Blast transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, and treatment outcome

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1 RESEARCH ARTICLE Blast transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, and treatment outcome AJH Mrinal M. Patnaik, 1 Emnet A. Wassie, 1 Terra L. Lasho, 2 Curtis A. Hanson, 3 Rhett Ketterling, 4 and Ayalew Tefferi 1 * Among 274 patients with chronic myelomonocytic leukemia (CMML) and followed for a median of 17.1 months, blast transformation (BT) occurred in 36 (13%). On multivariable analysis, risk factors for BT were presence of circulating blasts (HR 5.7; 95% CI ) and female gender (HR 2.6; 95% CI ); the results remained unchanged when analysis was restricted to CMML-1. ASXL1/SRSF2/SF3B1/U2AF1/SETBP1 mutational frequencies were not significantly different between time of CMML diagnosis and BT. Median survival post-bt was 4.7 months (5-year survival 6%) and better with allogeneic stem cell transplant (SCT) (14.3 months vs. 4.3 months for chemotherapy vs. 0.9 months for supportive care; P ). Neither karyotype nor mutational status was independently associated with risk of BT or post-bt survival. We conclude that female patients with CMML and those with circulating blasts are at a higher risk of BT. Post- BT survival is dismal and our observations suggest consideration of allogeneic SCT prior to BT. Am. J. Hematol. 90: , VC 2015 Wiley Periodicals, Inc. Introduction Chronic myelomonocytic leukemia (CMML) is a clonal, hematopoietic stem cell disorder, characterized by the presence of peripheral blood (PB) monocytosis, with overlapping features between myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), and an inherent risk of transformation to acute myeloid leukemia (AML) [1]. Recent communications have underscored significantly shortened survival in CMML (median months) [2 4] and have identified ASXL1 mutations (non-sense and frame shift) [2,5], high risk karyotype (Spanish cytogenetic risk stratification and the Mayo-French cytogenetic stratification) [4,6 8], age >65 years, leucocyte count > (9)/L, absolute monocyte count (AMC) > (9)/L, anemia, hemoglobin <10 g dl 21, red cell transfusion need, higher serum lactate dehydrogenase, platelet count < (9)/L, circulating immature myeloid cells (IMC) and CMML morphological subtypes as independent predictors of poor survival [2 4]. Based on the aforementioned clinical and genetic parameters, the two contemporary, molecularly integrated CMML prognostic models, predicting for over-all survival (OS) include; Molecular Mayo Model (MMM) and the Groupe Français des Myelodysplasies (GFM) model [2,5]. Blast transformation (BT) is one of the main causes of death in CMML and its reported incidence ranges from 15 to 29% [2 4]. This finding is also true in young patients (age <65 years) [9]. In a recent, multi institutional study, blast transformation was reported in 72 (28%) of 261 young CMML patients [9]. Reported risk factors for BT in CMML have included high risk karyotype [4,8], circulating blast count [3,5], circulating IMC [5], AMC > (9)/L [3,5], CMML morphological subtype [4,5] and red cell transfusion need [4]. Similarly, in the young CMML patients, predictors for BT include; circulating blast count, BM blasts and circulating IMC [9]. Predictors and outcomes for BT have been well documented in other chronic myeloid neoplasms, such as, primary myelofibrosis (PMF), chronic myeloid leukemia and MDS [10,11]. In a large single institution study, 91 of 2,333 patients with PMF were noted to have BT [11]. In this group, the case fatality was 98% with a median OS of 2.6 months (range; ) and not a single patient achieved a complete remission with induction chemotherapy [11]. In addition, in this group, AML like induction therapy was associated with a treatment-related mortality of 33% [11]. In patients with CMML, while attempts at identifying predictors for BT have been made, not much is known on the treatment modalities and clinical outcomes of patients with BT [12]. In the current study, we were particularly interested in (i) the effect of karyotype and mutational status, obtained both at time of initial CMML diagnosis and at time of BT, on the risk of developing BT and post-bt survival and (ii) survival and treatment outcome in blast phase (BP)-CMML. Methods After receiving approval from the Mayo Clinic institutional review board, clinical and laboratory data were collected both at the time of the initial CMML diagnosis and at the time of BT. Study eligibility criteria included availability of PB smear, BM histology and cytogenetic information at time of diagnosis and at the time of BT. The diagnosis Additional Supporting Information may be found in the online version of this article. 1 Division of Hematology, Mayo Clinic, Rochester, Minnesota; 2 Division of Hematology, Department of Internal Medicine, Hematology Mayo Clinic, Rochester, Minnesota; 3 Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota; 4 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota *Correspondence to: Ayalew Tefferi, MD, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN tefferi.ayalew@mayo.edu Received for publication: 25 January 2015; Accepted: 28 January 2015 Am. J. Hematol. 90: , Published online: 31 January 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: /ajh VC 2015 Wiley Periodicals, Inc. doi: /ajh American Journal of Hematology, Vol. 90, No. 5, May

2 Patnaik et al. of CMML, including sub-classification into CMML-1 or CMML-2, and BT were according to the 2008 World Health Organization (WHO) criteria [13]. Cytogenetic analysis was done according to the International System for Human Cytogenetic Nomenclature. A complex karyotype was defined as the presence of 3 or more distinct structural or numeric abnormalities. Monosomal karyotype (MK) was defined as 2 or more distinct autosomal monosomies or single autosomal monosomy associated with at least one structural abnormality [14]. Karyotype risk designation and risk stratification were according to the Spanish cytogenetic risk stratification system [6], Mayo-French cytogenetic stratification [8], MD Anderson prognostic scoring system (MDAPS) [15], Mayo prognostic model [3], Molecular Mayo Model [5], and the GFM CMML model [2]. DNA analysis for spliceosome component mutations (SRSF2, SF3B1, and U2AF1), JAK2, ASXL1, and SETBP1 mutations were carried out on specimens obtained at time of diagnosis and at BT (where available), according to previously described methods [5,16 18]. Covariates used in analyses of risk factors included age, gender, mutational status, cytogenetic risk categories per the Spanish [6] or the Mayo-French [8] systems, hemoglobin, leukocyte count, AMC, absolute lymphocyte count (ALC), platelet count, PB and bone marrow blast counts, presence of circulating IMC, WHO subcategories (CMML-1 vs. CMML-2), and the above mentioned prognostic systems. Treatment data collected included supportive care measures (e.g., hydroxyurea, red blood and platelet transfusion need), the use of hypomethylating agents (5-azacytidine and decitabine), induction chemotherapy regimens (anthracycline 1cytarabine and clinical trials) and allogeneic stem cell transplant (SCT). Statistical analyses for determination of leukemia-free survival (LFS) considered clinical and laboratory parameters obtained at time of CMML diagnosis and for determination of post-bt survival those obtained at time of BT. Differences in the distribution of continuous variables between categories were analyzed by either Mann Whitney or Kruskal Wallis test. Patient groups with nominal variables were compared by chi-square test. Overall and leukemia-free survival curves were prepared by the Kaplan Meier method and compared by the log-rank test. Cox proportional hazard regression model was used for multivariable analysis. P values less than 0.05 were considered significant. The Stat View (SAS Institute, Cary, NC) statistical package was used for all calculations. Results Two hundred and seventy four consecutive CMML patients, with a median age of 71 years (range 18 91), 67% males, seen at the Mayo Clinic from 1990 to 2013, were included in this study. Table I lists the clinical and laboratory details of these patients obtained at the time of their CMML diagnosis (column A). Two hundred and thirty one (84%) had CMML-1 while 43 (16%) had CMML-2. Eighty seven (32%) had an abnormal karyotype at CMML diagnosis, including 16 (44%) of the 36 that underwent BT. The respective ASXL1/SRSF2/ SF3B1/U2AF1/SETBP1 mutational frequencies were 39%, 45%, 5%, 10%, and 5%, respectively. Table I also includes the cytogenetic risk stratification by the Spanish cytogenetic risk stratification system and the Mayo-French cytogenetic stratification, along with risk distribution according to the Mayo Molecular [5], GFM [2], and MD Anderson [15] prognostic models. After a median follow-up of 17.1 months (range ), 36 patients (13%) experienced BT. Table I lists the clinical and laboratory features of these cases obtained both at the time of their initial CMML diagnosis, (column B) and at the time of their BT (column C). Comparison of columns A vs. C revealed a higher incidence of females (P ), lower hemoglobin level (P ), higher ALC (P ), lower platelet count (P ), higher PB and BM blast counts (P < ), higher frequency of abnormal karyotype (P ) and higher frequency of high risk karyotype (P ), at the time of BT (Table I); of note, there was no significant difference in ASXL1 or SRSF2 mutational frequencies. Analysis restricted to the 36 patients with BP-CMML (i.e., columns B vs. C) showed similar results in terms of mutations and platelet and blast counts but significance was lost for karyotype, ALC and hemoglobin level (Table I). Comparison of clinical and laboratory parameters obtained at time of CMML diagnosis, between the 36 patients with BP-CMML and the 238 without BT revealed the former to be associated with younger age (P ), female gender (P ), anemia (P ), higher ALC (P ), higher PB (P ), and BM (P ) blast count and CMML-2 (P ) (Supporting Information Table I); of note, there was no difference in ASXL1/SRSF2/SF3B1/U2AF1/ SETBP1 mutational frequencies. In univariate analysis, the risk of developing BT among all 274 patients was predicted by younger age, female gender, lower hemoglobin level, higher leukocyte count, higher AMC, higher ALC, higher PB or BM blast count, presence of PB IMC, high risk karyotype per the Spanish [6] or the Mayo-French [8] cytogenetic risk stratification and WHO CMML-2 subtype (P < 0.05 in all instances). However, during multivariable analysis, only presence of circulating blasts (HR 5.7; 95% CI ) and female gender (HR 2.6; 95% CI ) remained significant; the results were the same when analysis was restricted to patients with CMML-1. Table II lists all 36 BP-CMML patients with their individual clinical and laboratory features at the time of their initial CMML diagnosis as well as time of BT. Eight (24%) of 34 patients with BT and available cytogenetic information experienced changes in karyotype between the time of CMML diagnosis and BT (Table II). Among these eight patients, five had normal karyotype at the time of CMML diagnosis and each acquired, during BT, MK, monosomy 7, trisomy 11, trisomy 8 and trisomy 21, respectively; the remaining three patients changed from sole monosomy 7 to MK (n 5 2) and one patient with Y acquired additional monosomy 7 abnormality. There were much fewer changes in mutational status (Table II). At the time of BT, 1 of 29 informative patients acquired ASXL1 mutation and one of 16 SRSF2 mutations. At time of BT, none of the patients lost mutations that were documented at time of CMML diagnosis. Survival after BT was very poor with median OS of only 4.7 months (5-year survival 6%) (Fig. 1a,b). Six (17%) patients received induction chemotherapy followed by allogeneic SCT. Three (50%) of the six were alive at last follow up with a median OS of 14.3 months. Transplant conditioning was myeloablative in 4 (66%) cases and reduced intensity in 2 (33%) cases. One patient directly proceeded with a myeloablative matched sibling donor allogeneic SCT. He died from disease relapse 6 months after transplant. Fourteen (39%) patients received either induction chemotherapy (9/14) or hypomethylating agents (5/14; 3-5 azacytidine and 2 decitabine) and were not able to proceed with allogeneic SCT, either due to comorbidities/ recipient ineligibility or lack of donors. The median survival of this group was 4.3 months, with most patients dying from primary induction failure or disease relapse. Sixteen (44%) patients received BSC options, including hydroxyurea and transfusions, mainly due to ineligibility for induction chemotherapy or hypomethylating agents. The median survival of this group was 0.9 months. In univariate analysis, post-bt survival was adversely affected by higher PB blast count (P ) and favorably affected by SCT (P ); the latter remained significant in multivariable analysis. Neither karyotype nor mutational status was associated with post-bt survival. Discussion RESEARCH ARTICLE Blast transformation, an often fatal complication in patients with CMML, has been reported in 15 29% of patients [2,3,5,8,15,19]. In the GFM cohort, BT was seen in 68 (22%) of 312 patients and the GFM prognostic model did predict for LFS [2]. In the larger Mayo- French cohort, BT was seen in 75 (16%) of 466 patients and predictors for shortened LFS included; circulating blasts, circulating IMC, increased AMC, WHO morphological categories and high risk stratification by the Spanish cytogenetic risk stratification system [5]. Interestingly, in the Mayo-French cohort, clonal ASXL1 and SETBP1 mutations were not independently prognostic for LFS. In addition, the recently developed Mayo-French cytogenetic stratification accurately stratified for LFS; with the 2 year leukemic transformation rates being, 40% for high, 25% for intermediate and 10% for the low risk 412 American Journal of Hematology, Vol. 90, No. 5, May 2015 doi: /ajh.23962

3 RESEARCH ARTICLE Blast transformation in chronic myelomonocytic leukemia TABLE I. Clinical and Laboratory Features of 274 Patients With Chronic Myelomonocytic Leukemia (CMML), Including 36 who Experienced Blast Transformation During Follow-up Variable All patients N (parameters at time of CMML diagnosis) (A) Patients with blast transformation N 5 36 (parameters at time of CMML diagnosis) (B) Patients with blast transformation N 5 36 (parameters at time of blast transformation) (C) P value A vs. C P value B vs. C Age in years; median (range) 71 (18 91) 66 (18-86) 68 (18 86) Age>65 n (%) 195 (71%) 20 (56%) 22 (61%) Males; n (%) 184 (67%) 16 (44%) 16 (44%) NA Hemoglobin g dl 21 ; median (range) 10.4 ( ) 9.8 ( ) 9.3 ( ) WBC /L; median (range) 13.7 ( ) 16.4 ( ) 21.1 ( ) ANC / L; median (range) 6.1 ( ) 6.6 ( ) 7.1 (0 82.4) AMC / L; median (range) 2.8 (1 40) 3.1 (1 30.7) 2.0 (0 34.5) ALC / L; median (range) 1.7 (0 22) 2.1 (0.2 22) 2.3 (0 19.8) Platelets / L; median (range) 95 (8 1110) 90 (10 293) 49 (7 210) PB blast %; median (range) 0 (0 19) 1 (0 19) 15 (0 85) < < BM blast %; median (range) 4 (0 19) 5 (0 18) 32 (14 90) < < BM blast 10% 38 (14%) 10 (28%) NA NA NA Circulating immature myeloid cells; n (%) 142 (52%) 23 (64%) NA NA NA WHO morphological subtype; n (%) NA NA NA CMML (84%) 23(64%) CMML-2 43 (16%) 13 (36%) Abnormal karyotype, N (%) N evaluable (32%) 16 (44%) 18/34 (52.9%) Spanish cytogenetic stratification N evaluable Low 198 (73%) 23 (64%) 17 (50%) Intermediate 36 (13%) 6 (17%) 6 (18%) High 39 (14%) 7 (19%) 11 (32%) Mayo-French revised cytogenetic stratification N evaluable Low 202 (74%) 24 (67%) 18 (53%) Intermediate 57 (21%) 11 (28%) 12 (35%) High 14 (5%) 2 (5%) 4 (12%) ASXL1 mutations N evaluable (39%) 12/35 (34%) 13/29 (44.8%) SRSF2 mutations N evaluable (45%) 13 (37%) 9/16 (56.3%) SF3B1 mutations N evaluable (5%) 2 (6%) ND ND ND U2AF1 mutations N evaluable (10%) 4 (11%) ND ND ND SETBP1 mutations N evaluable (5%) 1 (3%) ND ND ND MD Anderson prognostic risk categories; n (%) NA NA NA Low 128 (47%) 9 (25%) Intermediate-1 80 (29%) 14 (39%) Intermediate-2 53 (19%) 7 (19) High 13 (5%) 6 (17%) Mayo Molecular Model N evaluable NA NA NA Low 24 (9%) 3 (9%) Intermediate-1 77 (29%) 7 (20%) Intermediate-2 75 (29%) 11 (31%) High 85 (33%) 14 (40%) GFM prognostic risk categories; NA NA NA n (%) N evaluable Low 100 (38%) 16 (46%) Intermediate 103 (40%) 12 (34%) High 58 (22%) 7 (20%) Median Follow-up in months (range) 17.1 ( ) 21.9 ( ) 4.7 ( ) NA WHO, World Health Organization; CMML, chronic myelomonocytic leukemia; WBC, white blood cell count; ANC, absolute neutrophil count; AMC, absolute monocyte count; ALC, absolute lymphocyte count; PB, peripheral blood; BM, bone marrow, GFM, Groupe Francais des Myelodsyplasies; SF3B1, splicing factor 3B subunit 1; SRSF2, serine/arginine-rich splicing factor 2; U2AF1, U2 small nuclear RNA auxiliary factor 1; ASXL1, additional sex combs 1 gene; SETBP1, SETbinding protein 1; NA, not applicable; ND, not done. (P ) groups, respectively [8]. The high risk group consisted of CMML patients with complex and monosomal karyotypes. In the current study BT was seen in 36 (16%) of 274 patients with CMML; 44% being males. The median age was 66 years and 46 (70%) were <65 years in age ( young CMML). Forty-four percent of patients that had BT had an abnormal karyotype at CMML diagnosis, in comparison to 32% for the overall cohort. There was no difference in ASXL1, SETBP1and spliceosome component mutational frequencies. At CMML diagnosis, on comparing the 36 patients with BP- CMML and the 238 without BT; the former was associated with a younger age, female gender, anemia, higher ALC, higher PB and BM blast count and CMML-2. Cytogenetic clonal evolution is common in patients with myeloid neoplasms undergoing BT. In PMF, majority (>90%) of patients demonstrated cytogenetic clonal evolution at time of BT, with 43% displaying evolution of an existing clone and 57% developing one or more additional abnormal clones [11]. In the current study, 24% of patients with BT and available cytogenetic information experienced changes in karyotype between the time of CMML diagnosis and BT. Among these eight patients, five had normal karyotype at the time of CMML diagnosis and each acquired, during BT, MK, monosomy 7, trisomy 11, trisomy 8 and trisomy 21, respectively; the remaining three patients changed from sole monosomy 7 to MK (n 5 2) and one patient with Y acquired additional monosomy 7 abnormality. doi: /ajh American Journal of Hematology, Vol. 90, No. 5, May

4 Patnaik et al. RESEARCH ARTICLE TABLE II. Clinical and Molecular Features of 36 Chronic Myelomonocytic Leukemia Patients With Blast Transformation and Their Outcome Pt. Age Sex WBC (x10 9 /dl) PB blast (%) Karyotype at BT Karyotype at CMML diagnosis Mutations at BT Mutations at CMML diagnosis Post-BT survival (Months) Treatment Response to treatment Current status 1 84 F NA Normal ASXL1 ASXL SC NA Dead U2AF M Normal Normal ASXL1 ASXL1 0.7 SC NA Dead SRSF2 SRSF M Normal Normal SRSF2 SRSF2 1.1 Induction withouttransplant No response Dead 4 69 F Normal Normal ND None 0.6 SC NA Dead 5 61 F Normal Normal ND SRSF2 8.1 SC NA Dead 6 76 F Normal Normal ND SF3B1 0.2 SC NA Dead 7 85 M Normal ASXL1 ASXL1 2.0 SC NA Dead 8 84 M NA -Y ASXL1 ASXL1 4.2 SC NA Dead 9 81 F Normal Normal ASXL1 ASXL1 7.3 SC NA Dead F Normal Normal ND None 2.6 Induction without transplant No response Dead F Normal Normal ND None 6.6 Transplant without induction CR Dead F Normal ASXL1 ASXL HMA Induction CR then relapse No response Dead F 2 2 MK Normal SRSF2 None 0.9 SC NA Dead F MK -7 ASXL1 ASXL Transplant after induction CR post-induction No Dead response from transplant M Normal Normal ND None 1.9 Induction without transplant No response Dead M Normal Normal ASXL1 ASXL SC NA Dead SRSF F q- and 113 8q- and 113 ASXL1 ASXL1 3.9 Induction without transplant No response Dead M q-, t(13;15) 7q-, t(13;15) SRSF2 SRSF2 4.3 Induction without transplant CR followed by relapse Dead M Normal ND SRSF2 2.9 SC NA Dead F Complex but not MK Complex but not MK ASXL1 None 13.4 Induction without transplant No response Dead M and - Y -Y ND ASXL Induction without transplant CR followed by relapse Dead SRSF M Y -Y None None 27.9 Induction without transplant No response Dead F and SRSF2 SRSF2 0.8 SC NA Dead U2AF F and add(6q) 18 and add(6q) SRSF2 SRSF2 0.4 SC NA Dead M Normal Normal ASXL1 U2AF HMA No response Dead M Normal None None 5.1 Induction without transplant No response Dead M MK -7 ND ND 0.5 SC NA Dead F ASXL1 ASXL HMA Noresponse Dead ND SRSF F Normal Normal ND U2AF Induction followed by transplant CR Alive M der(3q) der(3q) ND ASXL1 3.0 Induction without transplant No response Dead SF3B M Normal Normal SRSF2 SRSF HMA Induction No response CR then relapse Dead F Normal Normal ND None 67.0 Induction followed by transplant CR Alive F Normal Normal ND SETBP HMA CR followed by relapse Dead F Normal Normal SRSF2 SRSF Induction followed by transplant CR post-induction No Dead response from transplant M MK MK None None 14.4 Induction followed by transplant CR followed by relapse Dead F der(7:13) der(7:13) ND None 17.7 Induction without transplant CR Alive AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; WBC, white blood count; PB, peripheral blood; BT, blast transformation; SC, supportive care; Allo SCT, allogeneic stem cell transplant; CR, complete remission; FLT3, Fms like tyrosine kinase 3; NPM1, nucleophosmin; GVHD, graft versus host disease; NA, not applicable; HMA, Hypomethylating agents. 414 American Journal of Hematology, Vol. 90, No. 5, May 2015 doi: /ajh.23962

5 RESEARCH ARTICLE Blast transformation in chronic myelomonocytic leukemia Figure 1. (a) Overall survival of 36 patients with Chronic myelomonocytic leukemia that underwent blast transformation. (b) Overall survival of 36 patients with Chronic myelomonocytic leukemia that underwent blast transformation, stratified by post-blast transformation treatment modalities.. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] Unlike PMF, where two patients developed favorable (core-binding factor) cytogenetic abnormalities [11]; all cytogenetic changes in BP- CMML were associated with high risk features. There were much fewer changes in mutational status. At the time of BT, 1 of 29 informative patients acquired ASXL1 mutation and one of 16 SRSF2 mutations and none of them lost mutations that were documented at time of CMML diagnosis. In univariate analysis, the risk of developing BT was predicted by younger age, female gender, lower hemoglobin level, higher leukocyte count, higher AMC, higher ALC, higher PB or BM blast count, presence of circulating IMC, high risk karyotype, and WHO CMML-2 subtype. However, during multivariable analysis, only presence of circulating blasts (HR 5.7; 95% CI ) and female gender (HR 2.6; 95% CI ) remained significant. Hence the current study identifies female gender and presence of circulating blasts as independent predictors of BT in CMML and underscores the dismal prognosis of BP-CMML. Patients receiving SCT appeared to fare somewhat better but the results are still bad enough to warrant consideration of SCT prior to BT. In the current study, we were not able to demonstrate prognostic relevance of karyotype or ASXL1/SRSF2 mutations in predicting outcome post-bt, probably because of the lack of effective therapy, in general. More studies with larger number of patients are necessary to validate our observations. References 1. Swederlow S, Camp E, Harris NL, et al., editor. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon: International Agency for Research on Cancer; Itzykson R, Kosmider O, Renneville A, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013;31: Patnaik MM, Padron E, LaBorde RR, et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 2013;27: Such E, Germing U, Malcovati L, et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 2013;121: Patnaik MM, Itzykson R, Lasho TL, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: A two-center study of 466 patients. Leukemia 2014;28: Such E, Cervera J, Costa D, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011;96: Tang G, Zhang L, Fu B, et al. Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution. Am J Hematol 2014;89: Wassie EA, Itzykson R, Lasho TL, et al. Molecular and prognostic correlates of cytogenetic abnormalities in chronic myelomonocytic leukemia: A mayo Clinic-French consortium study. Am J Hematol 2014;89: Patnaik MM, Wassie EA, Padron E, et al. Chronic myelomonocytic leukemia in younger patients: Molecular and cytogenetic predictors of survival and treatment outcome. Blood Cancer J 2015;4:e Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012;120: Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: A single-institution experience with 91 cases. Blood 2005;105: Patnaik MM, Parikh SA, Hanson CA, et al. Chronic myelomonocytic leukaemia: A concise doi: /ajh American Journal of Hematology, Vol. 90, No. 5, May

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