Abstract: Introduction: CMML is a clinically heterogeneous myeloid neoplasm hallmarked by the coexistence of dysplastic and proliferative patho-clinical features, which can include cytopenias, constitutional symptoms, splenomegaly, and leukocytosis. However, according to the FAB classification schema, CMML may be differentiated in dysplastic and proliferative subgroups only by the presence of leukocytosis in the latter (WBC ≥13 x 109/L). We hypothesize that incorporation of other clinically discriminating features may yield a more informative CMML stratification system. To address this, we propose three distinct CMML categories and explore their clinical relevance leveraging our existing international CMML database (Padron E et al. Blood Cancer J. 20151). Method: 1622 WHO-defined CMML cases diagnosed between 1973 and 2014 were collected from eight large cancer centres that include up to 80 discrete data elements as previously described1. Cases were placed into three clinically distinct groups and the Pearson Chi-Square test and the Kruskal-Wallis test were applied respectively to compare categorical and continuous characteristics. The Kaplan-Meier (KM) method was used to estimate median OS and the log rank test was used to compare survival curves.Cox models whereapplied to obtain univariate and adjusted hazard ratios. Identification of optimal cut-off values for continuous variable was supported by graphical inspection of martingale residuals from the null Cox model. Statistical analyses were done in SPSS v23 and R v.3.3.0. Results: We propose three categories to delineate clinically distinct CMML subtypes: (1) Myelodysplastic (MD)-CMML: WBC≤10 x 109/L, PB-immature myeloid cells (IMC) = 0%, no splenomegaly (2) MD/MP-CMML: WBC 10-20 x 109/L or WBC ≤10 x 109/L but PB-IMC 〉 0% and/or splenomegaly (3) Myeloproliferative (MP)-CMML: WBC 〉 20 x 109/L. A recursive partitioning approach was used to identify the WBC cut points, with splenomegaly and IMC added to more accurately depict the MPN aspect of CMML. Numbers of patients included in the MD-, MD/MP-, and MP-CMML subcategories were 319 (19.7%), 789 (48.6%) and 514 (31.7%), respectively (Table 1). According to the FAB criteria, the MD/MP group included 521 (66%) MD- (WBC ≤13 x 109/L) and 268 (34%) MP-CMML (WBC 〉 13 x 109/L) patients suggesting that the proposed classification clinically reclassifies FAB-defined CMML. Within the MD/MP group, 344 patients (21.2%) had a WBC 〈 10 x 109/L but with IMC 〉 0% and/or splenomegaly. Comparison of overall survival (OS) among proposed groups demonstrated that this classification schema was capable of discriminating the CMML natural history (Figure 1). In comparison to MD/MP-CMML, the unadjusted OS Hazard Ratio (HR) was 0.60 (95% CI 0.49-0.73) for MD-CMML and 1.57 (95% CI 1.36-1.81) for MP-CMML (p 〈 0.001 for both). This difference was retained after adjusting for BM-Blasts ( 〈 vs ≥5%), IPSS or CPSS cytogenetics (High-risk vsInterm/low-risk), and elevated levels of LDH (HR was 0.73 with 95% CI 0.57-0.93, p=0.011 for MD-CMML, and 1.33 with 95% CI 1.12-1.58, p=0.001 for MP-CMML, respectively). We next explored whether each proposed group may have distinct variables that uniquely govern its prognosis. Peripheral blood blasts 〉 5%, RBC- and PLT-transfusion-dependence predicted poor OS only in the MD and MD/MP-subcategories (p 〈 0.005), but had no impact in the MP-CMML. Male gender and elevated LDH were only significantly associated with prognosis in the MD/MP group (p 〈 0.05 and p 〈 0.005, respectively) while absolute lymphocyte count 〉 2.5 x 109/L and absolute monocyte count 〉 10 x109/L were uniquely predictive for shorter survival in the MP-CMML subcategory (p 〈 0.005). Notably, we additionally identified gene mutations that uniquely predicted prognosis in each proposed group (Table 2). Conclusions: We demonstrate that our proposed 3-group clinical classification schema is capable of independently stratifying prognosis. Further, our analysis identified clinical and genetic variables that uniquely govern each group's prognosis, suggesting independent clinical behaviour. Further investigations are warranted to validate these groups. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau.

Abstract: Abstract 3997 We have shown previously that cells identified as monocytes in the peripheral blood of patients with chronic myelomonocytic leukemia (CMLL) included a variable proportion of CD14-negative, CD24-positive immature granulocytes. These cells synthesize and secrete alpha-defensin 1–3 that inhibit M-CSF-driven monocyte differentiation into macrophages through interaction with the P2Y6 purinergic receptor (Droin N et al, Blood 2010). In the present study, we show that these CD14-,CD24+ immature granulocytes also inhibit the proliferation of autologous lymphocytes activated with anti-CD3 and anti-CD28 antibodies through cell-cell contact. This functional property suggested that these cells could be “myeloid-derived suppressive cells” (MDSC), which was supported by their phenotype that included expression of CD15 marker at their surface and survivin, S100A8 and S100A9, Cyclin D2 and Cyclin D3 at the mRNA level. STAT3 and STAT6 were found constitutively phosphorylated in these immature granulocytes that responded to Toll-like receptor agonists such as LPS or Pam-6. CD14-positive monocytes of the leukemic clone activated these MDSC through production of IL-13 and induction of arginase 1 mRNA, which could be reproduced by recombinant IL-13. On the other hand, activation of these MDSC did not require induction of the nitric oxide synthase mRNA, in agreement with their granulocytic origin. We were able to generate immature myeloid cells expressing CD24 with morphology similar to that of peripheral blood MDSC by in vitro culture of various subpopulations of bone marrow CD34-positive cells obtained from CMML patients, including the most immature CD34+/CD38-/CD90+ cells. Furthermore, generation of these cells could be recapitulated in vivo by xenotransplantation of CMML CD34+ cells in NOG mice, albeit with lower efficacy than CD14+ cells. In patients with high grade CMML included in a phase II clinical trial, decitabine was observed to decrease both CD14+,CD24- monocytes and CD14-,CD24+ immature granulocytes. Altogether, these data suggest that CMML initiating cells generate CD14-positive monocytes and, in most patients, an additional population of CD14-negative immature granulocytes with suppressive properties towards innate and acquired immune response. Generation of these cells may account for the high sensitivity of CMML patients to autoimmune and infectious diseases. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.

Abstract: Abstract 4023 Background: Treatment of CMML remains difficult, with no drug having shown a clear clinical benefit. AZA has demonstrated a survival benefit in higher risk MDS, in a study that included a small number of CMML (Lancet Oncol, 2009). Several small series of CMML treated by Decitabine (Wijermans, Leuk Res. 2008, Aribi A, Cancer. 2007 and Kantarjian H, Blood. 2007), and AZA (Scott, Br J Haematol. 2010) have been reported, but pts were often very heterogeneous in terms of risk factors and treatment, while in the AZA paper, patients also received etanercept in combination. Methods: The French health agency (AFSSAPS) designed, between 2004 and 2008, a pt named program (ATU) of AZA in higher risk MDS and poor risk AML. 38 pts with CMML or AML arising from CMML included in this program before April 08 and having completed ≥ 1 cycle of AZA (75 mg/m2/d during 7 days every 28 d) are analysed here. As CMML has features of both MDS and MPD, its risk factors are somewhat composite. Based on our previous experience (JCO 1988 6:1417, Blood 1996 88:2480) and on IPSS, pts with WBC 〈 13 G/L were classified according to IPSS, and, in those with WBC 〉 13 G/L, risk factors were based on: marrow blasts≥5%, Hb 〈 10g/dl, plts 〈 100G/l, abnormal cytogenetics, splenomegaly 〉 5cm below costal margin (SMG 〉 5cm) and extramedullary disease (EMD). Response was evaluated according to IWG 2006 criteria in pts with WBC 〈 13G/L, also took into account “proliferative” features of CMML (splenomegaly, increased WBC and blood monocytes, extra medullary disease) in pts with WBC 〉 13G/L, and IWG-AML 2003 criteria for AML. Results: median age was 71 y (range 50–87), M/F: 28/10. Median interval from diagnosis to treatment was 22 months (range 0.2–74 months). Previous treatment was low dose chemotherapy (CT) (n= 10, low dose Arac n=2, HU n=8), Intensive CT (n=12), allogeneic SCT (n=1), ATO (n=2). At inclusion, 9 pts had CMML-1, 17 CMML-2 and 12 AML secondary to CMML according to WHO. Karyotype was normal (n=16), isolated –7/7q- (n=2), +8 (n=1), del 20q (n=1), complex (n=2), -Y (n=2) and a failure (n=2). In the 14 CMML with WBC 〈 13G/L, IPSS was low in 1, int-1 in 3 pts, int-2 in 8 pts and High in 2 pts. In the 12 CMML with WBC 〉 13G/L, 10 had more than 3 risk factors defined in Blood 1996 88:2480. The median number of cycles of AZA administered was 4 (range 1–26). 6 pts received also HU during the first cycles to reduce WBC count. 9 pts received less than 4 cycles due to early death (n=4), progression (n=3) and haematological toxicity (n=2). 20 pts (53%) responded including 9 CR, 3 marrow CR,8 HI-E and 1 partial remission. 19 (68%) of the 28 pts who received more than 4 cycles responded, including 9 CR, 3 mCR, 1 PR and 6 HI. Of the 26 CMML without AML progression, 15 (58%) responded (7 CR, 2 marrow CR and 6 HI-E). Of the 12 AML arising from CMML, 5 (42%) responded (2 CR, 1 marrow CR, 1 PR and 1 HI-E). Median number of cycles of AZA to achieve best response was 4 (range 3–12). Age (p=0.38), WBC count (p=0.76), Hb level (p=0.987), platelet count (p=0.07), blood monocytes (p=0.4823), Sex (p=0.28), CMML 1 vs 2 (p=0.48), splenomegaly (p=0.7), normal karyotype (p=1), -7/del7q(p=0.65), concomitant treatment with HU (p=0.6), 〉 3 risk factors in CMML with WBC 〉 13 G/l, and previous treatment (p=0.506) had no impact on response. 9 of the 20 responders relapsed after a median of 10.6 months (range 3–23), including 4/9 (44%), 1/3 (33%), 0/1, 4/8 (50%) of the pts who had achieved CR, mCR, PR and HI respectively, 10 remained responders after a median of 26 months (16-35) and 1 pt with HI died without relapse. Median overall survival (OS) was 24 months in CMML compared to 7 months in AML arising from CMML (p= 0.0081). Presence of splenomegaly, WBC 〉 13 G/l, previous treatment (excluding ESA), Sex, -7/del7q and normal karyotype had no impact on OS. Conclusion: In this series of CMML which had on average more unfavourable prognostic factors than in previous series of CMML treated with Decitabine or AZA (10/14 with WBC 〈 13G/L were IPSS int 2 or high, 10/12 with WBC 〉 13 G/L had at least 3 risk factors, and 12 had progressed to AML), AZA showed clear efficacy, but mainly in pts who had not progressed to AML. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Abstract: Abstract 443 Background: AZA is the current standard of care for IPSS int-2 and high (“higher”) risk MDS. However, most pts will experience primary or secondary treatment failure. To date, there is no published data on the outcome of those pts. Design: 565 patients from 4 independent cohorts, who had not responded to or relapsed after response to AZA, were included. The datasets included 3 prospective trials (AZA001 (n=138; Lancet Onc, 2009), J9950 (n=26; Cancer Res 2006), J0443 (n=32; NCT00101179) trials) and data from the French ATU compassionate use program (n=369). Two cohorts administered AZA as single agent (AZA001 and French ATU) while two combined AZA with a histone deacetylase inhibitor (J9950, sodium phenylbutyrate; J0443, entinostat). 339 patients had no clinical response to AZA while 226 relapsed after initial response. The influence of pre treatment variables and salvage treatment options on the outcome after AZA failure was analyzed. Survival was measured from the date of failure of AZA. Results: The cohort included 475 MDS (including 117 RAEB-T) and 90 sAML (AML secondary to MDS). Median age was 69 years and the median number of cycles of AZA before failure was 6 (range [1-41]). Patients were randomly assigned to one learning (n=377) and one validation (n=188) set stratified on the number of deaths. There was no difference in the baseline characteristics of the 2 sets. With a median follow-up of 15 months after AZA failure, the median overall survival (OS) was 6 months and the 2-year probability of OS was 15%. The multivariate model constructed with the learning set showed that age (HR 1.02/y, 95%CI [1.01-1.03] , p=0.002), sex (female 7 months vs male 5.6 months HR 1.3 [1.01-1.67] p=0.04), cytogenetics (favorable 8 months vs intermediate 5.9 months HR 1.49 [1.06-2.08] p=0.02, vs high risk 4.6 months HR 2.19 [1.63-2.91] p 〈 0.001), bone marrow blast % before AZA (below 10% 7.8 months vs 10 to 20% 5.8 months HR 1.34 [0.97-1.84] p=0.07, vs 21%+ 4.3 months HR 1.92 [1.36-2.7] p 〈 0.001), and the number of cycles of AZA (6 or less 4.7 months vs more 7.2 months HR 0.69 [0.54-0.9] p=0.005) were significantly associated with survival. Initial response to AZA was significant in univariate analysis (non responders 4.7 m vs 7.3 m in responders, p=0.02) but did not retain significance in the multivariate model. These results were confirmed with the validation set. Data on the treatment administered after AZA failure were available for 350 patients. Allogeneic transplantation (n= 50) (median OS 18.3 months, range [3-55+] ) and investigational therapies (n= 56, including epigenetic drugs, IMIDs, and non registered compounds; median OS 13.2 months, range [1-36+]) were associated with significantly better survival than palliative care (median OS 3.3 months) or conventional cytotoxic chemotherapy (median OS 7.6 months, including AML like induction chemo and low dose chemo such as cytarabine or 6-MP). Conclusions: Outcome of patients with AZA failure was poor, although pts receiving allo SCT or investigational treatments had a somewhat better outcome. This work highlights the potential predictors of outcome and defined the baseline survival data that will help in the design of second line trials in higher risk MDS having failed treatment with AZA. *: Overall response rate for each treatment group is presented with the number of patients evaluable for response in each cohort. For the CT group, response rate for low dose chemotherapy and high dose (AML like, marked with **) chemo have been individualized. Univariate analysis (log-rank test) showed significant difference between PC and CT (p=0.002), IT (p 〈 0.001) or ASCT (p 〈 0.001). There was also significant differences between CT and IT (p=0.004) or ASCT(p=0.001). Difference between IT and ASCT reached borderline significance (p=0.053). Disclosures: Gore: Celgene: Research Funding, Stock options. Beach:Celgene: Employment.

Abstract: Context : Response to treatment in CMML is difficult to evaluate. Most clinical trials so far included CMML patients (pts) together with MDS pts and assessed response with MDS IWG 2006 criteria (Cheson, Blood 2006), which poorly predict overall survival (OS) with HMA. Recently, an International Consortium has proposed MDS/MPN response criteria (IC-MDS/MPN), considering reduction in blasts (marrow response), but also correction of cytopenias or of myeloproliferation (clinical benefit; Savona, Blood 2015). These new criteria have never been compared to IWG 2006 and their prognostic relevance is unknown. Methods : We analyzed a retrospective cohort of advanced CMML pts treated ith AZA (within EMA label) or DAC (in GFM trials) in GFM centers and Dresden. All analyses were stratified on HMA. Agreement between criteria was assessed by Cohen's kappa, a measure of reproducibility ranging from 0 (no concordance) to 1 (perfect concordance). Survival analysis was censored at transplant and Cox models were performed by Mantel-Byar method, considering achievement of response at first assessment as a time-dependent variable. Results : The cohort included 80 pts (M/F: 56/24) with a median age of 70y (range: 41-91). HMA was AZA and DAC in 49 and 31 pts, respectively (resp.). Median interval between diagnosis and onset of HMA was 4.3 months. At onset of HMA, WHO diagnosis was CMML-1 and CMML-2 in 56% and 44%, resp. Splenomegaly was present in 40%. Median WBC, Hb and Plt counts were 14.7 10^9/L, 9.6 g/dL and 103 10^9/L, resp.; 48% pts were RBC-TD. Cytogenetic risk according to CPSS (Such, Haematologica 2011) was fav/int/low in 63/13/24% resp. CPSS risk category (Such, Blood 2013) was low/int-1/int-2/high in 10/21/54/15%, resp. ASXL1 was mutated in 43% of pts and GFM risk (Itzykson, JCO 2013) was fav/int/low in 29/36/35%, resp. DAC and AZA were administered at standard regimens (20 mg/m2/d x5d/28d; 75 mg/m2/d x7d/28d), for a median of 9 and 7 cycles in DAC and AZA pts, resp. (p=.96). AZA regimen was intensified or reduced in 2 and 5 pts, resp. HY was administered concomitantly for the first cycles in 11%. Median follow-up was 59 months, during which 12 pts were transplanted. Median OS and AML-free survival (AMLFS) were 25.7 and 21.0 months, resp. Initial response was assessed after a median of 4 cycles (AZA/DAC: 5/3, p 〈 .0001); overall response rate (ORR) according to IWG 2006 was 45%, including 14% CR, 11% marrow CR (mCR), no PR, 20% stable disease with HI, while the remaining 55% had stable (SD: 21%) or progressive (PD: 34%), disease. ORR according to CI-MDS/MPN was 65%, including CR in 6%, optimal (OMR) and partial (PMR) marrow response in 44 and 4% resp. and clinical benefit (CB) in 11%. Best IWG 2006 and IC-MDS/MPN response were achieved after a median of 5 (range: 1-18) cycles, without difference between HMA. Improvement from initial assessment to best response was noted in 12 and 11 pts with IWG 2006 and IC-MDS/MPN criteria, resp., leading to ORR of 56% (CR 21%, mCR 11%, HI 24%) and 71% (CR 12%, OMR 28%, PMR 1%, CB 30%), resp. PR was not observed with either set of criteria. A moderate agreement was found between these two sets of criteria at initial evaluation (agreement in 78% cases, Cohen's kappa: .56), with better agreement for best response (85% cases, kappa: .68). Responses according to IC-MDS/MPN criteria were more prolonged than those defined by IWG 2006 (median duration: 19.3 vs 10.8 months, resp. p=.0004), possibly because the former, but not the latter, require additional criteria in addition to blast increase to define progression. CPSS risk category did not predict IWG 2006 or IC-MDS/MPN response (p 〉 0.2), but higher GFM risk tended to predict lower rates of IWG 2006 (p=.06) or IC-MDS/MPN (p=.15) response. Achievement of IWG 2006 (HR=.45, p=.011) or of IC-MDS/MPN (HR= .33, p=.001) response both lead to prolonged OS. Further dissecting IC-MDS/MPN response subtypes, a significant OS benefit was found in patients achieving OMR or CR (p=.003, Figure), but not in those achieving only CB (p=.31) or partial marrow response (p=.76). Similar findings were made for AMLFS. Conclusion : Compared to IWG 2006, IC-MDS/MPN responses to HMA in CMML are more frequent and more prolonged. CPSS and GFM risk scores do not predict response. Optimal marrow response (OMR, reduction of bone marrow blast 〈 5%) at first assessment predicts longer OS and AML-free survival and could be a relevant short-term endpoint for future clinical trials of HMA in CMML. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine (use off label in CMML). Platzbecker:AMGEN: Honoraria; NOVARTIS: Honoraria; CELGENE: Honoraria. Park:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. De Botton:Agios Pharmaceuticals: Research Funding. Fenaux:NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding. Itzykson:Oncoethix: Research Funding.

Abstract: Abstract 700 Purpose: Prognosis of lower (IPSS low/int-1) risk MDS is heterogeneous. Current prognostic systems rely on single time point cytopenia values (Hb level, ANC, PLT counts) at diagnosis (classical or revised IPSS [IPSS-R] Greenberg, Blood 2012) or during evolution (time-dependent IPSS/WPSS). Capturing the dynamics of continuous parameters can yield independent prognostic information as exemplified by lymphocyte time doubling in CLL. We analyzed the prognostic relevance of the kinetics of Hb, ANC and PLT in lower-risk MDS patients (pts) included in the prospective EUMDS registry. Methods: Among the first 1000 pts included in the EUMDS registry, those fulfilling the following criteria were analyzed here: a) IPSS low/int-1; b) ≥3 visits (planned every 6 months) with ≥12 months follow-up; c) not treated with hypomethylating agents, G-CSF, hydroxyurea or lenalidomide. Dynamics of Hb, ANC, and PLT were studied by deriving linear models of each variable for each pt. Only pts with ≥3 measures of Hb, ANC and PLT and with stable or worsening corresponding cytopenia (model slope ≤0) were considered in each analysis, regardless of the goodness of fit (R2) of models. Time (T) to lose 1 g/dL of Hb (THb), 1.0 x109/L of ANC (TANC) and 50 x109/L of PLT (TPLT) were derived with the formula: T ∼ 1/slope. All survival analyses were made from the date of registry entry to last follow-up, death, or progression to AML. Unless specified, survival analyses were Cox models using continuous variables accounting for interactions. Results: 530 pts met study inclusion criteria (M/F: 314/216, median age: 73y). WHO diagnosis was 5q- syndrome, RA, RARS, RCMD, RCMD-RS, RAEB-1 and MDS-U in 5, 21, 20, 38, 7, 8 and 2% respectively (resp). IPSS risk was low, int-1 and low/int-1 (cytogenetics not available) in 55%, 38% and 7% resp. At registry entry, median Hb, ANC and PLT were 10.4 g/dL, 2.4 x109/L and 187 x109/L resp. and 23% were RBC transfusion-dependent; 293 received an ESA. The median number of available blood counts was 4 (range 3–9). THb, TANC and TPLT could be determined because of a stable or worsening cytopenia (slope ≤0) in 250/508, 258/495 and 301/509 pts with ≥3 values. There was no significant correlation between the number of values available and the goodness-of-fit (R2) of linear models (all P 〉 0.3). Median THb TANC and TPLT were 23.5 (interquartile range [IQR]: 42.2), 28.7 (IQR: 52.1) and 26.9 (IQR: 49.2) months respectively. Because these figures are derived from linear models, they can be simply rescaled by a proportional extrapolation for daily practice (eg. −1 x109/L ANC at 28.7 months = −0.41 x109/L [12/28.7] at 12 months). THb, TANC and TPLT were not correlated to age, cytogenetic risk, IPSS, IPSS-R or baseline simplified WPSS (Malcovati. Haematologica 2011; all P 〉 0.2). TANC and TPLT (but not THb) were shorter in pts with baseline RBC transfusion dependence (P=.02 and .003, resp.). With a median follow-up of 20.9 months in the 530 pts, 19 patients have progressed (AML: 14, RAEB: 5) and 71 patients have died; 3-year estimates of overall (OS) and progression-free (PFS) survivals were 74.4% and 73.6%. All further analyses are shown for OS and give similar results for PFS. In univariate analysis, longer TANC (hazard ratio [HR] for 6-months increments: 0.88 [95% CI: 0.80–0.97] , P=.008) and TPLT (HR: 0.01 [95% CI: 0.001–0.30], P=.007) but not THb (P=.07) were associated with prolonged OS. Pts with a ≥1 x109/L decrease in ANC in less than the median time of 28.7 months (N=129) had a 3-year OS of 66.3% [95% CI: 55.0–79.9%] vs 89.3% [79.7–100%]. Pts with a ≥50 x109/L decrease in PLT in less than the median of 26.9 months (N=151) had a 3-year OS of 59.4% [46.8–75.4%] vs 85.6% [77.5–94.6%] (Figure, both P 〈 10−4). There was no significant difference in the cause of death between those subgroups. In multivariate analysis, the prognostic impact of TANC and TPLT remained independent of baseline IPSS (P=.006 and P=.01 resp.) or IPSS-R (both P=.01), and of simplified time-dependent WPSS (P=.004 and P=.03). A landmark analysis at 2 years, using only retrospective data to derive TANC and TPLT is planned. Conclusion: In lower-risk MDS with stable or worsening cytopenias, kinetics of decline can be approximated to be linear to allow easy prognostic use in clinical practice. Faster decline of ANC and to a lesser extent of PLT counts, but not of Hb level (possibly because of transfusions and use of ESA), is associated with shorter OS and PFS, independently of IPSS, IPSS-R and WPSS. Disclosures: Germing: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Chronic graft-versus-host disease is associated with a global Breg defect. This defect is particularly accentuated in the CD24hiCD27+ Breg compartment.

Abstract: Context. The perhaps only CMML-specific Randomized Clinical Trial (RCT) established hydroxyurea (HY) as the main treatment (Tx) for advanced proliferative CMML (Wattel Blood 1996). In Europe, the only hypomethylating agent (HMA) approved in CMML is AZA in non proliferative CMML-2. Phase 2 trials reported the activity of decitabine (DAC) in advanced proliferative CMML (Braun Blood 2011, Santini Leukemia 2018). We performed a RCT of DAC (±HY during the first 3 cycles) vs HY alone in those pts. Methods. The DACOTA trial (EudraCT 2014-000200-10) accrued pts with previously untreated (or & lt; 6 weeks of HY), proliferative (WBC ≥ 13x109/L) CMML with advanced disease defined per Wattel et al as presence of extramedullary disease or ≥2 criteria among: BM blasts ≥5%, abnormal karyotype (except -Y), ANC ≥ 16x109/L, Hb & lt; 10 g/dL, platelets & lt; 100 x109/L or splenomegaly & gt; 5 cm below costal margin. Pts were randomized 1:1 to DAC (20 mg/m2/d IV 5d/28d) or HY (1g/d, adjusted on WBC, 28d cycles) and treated until death, AML transformation or progression. The primary endpoint was EFS, events being death, transformation to AML, progression of myeloproliferation after 3+ cycles or progression of blasts and cytopenias after 6+ cycles. Response was assessed with IWG 2006 criteria modified to account for improvement of myeloproliferation, after central morphology review. Intent-to-treat analyses were done considering missing responses as failures. Results. From Oct 2014 to Sep 2019, 217 pts from 47 centers were screened and 170 randomized (84 DAC and 86 HY), including 12 pts (6 DAC and 6 HY) who never started Tx. Median age was 73 years (IQR 68-78). WHO was CMML-NA/1/2 in 2, 114 and 54 pts, respectively (resp). Median WBC 34.9 x109/L (IQR 22.9-55.7). Cytogenetic risk (Such Haematologica 2011) was fav 69%, int 12%, adv 18% NA 1%. Mutations in TET2, SRSF2, ASXL1 and signaling genes (CBL, JAK2, FLT3, KIT, NRAS, KRAS and CSF3R) were present in 64%, 51%, 62% and 57% resp. 72 pts had received HY for a median 27 days prior to randomization. Aside from older age in the HY arm (median 74 vs 71.5y in the DAC arm), there was no imbalance between Tx arms. DAC and HY pts received a median of 5 (IQR 3-12) and 6 (IQR 3-14) cycles, resp. As of 15th June 2020, 5 and 10 DAC and HY pts were still on Tx. Reasons for Tx cessation in the DAC arm were death (n=19), AML transformation (n=16), progression (n=9) , hematological toxicity (n=13) or other (n=21). Reasons for Tx cessation in the HY arm were death (n=14), AML transformation (n=13), progression (n=18), hematological toxicity (n=6) or other (n=20). 126 and 85 pts received 3 and 6 cycles, resp. In the ITT population, ORR at 3 cycles was 56% (7CR, 25 mCR±HI, 15 SD+HI) and 30% (0 CR, 8 mCR±HI, 18 SD+HI) in the DAC and HY arms, resp (p=0.0011) and ORR at 6 cycles was 32% (6 CR, 9 mCR±HI, 12 SD+HI) and 17% (2 CR, 4 mCR±HI, 9 SD+HI) in the DAC and HY arms, resp (p=0.033). Median response duration was 15.9 vs 18.2 months (mos) in the DAC and HY arm, resp (p=0.81). Infection and hemorrhage occurred at least once in 49% and 31% of pts, resp. 55% of DAC pts and 38% of HY pts required hospitalization at least once (p=0.05). Non-heme ≥ grade 2 AEs occurred in 79% and 63% of DAC and HY arms, resp (p=0.03). Grade ≥3 cardiac AEs occurred in 13 DAC and 4 HY pts, resp. With a median follow-up of 13.9 mos, median EFS was 12.6 vs 10.3 mos in the DAC and HY arms, resp (reference DAC arm, HR= 1.14 CI95 0.8-1.64, p= 0.46). Median AML-free survival (AMLFS) was 13.6 and 15.8 mos in the DAC and HY arms resp (p=0.86). Median OS was 18.4 and 23.1 mos in the DAC and HY arms, resp (p=0.72). Considering death and AML transformation as competing risks there was no significant difference in cumulative incidence of AML (p=0.1) or death without transformation (p=0.06) between arms. 30 pts from the HY arm received an HMA (DAC n= 13, AZA n= 16, both=1) after study exit. Censoring at HMA onset in the HY arm, median OS was 18.4 vs 30.4 in the DAC and HY arm, resp (p=0.15). 13 pts were transplanted (DAC n= 10, HY n= 3). There was no interaction between Tx arm and CMML-0/1 vs -2, platelets ≥ vs & lt;100 x109/L and anemia (Hb & lt; 8 g/dL or RBC-TD vs Hb ≥8) on both EFS and OS (all p & gt;0.05). Conclusion. RCTs are feasible in advanced proliferative CMML, which remains an unmet medical need. In these pts, DAC did not provide an overall or event-free survival advantage over HY. HY remains a valid option in advanced proliferative CMML. However, one third of HY pts subsequently received an HMA and more DAC pts achieved a response and were bridged to HSCT. Figure Disclosures Itzykson: Abbvie: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncoethix (now Merck): Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Santini:BMS, J & J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Lionel:Abbvie: Consultancy; Takeda: Consultancy; Celgene/BMS: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Luebbert:Janssen: Research Funding. Park:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Stamatoulas Bastard:Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Solary:Janssen: Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. OffLabel Disclosure: Decitabine for CMML with WBC & gt; 13 x109/L.

Abstract: Background: CMML is a heterogeneous disease with overlapping features of MDS and MPN. Several risk scores have been proposed in CMML, including CPSS (Such Blood 2013) that identifies 4 risk groups (low, intermediate-1 [int-1], int-2 and high risk) with median overall survival (OS) ranging from 12 months to 〉 5 years. HSCT is the only curative treatment in CMML, with an expected 20-40% post-transplantation OS. Current guidelines, common to MDS and CMML recommend rapidly transplanting higher-risk CMML and delaying transplant in lower-risk disease (de Witte Blood 2017). Retrospective transplant studies have shown better outcome in lower-risk CMML (Liu et al BBMT 2017). Whether this translates into a survival benefit compared to a delayed transplant strategy requires prospective studies. Multistate models based on retrospective data from transplant and non-transplant patients (pts) have addressed similar issues in MDS (Koreth JCO 2013, Della Porta Leukemia 2017). Through a large collaborative study, we address the question of optimal timing for HSCT in CMML patients through a similar large international collaborative study. Method: We retrospectively selected pts from 2 registries: International MDS/MPN Working Group (IWG cohort, Padron Blood Cancer J 2015) and EBMT with the following criteria: WHO-defined CMML, age ≤ 70y, ECOG 0-2, diagnosis after 2000, available CPSS at the time of diagnosis. Different states were considered in higher- (CPSS int-2 and high) and lower- risk (CPSS low/int-1) pts: diagnosis, AML transformation, transplantation and death. IWG data was used to estimate transition probabilities from diagnosis to AML, transplantation and death and from AML to transplantation and death. EBMT data was used for transplantation to death transitions (Figure 1). Results: 719 and 403 pts were identified in the IWG and EMBT registry, respectively (resp). Median age was 64 (range 16-70) in IWG and 58 (19-70) years in EBMT cohort. Patients were male in 69% and 67% of IWG and EBMT cohorts, respectively (resp). CPSS was low in 22% and 13%, int-1 in 31% and 31%, int-2 in 40% and 45% and high in 8% and 11% of the IWG and EBMT pts, resp. In the IWG cohort, the 1 year cumulative incidence of transformation into AML were 7.3% and 18.2% in lower and higher risk patients, resp. Among the 719 pts from IWG, 102 received HSCT. At the time of diagnosis the expected life time of higher risk (int-2 and high) patients was 25.2 months while it was 44.1 months in lower risk (int-1 and low) patients. Table 1 reports gain or loss in expected life time (until 60 months after diagnosis) for transplantation at different intervals from diagnosis (within 6, 12, 18 and 24 months) for patients who have survived and not transformed to AML until the prediction time point, taking into account CPSS at diagnosis. Expected life time is also given separately for higher risk pts after transformation into AML. There was a modest gain of life expectancy with transplantation in higher risk patients (CPSS int-2 and high) while it was not the case in lower risk patients. The survival gain in higher risk pts with HSCT rose from 1.11 at 6 months to 3.4 months at 24 months. There was also a survival benefit of HSCT in higher risk pts who were transformed to AML during their follow-up which was even higher in terms of gain of months: from 9.89 month if HSCT performed within 6 months to 14.25 months if performed within 18 months. Of note, the loss of survival in lower risk patients who underwent HSCT decreased over time: 11.1 months if HSCT is performed within 6 months and 3.7 months if HSCT is performed within 24 months, probably owing to transition to higher-risk CMML at this stage in some pts, a transition that could not be captured in the present dataset. Conclusion: For the first time, using a multistate model, we could provide evidence that the transplant benefit in CMML is restricted to higher-risk pts, in line with findings in MDS and current guidelines. More analyses will be performed to analyze other subgroups of patients, especially regarding their risk (other classification than CPSS, the role of somatic mutation…). More studies are needed to analyze the role of pre HSCT treatment and its potential impact on post-transplant outcome. Disclosures Robin: Novartis Neovii: Research Funding. Beelen:Medac GmbH Wedel Germany: Consultancy, Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Kroeger:Riemser: Research Funding; Novartis: Honoraria, Research Funding; Medac: Honoraria; DKMS: Research Funding; Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi-Aventis: Honoraria. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Rampal:Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Finke:Riemser: Honoraria, Other: research support, Speakers Bureau; Neovii: Honoraria, Other: research support, Speakers Bureau; Medac: Honoraria, Other: research support, Speakers Bureau. Komrokji:Agios: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy. Killick:JAZZ: Honoraria; Celgene: Honoraria; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; ALEXION: Honoraria. Blaise:Molmed: Consultancy, Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.