS (P =0.64). Conclusions : ASXL1 mutations might not affect survival in MDS patients with ≥15% BM RS, including those with RARS or RCMD-RS. Furthermore, an apparent survival disadvantage seen in ASXL1 -mutated MDS patients with ≥1% BM RS was accounted for by IPSS-R. Disclosures Pardanani: Stemline: Research Funding.

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