ALBERT

Description: Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p

Description: Ten-eleven translocation 2 (TET2) dioxygenase mutations resulting in enzymatic deficiency are among the most frequently reported molecular aberrations in myeloid neoplasms. Accumulating evidence indicates that biological interactions between TET2 deficiency and other molecular lesions are important drivers of myeloid disorder. For example, microbial-mediated innate immune signaling was demonstrated to play a critical role in promoting myeloproliferation in mice with TET2 deficiency. Histone demethylase KDM6B is an innate immune signal activator downstream of Toll like receptors (TLR) and is overexpressed in bone marrow (BM) hematopoietic stem and progenitor cells (HSPC) from patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). We previously demonstrated that overexpression of KDM6B in the hematopoietic compartment of mice led to a MDS-like phenotype and hyperactivation of innate immune signals (Wei Blood Advances 2018). These observations suggest that KDM6B overexpression and consequent innate immune deregulation may cooperatively interact with TET2 deficiency to drive myeloid disorders. In support of this hypothesis, transcriptomic analysis in the BM HSPCs of patients with MDS and CMML revealed that patients with concurrent KDM6B overexpression and TET2 deficiency had significantly increased activation of innate immune genes and signals. To investigate the interaction between KDM6B overexpression and TET2 deficiency, we developed a "double lesion" mouse model with both KDM6B overexpression and TET2 deficiency by crossing Vav-KDM6B mice with TET2flox/flox/Vav-Cre mice. Double lesion mice exhibited significant monocytosis compared to Vav-Cre or TET2 deficient mice (p=0.02 and p=0.03). Double lesion mice also experience reduced hemoglobin (p=0.01 and p=0.01) and splenomegaly (p=0.004 and p=0.01). Myeloid skewing was observed in the BM of double lesion mice as large expansile aggregates of immature myelomonocytic precursors, increase of Gr-1+ myeloid cells (p=0.001 and p=0.01), and decrease of Ter119+ erythroid cells (p=0.01 and p=0.02). An increase in the BM Lin-/Sca1+/cKit+ (LSK) population was also observed in double lesion mice (p=0.004 and p=0.05) particularly in aged mice (50-60 week old). Moreover, the BM of double lesion mice exhibited increased repopulating function, illustrated by higher chimerism of CD45.2 donor cells in CD45.1 recipient mice 6 months following competitive transplantation (p=0.004 and p=0.04). Overall, the MDS/CMML-like hematopoietic phenotype observed in double lesion mice, which was more significant than that observed in TET2 deficient single lesion mice, indicated that overexpression of KDM6B and TET2 deficiency cooperatively altered hematopoiesis and promoted development of myeloid disorders. To identify the biological mechanisms underlying the cooperative impact of KDM6B overexpression and TET2 deficiency in BM HSPCs, we performed transcriptomic analysis on LSKs collected from double lesion, TET2 deficient, Vav-KDM6B, and Vav-Cre mice. RNA-Seq illustrated hyper-activation of multiple innate immune pathways in the LSK of double-lesion mice compared to the other groups. Consistently, peripheral blood cytokine levels of TNF, IL-1, and IL-6 were significantly elevated in double lesion mice. RNA-Seq also revealed that the LSKs of double-lesion mice displayed significant down-regulation of cell cycle checkpoint and DNA repair signals. This finding was confirmed by the observation of increased phosphorylated γH2AX and aneuploidy in hematopoietic cells from double lesion mice. Finally, we applied GSK-J4, an inhibitor KDM6 proteins, to the BM LSKs from each mouse cohort and performed methylcellulose medium supported colony formation assays. Significantly reduced colony formation was observed in both the double lesion and TET2 deficiency groups (p

Description: INTRODUCTION: Most clinical trials exclude patients with poor performance, organ dysfunction, and presence of other active malignancies or comorbidities. Although some of these criteria are based on clinical reasoning, patients with such clinical features have dismal expected outcomes and limited therapeutic options and could therefore have a more favorable risk/benefit ratio if treated with a low intensity investigational intervention. The current study was designed to test whether it is feasible to treat patients not eligible for conventional studies in a clinical trial. METHODS: We conducted an initial Bayesian designed single-arm study and a subsequent randomized study for patients with AML or higher-risk MDS (intermediate-2 or high risk by IPSS) with either ECOG performance status (PS) ≥3, creatinine or bilirubin ≥2mg/dL, presence of other malignancy or other comorbidities. Primary endpoint was survival at day 60. The study included stopping rules for survival, response and toxicity. All patients received azacitidine 75mg/m2 sc daily for 5 days. Patients in the single-arm study and in the combination arm of the randomized study also received vorinostat 200mg tid for 5 days. Cycles could be repeated every 3-8 weeks. Responses were evaluated following the revised 2006 IWG criteria for patients with MDS and the IWG 2003 recommendations for patients with AML. Comorbidities were evaluated using the Adult Comorbidity Evaluation-27 (ACE-27) index. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 30 patients (16 with MDS, 14 with AML) were enrolled in the initial single-arm study. Patient characteristics and inclusion criteria are detailed in Table 1. Median age was 73 years (44-83). Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. Median number of cycles administered was 3.5 (1-12). The overall response rate (ORR) was 40% with 8 (27%) patients achieving CR, 4 with AML and 4 with MDS. Median OS was 7.8 months (0.3-29, CI 7.54-8.03) (Figure 1A) and median EFS was 5.1 months (0.3-15.9, CI 4.87-5.37) (Figure 1B). Stopping rules for survival and response were not met. Main adverse events (AEs) where grade 1-2 gastrointestinal toxicities. Mortality at 4 and 8 weeks was 10 and 20% respectively. A total of 79 patients were enrolled in the subsequent randomized study: 27 to azacitidine (A) and 52 to azacitidine and vorinostat (A+V). Patient characteristics and inclusion criteria are also shown in Table 1. Median age was 70 years (30-90). Forty-seven (59%) patients had MDS and 32 (41%) had AML. Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rates were 67% (A) and 85% (A+V), respectively (p=0.07). No differences in ORR (48% vs 46%, p=0.87), OS (6.1 vs 7.6 months, p=0.49) (Figure 1C) or EFS (3 vs 5.5 months, p=0.05) (Figure 1D) were observed between groups. Main AEs included grade 1-2 gastrointestinal toxicities with a higher proportion of AEs with A+V (81 vs 56%). Mortality at 4 and 8 weeks was 10% (A: 4, A+V: 4) and 19% (A: 9, A+V: 6) respectively. By univariate analysis neither PS ≥3, creatinine or bilirubin ≥2mg/dL nor presence of other malignancy were predictive for 60-day survival, OS or EFS. There were no significant differences in survival between patients with ACE-27 scores of 0-1 compared to 2-3 both in the single-arm (6.3 vs 7 months, HR=0.88, 95% CI 0.41-1.91, p=0.75) and the randomized phase of the study (A: 13.5m vs 6.1m, HR 0.93, 95% CI 0.27-3.17, p=0.9 and A+V: 12.1m vs 7.4m, HR 1.38, 95% CI 0.61-3.14, p=0.4). CONCLUSION: Most enrolled patients met the study's primary endpoint of survival at 60 days without major toxicity. Patients obtained clinical benefit with acceptable responses and survival despite their high comorbidity burden. Our results support the feasibility of treating patients with MDS or AML not eligible to other clinical trials due to poor performance status, comorbidities or organ dysfunction, with low intensity therapies within a clinical trial. These findings suggest relaxation of such criteria may likely increase the pool of clinical trial patient candidates and allow access to potential beneficial therapies for patients with otherwise dismal prognosis. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DiNardo:Abbvie: Research Funding; Novartis: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Abbvie: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Jain:Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria.

Description: Background: Myelodysplastic syndrome (MDS) is a heterogeneous malignant myeloid neoplasm of hematopoietic stem cells due to cytogenetic alterations and somatic mutations in genes (DNA methylation, DNA repair, chromatin regulation, RNA splicing, transcription regulation, and signal transduction). Hypomethylating agents (HMA) are the standard of care for MDS, and 40-60% of patients achieved response to HMA. However, the prediction for response is difficult due to the nature of heterogeneity and the context of clinical conditions such as the degree of cytopenias and the dependency on transfusion. Machine learning outperforms conventional statistical models for prediction in statistical competitions. Prediction with machine learning models may predict response in patients with MDS. The aim of this study is to develop a machine learning model for the prediction of complete response (CR) to HMA with or without additional therapeutic agents in patients with newly diagnosed MDS. Methods: From November 2012 to August 2017, we analyzed 435 patients with newly diagnosed MDS who received frontline therapy as follows; azacitidine (AZA) (3-day, 5-day, or 7-day) ± vorinostat ± ipilimumab ± nivolumab; decitabine (DAC) (3-day or 5-day) ± vorinostat; 5-day guadecitabine. Clinical variables, cytogenetic abnormalities, and the presence of genetic mutations by next generation sequencing (NGS) were included for variable selection. The whole cohort was randomly divided into training/validation and test cohorts at an 8:2 ratio. The training/validation cohort was used for 4-fold cross validation. Hyperparameter optimization was performed with Stampede2, which was ranked as the 15th fastest supercomputer at Texas Advanced Computing Center in June 2018. A gradient boosting decision tree-based framework with the LightGBM Python module was used after hyperparameter tuning for the development of the machine learning model with training/validation cohorts. The performance of prediction was assessed with an independent test dataset with the area under the curve. Results: We identified 435 patients with newly diagnosed MDS who enrolled on clinical trials as follows: 33 patients, 5-day AZA; 23, 5-day AZA + vorinostat; 43, 3-day AZA; 20, 5-day AZA + ipilimumab; 19 patients, AZA + nivolumab; 7, AZA + ipilumumab + nivolumab; 114, 5-day DAC; 74, 3-day DAC; 4, DAC + vorinostat; 97, 5-day guadecitabine. In the whole cohort, the median age at diagnosis was 68 years (range, 13.0-90.3); 117 (27%) patients had a history of prior radiation or cytotoxic chemotherapy; the median white blood cell count was 2.9 (×109/L) (range, 0.5-102); median absolute neutrophil count, 1.1 (×109/L) (range, 0.0-55.1); median hemoglobin count, 9.5 (g/dL) (range, 4.7-15.4); median platelet count, 63 (×109/L) (range, 2-881); and median blasts in bone marrow, 8% (range, 0-20). Among 411 evaluable patients for the revised international prognostic scoring system, 15 (4%) had very low risk disease; 42 (10%), low risk; 68 (17%), intermediate risk; 124 (30%), high risk; and 162 (39%), very high risk. Overall, 153 patients (53%) achieved CR. Hyperparameter tuning identified the optimal hyperparameters with colsample by tree of 0.175, learning rate of 0.262, the maximal depth of 2, minimal data in leaf of 29, number of leaves of 11, alpha regularization of 0.010, lambda regularization of 2.085, and subsample of 0.639. On the test cohort with 87 patients, the machine learning model accurately predicted response in 65 patients (75%); 53 non-CR among 56 non-CR (95% accuracy); and 12 CR among 31 CR (39% accuracy). The trend of accuracy improvement by iteration (i.e., the number of decision trees) is shown in Figure 1. The area under the curve was 0.761521 in the test cohort. Conclusion: Our machine learning model with clinical, cytogenetic, and NGS data can predict CR to HMA in patients with newly diagnosed MDS. This approach can identify patients who may benefit from HMA therapy with and without additional agents for response, and can optimize the timing of allogeneic stem cell transplant. Disclosures Sasaki: Otsuka: Honoraria; Pfizer: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:syros: Honoraria; jazz: Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Takeda: Honoraria; BMS: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding. 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.

Description: Introduction Patients with AML are inmmunocompromised because of the disease itself and the use of chemotherapy, increasing endemic opportunistic infections. The main complication is secondary infectious diseases, which we have to consider TB. In cancer patients infected with TB frequently manifest more atypical. Clinical signs and symptoms include lung disease which is still the most commonly involved site, extra pulmonary tuberculosis is not uncommon. Even that we're in an endemic country we still have some delay in the diagnosis of such disease. Objective To characterize the clinical and factors that contributes to the delay on the diagnosis of tuberculosis in patients with AML. Methods We did a chart review of patients with the diagnosis of TB and AML in the Instituto Nacional de Cancerologia, Mexico City, from January 2014 to July 2019. We analyze the clinical presentation of and the time to diagnosis TB in those patients. Results We analyze a cohort of 5 patients, three male and two female with a median age of 44 years old. The majority of patients were on induction chemotherapy. The main clinical presentation was persistent fever that begins in the nadir of chemotherapy. We observed a median of days for the diagnosis of tuberculosis of 37 days (9-82), the diagnosis was made by histopathology supported by special stains, and were required at least two biopsies for the diagnosis. One patient has pulmonary tuberculosis, one nodal presentation, two have a hepatosplenic presentation, and in the last patient was conclude latent TB. Just in one patient was available the microbiological identification, Mycobaterium bovis. Four patients started the approved treatment in Mexico, intensive phase with rifampicin, pyrazinamide, ethambutol and isoniazid. One patient develop Drug induce liver injury (DILI) so she couldn't continue the first line treatment and have to receive the second line which it is not standardize. After the initiation of the treatment, patients went out of fever and improve their condition. The patients were followed during the maintenance phase with rifampicin, and isoniazid. All of the patients are alive at the moment of the study. Conclusion: Febril neutropenia is a common complication in patients with AML, and in patients with persistent fever, tuberculosis should be include in the differential diagnosis. In México we have limited access to all the diagnostic tools available in our center. Culture is not always a way to identify TB, most of our patients were diagnosed by biopsy, median number of procedures were 3. Patient number 5 was followed by the infectology service after the whole protocol of culturing TB were concluded with no evidence of the disease and they decide to stop the treatment, and they manage the patient as latent TB. The availability of the techniques is the main factor which contributes to the diagnosis delay of TB. After the treatment was started, patients have a significant clinical improvement. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: The hypomethylating agents (HMA) are the standard of care for a majority of patients with higher-risk MDS. SGI-110 is a second generation HMA that molecularly is a dinucleotide derivative of decitabine and therefore a more potent inhibitor of DNA methyltransferase activity. SGI-110 is currently being studied in front-line AML and second-line MDS multicenter studies. Here we present results of a single arm phase II trial of SGI-110 for patients with previously untreated MDS. Methods: Patients, age 18 or older, with adequate renal and hepatic functions, with int-2 or high risk MDS by IPSS or more than 10% blasts in bone marrow were eligible. One prior cycle of azacitidine or decitabine was allowed. No prior other therapies were allowed. SGI-110 was administered at a dose of 60 mg/m2 SC daily x 5 days every 4 weeks. The study was designed with stopping rules for response, toxicity, and mortality (first 3 months). A maximum of 100 patients could be treated. Results: From 11/14/2014 to 7/31/2018, 94 patients have been treated. Median age was 69 years (22.7-91.9), 72 patients (77%) had INT-2, 13 patients (14%) high risk. Median % of marrow blasts was 10 (range, 0-20). Median white blood cell count and platelet count were 2.5 (×106/L), and 52 (×106/L) respectively. Twenty two patients (23%) were diploid, 36 (38%) complex, and 33 (35%) others. Mutation distribution was as follows: TP53, 29 (31%); ASXL1, 26 (28%); TET2, 20 (21%); RUNX1, 19 (20%); RAS, 12 (13%); DNMT3A, 10 (11%); EZH2, 9 (10%); SRSF2, 6 (7%); PHF6, 4 (4%); BCOR, 3 (3%); CEBPA, 3 (3%); SF3B1, 3 (3%); IDH2, 3 (3%); BRAF, 2 (2%); CBL 2 (2%); MPL, 2 (2%); NPM1, 2 (2%); U2AF1, 2 (2%); WT1, 2 (2%); CREBBP, 1 (1%); ETV6, 1 (1%); FLT3-ITD, 1 (1%); GATA2, 1 (1%); IDH1, 1 (1%); SETBP1, 1 (1%); ZRSR2, 1 (1%). The median number of cycles received was 5 (range 1 - 32). Ninety four (100 %) patients are evaluable for toxicity. Early mortality was 0%. Common toxicities were fatigue (61%), infection (46%), nausea (27%), pain (19%), and constipation (16%), mucositis (16%), dyspnea (15%), local injection toxicity (15%), and diarrhea (12%). Eighty seven (93%) patients were evaluable for response. The median number of cycles to response was 3 (range 1 - 11). Overall response rate was 53 (61%); CR 19 (22%), CRp 3 (3%), HI 31 (36%), SD 5 (6%), NR 27 (31%), and died 2 (2%). With a median follow-up of 15 months, the median OS was 15 months and the median EFS was 14 months (Figure 1). By UVA, higher ACE-27 score showed tendency of lower rates of response (p=0.063; hazard ratio [HR], 1.383; 95% confidence interval [CI], 0.982-1946). However, MVA did not show any prognostic factors for response. By MVA characteristics associated with survival were: complex karyotype (p=0.036; HR, 2.345; 95% CI, 1.055-5.210), and response to therapy (p=0.003; HR, 0.272; 95% CI, 0.114-0.648). In conclusion: SGI-110 is well tolerated in previously untreated MDS. ORR appears to be better than expected compared to azacitidine or decitabine. Longer follow-up and randomized trials will be needed to understand effect on survival. Figure. Figure. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Bose:Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Pfizer, Inc.: Research Funding. Daver:Pfizer: Consultancy; Karyopharm: Research Funding; Novartis: Consultancy; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; ARIAD: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Incyte: Consultancy; BMS: Research Funding; Otsuka: Consultancy; Alexion: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding. Ravandi:Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. DiNardo:Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Abbvie: Honoraria; Bayer: Honoraria; Medimmune: Honoraria. Pemmaraju:SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Kadia:Novartis: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Takeda: Consultancy.

Description: Background We conducted an investigator-driven, multicenter, open label, randomized study to establish whether the source of factor VIII (FVIII) replacement (plasma-derived, pd; or recombinant, r) affects the rate of inhibitory alloantibodies in previously untreated patients (PUPs) with severe hemophilia A. Methods Between 2010 and 2014, 303 PUPs who provided consent through their tutors were screened at 42 participating sites in 14 countries from Africa, the Americas, Asia and Europe. The original aim was to screen 300 patients, randomize 270 (10% screening failure) and follow them for 50 exposure days (ED) or 3 years. Once the intended numbers were included, follow-up was terminated due to logistic and budgetary reasons. Screening criteria were age 5 treatments with blood components and 10 were not infused after randomization. The remaining 251 patients were analysed and 35 had truncated follow-up (25 dropout, 10 study termination). Patients were aged 0-81 months at randomization (median 14 months) and received between 1 and 50 infusions of FVIII concentrates (median 22). Of those who did not develop an inhibitor, over 70% had 〉20 ED. 76 patients developed an inhibitor, of which 50 were high-titred. The cumulative inhibitor incidence was 35.4% (95% confidence interval (CI95) 28.9-41.9%). 90% of inhibitors developed within 20 EDs, both for all and high-titre inhibitors. After randomization 125 patients received pdFVIII and 126 rFVIII. The putative confounders were equally divided between the two product class arms. There were 29 inhibitors (20 high-titred) in the group treated with the class of pdFVIII and 47 (30 high-titred) in those treated with rFVIII. The cumulative inhibitor incidence was 26.7% (CI95 18.3-35.1%) for pdFVIII and 44.5% (CI95 34.7-54.3%) for rFVIII (Figure). For high-titre inhibitors the cumulative incidence was 18.5% (CI95 12.1-26.9%) for pdFVIII and 28.4% (CI95 19.6-37.2%) for rFVIII. By univariate Cox regression analysis rFVIII was associated with an 87% higher incidence of inhibitors than pdFVIII (hazard ratio (HR) 1.87, CI95 1.18-2.97). For high-titre inhibitors the rate was 70% increased (HR 1.70, CI95 0.96-2.99). The associations did not materially change after adjustment for putative confounders: in adjusted models the rate remained 70-90% elevated for rFVIII vs pdFVIII. When analysis was restricted to sites that had not randomized patients to a second generation full length rFVIII or pdFVIII (n=131 patients, 25 inhibitors), the risk of other rFVIII concentrates vs pdFVIII was still twofold increased (HR 1.99, CI95 1.00-3.99). Conclusions The rFVIII product class was associated with a 1.87-fold higher incidence of inhibitors than the pdFVIII class. This difference remained even when second generation full length rFVIII concentrate was excluded from the analyses. The results of this randomized study have implications in the choice of product for management of PUPs, as inhibitor development remains a major challenge in the management of haemophilia A. (Funded by the Angelo Bianchi Bonomi Foundation, Italian Ministry of Health, Grifols, Kedrion and LFB - Registed at EudraCT 2009-001186-88). Figure 1. Figure 1. Disclosures Peyvandi: Octapharma: Other: Investigator; LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding. Mannucci:Novonordisk, Grifols, Kedrion, Bayer, Biotest, Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Karimi:Octapharma: Other: Investigator. Young:Baxter, Grifols: Consultancy, Honoraria. Santagostino:Roche: Speakers Bureau; Bayer: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Octapharma: Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Speakers Bureau; Biogen/Sobi: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Mancuso:Baxter, Pfizer, CSL Behring, Baxter, Sobi/Biotest: Consultancy; Novo Nordisk, Bayer: Speakers Bureau. Mahlangu:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bonanad:Baxalta: Research Funding. Ewing:Baxter, Novo Nordisk, Grifols, Bayer, Kedrion: Honoraria. Owaidah:King abdulaziz city for science, Novo Nordisk, Bayer: Honoraria, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Kavakli:Baxter: Other: advisory board member and received educational and investigational support; Bayer: Other: advisory board member and received educational and investigational support; Novo Nordisk: Other: advisory board member and received educational and investigational support; Pfizer: Other: advisory board member and received educational and investigational support; Bio Products Laboratory: Other: received educational and investigational support; CSL Behring: Other: received educational and investigational support; Octapharma: Other: received educational and investigational support. Manco-Johnson:Baxter, bayer, biogen, CSL Behring, NovoNordish: Honoraria. Neme:Novo Nordisk and Pfizer: Other: fees for speaking. Wicklund:NovoNordisk, Bayer, Baxter (now Baxalta), Biogen-Idec, CSL-Behring, National Hemophilia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zulfikar:Eczacýbaþý-Baxter, Pfizer, Novo Nordisk: Consultancy, Honoraria, Research Funding.

Description: Background Multi-agent combination chemotherapy regimens for the treatment of ALL are considered a cancer success story in the pediatric setting. For adults, the same magnitude of success has not been realized using similar strategies. These regimens produce high complete remission (CR) rates of 80-90% but the cure rates are 40-50%. The incorporation of targeted agents (tyrosine kinase inhibitors and monoclonal antibodies) has improved survival and cure rates in adult ALL subsets. Blinatumomab, a bispecific T-cell engaging (BiTE) CD19-CD3 antibody, is effective in patients with relapsed/refractory disease and in patients with measurable residual disease (MRD). Better outcomes were obtained when blinatumomab was administered earlier in the course of the disease. We hypothesized that incorporating blinatumomab in sequential combination with Hyper-CVAD in previously untreated patients with ALL would improve the eradication of MRD, decrease the need for intensive chemotherapy, and improve survival. Methods Patients were eligible to participate in this phase 2 single-arm study if they were at least 14 years old, had newly diagnosed untreated Philadelphia-negative B-ALL or B-cell lymphoblastic lymphoma, had ECOG performance status (PS) of 0-3, and normal liver, kidney and cardiac function. Patients in CR after one prior course of chemotherapy were also eligible. Therapeutic regimen consisted of 4 alternating cycles of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone, cycles 1 & 3) and high-dose methotrexate/cytarabine (cycles 2 & 4) followed by 4 consecutive cycles of blinatumomab (4 weeks every 6 week-cycle). All patients received 8 prophylactic intrathecal injections with methotrexate and cytarabine during the first 4 cycles of treatment. Additionally, patients with CD20+ ALL (≥ 1% cells) received a total of 8 doses of rituximab (375 mg/m2) or ofatumumab (2000 mg) during the hyper-CVAD cycles. Maintenance phase consisted of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) on cycles 1-3, 5-7, 9-11 and 13-15 alternating with blinatumomab on cycles 4, 8 and 12. The primary outcome was relapse-free survival (RFS) and secondary outcomes were overall survival (OS), overall response rate and MRD negativity rate. Results To date, 17 patients were treated, three of them enrolled in CR after 1 cycle of Hyper-CVAD. Patient's characteristics are summarized in Table 1. Median age is 43 years (range, 20-59). All but one patient had CD20 expression. Six patients (35%) had TP53 mutations. Four patients (24%) had low hypodiploidy-near triploidy. One patient (6%) had CRLF2 overexpression. All 14 evaluable patients achieved CR for an overall response rate of 100%. Minimal residual disease (MRD) negativity, assessed by 6-color multicolor flow, was achieved in 93% of the patients after one cycle of therapy. No early death within 6 weeks was reported. Patients have received a median of 4 cycles (1-4) of chemotherapy and 4 cycles (0-4) of blinatumomab. Two patients had early relapse during the Hyper-CVAD cycles after 2 and 4 cycles, respectively. Three patients underwent allogeneic stem cell transplantation (HSCT) (1 with histiocytic proliferation in the bone marrow, 1 with t(4;11) and 1 with CRLF2+ ALL). A total of 14 patients have initiated the blinatumomab phase. Nine patients received the total 8 courses of hyper-CVAD and blinatumomab and are currently receiving maintenance in CR. The treatment was well tolerated. Grade 3-4 adverse events attributed to blinatumomab occurred in 2 patients (12%) and were manageable and reversible. One patient developed transient Grade 3 cytokine release syndrome and one had Grade 3 ataxia. Both recovered after holding blinatumomab therapy and dexamethasone administration. Treatment was resumed thereafter with no recurrence. With a median follow up of 14 months (range, 3-20 months), 16 patients (94%) are alive (14 of them in first CR); one patient died after HSCT of a transplant-related complication. The 1-year RFS rate was 77% (95% CI 42-93%) (Figure 1A) and the 1-year OS rate was 90% (95% CI 47-99%) (Figure 1B). Conclusion The sequential combination of Hyper-CVAD and blinatumomab in newly diagnosed adult patients with B-ALL is safe and highly effective. These early results are favorable. The study continues to accrue patients. Disclosures Short: Takeda Oncology: Consultancy. Ravandi:Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria. Cortes:Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Jain:BMS: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Servier: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Verastem: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Cellectis: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Jabbour:Abbvie: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

Description: Background: Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5-10% of patients (pts) with myelodysplastic syndrome (MDS) and are frequently associated with intermediate-risk cytogenetics, excess bone marrow blasts, neutropenia and sustained platelets. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). This study was designed to evaluate the efficacy and tolerability of ENA alone and in combination with azacitidine (AZA) in pts with high-risk IDH2-mutated MDS. Methods: This is a multicenter Phase II trial for pts with IDH2-mutated MDS, AML with 20-30% marrow blasts, or chronic myelomonocytic leukemia. The study includes two cohorts: HMA-naïve pts with high-risk MDS (IPSS int-2 or high-risk; IPSS-R high-risk or very high risk; or high-risk molecular features including TP53, ASXL1, EZH2 and/or RUNX1 mutations) (Arm A) receive AZA + ENA; pts relapsed/refractory with prior HMA therapy (Arm B) receive ENA alone. All pts receive ENA at a dose of 100 mg orally daily, on days 1-28 of each 28-day cycle. In Arm A, ENA is given in combination with AZA 75 mg/m2 IV or SC on days 1-7 of each cycle. The primary efficacy endpoint is overall response rate (ORR), including complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI) based on the Modified International Working group (IWG) Response Criteria for MDS. The primary safety endpoint is the incidence and severity of adverse events using the Common Toxicity Criteria for Adverse Events v4.0. Results: Using a pre-specified data cutoff of July 1st 2019, 25 pts have been enrolled with a median follow-up of 6.4 months (range, 2.4 - 17.1); 10 HMA-naïve pts (Arm A) and 15 HMA-failure pts (Arm B). The median age was 71 years (range, 46-83) (Table 1). Sixteen pts (64%) had neutropenia (absolute neutrophil count 〈 1.0 x 109/L) and 20 pts (80%) had anemia (hemoglobin 〈 11 g/dL), including 12 (48%) red blood cell (RBC) transfusion-dependent (TD) pts at baseline. Seventeen pts (68%) had high or very high risk IPSS-R. Nineteen pts (76%) had diploid or +8 cytogenetics, and 5 pts (20%) had -7 or complex karyotype. High-risk co-occurring mutations included ASXL1 (46%), RUNX1 (17%), EZH2 (8%) and TP53 (8%). Among 18 evaluable pts (7 too early for response assessment), the ORR was 67% (12/18) (Table 2). In HMA-naïve pts, 6/6 (100%) responded to therapy, including 2 CRs and 4 mCRs (1 with HI for neutrophils [HI-N]). In HMA-failure pts, 6/12 (50%) responded, including 2 CRs, 1 PR, 1 mCR (with HI-N) and 2 with stable disease with HI (1 with HI-N, 1 with HI erythroid). Interestingly, 3 pts who achieved CR also had clearance of the IDH2 mutation (1 in Arm A; 2 in Arm B). Two of 5 pts (40%) and 3/7 pts (43%) with neutropenia at baseline achieved HI-N in Arm A and B, respectively. Median time to first and best response were both 1.3 months (range, 0.9-2.1) in Arm A and 1.8 months (range, 0.9-3.7) and 2.7 months (0.9-4.6), respectively in Arm B. Among evaluable pts with RBC TD at baseline, 0/2 pt and 3/8 (38%) pts achieved transfusion independence, in Arm A and B, respectively. At last follow-up, 16 pts remain on treatment (7 with ongoing response) and 9 pts stopped treatment: 4 due to progression, 1 pt decision, 1 underwent allogeneic transplant and 3 responding pts with mCR died from pneumonia or other infectious complications while on study (Figure 1). Adverse events (AEs) of any grade were reported in 17/25 pts (68%) and grade 3-4 AEs were reported in 11/25 pts (44%). Most AEs were manageable without dose interruption. The most common non-hematological AEs were unconjugated hyperbilirubinemia (39%), nausea (33%), fatigue (33%), pneumonia (22%) and diarrhea (17%). Possible differentiation syndrome (DS) was reported in 3 pts on days 31, 38 and 42 of treatment; 2 pts received dexamethasone with resolution, and 1 pt required hydrea and was ultimately determined to have progression to AML. Four pts developed leukocytosis (white blood cell count of 15.3, 28.3, 35.7, 56.6 x 109/L), with 3 at the time of possible DS and 1 at day 119 considered unrelated to DS. Conclusion: Enasidenib is well tolerated and shows promising efficacy in IDH2-mutated high-risk MDS. The ORR was 67%, including 100% in newly diagnosed pts receiving the combination of azacitidine plus enasidenib and 50% ORR in HMA-failure pts receiving enasidenib alone. The study continues to accrue and updated results will be presented at ASH. Disclosures DeZern: Celgene: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Konopleva:Astra Zeneca: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Loghavi:MDACC: Employment; GLG Consultants: Consultancy; AlphaSights: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Ravandi:Selvita: Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Nazha:Abbvie: Consultancy; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Tolero, Karyopharma: Honoraria. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding. 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. DiNardo:medimmune: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: Enasidenib is not approved for the treatment of myelodysplastic syndrome

Description: Background: Mantle cell lymphoma (MCL) remains challenging particularly in the relapsed/refractory setting, where patients often show chemoresistance. Novel molecular-based therapies have shown impressive and durable activity in that setting, although primary and acquired resistance remains problematic. A recent retrospective series of 114 patients who had failed ibrutinib (median of 4.7 month exposure) showed very short median overall survival of 2.9 months after ibrutinib cessation (Martin et al. Blood 2015). Here we report the results from the observationalMCL-004 study investigating outcomes of patients treated with lenalidomide (an IMiD® immunomodulatory agent) after failing ibrutinib; patients were either relapsed, progressed, refractory, or intolerant to ibrutinib. The objective here is to evaluate the clinical effectiveness of lenalidomide monotherapy or a lenalidomide-containing regimen in relapsed/refractory MCL after ibrutinib failure or intolerance. Methods: MCL-004 is a multicenter study in patients with MCL who relapsed/progressed after or were refractory/intolerant to ibrutinib, and were subsequently treated with lenalidomide. With patient informed consent, data were collected retrospectively from patients who, after their disease failed to respond to ibrutinib, received lenalidomide-based therapy from March 1, 2009 to June 9, 2015. The primary endpoint was investigator-assessed overall response rate (ORR) based on 2007 International Working Group criteria, with required patient monitoring and routine imaging. Results: Thirty patients were enrolled at 7 US sites and 1 EU site, including patients receiving lenalidomide monotherapy (n=8), lenalidomide + rituximab (n=8), and lenalidomide + other treatment (n=14). Lenalidomide + other treatment included combination with rituximab, carfilzomib, and dexamethasone (n=3); other combinations were given in ≤2 patients. Patients had a median age of 69 years (range, 50-84), and median time from last dose of ibrutinib to first dose of lenalidomide was 1.3 weeks (range, 0.1-21.7). All patients received ≥2 prior lines of therapy, and 83% received ≥3 prior therapies (median prior therapies, 3.5; range, 2-8). With prior ibrutinib, the best responses achieved were 10% complete response (CR), 43% partial response (PR), 3% stable disease, 40% relapse/progressive disease (PD), and 3% unknown. Primary reasons for ibrutinib discontinuation were 50% relapse/PD, 40% refractory, and 10% intolerance. Patients received a median of 2 cycles (range, 1-11) of lenalidomide-based treatment. Eight patients' disease responded (4 CR, 4 PR), resulting in an ORR of 27% (95% CI, 12%-46%). Five of 8 maintained their response at data cut-off (3 CR, 2 PR). ORR was similar for patients with relapse/PD vs. those refractory to ibrutinib (29% vs. 33%, respectively). Median duration of response (DOR) was 18 weeks (95% CI, 2.9-25+) for all patients. Median DOR was not reached in patients who previously relapsed/progressed with ibrutinib compared with a median of 11 weeks for those whose disease was refractory to ibrutinib. Most common treatment-emergent adverse events (TEAEs) were 33% fatigue; 27% nausea; and 23% each dyspnea, neutropenia, dizziness, or rash. In general, TEAEs were less common with lenalidomide monotherapy. The most frequently reported serious AEs were pneumonia, dyspnea, deep vein thrombosis, hypotension, and acute kidney injury (7% each). At data cutoff, 15 patients (50%) had died, mostly due to MCL and none due to second primary malignancy. Conclusions: Most patients received ≥3 prior lines of treatment, and median time from last dose of ibrutinib to first dose of lenalidomide was short. Lenalidomide-based treatment showed clinical activity in this difficult-to-treat patient population, including 27% ORR and 13% CR. No new safety signals for lenalidomide were identified. Overall, our results show that lenalidomide is active in a selected group of patients with relapsed/refractory MCL that previously failed ibrutinib. Disclosures Wang: BeiGene: Research Funding; Asana BioSciences: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Onyx: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin:Acerta: Consultancy; Teva: Research Funding; Novartis: Consultancy; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamadani:Takeda: Research Funding. Ghosh:Gilead: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Reeder:Millennium: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding.