Gore, Steven D.

Background: Chronic myeloid leukemia (CML) is driven by the activity of the oncogenic BCR-ABL tyrosine kinase, which can be effectively inhibited by tyrosine kinase inhibitors (TKIs) leading to prolonged overall and disease-free survival. Despite their effectiveness, disease can progress on TKI therapy, and lifelong treatment with TKI can have substantial negative effects on quality of life and financial health. Studies assessing the safety of TKI discontinuation in CML patients in molecular remission showed that TKIs can be discontinued in up to 45% of patients without disease recurrence. Programmed death receptor-1 (PD-1) is an inhibitory immune checkpoint receptor expressed by T-cells that can be inhibited by the anti-PD-1 monoclonal antibody pembrolizumab. Preclinical data have shown that PD-1 is highly expressed on CML-specific cytotoxic T-cells and PD-1 ligand (PD-L1) is present on CML cells. In murine CML models, the administration of anti-PD-L1 antibodies prolonged survival. As these studies suggest that disease relapse might be due to PD-1/PD-L1 mediated immune escape by CML cells, we designed the BLAST MRD CML 1 trial to study whether adding pembrolizumab to TKI is safe, increases the rate of conversion to undetectable minimal residual disease (UMRD) and allows a higher rate of TKI discontinuation. Methods: The primary endpoint of this ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial is to assess the proportion of CML patients on stable-dose TKI who convert to UMRD during or within 2 years of initiating pembrolizumab therapy (NCT#03516279). Secondary endpoints are (I) the proportion of CML patients who maintain UMRD for 6 months and 12 months, (II) the proportion of CML patients who discontinue TKI after achieving UMRD, (III) the proportion of patients who maintain UMRD off TKI at 2 years after first determined UMRD, and (IV) the incidence of grade 3 or 4 immune related adverse events related to pembrolizumab treatment during the first 2 years after registration. UMRD state is defined as an undetectable BCR-ABL using the central RQ-PCR assay with a sensitivity of 4.5 [MR4.5] on 2 consecutive occasions separated by at least 4 weeks with the date of achievement of UMRD constituting the date of first test. Immune related and other adverse events will be assessed according to CTCAE v 5.0 terminology and grading. Adult (≥18 years) patients with pathologically-confirmed CML and who have achieved major molecular response (MR3) but not UMRD at time of screening are eligible. Eligibility was recently expanded to allow third line TKI. Therefore, currently eligible patients must have been on first, second, or third line TKI therapy with either dasatinib, imatinib, nilotinib, or bosutinib for at least 2 years prior to enrolment. Patients with accelerated or blast phase CML or who have received prior allogeneic hematopoietic stem cell transplant or anti-PD-1/PD-L1 therapy are excluded. Patients will continue a standard dose of TKI therapy and receive pembrolizumab at 200 mg IV every 21 days (Figure 1). MRD status will be assessed centrally every 4 cycles. Patients who achieve UMRD at or prior to cycle 17 will discontinue TKI and pembrolizumab. If MRD remains positive prior to cycle 17, TKI and pembrolizumab will be continued for an additional 18 cycles. If MRD is still detectable after the second year of combined therapy, patients will come off study. If patients are in an UMRD state by the end of year 1 or 2 of pembrolizumab therapy, pembrolizumab will be discontinued. Patients who remain in UMRD status for one year after the first UMRD result will discontinue TKI therapy. Once TKI is discontinued, BCR-ABL will monitored q4 weeks for the first six months post TKI discontinuation, then q8 weeks for the subsequent six months, then q12 weeks for another year. Assuming that the addition of pembrolizumab to TKI will increase the conversion rate to UMRD from 20% to 40%, enrollment of 36 patients (40 patients to allow for 10% drop-out) would give this trial 91% power with a one-sided type-I error of 0.089. The combination therapy will be considered promising if 11 or more patients meet the criteria for TKI discontinuation. Toxicity will be monitored and reviewed every six months. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Cardinal Health: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Taiho: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; CCITLA: Other; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; ADC Therapeutics: Research Funding. Radich:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Bhatt:Incyte: Consultancy, Research Funding; Takeda: Consultancy; Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Abbvie: Consultancy, Research Funding; Pfizer: Research Funding; Partnership for health analytic research: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Hoffman La Roche: Research Funding; Ariad: Research Funding; Biosight: Research Funding.

Introduction: Myelodysplastic syndromes (MDS) are a heterogenous group of blood disorders defined by peripheral cytopenia(s), bone marrow failure, morphological dysplasia, and risk of progression. To understand the genetic, epigenetic and biological factors associated with the initiation and progression of MDS, NHLBI created the National MDS Study (NCT02775383). This is a prospective cohort study conducted at 92 community hospitals and 29 academic centers enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Eligible patients have yet to receive any therapy directed at their cytopenias. Previously untreated cytopenic participants underwent centralized histopathology and data review at the time of enrollment for assignment into distinct subcategories: MDS, MDS/MPN overlap, AML, and Other. Targeted exon sequencing of 96 genes was performed using marrow specimens from the first 300 consecutive individuals in the study. Here we report the genetic mutations for this cohort. Methods: NovaSeq 6000 was used for deep sequencing at a mean coverage of 1,286X and mean breadth (bases covered at ≥100X) of 99.8%. Reads were aligned against build GRCh38 using BWA-MEM, and VarScan2 was used to detect SNVs and INDELS. Variants were filtered for those with an allele base quality of >25 in combination with rule-based and manual review criteria. Subjects in the Other category without an identified malignancy were considered clonal cytopenias of undetermined significance (CCUS) when a mutation or a clonal cytogenetic change was present. Fisher's exact and Wilcoxon rank sum tests in combination with Bonferroni correction were applied to compare groups. Results : A total of 350 putative nonsynonymous pathogenic variants in 36 genes with an allele frequency of >.05 were identified across 150 patients (50%). At least one variant was noted in the following proportion of individuals: 61/72 (85%) with MDS, 13/13 (100%) with MDS/MPN, 15/17 (88%) with AML, and 61/198 (31%) in the Other category, of which 48 were CCUS and 13 were other cancers. Two CCUS patients only had a cytogenetic abnormality. Table 1 shows the distribution of variants in each subcategory of patients for the most commonly mutated genes in our cohort of 300 subjects. Mutations in these genes were enriched in specific groups: SF3B1, STAG2,TP53, and ASXL1 in MDS; TET2 in MDS/MPN; and IDH2 and TP53 in AML (one-sided p<0.0012). None were enriched in the Other group. Within the CCUS subset, 21 genes were mutated, with 37 of 50 (74%) patients having a mutation in TET2, ASXL1, SRSF2, SF3B1, or DNMT3A. The heatmap presented in Figure 1 summarizes variants by subject and allele frequency. Pair-wise comparisons of baseline characteristics of subjects between MDS, MDS/MPN, AML, or CCUS groups revealed no significant differences for age or sex. The CCUS group had significantly higher hemoglobins than the MDS group with median hemoglobin levels of 11.35 and 9.40 g/dL, respectively (p<0.0084). AML had significantly lower platelets compared to all other groups (median of 53 vs. > 110x109/L , respectively, p<0.0084). All groups significantly differed in their median ANC with AML having the lowest (0.8x109/L), followed by MDS (1.5x109/L), CCUS (2.45x109/L), and MDS/MPN overlap (5.95x109/L) (p<0.0084). There was no difference in the median number of variants per patient between groups or correlation with age (rs=0.11, p=0.18). The maximum variant allele frequency (maxVAF) per patient was highest in the MDS/MPN group (median = 0.42, range = 0.38-0.91) and lowest in the CCUS group (median = 0.37, range =0.06-0.98) with the MDS/MPN group having a significantly higher maxVAF compared to the MDS and the CCUS groups (p<0.0084). The proportions of subjects with mutations was similar for those who had abnormal (92% [34/37]) and normal (91% [80/88]) cytogenetics. Conclusions: Incorporation of gene-panel sequencing in the comprehensive evaluation of 300 adult cytopenic patients identified half of the cohort with potentially pathogenic variants. Ultimately, a diagnosis of CCUS was possible in 48 of 183 subjects (26%) not diagnosed with MDS, MDS/MPN overlap syndrome, AML, other cancers or clonal cytogenetics. This study continues to serially bank samples from patients with CCUS, in addition to MDS, MDS/MPN, and ICUS, with the goal to better understand the natural history of these diseases and their progression. Disclosures Lindsley: Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Bejar:Celgene: Consultancy; Takeda Pharmaceuticals: Research Funding; AbbVie/Genentech: Consultancy, Honoraria; Astex/Otsuka: Consultancy; Modus Outcomes: Consultancy; Daiichi-Sankyo: Consultancy. Al Baghdadi:Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Tracon: Equity Ownership; Epizyme: Equity Ownership; Bristol Myer Squibb: Consultancy, Honoraria; Sunesis: Equity Ownership; Portola: Equity Ownership; Heron therapeutics: Equity Ownership; Cardinal health: Consultancy, Honoraria; Bristol Myer Squibb: Equity Ownership; Celgene: Equity Ownership; Spectrum pharmaceutical: Equity Ownership; Astrazeneca: Equity Ownership; Seattle genetics: Equity Ownership; Roche: Consultancy, Honoraria. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Foran:Agios: Honoraria, Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Komrokji:DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; pfizer: Consultancy; celgene: Consultancy; Incyte: Consultancy; JAZZ: Consultancy. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Starczynowski:Kurome Therapeutics: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Background Therapy-related myeloid neoplasm (tMN) includes t-myelodysplasia (tMDS) and t-acute myeloid leukemia (tAML) and are serious late effects of the treatment of cancer. Prognosis of tMN is poor, related to the increased frequency of adverse cytogenetics and other clinical features which predict poor response to conventional treatment. Over the last years, azacitidine (AZA) has become the standard of treatment for high risk MDS (Silverman, JCO 2002; Fenaux, Lancet Oncol 2009) and has shown efficacy in AML. AZA represents an interesting option for patients with tMN considering its safety profile and its efficacy in poor prognosis subgroups of apparently de novo MDS patients including those with monosomy 7. Most prospective trials of AZA have excluded patients with tMN. Most tMN data are retrospective or registry studies (Bally, Leuk Res 2013). This abstract presents the results of 47 t-MN patients prospectively enrolled as a specific cohort in the E1905 study. Methods E1905 study is a randomized phase 2 study from the North American Leukemia Intergroup (NCT00313586, Prebet , ASH 2010) testing 10 days of AZA (50mg/m2/d s.c.) vs. 10 days of AZA + the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). 6 cycles of treatment were planned; responding patients could receive up to 24 cycles. MDS, CMML, and AML with myelodysplasia-related changes were included. Patients with tMN were subsequently accrued as a separate cohort after amendment of the protocol. Response was assessed using IWG 2000 criteria (Cheson et al, Blood 2000); the primary endpoint of the overall trial was achievement of a normal hemogram in 25% of treated patients in either treatment arm. Results A total of 47 patients were included. Median age was 70 years (39y-83y), 45% male, and 94% of patients had ECOG PS 0-1. 29 patients could be subclassified as t-MDS and 18 as t-AML. At inclusion, median peripheral blood counts were: neutrophils 1.0 G/l, Platelets 35 G/L, Hemoglobin 9.2 g/l, peripheral blood blasts 0%, marrow blasts 14.0%. 68% of patients were RBC transfusion dependent and 40% platelet transfusion dependent. As expected, the cytogenetic evaluation showed a high frequency of unfavorable risk cytogenetics (74%) as compared to normal or intermediate risk cytogenetics (26%). Baseline characteristics were not statistically different between the 2 arms. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4 and was significantly higher in patients treated with AZA monotherapy (6 cycles vs.3 cycles, p=0.008). 8 patients in the combination arm and 1 patient in the AZA monotherapy arm died of infection or hemorrhage before cycle 3. In an intent to treat analysis, overall response rates (CR, PR, or trilineage Hematologic improvement) were 11/24 (46%) in AZA monotherapy (95% CI 26 – 67%) and 4/23 (17%) in the combination arm (95% CI 5 – 39%, p=0.06 comparing the two arms). Median overall survival in the two arms were 12.8 months and 5.7 months (p=0.008). Conclusions In this group of very high risk patients with therapy-related myeloid neoplasms, the use of the novel 50 * 10 schedule of azacitidine monotherapy appears effective, with response rates comparable to those for patients with de novo MDS/AML treated on the same protocol (74 pts, 40% with unfavorable cytogenetics, ORR=32%, median OS=18 months). Because there are no prospective data examining the approved dose schedule of AZA (75 mg/m2/day * 7 days), it is not clear if this surprisingly high response rate derives from the current extended schedule of lower dose AZA, or would be true with standard dose AZA as well. This high response may enable many of these patients to proceed to allogeneic stem cell transplant. Entinostat combined with azacitidine at the dose and schedule applied in E1905 does not appear to be effective and tolerable as compared to azacitidine alone. Disclosures: Prebet: CELGENE: Honoraria. Off Label Use: Use of azacitidine in acute myeloid leukemia. Gore:CELGENE: Equity Ownership, Research Funding.

Abstract Background. Gene mutation profiling is increasingly employed for diagnosis, risk stratification, and clinical management in patients with MDS. However, current World Health Organization MDS classification is still based on histologic findings (with the exception of SF3B1 for MDS-RS), and guidelines generally suggest that clinical decisions be guided by clinico-pathologic risk stratification tools such as Revised International Prognostic Scoring System (IPSS-R). We sought to study beliefs and patterns of practice with respect to gene mutation profiling among health care providers who manage patients with MDS. Methods. A link to a 23-question web-based survey was emailed to members of the Eastern Cooperative Oncology Group (ECOG)-ACRIN Cancer Research Group, Alliance for Clinical Trials in Oncology (Alliance), and the Southwest Oncology Group (SWOG), and the Cancer Trials Support Unit (CTSU) on 5/1/2018 with 6 subsequent weekly reminders. The Qualtrics survey platform was used to record anonymous responses. We used descriptive statistics to analyze the data. No incentive was provided for responses. Results. Of 371 received responses, 262 were received from providers who did not manage MDS patients or lacked analyzable data and therefore were excluded. Of 109 eligible responses, 108 responders were from institutions representing 31 US states (one respondent was from South America). Median age of respondents was 48 years (range, 33-75); 43 (39%) were women. A third of responders (32%) worked at a university hospital, while 25%, 17%, and 5% worked at a community hospital, private practice, or other settings, respectively. While 37% of participants worked at institutions with guidelines for clinical care of MDS patients, 28% reported that their institutional guidelines recommended MDS-specific gene mutation profiling. Such testing was performed at institutions of 13% participants; institutions of 26% of responders tested a general AML panel that included MDS-specific genes. The total number of respondents whose institutions sent out either an MDS-specific gene panel or a general AML gene panel with MDS-specific genes was similar, 25% and 12%, respectively (Fig. 1). Of those who routinely perform molecular testing, 94% do so at diagnosis, 56% at relapse, 33% during preparation for stem cell transplant, 31% after the failure of hypomethylating agents (HMA), 24% during screening for a clinical trial, and 15% at initial treatment (Fig. 2). MDS gene mutation profiling was felt to be most helpful in diagnosis (rarely 11%; sometimes 49%; often 30%; always 9%), risk stratification (sometimes 31%; often 51%; always 15%), and prognosis (sometimes 31%; often 51%; always 14%); its role was more limited in response assessment (never 12%; rarely 25%; sometimes 44%; often 14%) and to predict responses to HMAs (never 5%; rarely 28%; sometimes 52%, often 14%) (Fig. 3). Various types of evidence were used to stratify MDS risk and prognosis: genetic mutations were used by nearly everyone (95%); 70% relied on morphologic findings, while gene expression/transcriptome profiling was used by 40%. Eighty-four percent of responders reported relying on conventional prognostic models like IPSS-R to identify high-risk patients for whom they would consider intensive treatment options. For this purpose, 62% would also rely on mutation profiling, and 32% would also consider higher frequency of gene mutations. While mutations in the p53 pathway were felt to be helpful in terms of risk stratification and treatment decisions by 70% of responders, 43%, 39%, 31%, 26% 23%, 20%, and 3% considered mutations in spliceosome, DNA methylation, transcription factors, histone modification, signaling, RAS pathway, and cohesin genes, respectively, to be useful as well. Approximately 31% of responders were not certain as to which mutations would affect risk stratification and management choices and said they needed to review literature. The respondents also cited multiple limitations to wider clinical use of MDS gene mutation profiling (Fig. 4). Conclusions. Our survey demonstrates widespread use of gene mutation profiling in the management of patients with MDS, but also reveals substantial variability in beliefs, practices, testing logistics, and interpretation of molecular profiling. Our findings emphasize the need for high-quality data to develop consensus evidence-based guidelines for gene profiling of MDS patients. Disclosures Sekeres: Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Bejar:AbbVie/Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Foundation Medicine: Consultancy; Astex/Otsuka: Consultancy, Honoraria; Modus Outcomes: Consultancy; Takeda: Research Funding; Genoptix: Consultancy. Gore:Celgene: Consultancy, Research Funding. Zeidan:Ariad: Consultancy, Speakers Bureau; Gilead: Consultancy; Incyte: Employment; Celgene: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy.

Abstract Background: The few therapies available to treat higher-risk MDS and CMML have limited impact on outcome. We previously reported initial results of S1117, which compared overall response rates (ORRs) of azacitidine (AZA) monotherapy to AZA combined with the histone deacetylase inhibitor vorinostat (VOR), or the immunomodulator lenalidomide (LEN)( ASH 2014 LBA-5). We now report updated response data and overall survival (OS), subgroup analyses, impact of cytogenetics, and effect of treatment center volume/centers of excellence on outcome. Methods: This randomized, Phase II study (ClinTrials.gov # NCT01522976) enrolled higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts ≥5%) and CMML adult patients (pts) with <20% blasts from 3/12-6/14 to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Pts continued treatment until treatment failure, defined as disease progression, relapse, significant or unresolved toxicity, or lack of response. Dose reductions occurred for grade ≥3 adverse events (per NCI CTCAE) or delayed count recovery. Cytogenetic risk groups were defined per IPSS-R. The primary endpoint was improvement in ORR, by intention to treat and reviewed centrally, of one of the combination arms vs. AZA per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). OS was from study entry. MDS Centers of Excellence (MCE) were defined per MDS Foundation; center volume was defined as low (1-4 pts enrolled) or high (5-17 pts). Results: Of 277 pts, 92 received AZA, 93 AZA+LEN, and 92 AZA+VOR. Baseline characteristics, previously reported, were similar across arms. Pts received a median of 22 weeks of therapy and were followed for a median of 10 months (range: 0-30). Non-protocol defined dose modification and protocol discontinuation due to toxicity occurred more frequently in combination arms vs. AZA (p=.0014 and p=.018, respectively). Responses are now assessable in all pts (Table 1). ORR was statistically similar for combination arms vs. AZA, with a trend for longer response duration (p=.083) for combinations. Within HI, AZA+LEN pts had higher HI-n than AZA pts (16% vs. 5%, p=.031). ORR for CMML pts was significantly higher for LEN+AZA vs. AZA (63% vs. 29%, p=.04), with a trend for longer response duration for combinations (p=.06); no differences in ORR were seen for therapy-related MDS, IPSS subgroups, or transfusion-dependent pts. Allogeneic transplantation rates were similar. Median OS (Figure) for AZA:AZA+LEN:AZA+VOR was 15:18 (p=.38):17 (p=.17) months; p=.19 for combination arms vs. AZA. Median OS after failure was 7:9 (p=.6):9 (p=.05) months; p=.15 for combination arms after failure vs. AZA. For pts on therapy >6 months, there was a trend (p=.08) for higher ORR for AZA+LEN vs. AZA, though response duration was similar; median OS was 18:21 (p=.44 vs. AZA):21 months (p=.45 vs. AZA). Cytogenetic risk category distribution and ORR was similar across arms. OS (compared to Very Good/Good) was worse for Poor (HR 2.07, p=.022) and Very poor (HR 4.41, p<.001), without significant modification by treatment arm (Table 2). Compared to pts without identified cytogenetic abnormalities (abn), ORR across arms was better for pts with Chr 5 abn (OR 2.38, p=.004); OS was better for normal (HR .42, p<.001) and worse for Chr 5 abn (HR 3.1, p<.001), -7 (HR 2.69, p<.001), and 17p (HR 2.61, p<.001). While small numbers prevented definitive conclusions for treatment arm effect, combinations trended towards improving OS in Normal and Chr 5 abn only. The outcome of all pts and pts on discrete study arms treated at MCE (n=75) or high volume (n=138) sites were similar to non-MCE or low-volume sites for ORR, non-protocol defined dose modifications, dose adjustment in first 4 cycles, time to off-protocol (HR 1.2, p=.21 and HR .94, p=.64), and OS (HR .81, p=.3 and HR .77, p=.12). Conclusions: In higher-risk MDS pts, ORR and OS was similar for AZA monotherapy compared to combination arms, while for CMML pts, ORR was significantly higher with AZA+LEN. For cytogenetic subgroups, OS was worse for Chr 5 abn, -7, and 17p, and may be improved by combinations in normal or Chr 5 abn. MCE or treatment at a high volume site did not impact these effects or outcomes. Figure 1. Responses Figure 1. Responses Figure 2. Cytogenetics Figure 2. Cytogenetics Figure 3. Figure 3. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Honoraria, Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Merck: Consultancy; Celgene: Consultancy. Gore:Celgene: Consultancy, Honoraria, Research Funding. Buckstein:Celgene: Honoraria, Research Funding. Fang:Affymetrix: Research Funding. Attar:Agios Pharmaceuticals: Employment. Erba:Ariad: Consultancy; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees; Seattle Genetics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Millennium/Takeda: Research Funding; Celator: Research Funding; Celator: Research Funding; Astellas: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees; Jannsen (J&J): Other: Data Safety and Monitoring Committees.

Abstract Abstract 4013 Background: In recent years, azacytidine (AZA) has become the standard of treatment for high risk myelodysplasia (MDS). The approved schedule of AZA uses a 75mg/m2/d s.c. regimen for 7 days based on the CALGB-9221 (Silverman, JCO 2002) and the AZA-001 studies (Fenaux, Lancet Oncol 2009). The clinical response rates after AZA have been extensively presented but there is only limited data on the rates of cytogenetic response (CyR). Based on the review of the literature, there are no specific cytogenetic data published on prospective trials. Methods: We based our analysis on a randomized phase 2 study from the US Leukemia Intergroup (E1905 study, NCT00313586) testing 10 days of AZA (50mg/m2/d s.c.) vs 10 days of AZA+ the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). MDS, CMML, and AML with myelodysplasia-related changes were included. This analysis includes all patients with cytogenetic abnormalities (at baseline or acquired following treatment) with available cytogenetic follow-up (cycle 6). Of 150 patients, 70 demonstrated baseline cytogenetic abnormalities. To date, forty patients (27 MDS and 13 AML) were evaluable for both time points. Karyotypes were performed at local laboratories, and reviewed centrally (RPK and GH). Cytogenetic response was assessed using IWG 2000 (Cheson et al, Blood 2000) criteria. Results: The clinical response rate (CR+PR+ trilineage HI) according to IPSS cytogenetic risk stratification were of 20%, 33%, and 35% for favorable, intermediate and poor cytogenetic risk groups respectively (p=NS). Patients with Chr 7 abnormalities (i.e. -7 or -7q, n=18) had a response rate of 28% including 17% CR. Of patients with complete cytogenetic data, the rate of overall CyR was 52% (n=21): 22% (n=9) complete CyR, 30% (n=12) partial CyR. This represents a complete CyR of 13% and a partial CyR of 23% as a proportion of all treated patients with initial cytogenetic abnormalities (including those who did not receive six cycles of therapy). To date, confirmatory FISH analyses were available for 4 patients with CyR (2 CCyR and 2 PCyR). All four had complete clearance of their cytogenetic clone. Among the cytogenetic responders, 15 had MDS and 6 had AML (p=NS). CyR did not differ between the two treatment arms. CyR and clinical response were highly correlated (p<0.001): all patients with complete CyR and 7/10 partial CyR had a clinical CR. Only 3 patients (1 CCyR and 2 PCyR) had a CyR without associated clinical response. Among 8 patients with cytogenetic progression, 3 pts showed increased frequency of a known aberration and 5 showed new or additional aberration including 2 cases involving Chr7. 65 AZA-treated patients from AZA001 had comparable cytogenetic results available. Only 3 patients experienced complete CyR 4.6% with 33.8% partial CyR (n=22). In contrast, the reported rate of clinical response was similar in the two studies. Complete CyR were more frequent in the E1905 10 days AZA schedule compared to the 7 days AZA schedule (p=0.007). There was no difference in overall CyR between the two studies. Conclusions: Both the standard AZA schedule and the 10 day schedule administered on E1905 lead to high rates of cytogenetic response. The novel schedule explored in E1905 demonstrated a particularly high rate of complete CyR (22%) with complete clearance of abnormal clone by FISH in 4 tested patients. Further prospective comparison of different AZA schedules will be needed to confirm this higher rate of complete CyR and determine its clinical significance. Disclosures: Beach: Celgene: Employment. Gore:Celgene: Consultancy, Research Funding, stock options; Syndax: Consultancy.

Abstract Background. Transfusion of blood products is an integral component of the management of patients with acute leukemias. However, high-quality evidence and clinical trial data to support specific practices of blood product transfusion in this population are limited. We hypothesized that there is wide variation in blood product transfusion practices among providers in North America who manage patients with acute leukemia. Methods. A 30-question web-based survey about transfusion practices was emailed to members of the Eastern Cooperative Oncology Group (ECOG)-ACRIN Cancer Research Group, Alliance for Clinical Trials in Oncology (Alliance), and the Southwest Oncology Group (SWOG), and the Cancer Trials Support Unit (CTSU) on 7/6/2015 with 4 subsequent weekly reminders. The distribution list included 9,859 recipients, of whom at least 741 were providers who treated patients with acute leukemia. Responses were anonymous, and the survey distribution was approved by the respective cooperative group chairs. Descriptive statistics were used to analyze the data. Results. Of 254 responses received, 113 were excluded as they were returned by recipients not directly treating patients with acute leukemia. Another 30 responses were excluded due to incomplete data, leaving 111 responses (43.7%) eligible for the primary analysis. Of those, 109 responders were from North America representing 83 institutions in 33 states and the province of Ontario. Eighty-four of the included responders (75.7%) were physicians, and 44 (39.6%) were females. Median age of responders was 44 years (range, 26-76). A hemoglobin (Hb) level of ≤7 g/dL was the most commonly used threshold (44%) for red blood cell (RBCs) transfusions to asymptomatic stable hospitalized patients, followed closely by 8 g/dL (38%) (Figure 1). In the outpatient setting, the most commonly reported threshold was 8 gm/dL (49%) (Figure 1). Most providers reported that they "always" use leukocyte-reduced (93%) and irradiated (79%) RBCs. A platelet level of 10,000/µL was the threshold for platelet transfusions in the stable non-bleeding hospitalized patients cited by the majority of responders (76%) (Figure 2). This platelet level remained the most common threshold for platelet transfusions for non-bleeding patients in the outpatient setting (49%), although 31% of responders reported a higher threshold of 20,000/µL. A preference for single-donor apheresis platelets was reported by 81% respondents, and 57% use these products exclusively. Most providers (70%) reported always using irradiated platelets. With respect to cryoprecipitate and plasma infusions, nearly half of the respondents reported a threshold fibrinogen level of 100 mg/dL as a trigger for administering a product to a stable non-bleeding patient (Figure 3). The most commonly reported platelet threshold for performing a bone marrow biopsy (BMB) was 10,000/μL (69% of responders), followed by 20,000 (21%), 50,000 (6%), and 30,000 (4%). Therapeutic anticoagulation was held by most responders (80%) before performing a BMB. Most responders (73%) reported a platelet level of 50,000/µL as the lowest level for performing a lumbar puncture (LP) without prophylactic platelet transfusion. Conclusions. This survey demonstrates wide variability in blood product transfusion patterns among providers who treat patients with acute leukemias. A platelet level of 10,000/µL is the most common trigger for platelet transfusions for stable non-bleeding patients in both inpatient and outpatient settings. This, along with a platelet threshold of 50,000/µL for performing an LP, appear to be most widely accepted practices. Our findings emphasize the need to obtain high-quality data to develop consensus evidence-based guidelines for transfusion practices in acute leukemia with the goal of limiting unnecessary transfusions without compromising patient outcomes. Figure 1. The most common reported hemoglobin level thresholds for red blood cell transfusions in the inpatient and outpatient settings. Figure 1. The most common reported hemoglobin level thresholds for red blood cell transfusions in the inpatient and outpatient settings. Figure 2. The most common reported platelet level thresholds for platelet transfusions in the inpatient and outpatient settings. Figure 2. The most common reported platelet level thresholds for platelet transfusions in the inpatient and outpatient settings. Figure 3. The most common reported fibrinogen level thresholds for cryoprecipitate or plasma transfusions in the inpatient and outpatient settings. Figure 3. The most common reported fibrinogen level thresholds for cryoprecipitate or plasma transfusions in the inpatient and outpatient settings. Disclosures Sekeres: TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Onconova: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Prebet:CELGENE: Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding. Stone:Merck: Consultancy; AROG: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Novartis: Research Funding; Juno: Consultancy; Amgen: Consultancy; Roche/Genetech: Consultancy; Celator: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy. Erba:GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; Millennium/Takeda; Celator; Astellas: Research Funding; Seattle Genetics; Amgen: Consultancy, Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Barbarotta:Celgene, BMS, Novartis: Speakers Bureau. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract Among mechanisms underlying cytotoxic drug resistance is activation of diverse DNA damage response (DDR) pathways. Poly(ADP-ribose) polymerases (PARP)-1/2 facilitate both single- and double-strand break (DSB) repair and play a key role in the base excision repair (BER) of chemotherapy-damaged DNA. The PARP inhibitor veliparib (V) potentiates the cytotoxicity of different chemotherapeutics, including temozolomide (TEM). TEM induces distinct alkylating events in neoplastic cells whose ultimate outcome depends on the interaction of BER, mismatch repair (MMR), O(6)-methylguanine-DNA methyltransferase (MGMT), and DSB repair. While clinical activity of TEM has been mainly observed in MGMT-deficient AML, V potentiated cytotoxicity of TEM in leukemia cells in vitro in the setting of MGMT overexpression or deficient MMR pathway (Mol Cancer Ther, 2009). Methods: We conducted a Phase I study to determine maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of V+TEM, using a 3+3 dose escalation. Patients (pts) ≥60 years (yrs) with newly diagnosed poor cytogenetic-risk AML/ALL who were not candidates for intensive therapy, or ≥18 yrs with relapsed/refractory AML/ALL, secondary AML (therapy-related or arising from MDS or MPN), and CMMoL-2 were eligible. Any number of prior regimens, including allogeneic transplant (alloSCT), were allowed. V was given orally day (d)1 once, then twice a day on d4-12 at one of 6 dose levels (DL) (DL1A-B 20mg; DL2-DL3-DL4-DL5-DL6: 40-80-120-150-200 mg). TEM was given orally once a day on d3-9 (DL1A 150 mg/m2/d; DL1B-DL6 200 mg/m2/d). 28-day cycles (cy) were repeated depending on response/tolerability (4-6 weeks delay allowed) with V on d1-8 and TEM d1-5. TEM was taken on empty stomach with antiemetics and V was taken irrespective of meals. Results: Forty-nine pts with median age 69 yrs (range, 22-88; 47% ≥70) were treated. Of 47 AML pts, 29 (62%) had secondary AML and 27 (57%) adverse karyotype. Median number of prior treatments for AML was 1 (range, 0-6): 18 (38%) had median 1 prior therapy (range, 1-3) for MDS; 30 (64%), 9 (18%), 34 (69%) received hypomethylating agents, alloSCT and intensive chemotherapy, respectively. Overall 42 (85%) pts were refractory to their last treatment. Pts received a median of 1 (range, 1-7) cy of therapy. Two did not complete cy 1, pt withdrawal d5 and progressive fungal pneumonia d9 with death d15 of progressive disease (PD). The MTD/RP2D was defined at V 150 mg and TEM 200 mg/m2; 2 of 4 pts treated at V 200 mg and TEM 200 mg/m2 developed dose-limiting toxicity of grade (gr) 3 oral mucositis/esophagitis. The most frequent drug-related toxicities (NCI CTC v4) were gr 1/2 nausea/vomiting (39%), fatigue (26%), oropharyngeal mucositis (26%), constipation (12%), and diarrhea (10%). Other common toxicities were infectious, including febrile neutropenia (29%), pneumonia (20%), bacteremia (18%). One (2%) pt died ≤d30 and 12 (24%) ≤d60 mainly of PD (1 pt fungal pneumonia before count recovery d31). Overall response rate was 33% (complete remission (CR), hematologic improvement (HI)/stable disease) with 8 (16%) pts achieving CR (1 CRi). Median overall survival was 5.03 months, for all responders 11.58 months, and for CR pts 19.89 months (Fig 1). Responses occurred at all DLs. Three CR pts underwent alloSCT; 2 remain in CR at ~3 yrs. Pharmacokinetics (PK): V or TEM PKs were not altered with co-administration. There was a correlation between the DLT of mucositis and V single (Cmax P=0.005; AUC P=0.009) and multiple dose exposure (Cmax P = 0.02; AUC P=0.03). Pharmacodynamics and pharmacoepigenetics: Four of 39 pts examined had MGMT methylation (3 CR; 75%) and 2 had BRCA-1 methylation (1 HI) in peripheral blood (PB) or bone marrow (BM) mononuclear cells (MC). Defective FancD2 pathway was observed in the BMMC of 19/19 pts using FancD2 ubiquitylation assays but did not correlate with response. V reduced PAR levels by >75% in PBMC of most pts and in the presence of TEM. Induction of γ-H2AX in CD34+ cells was seen upon V/V+TEM treatment. Conclusion: V plus TEM demonstrated safety and activity in this resistant and elderly leukemia population. Response rate was higher in MGMT methylated pts, but responses were also seen in pts who had no MGMT methylation, had failed multiple therapies, had secondary AML and/or adverse karyotype. Future clinical study should aim to identify pts with defective DDR pathways who are most likely to respond to this therapeutic approach. Figure 1. Figure 1. Disclosures Off Label Use: Temozolomide is not approved for AML. Beumer:Millenium: Other: Research support. Gore:Celgene: Consultancy, Honoraria, Research Funding.

Abstract Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown. Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%. Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA). Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. Table Table. Figure Figure. Disclosures Sekeres: Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.