Abstract: Abstract 3820 Poster Board III-756 Background AZA provides 50-60% responses and improves OS in higher-risk MDS (Lancet Oncol 2009) but prognostic factors of response and OS remain largely unknown. Methods An AZA compassionate program (ATU) was opened in France between Dec 2004 and Dec 2008 for higher risk MDS, and for AML not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed the outcome of higher risk MDS (including RAEB-t) patients (pts) included in this program in the 42 centers with complete patient (pt) reporting, having received ≥ 1 cycle of AZA, and excluding those who had received prior allo SCT, IC, or a hypomethylating agent. Results 233 pts (M/F: 145/88) with a median age of 71y (range 20-91) were included. Diagnosis (WHO classification) was: RA±RS: 2, RCMD±RS: 7, RAEB-1: 48, RAEB-2: 123, and RAEB-t: 53; IPSS cytogenetic risk was favorable (fav) in 75 (32%), int (intermediate) in 35 (15%), and unfavorable (unfav) in 112 (48%) (failure in 11, 5%); IPSS was: int-2 in 133 (57%), high in 97 (42%), NA in 3 (1%). Median time since diagnosis was 5 months (range 0–209). 29 patients (12%) had previously received low dose Arac (LD AraC). 162 pts (70%) were RBC transfusion dependent, including 49% requiring ≥ 4 RBC units/8 weeks. Median follow-up was 13 months. Patients received a median of 5 cycles (range 1-26) of AZA, at FDA/EMEA-approved schedule (75 mg/m2/d x7d /4 week) in 70% patients and a less intensive schedule (5d/4w, or 〈 75 mg/m2/d) in 30% patients, while 16% received concomitant valproic acid (VPA). First response was evaluated after 3-4 cycles. Best response (IWG 2006 criteria) was CR in 22 pts (9%), PR in 6 (3%), marrow CR (mCR) in 25 (11%), stable disease (SD) with HI in 34 (15% including HI-E ± HI-N/HI-P in 13, HI-P±HI-N in 17, and isolated HI-N in 4) leading to an overall response rate of 38%. Moreover, SD without HI was observed in 26%, progression in 26%, death before 4 cycles in 7% and AZA discontinuation before 4 cycles in 3%. Overall, HI-E was obtained in 48/162 anemic pts (23%). 38% of the responders progressed after a median time of 13 months (range 3-26), and 62% remained responders after a median time of 11 months (range 1-35). Median response duration was 10.2 months in CR pts, not reached in PR pts, 13 months in mCR pts, and 25 months in pts who achieved SD with HI. No pre-treatment characteristic including age, sex, time since diagnosis, WHO, karyotype, importance of cytopenias, BM or PB blast %, IPSS, RBC transfusion dependency, nor VPA addition was predictive of response, but pts with prior LD-AraC had a significant lower reponse rate (24% vs 50% in LD-AraC naive pts, p=0.01). Considering specific cytogenetic abnormalities, response rates were 42% in del5q/-5 (n=59), 38% in del7q/-7 (n=65), 38% in +8 (n=26), 39% in complex karyotype (n=67) and 49% in normal karyotype (n=57) (p=NS). 1 and 2-year OS were 57.9% and 29.7%, respectively, and median OS was 13.7 months. By univariate analysis, pre-treatment parameters negatively influencing OS were transfusion dependency, presence of PB blasts, cytogenetic risk (IPSS), and IPSS high risk. By multivariate analysis, OS was independently influenced by baseline transfusion dependency (≥4 RBC units/8 weeks; 1y-OS 57.5% vs 71.5%, p=0.01), presence of PB blasts (1y-OS 44.6 % vs 74.4%, p=0.02) and cytogenetics (1 y OS 78.2%, 55.8% and 46.4% for fav, int, and unfav, respectively (p=0.009)). In a landmark analysis of OS from first evaluation date, pts with CR, PR or SD with HI-E had improved OS compared to those with marrow CR or SD without HI-E (1-y OS: 71.5% vs 49.6%, p=0.03) and to those who progressed (1y OS=24.4% p=0.002). Overall Survival was significantly longer in pts who achieved HI-E (n=48; 1-y OS from evaluation: 65.4% vs 35.4%, p=0.003), but not in pts achieving HI-N (n=33, p=0.2) or marrow response (ie 〈 5% blasts with 〉 50% decrease; n=47; p=NS), while reaching HI-P had a borderline favorable effect on OS (n=51, p=0.07). Conclusion No pre-treatment parameter (apart from prior LD-AraC treatment) predicted response to AZA. Regarding OS, presence of PB blasts, intermediate or unfavorable cytogenetics and transfusion dependency were associated with poorer survival. Improvement of anemia (and to a lesser extent of platelets) rather than BM blast reduction were associated with survival improvement. Whether other tests, including methylation profiles, may provide further information predicting response to AZA is being evaluated. Disclosures: Fenaux: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Abstract: Background :AZA improves overall survival (OS) in higher risk MDS, but only 50-60% of the patients respond, and median OS with AZA is only 20-24 months. As OS improvement is obtained at modest response rates, OS rather than response should probably remain the primary endpoint for all combinations with AZA, requiring large phase III trials with significant follow up. On the other hand, combinations that do not increase response will likely not improve OS. We therefore tested, based on a "pick the winner" approach, AZA combinations with the HDAC inhibitor VPA, LEN or IDA to identify, based on response, the most promising combination with AZA in higher risk MDS, that could be subsequently compared with AZA alone in a larger phase III study. Methods : AZA-PLUS (#NCT01342692)was an adaptive two-stage phase II trial based on Jung design (Stat Med.2008;27:568) that randomly assigned higher-risk MDS, low blast count AML (20-30%) and CMML to: AZA (75 mg/m2/d d1-7 of 28-day cycles); AZA plus LEN (10 mg/d on d1-14); AZA plus VPA( 50 mg/kg/d on d1-7; 35 mg/kg/d in patients 〉 60y) or AZA plus IDA (10 mg/m2on d1 for the first 9 cycles). The primary end point was response rate (RR, including CR, PR, marrow CR, based on IWG 2006) of the combination arms vs AZA alone. Given a 30% RR with AZA alone, we considered that a ≥45% RR would make combination(s) promising. Controlling for type I and type II errors at 0.15 and 0.20, 40 patients per arm were to be enrolled at each stage. Any experimental arms with RR lower than those observed in the AZA arm at the first stage should be stopped. At the second stage, any arm with 〉 6 more responses than AZA alone should be selected for further testing. Secondary endpoint were ORR (RR+ stable disease with HI (HI) and OS. Results : After inclusion of 40 pts/arm (first stage) all experimental arms had at least the same number of responses as the control arm and were continued in second stage. Overall, 322 pts were enrolled from 06/2011 to 07/2017: 81, 80, 80, 81 in the AZA, AZA+VPA, AZA+LEN and AZA+IDA arms, respectively. Baseline characteristics were well-balanced across arms. Median age was 74.6 y, 213 pts were male, IPSS was INT-2 in 54% and High in 46%. IPSS Karyotype was fav, int and poor in 40%, 26% and 34%, respectively. Pts received a median of 7 cycles and median follow-up was 15.1 months. Prevalence of trial discontinuation due to adverse events was 32%, 29%, 28% and 31% in the AZA , AZA+VPA , AZA+LEN and AZA+IDA arms, respectively (p=0.95). Rates of hospitalization during the first 6 cycles were 38%, 44.7% , 55.1%, 59.7% in the AZA, AZA +VPA, AZA+LEN and AZA+IDA arms, respectively (p=0.028), suggesting increased myelosuppression in the experimental arms, especially in the LEN and IDA arm. In the control arm, 29 responses (CR+PR+mCR) after 6 cycles were observed, with 29, 25 and 29 responses observed in AZA+VPA , AZA+LEN and AZA+IDA arms, respectively. Thus, no combination demonstrated benefit over AZA. The RR was estimated at 34.8% (18.6% CR, 3.1% PR, and 13.0% mCR) and the ORR after 6 cycles was 40.4%. The RR after 6 cycles (35.8% for AZA, 36.2% for AZA+VPA, 31.2% for AZA+LEN, and 35.8% for AZA+IDA) and the ORR after 6 cycles (41.9% for AZA; 41.2% for AZA+VPA, 40.0% for AZA+LEN and 38.3% for AZA+IDA) were close across study arms. By multivariate analysis, factors associated with better ORR were higher Hb level (p=0.05), low fibrinogen (p=0.008) and low LDH (p=0.01). 17 (5%) pts were bridged to allogeneic SCT: 6 on AZA, 5 on AZA+VPA, none in the AZA+LEN arm and 6 on AZA+IDA arm (p=0.03). At the reference date of July 2018, median EFS was 16.6 months for in AZA, 14.5 months for in AZA+VPA, 15.1 months for in AZA+LEN and 13.2 months for in AZA+IDA (p=0.74) (Fig A). Multivariable Cox model selected Hb level (p=0.02), presence of circulating blasts (p 〈 0.0001), LDH (p=0.006) and high IPSS (p 〈 0.0001) as prognostic.Median OS was 24.5 months for AZA, 18.9 months for AZA+VPA, 17.5 months for AZA+LEN and 20.1 months for AZA+IDA (p=0.50) (Fig B). Factors associated with OS were circulating blasts (p=0.003) and high IPSS (p 〈 0.0001). Conclusion : Although OS differences may occur with longer follow up, the combination of VPA, LEN or IDA to AZA did not improve response or OS over AZA alone and worsened myelosuppression. With newer, potentially more potent drugs that can be combined with AZA, the "pick the winner " approach may still be useful to select promising combinations based on response in phase II trials. Molecular data of the pt cohort will be presented at the meeting. Figure. Figure. Disclosures Ades: silent pharma: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; JAZZ: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Laribi:Novartis: Other: Grant and personal fees; Sandoz: Other: Grant; Teva: Other: Grant; Hospira: Other: Grant; Takeda: Other: Grant and personal fees; Roche: Other: Grant; Amgen: Other: Personal fees; Gilead: Other: Personal fees. Stamatoullas:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Consultancy. Beyne-Rauzy:Novartis: Research Funding. Cluzeau:MENARINI: Consultancy; CELGENE: Consultancy; JAZZ PHARMA: Consultancy. Quesnel:Sunesis: Honoraria; Astellas: Honoraria; Novartis: Honoraria; Celyad: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Abstract: Background: AZA significantly improves survival over conventional treatment in higher risk MDS, especially in case of −7/del 7q (ASH 2007, abst n°817). Del 5q is the most frequent cytogenetic abn in MDS. Lower risk MDS with del 5q respond dramatically to lenalidomide (LEN), but the response rate to LEN is lower in higher risk MDS and AML with del 5q, that still have a poor outcome (ASH 2007, abst n°820). We analyzed response to AZA in those pts. Methods: A multicenter patient named treatment program of AZA (75mg/m2/d for 7 days every 28 days) for higher risk MDS and AML (ATU program) was started in France in 2004. The first 195 pts having completed ≥ 1 cycle included 38 pts with del 5q treated in 16 centers, who are analyzed here. Results: Median age was 66y (range 45–82). M/F : 20/18, WHO at inclusion : AML in 14 pts (de novo : 8, post-MDS : 5, post-MPD : 1 ; first-line : 9, relapsing/refractory after intensive chemo : 5), MDS in 24 pts (RCMD-RS : 1; RAEB1 : 4; RAEB2 : 15; RAEBt : 1; CMML : 1; unclass : 2). Del 5q was isolated in 3/38 cases, and with 1 and & gt; 1 additional abn in 4 and 31 cases resp.(31 complex karyotypes). 22/38 pts had concomitant −7/del 7q. In MDS pts, IPSS was int-2 in 5 and high in 19 pts, resp. 6 pts had received LEN without response. Pts received a median of 3 cycles of AZA (range 1–17). The overall response rate (ORR, including CR+ PR+ marrow CR) of pts with del 5q was 11% (4% PR, 7% marrow CR, but no CR). An additional 4% of MDS achieved only HI-E. ORR of del 5q pts was lower than that of pts without del 5q (11% vs 30%, p=0.04). In del 5q pts, the ORR was similar in pts with and without concomitant −7/del 7q (6 vs 13%, p=.56). On the other hand, the ORR was 19% in −7/del7q pts (n=48) and tended to be lower in the presence than in the absence of concomitant del 5q (7% vs 27% resp., p=.09). In the overall group of pts with complex karyotype (n=46), the ORR was 18%, and also tended to be negatively affected by presence of del 5q (9% vs 27%, p=0.2). After adjustment on risk factors in the ATU cohort (including WHO diagnosis and age), del 5q pts still had a poorer ORR (HR=0.26 [0.07–0.91], p=0.035). Median survival after onset of AZA was 9 months in pts with del 5q vs 15 months in pts without del 5q (p=.007), and this difference was confirmed after adjustment on age and WHO diagnosis (HR=050 [0.28–0.89] , p=0.019). In pts with complex karyotype, there was a trend for lower OS in case of del 5q (median 10 m vs 7 m, p=0.25). Conclusion: Those findings suggest that higher risk MDS and AML with del 5q have poorer response rates and survival to AZA as single agent than other high risk MDS and AML, possibly also including pts with complex karyotype without del 5q. Novel therapeutic strategies, combining for example AZA and other drugs, may be required in those pts.

Abstract: In order to improve the outcome observed with azacitidine (AZA) in higher‐risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA‐PLUS was a phase II trial that, in a “pick a winner” approach, randomly assigned patients with higher‐risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six cycles, 69 (21.4%) CR + PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7 months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six cycles were higher in the AZA‐LEN And AZA‐IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy‐related MDS and, in the case of TP53 , PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our “pick a winner” randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA.

Abstract: The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia ( & lt;30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0] ; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23] , P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP & lt;50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count & lt;50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73] , P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Abstract: Despite a low frequency of mutations, BCOR might be considered as a key gene in risk stratification. Deep sequencing technologies show that BCOR mutations commonly arise after other concomitant mutations in MDS.

Abstract: Abstract 843 Background: AZA prolongs survival in higher-risk MDS including patients (pts) with 20-29 % marrow blasts, now considered WHO-AML ( Lancet Onc, 2009). However, no large AML cohorts (especially with '30% marrow blasts) treated upfront with AZA have been reported. Methods: An AZA compassionate program (ATU) was initiated in France in Dec 2004 for higher risk MDS, and AML considered not candidates or refractory to intensive chemotherapy (IC). We retrospectively analyzed WHO AML pts having received at least 1 cycle of AZA in the 42 centers with complete pt reporting, excluding those previously treated by IC, allo SCT, low dose AraC or a hypomethylating agent. Results: 138 pts were included between Dec 2004 and Dec 2008; M/F: 86/52; median age 73 years (y) (range 31-87), 117 pts (85%) were 〉 65 y and 54 (40%) 〉 75y. 65 pts (47%) had prior WHO MDS and 30 pts (22%) therapy related (tAML). 44 pts (32%) had 20-29% marrow blasts. Median WBC was 3.0 G/L [0.8-111.5]. Karyotype (MRC classification), was intermediate (int) in 60 pts,( including 38 normal (NK), and 7 isolated +8 ) adverse in 67 pts (including 42 -7/ del7q, 41 del5q/-5, 45 complex karyotype, two 3q26) and failed in 11 pts. With a median follow-up of 11.3 months, pts received a median of 4.5 AZA cycles (range 1-26). Treatment was according to FDA-EMEA approved schedule for MDS in 95 pts (69%) and a less intensive schedule (5d/4w, or 〈 75 mg/m2/d) in 31% pts, 29 pts (21%) received concomitant valproic acid (VPA). First evaluation was made after 3 to 4 cycles. An overall AML response (ie according to AML-IWG criteria) was observed in 29 pts (21%) including 19 CR (14%), 3 CRp (2%) and 7 PR (5%) after a median of 3 cycles (1 – 11). An additional 25 pts (who had no CR, CRi or PR) achieved hematologic improvement (HI, according to MDS-IWG 2006 criteria). Neither any pretreatment characteristic including age, preceding MDS, tAML, karyotype, WBC, marrow blast %, combination with VPA were correlated with AML response. Median time to progression after AML response was 7.6 months In the 138 pts, 1 y-OS was 40%, 2 y OS 18% and median OS 10.2 months. In univariate analysis, pre-treatment characteristics negatively influencing OS were higher WBC, adverse cytogenetics, higher absolute PB blasts and diagnosis of tAML. In multivariate analysis: higher WBC (p=0.018), and adverse cytogenetics (p=0.0006) retained prognostic significance for OS. In particular, pts with WBC 〉 10 G/L (32 pts in our cohort) carried poorer prognosis ( 1 y OS of 27% vs 44% ,p=0.01); NK had better OS (1-y OS: 66%) than adverse cytogenetics (1-y OS: 30%, p=0.01) but also other “intermediate-risk” abnormalities (1-y OS: 30%, p=0.03). Marrow blast % did not influence OS and survival, whatever the cut off chosen. In particular, pts with 20-29 % marrow blasts had 22% AML response and 1 y OS of 50%, compared to 21% and 1 y OS of 35%, respectively, in pts with 〉 30% marrow blasts (p=NS and NS, respectively). Prior MDS also had no influence on survival. Overall, 33 pts required hospitalization during treatment, mainly for neutropenic fever. A landmark analysis at the time of evaluation showed that achievement of CR, CRi or PR was associated with improved OS (1y-OS 55% vs 31%,p=0.007). In pts with no AML-IWG response, however, achievement of HI also predicted better survival: 1 y-OS 55% vs 19 %, p=0.02. In the 54 pts older than 75 y (ie pts generally considered unfit for IC), 12 (22%) had AML response including CR in 9 (17%) and 3 PR (5%). 1y-OS was 41 % vs 38% for younger pts (p=NS). Hospitalisation was needed in 31% of them vs 32% in younger pts (p=NS). Conclusion: In this untreated cohort of generally older AML pts considered non candidates for intensive chemotherapy, response rate was 21% and 1 y OS 40%. Higher WBC counts and adverse karyotype were associated with poorer OS, but marrow blast %, whatever the threshold chosen, had no influence on outcome. Age above 75 y was associated with similar response and 1y OS. Finally, pts without AML IWG responses but with improved cytopenias also appeared to have improved survival. Disclosures: Off Label Use: Azacytidine is approved by FDA and EMEA in the treatment of high risk MDS and AML up to 30% of bone marrow blast.. Fenaux:CELGENE: Research Funding; AMGEN: Research Funding.