Itzykson, Raphaël

Abstract Background: Most patients with chronic myelomonocytic leukemia (CMML) are elderly and age >65 years is an adverse prognostic factor (JCO 2013;31:2428). Our objective in the current study was to examine risk factors for survival and treatment outcome in younger patients (age ≤65 years), with emphasis on molecular and cytogenetic markers. Methods: DNA analysis for SRSF2, SF3B1, U2AF1, ASXL1 and SETBP1 mutations was carried out on specimens obtained at time of diagnosis. We used both conventional and revised (see accompanying ASH 2014 abstract) cytogenetic risk models to query their application in the current study population. Treatment data included outcome of allogeneic stem cell transplant (HCT) and treatment with hypomethylating agents (HMA), including azacitidine (AZA) and decitabine (DAC). Results: Survival: 259 patients (median age 59 years, range 18-65; 75% males) with WHO-defined CMML and age≤ 65 years were included in the study: 108 from the French consortium, 81 Mayo Clinic, 47 Moffitt Cancer Center and 23 University of Milan; 217 (84%) patients had CMML-1 and the remainder CMML-2. At a median follow-up of 26 months, 124 (48%) deaths and 79 (31 %) leukemic transformations were documented. Mutational frequencies were 34% (61/178) for ASXL1, 45% (74/165) for SRSF2, and 4% (7/168) for SETBP1. Cytogenetic data was available in 248 of 259 study patients; 56 (23%) patients displayed abnormal karyotype and the revised cytogenetic risk designations included 196 (80%) low, 29 (12%) intermediate, and 23 (9%) high. In univariate analysis, lower hemoglobin (p<0.0001), higher WBC (p=0.005), higher monocyte count (AMC) (P=0.004), lower platelet count (p=0.004), presence of circulating immature myeloid cells (IMC) (p=0.004), presence of circulating blasts (p<0.0001), bone marrow (BM) blasts ≥10% (p=0.005), WHO morphological subtype (p=0.0003), Spanish cytogenetic risk stratification (p=0.0002), revised Mayo cytogenetic risk stratification (p<0.0001), SRSF2 (p=0.03) and ASXL1 (p=0.03) mutational status predicted shortened survival. In multivariable analysis, lower hemoglobin (p<0.0002), presence of circulating blasts (p<0.0001), SRSF2 (p=0.03) and ASXL1mutational status (p=0.04) retained their negative prognostic impact. A similar analysis identified circulating IMC (p<0.0001), presence of circulating blasts (p<0.0001), and BM blast % (p=0.0002) as predictors of blast transformation (BT). Response to hypomethylating agents: Seventy-two (28%) patients received HMA (AZA-46, DAC-26, both-6). In the AZA group, median number of cycles was 5 (range; 1-44), median duration of therapy 5 months (range;1-59) with 4 (6%) receiving DAC on progression and 26 (42%) proceeding with HCT. Over-all response rate (ORR) was 25% (6/24) and included complete response (CR) in 2 (8%) patients, partial response (PR) in 2 (8%) and hematological improvement in 2 (8%). In the DAC group, median number of cycles was 6 (2-25), median duration of therapy 5 months (range;1-49), with 2 (8%) receiving AZA on progression; ORR was 50% (7/14) and included CR in 4 (29%) patients, PR in 1 (7%) and HI in 2 (14%). ASXL1 (p=0.4), SRSF2 (p=0.7) mutational status or karyotype (p=0.5 for Spanish and 0.3 for revised Mayo) did not correlate with response to HMA. Allogeneic stem cell transplant: 50 patients underwent HCT. Conditioning regimen was reported in 41 patients and included myeloablative (MA) in 14 (34%) (median age 51 years, 27-62) and reduced intensity (RIC) in 27 (66%) (median age 48 years, 18-65). Donor source was documented in 40 patients and included matched related in 19 (48%), matched unrelated in 12 (30%), mismatched unrelated in 4, haploidentical in 2 and umbilical cord transplant in one. 27 (63%) patients had chronic GVHD (50% in MA group and 80% in the RIC group). Among 40 evaluable patients, 23 (57%) achieved CR, 8 (21%) relapsed and 8 (21%) died from transplant-related complications. ASXL1 (p=0.9), SRSF2 (p=0.5) mutational status or karyotype (p=0.2 for Spanish and 0.3 for revised Mayo) did not affect transplant outcome. Conclusions: Survival in young CMML patients is poor and even worse in the presence of SRSF2 or ASXL1 mutations, anemia or circulating blasts. Treatment outcome was more impressive with transplant than it was with HMA and neither was influenced by karyotype or ASXL1/SRSF2 mutational status. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: CMML is a heterogeneous malignancy characterized by peripheral monocytosis and a propensity for AML transformation. Given the low incidence of CMML and its broad range complexity, a large disease-specific data set is necessary to discern independent co-variates predictive of disease behavior. Several prognostic models derived from smaller data sets have been developed to stratify CMML patients into distinct groups that are predictive for OS. However, the validity of these models in a large international data set has never been investigated. Here, we present the largest International CMML data base established to date and report key baseline characteristics predictive for disease outcome. We externally validate and perform a detailed statistical comparison between the International Prognostic Scoring System (IPSS), Revised (R)-IPSS, Global MD Anderson Scoring System (MDASC), MD Anderson Prognostic Score (MDAPS), Dusseldorf Score (DS), Mayo, and Spanish Scoring Systems (CPSS). Methods: Data were abstracted by each contributing institution and deposited for central data review at the Moffitt Cancer Center. Manual review of cases was performed to ensure data quality prior to analysis. Only WHO defined CMML was included. The primary objective of this study was to establish an international CMML data set and validate the above models calculated at the time of presentation to each center. All prognostic models were calculated as previously described. The Kaplan–Meier (KM) method was used to estimate median OS and the log rank test was used to compare KM survival estimates with SPSS version 21.0. Random Forest Survival (RSF) and ROC analysis was done with R. Results: Between July 1981 and June 2014, 1832 CMML patients were captured in the International CMML database. Median age at diagnosis was 70 (16-93) years with a male (67%) predominance. By the WHO classification, the majority of patients had CMML-1 (79.9% vs. 20.1%) and most patients were evenly subcategorized as MPN-CMML (49.8%) versus MDS-CMML (50.2%) by FAB criteria. Splenomegaly was demonstrable in 25%. Most patients had favorable cytogenetics by both IPSS (70%) and CPSS (67.6%) classification schemas. Mean BM blast % was 5.6 and mean monocyte count was 4.85x103/dL. Median OS of the entire data set was 31.6 months. All tested prognostic models were valid and able to predict OS (p<0.0001). To compare relative model performance, 1013 complete cases with sufficient data to calculate all risk models were compared using time dependent receiver operator characteristic (ROC) curves and their area under the curves (AUC). ROC curves were calculated for OS at 36 months. The R-IPSS model had the highest AUC (0.694) while the DS model had the lowest (0.635). The difference in AUC between the R-IPSS and DS models was statistically significant (p = 0.003) whereas there was no significant difference from other models tested. To determine which models were most vulnerable to reclassification from low-risk to higher risk, we calculated a vulnerability score defined by the number of models able to up-stage low-risk disease in more than 15% of cases. Using this metric, the Mayo and MDASC scores were least vulnerable to up-staging by other models. Lastly, we used an orthogonal method for determination of variable importance (RSF for OS at 36 months). RSF is an ensemble method of classification and regression tree methodology. Ranking of variables by their weighted importance determined by this procedure identified the top five variables were hemoglobin, circulating blasts, platelet count, number of cytopenias, and karyotype. A new risk model was developed using the results of the RSF with an AUC of 0.720, which was comparable but not significantly different than other modern scoring systems. Conclusions: This represents the largest international CMML-specific data set derived from eight unique centers of excellence. All modern prognostic models were valid and performed comparably. Despite novel strategies for variable importance discovery, an improved model could not be constructed. This data suggest that the power of clinical variables has reached an asymptote and highlights the need for incorporation of molecular and other novel biological features. This data set is currently being populated with molecular data and is being leveraged to test published CMML molecular prognostic models which will be disclosed at the time of presentation. Disclosures Garcia-Manero: Epizyme, Inc: Research Funding. Fenaux:Celgene, Janssenm, Novartis: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity (<=20% vs. > 20%), BM blast percentage (<=20% vs. >20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p <0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A]. In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1]. In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Key Points In the largest study of HMAs in RR-AML to date, 16% of patients achieved CR/CRi and experienced a median OS of 21 months. Low proliferative disease (peripheral blood blasts <5%) was associated with improved response and OS.

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

Four hundred and nine patients with chronic myelomonocytic leukemia (CMML) were included in the international collaborative study (268 (66%) and 141 (34%) from Mayo clinic and French consortium respectively). Thirty percent displayed an abnormal karyotype, including; 72% sole, 16% two, and 11% complex abnormalities. The most common abnormalities included; +8 (23%), ‐Y (20%), ‐7/7q‐(14%), 20q‐ (8%), +21 (8%), and der(3q) (8%). Patients with an abnormal karyotype were more likely to be elderly (P = 0.03), be anemic (P = 0.0009), have leukocytosis (P = 0.02) with neutrophilia (P = 0.03), demonstrate increased circulating immature myeloid cells (P = 0.0003), peripheral blood blasts (P < 0.0001), and bone marrow blasts (P < 0.0001). ASXL1 (P = 0.04) and SF3B1 (P = 0.03) mutations clustered with an abnormal karyotype, whereas SRSF2 (P = 0.02) mutations occurred more commonly with a normal karyotype. A step‐wise survival analysis resulted in three distinct cytogenetic risk categories: high (complex and monosomal karyotypes), intermediate (all abnormalities not in the high or low risk groups) and low [normal, sole ‐Y and sole der (3q)] with median survivals of 3 [hazard ratio (HR) = 8.1, 95% confidence interval (CI) = 4.6–14.2], 20 (HR = 1.7, 95% CI = 1.2–2.3) and 41 months, respectively. In multivariable analysis, this particular cytogenetic risk stratification remained significant in the context of the Molecular Mayo Model (P < 0.0001), MD Anderson prognostic model (P < 0.0001), the GFM CMML model (P < 0.0001) and was effective in predicting leukemic transformation (P = 0.004). Am. J. Hematol. 89:1111–1115, 2014. © 2014 Wiley Periodicals, Inc.