Hematologic Improvement Research Articles

A Pilot Study of Exjade (Deferasirox) As Monotherapy in Higher Risk MDS or Acute Myeloid Leukemia

Although deferasirox use is established in clinical practice for iron overload, there have been a spate of case reports describing hematologic improvement attributed to use of this agent in myelodysplastic syndrome (MDS) patients (Guariglia et al, Leuk Res, 2011, 35 (5), 566-570). In addition, a post-hoc analysis was conducted assessing hematologic improvement in patients enrolled on the Evaluation of Patients' Iron Chelation with Exjade (EPIC) trial of deferasirox chelation therapy in low or intermediate-1 risk MDS. Erythroid, platelet, and neutrophil responses were observed in 21.5%, 13.0%, and 22.0% of 341 patients after a median of 109, 169, and 226 days, respectively (Gattermann, N et al, Haematologica, 2012, 97 (9), 1364-1371). There has even been a case report of a patient with acute monocytic leukemia who achieved a complete remission after deferasirox therapy (Fukushima et al, Anticancer Res, 2011, 31 (5) 1741-1744). Preclinical data has suggested potential mechanisms for hematologic improvement, including modulation of reactive oxygen species and activating the MAP kinase pathway (Callens et al, J Exp Med, 2010, 37 (4), 731-750), increased labile plasma iron leading to reactive oxygen species induction (Naka K et al, Antiox Redox Signal, 2008, 10 (11) 1883-1894), or inhibition of nuclear factor Kappa B (Messa et al, Haematologica, 95 (8) 1308-1316). Given these intriguing findings, we performed a single-center, investigator-initiated pilot study of deferasirox in MDS International Prognostic Scoring System (IPSS) 1.5 or greater, intolerant of or with lack of response to hypomethylating agents, and acute myeloid leukemia (AML), either relapsed or refractory after treatment with a non-intensive regimen or newly diagnosed and not appropriate candidates for induction chemotherapy. As an inclusion criterion, baseline serum ferritin was > or = to 500 ng/mL. Prior therapy with iron chelating agents within the last 6 months was an exclusion criterion. Current therapy for AML or MDS, including hydroxyurea to control leukocytosis, was prohibited. Thirteen patients consented to the study. There was one screen failure and one patient withdrew from the study after one day. Eleven patients received deferasirox at an initial dose of 10 mg/kg/day which was increased to 20 mg/kg/day if tolerating well. Three of 11 patients (27%) responded. One of the three responding patients achieved red blood cell (RBC) transfusion independence (no RBC transfusions for 6 weeks before death related to infectious complications), one improved bone marrow blasts from 57% to 30% after one month of therapy and the third patient improved bone marrow blasts from 13% to 8% after one month of therapy. The patient who achieved RBC transfusion independence did not achieve any other measures of response. The two patients who responded in the bone marrow did not achieve a concomitant hematologic response. Of the 8 non-responding patients, one patient had stable disease and was on study for one year. One patient withdrew in the setting of neutropenic fever and mild transaminitis that was possibly attributable to deferasirox and was terminated from the study. One patient withdrew from the study due to personal choice and the remaining 5 patients came off study in the setting of complications from progressive disease. Study drug was generally well tolerated. Grade 3 adverse events (AEs) included three patients with elevated creatinine (27%) and 2 patients with diarrhea (18%). One responding patient had a lower gastrointestinal bleed that was possibly attributable to deferasirox and was terminated from the study for this reason. One patient had grade 4 dry mouth immediately after drinking deferasirox slurry that resolved by 30 minutes after ingestion. No other significant AEs occurred that were possibly attributable to deferasirox. In conclusion, deferasirox was generally well tolerated and showed modest activity as a single agent in higher risk MDS or non-proliferative acute myeloid leukemia. Further study of deferasirox in the phase II setting as monotherapy or in combination with other therapies such as hypomethylating agents (HMAs) or HMAs in combination with venetoclax is probably warranted. Disclosures Frey: Novartis: Research Funding. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Luger:Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Celgene: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Kura: Research Funding; Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding. OffLabel Disclosure: Presentation will discuss the off-label use of Exjade (deferasirox) as therapy for higher risk MDS or AML. Deferasirox on-label use is for iron chelation.

Predicting Response to Hypomethylating Agents in Patients with Myelodysplastic Syndromes (MDS) Using Artificial Intelligence (AI)

Introduction While the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) improve cytopenias and prolong survival in MDS patients (pts), response is not guaranteed. Timely identification of non-responders could prevent prolonged exposure to ineffective therapy, thereby reducing toxicities and costs. Currently no widely accepted clinical or genomic models exist to predict response or resistance to HMAs. We developed a clinical model to predict response or resistance to HMA after 90 days of initiating therapy based on changes in blood counts using time series analysis technology similar to the kind used in Apple's Siri or Google Assistant. In the setting of voice recognition, the sequence and context of words determines the meaning of a sentence; similarly, we hypothesized that the pattern of changes in MDS pts' blood counts would predict response or resistance early during treatment. Methods We screened a cohort of 107 pts with MDS (per 2016 WHO criteria) who received HMAs at our institution between February 2005 and July 2013 and had regular CBCs drawn during treatment. Mutations from a panel of 60 genes commonly mutated in myeloid malignancy were included. Responses were assessed after 6 months of therapy per International Working Group (IWG) 2006 criteria. Pts were divided randomly into training (80%) and validation (20%) cohorts. To address the potential for bias due to a small sample size, an oversampling algorithm was used to cluster similar pts based on their CBC data, Revised International Prognostic Scoring System (IPSS-R) score, and % bone marrow blasts at the time of diagnosis. CBC data from the first 90 days of treatment were fed into deep neural network (recurrent neural network) and decision tree algorithms, which were trained to predict whether pts would achieve a response (defined as complete remission (CR), partial remission (PR), or hematologic Improvement (HI)). Area under the curve (AUC) was used to assess model performance. Important features that impact the algorithm's predictions were extracted and plotted. Results 20747 unique data points were used, including CBC, clinical and genomic data. Among 107 pts, 61 (57.0%) received AZA only, 19 (17.8%) DAC only, 4 (3.7%) received both DAC and AZA, and 23 (21.5%) received HMA with an additional agent. Median age was 69 years (range: 37-100 years), and 27 (26.4%) were female. Forty pts (37.4%) were very low/low risk, 32 (29.9%) intermediate, 19 (17.8%) high, and 16 (14.9%) very high risk per IPSS-R. Responses included 23 (22.5%) CR, 2 (1.9%) marrow CR, 4 (3.9%) PR, and 20 (19.6%) HI. The most commonly mutated genes were ASXL1 (17.6%), TET2 (16.7%), SRSF2 (15.7%), SF3B1 (11.8%), RUNX1 (10.8%), STAG2(10.8%), and DNMT3A (10.8%). The median number of mutations per sample was 1 (range, 0-11), and 40 pts (39.2%) had > 3 mutations per sample. When trained using absolute values and changes in CBC values, the model's AUC was 0.95 in the training cohort and 0.83 in the validation cohort. When the cohort was oversampled to 1000 pts, the validation cohort AUC increased to 0.89. Feature extraction algorithms identified increases in MCV and RDW during weeks 2-8 of treatment, increased proportion of lymphocytes, decreased proportion of monocytes, and increased platelet counts during weeks 6-8 as factors favoring response to HMA. The model provides personalized, patient-specific predictions that correlate with blood counts (Figure 1). Conclusions We describe a machine learning model that monitors changes in blood counts during therapy with HMA to predict response or resistance to HMA in MDS pts. Such a model can be used to develop novel trial designs wherein pts predicted to not respond after 90 days of HMA treatment could be assigned to an investigational agent. Conversely, it would help inform the decision to continue HMA therapy in pts predicted to respond. Increasing sample size with oversampling dramatically increased model accuracy; a larger cohort of pts treated at different institutions is currently under development. Disclosures 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. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Nazha:Novartis: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee.

Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients

Multi-Center Phase 2 Study of Pembroluzimab (Pembro) and Azacitidine (AZA) in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) and in Newly Diagnosed (≥65 Years) AML Patients

A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome

A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine in Treatment-Naïve Patients with Higher-Risk Myelodysplastic Syndrome

APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM)

APR-246 Combined with Azacitidine (AZA) in TP53 Mutated Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). a Phase 2 Study By the Groupe Francophone Des Myélodysplasies (GFM)

Genomic Profiling in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) Following HMA Failure: Baseline Results from the Inspire Study (04-30)

Genomic Profiling in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) Following HMA Failure: Baseline Results from the Inspire Study (04-30)

Azacitidine in Pediatric Hematologic Myeloid Malignancies: A Retrospective Study

Purpose: Hypomethylating agents are approved in adults with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). By contrast, data in pediatric hematologic malignancies are scarce. Herein, we report the off-label administration of Azacitidine (Aza) in a cohort of children, adolescents and young adults (AYA). Methods: Patients from Robert-Debré, Saint-Louis and Armand-Trousseau University Hospitals (Assistance Publique-Hôpitaux de Paris), 25 year-old or younger at initiation of treatment and who received Aza between 2009 and 2019 were included. Data on indication, efficacy and toxicity of the treatment were retrospectively collected. Results: As 3 patients (pts) were treated twice with Aza at different stages of their disease, 35 treatments in 32 patients were analyzed. Median age at diagnosis was 11.7 y (range 0.1-22.4). Diagnosis were: 16 Acute Myeloid Leukemias (AML), 6 Juvenile Myelomonocytic Leukemias (JMML), 7 Myelodysplastic Syndromes (MDS), 2 Mixed Phenotype Acute Leukemias (MPAL) and 1 Interdigitating Dendritic Cells Sarcoma. Aza was administrated after a median of 2 lines of treatment (range 0-6) and front line in 5 out of 32 pts (16%; MDS = 4, JMML = 1). Concomitant therapy was administrated in 15/35 treatments (43%) (Sorafenib = 6, Gemtuzumab Ozogamicin = 2, donor lymphocyte infusions = 2, other = 5). Fourteen out of 35 treatments (40%) were delivered in patients with a history of hematopoietic stem cell transplantation (HSCT). Aza was administrated either intravenously (n = 11) or subcutaneously (n = 24) at a dose of 75mg/m² for 7 (20/35, 57%) or 5 (6/35, 17%) consecutive days every 28 days, i.e. same daily dose as in adults; at reduced doses (≤ 50mg/m²) in 3/35 patients; at a dosing scheme varying from one cycle to another in 6/35 patients. Patients received a median of 3 cycles of Aza per treatment (range 1-31). A total of 137 cycles was delivered. Aza was well tolerated with only 5/137 cycles delayed due to hematological (n = 3) or non-hematological (n = 2) toxicity. Aza was discontinued due to toxicity in 2/137 cycles (1 rectal bleeding, 1 severe sepsis). Anemia was noted in 68/130 cycles (52%), thrombocytopenia in 68/128 cycles (53%), neutropenia in 84/127 cycles (66%) and febrile neutropenia in 25/131 cycles (19%). Two grade 5 side effects were observed: 1 patient died from cerebral hemorrhage in a context of anti-platelet poly-immunization, another from septic shock in a context of neutropenia. Most common non-hematological side effects included: nausea, vomiting, diarrhea, subcutaneous injections lesions (local inflammation or hematoma) and infections. Responses to Aza are detailed in the attached table. Best responses to Aza included: 2 complete remissions (CR) both after 3 cycles, 3 CR with incomplete hematologic recovery (CRi) after a median of 2 cycles (range 1-2), 2 partial remissions (PR) after 2 and 3 cycles, 6 stable diseases (SD) during a median of 2 cycles (range 2-12) and 2 hematologic improvements. Overall response rate (sum of CR, CRi, PRs), was 19% (6/32) (3 non evaluable responses). Three out of the 6 patients treated with Aza combined with Sorafenib (AML = 4, MPAL = 2) obtained a response (CR: 2, CRi: 1). The association led to HSCT for 2 of them; the third patient had a CR maintained almost 3 years without HSCT, before relapsing on therapy. One patient with MDS had a SD for 12 months after palliative treatment with Aza. Overall, Aza treatment allowed to proceed to HSCT in 8 out of 32 patients (25%), 7 out of 8 proceeding to a first HSCT [CR: 1 patient, CRi: 3 patients, PR: 2 patients, SD: 1 patient, progressive disease: 1 patient]. These 8 pts included: 4 pts with AML, alive in CR after a median follow-up of 29.5 months (2 of them received concomitant targeted therapy); 2 pts with JMML (1 alive in CR after a follow-up of 25 months); 2 pts with MDS (both died, 7 and 30 months after Aza initiation). Finally, 24 out of 32 patients died and overall survival at 5 years was 23% (IC95% [11;48]) with no difference according to diagnosis. Conclusion: In a cohort of pediatric and AYA patients with heavily pretreated myeloid malignancies, Aza was well tolerated, and allowed to bridge 25% of patients to HSCT. Further prospective studies are needed to explore combination of Aza with targeted therapy in pediatric patients. Disclosures Boissel: NOVARTIS: Consultancy.

Impact of Clinical Features, Cytogenetics, Genetic Mutations and Methylation of CDKN2B and DLC-1 Promoters on Treatment Response to Azacitidine

Introduction : Azacitidine (AZA) is a DNA hypomethylating agent used in myeloid neoplasms, however approximately half of patients show treatment failure or relapse. Last years, several studies have showed that genetic mutations may influence on response and survival of the treated patients. Other biomarkers that have traditionally been associated with the response to AZA are the recovery of the platelet count and the presence of abnormalities in the chromosome 7. Finally, the methylation dynamics of genes promoters could be a useful tool to predict the clinical response. Aim: To assess the predictive value on response to AZA of clinical features, cytogenetics, genetic mutations and the methylation dynamics of CDKN2B and DLC-1 promoters in a series of patients with myeloid neoplasms. Methods: We studied 85 patients with myelodysplastic syndromes (MDS) and 28 patients with acute myeloid leukemia (AML) who received AZA. Treatment schedules included 5-azacytidine 75 mg/m2/day for 7 days (n=62) and 5-azacytidine 75 mg/m2/day for 5 days (n=51). According to the International Working Group (IWG) 2006 criteria for MDS, responders were defined as patients achieving complete remission (CR), bone marrow CR (mCR), partial remission (PR) or stable disease with hematologic improvement (SDHI). Sixteen genes with prior implication in the pathogenesis of myeloid diseases were analyzed: NPM1, FLT3, CEBPA, TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, RUNX1, SETBP1, TP53, SF3B1, SRSF2, U2AF1 and ETNK1. For methylation assay, EZ DNA Methylation-Gold kit (Zymo Research) was employed for the bisulfite treatment of DNA. Methylation of CDKN2B and DLC-1 were qualitatively studied pre- and post-AZA with unmethylated and methylated primers and analysis of the PCR products in a QIAxcel System (Qiagen). Overall survival (OS) was measured from start of AZA treatment until the last follow-up or death from any cause. P values <0.05 were considered as statistically significant. Results: Of the 113 patients analyzed, 46 patients (41%) showed response to AZA (median cycles=6): CR=19, mCR=6, PR=12, and SDHI=9. Stable disease and treatment failure were observed in 20 (17%) and 47 patients (42%), respectively. Analysis of clinical features showed that platelet doubling after the first AZA cycle was significantly associated with a better response (58% vs. 31% responders, P=0.041). Forty-seven patients (42%) had chromosomal abnormalities. A positive co-occurrence between del(7q)/-7 and del(17p) was found (n=6, P<0.001) and was significantly associated with a worse response to AZA (P=0.039). Pre-treatment, genetic mutations were presented in 98 patients (87%) and methylation of CDKN2B and DLC-1 promoters were detected in 50 (44%) and 37 (33%) patients respectively (Figure 1). Patients with SF3B1 mutations showed a better response to AZA (68% vs. 35% responders, P=0.008) and a higher OS (30 vs. 15 months, P=0.019) than the remaining patients. In contrast, patients with mutations in transcription factors (RUNX1, SETBP1, NPM1) showed a worse response to AZA (20% vs. 47% responders, P=0.014) and a lower OS (10 vs. 19 months, P=0.010). Splicing genes mutations (SF3B1, SRSF2 and U2AF1) were related to favourable karyotypes (90% vs. 59%, P<0.001) and a lower DLC-1 methylation (31% vs. 57%, P=0.006). Interestingly, patients with DLC-1 methylation showed higher levels (>5%) of bone marrow blasts (63% vs. 40%, P=0.016), higher frequency of complex karyotypes (40% vs. 15%, P=0.002), a positive co-occurrence with TP53 alterations (38% vs. 16%, P=0.009) and its methylation dynamics showed a strong trend towards predict the response to AZA: 57% of patients without DLC-1 methylation or who reduced it post-treatment responded favourably to the drug and 65% of patients who maintained or increased it did not respond (P=0.053). In addition, leukemia transformation was higher in MDS patients with DLC-1 methylation post-AZA than in the remaining MDS patients (58% vs. 21%, P=0.002). Conclusion: The combination of chromosomal alterations and genetic mutations together with the monitoring of platelet count and DLC-1 methylation could contribute to give light in myeloid neoplasms to the heterogeneity observed both in the response to AZA and in patient survival. Samples and data from patients included in this study were provided by the INCLIVA Biobank (PT13/0010/0004). Disclosures Hernandez Boluda: Incyte: Other: Travel expenses paid.

Combined Venetoclax and Hypomethylating Agent (HMA) Therapy Induces High Response Rates in Patients with Myelodysplastic Syndrome Including Patients Previously Failing HMA

Combined Venetoclax and Hypomethylating Agent (HMA) Therapy Induces High Response Rates in Patients with Myelodysplastic Syndrome Including Patients Previously Failing HMA

Prospective Comparison of Azacitidine Treatment between 7-Days and 5-Days Schedules for Patients with Higher-Risk Myelodysplastic Syndromes; Results of Japan Adult Leukemia Study Group MDS212 Trial

Prospective Comparison of Azacitidine Treatment between 7-Days and 5-Days Schedules for Patients with Higher-Risk Myelodysplastic Syndromes; Results of Japan Adult Leukemia Study Group MDS212 Trial

Pacifica: A Randomized, Controlled Phase 3 Study of Pacritinib Vs. Physician's Choice in Patients with Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post Essential Thrombocytopenia Myelofibrosis with Severe Thrombocytopenia (Platelet Count

Background: Myelofibrosis (MF) is a life-limiting condition with severe morbidity in advanced stages. Patients with MF and severe thrombocytopenia (platelet counts <50,000/mL) have a particularly poor prognosis, with more frequent anemia and leukopenia, higher rates of hemorrhagic and thrombotic complications, and worse overall survival (~15 months) compared to the overall MF population (Scotch AH, et al, Leuk Res. 2017; Masarova L, et al, Eur J Haematol. 2018). Moreover, effective treatment options are limited in this high-risk population as the currently approved JAK inhibitor, ruxolitinib (RUX), is associated with treatment-related thrombocytopenia and often requires dose reductions for patients with platelet counts <100,000/mL, with reduced efficacy compared to patients able to tolerate higher doses. Further, there is no approved dose of RUX for patients with platelet counts <50,000/mL, and NCCN guidelines encourage physicians to consider clinical trials for such patients given the lack of approved therapies. Pacritinib (PAC) is an oral JAK2/IRAK1 inhibitor that has demonstrated clinical activity in MF patients in two prior Phase 3 studies (PERSIST-1, PERSIST-2) as well as a Phase 2 dose-finding study (PAC203), including patients with severe thrombocytopenia. The PACIFICA trial has been designed to evaluate the efficacy and safety of PAC 200 mg BID vs. physician's choice (P/C) therapy in patients with MF and severe thrombocytopenia. Study Design and Methods: PACIFICA is a randomized, controlled Phase 3 trial of PAC vs. P/C in adult patients with primary or secondary MF who are not candidates for stem cell transplant, with DIPSS intermediate- or high-risk disease, ECOG PS ≤2, and platelet counts <50,000/mL, who have had up to 90 days of prior treatment with a JAK2 inhibitor or are JAK2 inhibitor-naïve. Additional exclusion criteria exist for patients with recent cardiac or hemorrhagic events, ejection fraction <50%, QTc >450 msec, or use of medications that increase the risk of hemorrhage or QT prolongation. On the PAC arm, patients receive continuous PAC 200mg BID. On the P/C arm, one of the following agents is selected prior to randomization: low-dose ruxolitinib (no more than 5 mg BID while platelet counts remain <50,000/mL), thalidomide, lenalidomide, corticosteroids, or hydroxyurea. The primary objective is to compare the efficacy of PAC vs. P/C based on the proportion of patients achieving a ≥35% spleen volume response (SVR) at Week 24. Secondary objectives include comparisons of the proportion of patients achieving a ≥50% reduction in total symptom score (TSS) at Week 24, overall survival, and proportion of patients who self-assess as "very much improved" or "much improved" as measured by the patient global impression of change (PGIC). Tertiary endpoints include alternative methods of evaluating SVR improvement, hematologic improvement (transfusion independence and improvement in anemia and thrombocytopenia), improvement in fatigue as measured by the PROMIS - Fatigue - Short form 7a, and changes in mutated allelic burden and gene expression (including correlation with response data). The study will enroll ~180 patients in a 2:1 ratio (PAC to P/C), which will have >80% power to achieve the primary endpoint. Enrollment is anticipated to begin in Q3 2019, as PACIFICA is expected to open as an amendment to the Phase 2 PAC203 study (NCT03165734) in select sites. Disclosures Harrison: Janssen: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Gilead: Speakers Bureau; AOP: Honoraria; Promedior: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria. Gerds:Roche: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Incyte: Consultancy, Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Buckley:CTI BioPharma: Employment, Equity Ownership. Smith:CTI BioPharma: Employment, Equity Ownership. Craig:CTI BioPharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verstovsek:Incyte: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; NS Pharma: Research Funding; Roche: Research Funding.

Molecular Characteristics That Predict Response to Azacitidine Therapy

Background DNA hypomethylating agents (HMAs), including azacytidine (AZA) and decitabine, have been established as key drugs for higher-risk myelodysplastic syndromes (MDS). Recently, a marked efficacy of decitabine has been reported in TP53-mutated myeloid malignancies, although it is not approved for MDS in many countries. Thus it is of an urgent interest whether the excellent response to TP53-mutated myeloid neoplasms is recapitulated with AZA and if so, what is the biomarkers reliably predicting response to AZA. Methods In this study we enrolled a total of 384 AZA-treated MDS patients, including 179 from a Japanese prospective study (JALSG MDS-212 trial), 163 from Karolinska Institute, and 42 from a Japanese multi-institutional registry, and analyzed mutations in 66 genes commonly mutated in myeloid neoplasms together with copy number abnormalities, using targeted-capture sequencing. For all patients, sequencing was performed on pre-AZA samples. Post-AZA samples were also analyzed for the majority (279/394, 73%) of patients. Results Analysis of pre-AZA specimens identified 1,085 driver mutations in 53 genes in 361 (94%) patients with a mean of 3.0 mutations/sample. CNAs were detected in 258 (67%) cases. Most frequently observed were mutations in TP53, RUNX1, TET2, SRSF2, and ASXL1, and other high-risk CNAs, such as -7/7q LOH, 5q LOH, and 17p LOH. TP53 lesions were found in 102 (27%) cases, of which 87 cases (85%) had biallelic lesions caused by either multiple mutations (N=28) or 17p LOH involving the TP53 locus (N=59). Sixty-seven cases (17%) achieved complete remission (CR) with a median observation period of 7.5 months. TP53 mutation, found in 48% of the cases, was the only lesion that was significantly associated with CR (OR=3.4, p<0.0001) together with hematological improvements (HI-E: OR=2.32, p=0.011, HI-N: OR=2.29, p=0.038, HI-P: OR=1.88, p=0.039). Marrow CR (mCR), PR, SD with HI were also achieved in additional 71 (18%), 11 (3%), and 37 (9.6%) cases, respectively. However, 51% of the cases that achieved any response had disease progression with a median duration of only 313 days. Despite favorable initial response, TP53-mutation was still associated with dismal long-term outcomes (median OS 374 days versus 687 days in TP53-unmutated cases, p<0.0001), which is in compatible with a short duration of remission period (median 199 days for CR cases and median 182 days for mCR/PR cases with TP53 mutation) in the former group. Given distinct characteristics in both genetic and clinical features in TP53 mutated cases, we subsequently inquired for additional biomarkers predicting outcomes according to the mutation status of TP53. In the TP53-mutated cases, platelet counts larger than median value of 7.1×104/μL was the only factor that predicted better survival (P=0.02). In the TP53-unmutated cases, higher age (>72 years old, hazard ratio: HR 1.36, p=0.03) and high karyotype risks (Very High/High according to IPSS-R-based classification system, HR 1.31, p=0.04) were associated with a shorter OS, while mutations in DDX41 predicted a significantly better OS (HR 0.62, p<0.001). Notably, those who received transplantation following AZA therapy (N=14) had a significantly prolonged survival with a median OS of 758 days for TP53-mutated cases, where TP53 mutations had disappeared after AZA treatment in six cases and decreased to <10% in VAF in other 4 patients. Clonal dynamics was evaluated by measuring change of copy number-adjusted variant allele frequency (aVAF) between pre- and post-AZA samples. Both post-AZA mutational burden (p<0.0001) and the size of reduction in aVAF during treatment (p<0.0001) significantly correlated with clinical response (trend test). Conclusions Our study revealed distinct response profile to AZA treatment according to TP53 mutation status, underscoring the need of different tools to estimate treatment outcomes for them. High remission rate in TP53-mutated cases does not lead to long-term outcomes due to short remission duration, if ever obtained. Successive transplantation to AZA treatment during remission phase might rescue patients from this intractable disease. Disclosures Takaori: Novartis: Honoraria. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria. Papaemmanuil:Celgene: Research Funding. Ogawa:Asahi Genomics: Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Qiagen Corporation: Patents & Royalties; RegCell Corporation: Equity Ownership; Kan Research Laboratory, Inc.: Consultancy.

T-Cell Mediated Cytopenias in Patients with Myelodysplastic Syndromes Respond to Intravenous Immunoglobulin

Background: Patients with Myelodysplastic Syndrome (MDS) with cytopenias have limited treatment options to improve blood counts apart from immune-modulatory drugs (IMIDS), hypomethylating agents (HMA), cytokines and transfusional support. Immune dysregulation is common in MDS and occurs in up to 35% of pts (LR Silverman, Cancer Med, 2017). Expanded T-cell clonal populations in the peripheral blood and bone marrow in the presence of MDS may play a role in aggravating MDS related cytopenias, increasing the need for transfusions or exacerbating symptoms. Intravenous immunoglobulin (IVIG) may interact with Fc receptors on T cells or have suppressive effects on the concurrent large granular lymphocytic leukemia (LGL) clone. Targeted therapy with IVIG could be a novel strategy to mitigate the cytopenias in MDS and other bone marrow failure pts. Methods: We reviewed in a single-center series 27 consecutive pts who had either MDS, aplastic anemia (AA), or a myeloproliferative neoplasm (MPN) along with an LGL clone seen on TCR-rearrangement studies and/or peripheral blood flow cytometry in the blood and/or bone marrow. Of the 27 pts, 22 had MDS, 2 had MPN, and 1 each with AA, LGL, or Multiple Myeloma. IVIG was initially used as a single agent administered at a dose of 500mg/kg/day over 4 hours once weekly x4 weeks. After "induction", administration was changed to every other week, and then in responding pts, the interval was extended to every 3-4 weeks. In pts with a stable response, IVIG was discontinued and pts observed. After the initial 4 pts, pts were treated concurrently with prednisone 20 mg/d with a taper over 4 weeks, except in pts in which prednisone was a relative contra-indication. Overall hematologic improvement was determined by MDS IWG 2006 criteria, while hemolytic response was determined to be either a complete normalization (CR) or a partial normalization (PR) if there was >50% improvement in deviation from normal LDH, reticulocytes, indirect bilirubin, or haptoglobin values from baseline. Results: All pts received IVIG administered at 500mg/kg, once weekly, to be spaced out maximally as tolerated. 74% (20/27) of pts received steroids. Baseline characteristics of the pt population: median age of 70 years (range 39-87), representing 21 males and 6 females. Of the pts with MDS evaluable for risk stratification by IPSS-R criteria [n=18], 3 were very low, 5 low, 6 intermediate, 2 high, and 2 very high risk categories. By WHO criteria, the greatest representation was 11/20 RCMD, followed by 3/20 with RAEB2. Baseline cytogenetics [n=21] included 3 pts with very poor, 2 poor, 3 intermediate, 11 good, and 2 very good risk profiles. Pts had a range of 0-6 mutations, most common were SETBP1, ASXL1, TP53 (n=4) and SRSF2, U2AF1, PDGFRB (n=3). 24/27 pts had positive TCR beta and 13/27 had positive TCR gamma gene rearrangements. ORR for any cytopenia was 77.8% (21/27), and for any hemolytic response was 76.2% (16/21). ORR for individual cell lines included: 59.2% (16/27) erythroid, 48.1% (13/27) neutrophil, and 33.3% (9/27) platelet responses. For hemolytic responses, CR/PR rate were measured by LDH (29.6%/11.1%), bilirubin (22.2%/14.8%), retic (33.3%/14.8%), and haptoglobin (22.2%/11.1%). For the 14 MDS pts with very low, low, and intermediate IPSS-R risk, ORR was: 64.3% (9/14) any cytopenia, 35.7% (5/14) erythroid, 50.0% (7/14) neutrophil, 14.3% (2/14) platelets. Combined CR+PR rates for hemolysis in the lower risk categories were 42.9% LDH, 21.4% bili, 42.9% retic, 28.6% haptoglobin responses. For the 5 non-MDS pts, ORR for any cytopenia was 100%, and 60% for any hemolytic response. There were no reported significant adverse events with IVIG administration. Conclusions: IVIG can be used as a first line treatment for pts with autoimmune cytopenias associated with LGL clones and MDS (along with other hematological malignancies). Treatment with IVIG yields an ORR of 77.8% in the entire cohort and 64.3% in pts with lower risk MDS, with a reduction in hemolysis as well. This report expands on a previous analysis and demonstrates further evidence of efficacy for the use of IVIG in treating cytopenias exacerbated by LGL T-cell clones. IVIG therapy can permit a delay in the start of an HMA or IMID treatment, lowering transfusion burden, and increasing ANC to help prevent infectious complications. Further evaluation in a larger cohort of pts is warranted. Studies exploring the mechanism of action are underway. Disclosures Navada: Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Patents & Royalties, Research Funding; Celgene: Research Funding; Medimmune: Research Funding.

A Phase I/II Study to Investigate the Safety and Clinical Activity of the Protein Arginine Methyltransferase 5 Inhibitor GSK3326595 in Subjects with Myelodysplastic Syndrome and Acute Myeloid Leukemia

A Phase I/II Study to Investigate the Safety and Clinical Activity of the Protein Arginine Methyltransferase 5 Inhibitor GSK3326595 in Subjects with Myelodysplastic Syndrome and Acute Myeloid Leukemia

Can Monosomy 7 be Targeted By Next Generation Cereblon-Modulating Agents?

Genomic advances have initiated a new era of precision oncology. Targeted therapeutics can rationally select potentially responsive patient populations and exclude resistant patients based on molecular mechanisms of action. The application of immunomodulatory drugs (IMiDs) evolved from unselective usage to the identification of del(5q) as a target, which then led to mechanistic clues and clarification of its mode of action. Lenalidomide (LEN) has been used in non del(5q) patients with a variable response rate, but the molecular underpinnings for LEN efficacy in this setting are not known. Genomic analyses (Negoro et al., Leukemia 2016) have provided only a marginal improvement in response prediction, suggesting that other factors might be relevant in sensitizing cells to LEN. The effects of LEN are related to its binding affinity to cereblon (CRBN), the substrate adaptor of the CRL4CRBN E3 ubiquitin ligase, a cullin-ring ligase consisting of damaged DNA-binding protein1(DDB1), cullin4a (CUL4A), and regulator of cullins-1 (ROC1). LEN selectively activates CRL4CRBN E3 ubiquitin ligase to selectively degrade CSNK1A1 leading to synthetic lethality in patients with del(5q) that are haploinsufficient (HI) for CSNK1A1. However, LEN and the new generation compounds pomalidomide and iberomide (CC-220) also trigger recruitment and degradation of the zinc finger transcription factors IKAROS (IKZF1, 7p12.2) and AIOLOS (IKZF3, 17p12-q21.1) through CRBN, and therefore promote their proteosomal degradation. The synthetic lethality of these immunomodulator agents relies on expression levels of AIOLOS and IKAROS. Response to those agents depends strictly on low expressions of AIOLOS and IKAROS sensitizing certain cell types (e.g., myeloma). We hypothesized that levels of LEN sensitivity might correlate with expression levels of its targets in selected disease subtypes of myeloid neoplasia (MN). We studied a large cohort of patients with MN (n=3,328) and we identified 122 patients with -7 and 194 patients with del(7q). We noted that for those cases with informative RNA-seq expression, IKAROS exhibited haploinsufficient (HI) mRNA levels in 67% of patients with -7 and 40% in del(7q), as defined based on levels <25%tile of the diploid expression of cases (Kerr, ASH 2019). Since IKAROS is described to be a target of iberomide, we hypothesized that monosomy 7 (-7) but not del(7q) could selectively benefit from this agent, analogous to LEN in del(5q). Consistent with this proposition we further selected 160 hematopoietic cancer cells with available IKZF1 CNV status in a publicly available database of cell drug sensitivity (cancerrx). For all cell lines, the anti-proliferative effect of LEN was described. Cells with monosomy of IKZF1 (CNV=1) had an increased sensitivity to LEN as their IC50 was lower than compared to that of cells with IKZF1 with CNV ≥ 2 (6.1μM vs. 24.3μM). To further validate this prediction, we revisited the responsiveness to LEN (defined by Negoro et al., Leukemia 2016) of non-del(5q) MDS patients (n=79) showing an ORR of 40%. By focusing on patients with alterations in chr7 we identified 10 patients with MDS and high or very high International Prognosis Scoring System-Revised (IPSS-R) risk [6 patients with -7 and 4 patients with del(7q)]. In this cohort LEN response was assessed at 3 and 6 months; 4 out 6 patients with -7 responded to LEN, while del(7q) patients were all refractory (n=4). Responding monosomy 7 patients with complete bone marrow response (n=3) received 10 or 50mg doses of LEN (2 patients had a complex karyotype and 1 had isolated -7). The remaining responding patient had a partial response with hematological improvement. Interestingly, this patients was treated with a 5mg dose of LEN and had a TP53 mutation. In the other 2 patients: one with -7, LEN was discontinued because of pancytopenia associated with treatment, while in the other one -7 could not be confirmed by FISH. In the group of del(7q) patients, complex karyotypes and the presence of del(5q) in 2 did not predict for better response. Our preliminary results suggest that selective application of new generation IMiDS targeting IKAROS have clinical potential in patients with -7. Supportive data from in vitro cellular models will be comprehensively presented. Disclosures Walter: MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Nazha:Tolero, Karyopharma: Honoraria; Incyte: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Daiichi Sankyo: Consultancy; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome

Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (e.g. p53, IκB), and promotes the translation of eIF4E-bound mRNAs coding oncoproteins (e.g. c-MYC, BCL-2, AR). Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Eltanexor (elta), a second-generation SINE compound, has demonstrated reduced brain penetration and improved tolerability compared to selinexor in non-clinical animal models, and preliminary anti-tumor activity in clinical trials of hematologic and solid tumor malignancies. The primary objective of this study was to assess the safety, tolerability and anti-tumor activity of elta in patients (pts) with higher risk (HR)-Myelodysplastic Syndrome (MDS). Methods: This is part of a Phase 1/2 study (NCT02649790) to determine the safety, tolerability and anti-tumor activity of elta in advance malignancies. This trial planned to evaluate single agent activity of elta in an expansion cohort of 20 pts with HR-MDS (intermediate-2 [Int-2] or high-risk by the International Prognostic Scoring System [IPSS]). Other key eligibility criteria included: age ≥18, ECOG ≥1, adequate organ function, and documented evidence of progressive disease as defined by the 2006 International Working Group (IWG) Response Criteria for MDS, which includes hypomethylating agent (HMA) failure. The dose levels evaluated in the MDS cohort were 10 and 20 mg elta taken orally once daily for 5 consecutive days per week in a 28-day cycle. A key efficacy endpoint is overall response rate (ORR) which includes complete response (CR), partial response (PR), marrow CR (mCR), and hematologic improvement (HI) using the 2006 IWG Response Criteria for MDS. Results: Twenty pts (median age 77 years-old; range 62-89; 55% male) were enrolled as of 15 July 2018 (n=15 at 20 mg and n=5 at 10 mg). All pts were refractory to HMA with a median of 2 prior therapies (range 1 - 5) and 90% high risk via IPSS (11 pts high, 7 pts Int-2, 2 pts Int-1 [IPSS-R high]). Fourteen of 20 pts were evaluable for response, 2 are pending disease reassessment and 4 were not evaluable (NE). Preliminary efficacy demonstrated best responses of 4 mCR (29%) and 6 stable disease (SD; 43%) and 4 progressive disease (PD; 29%). The disease control rate (mCR + SD) was 71%. The median time on treatment for all pts was 69 days (range 5+ - 379) with a median time on study of 115 days (range 5+ - 400). The most frequent (≥3 pts) treatment-related adverse events (TRAEs) any grade (Gr) included nausea (53%), decreased appetite (33%), diarrhea (27%), thrombocytopenia, anemia, neutropenia, vomiting and dysgeusia (20% each). The most frequent Gr≥3 TRAEs included thrombocytopenia and anemia which are expected in this immune compromised patient population. All AEs were reversible and manageable by supportive care and dose modification. The 4 pts NE for response were pts who discontinued from treatment before having the first disease response reassessment due to: Gr3 diarrhea related to eltanexor, Gr5 sepsis not related per investigator, Gr3 pneumonia not related, and withdrawal by pt. Conclusion: Oral eltanexor demonstrated preliminary anti-tumor activity as a single agent in elderly pts with HMA-refractory HR-MDS, including mCRs or disease stabilization, and a manageable tolerability profile. Further evaluation of efficacy and safety in HR-MDS is on-going. Disclosures Lee: Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Bhatnagar:Karyopharm Therapeutics: Other: Research support; Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties. Baloglu:Karyopharm Therapeutics Inc: Equity Ownership, Patents & Royalties; resTORbio: Employment. Wang:Karyopharm Therapeutics Inc: Employment. Shah:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Phase I Clinical Trial of CK0801 (cord blood regulatory T cells) in Patients with Bone Marrow Failure Syndrome (BMF) Including Aplastic Anemia, Myelodysplasia and Myelofibrosis

Background: Aplastic anemia is an autoimmune disease of the bone marrow (BM) characterized by defective and decreased regulatory T cells (Tregs) which results in unchecked cytotoxic T cell mediated bone marrow suppression [1]. In a xenogeneic model of induce BM aplasia, adoptive therapy with cord blood (CB) Tregs reverses such a defect (Fig 1A). Furthermore, as compared to peripheral blood (PB), CB Tregs show a higher expression of Helios, a marker of thymic derived Tregs (Fig 1B) and CB Tregs exert a superior suppression of proliferating conventional T-cells in CFSE assay (Fig 1C). In a xenogeneic mouse model of GVHD, CB Tregs can exert suppression across HLA barrier resulting in survival benefit (Fig 1D); and in another xenogenic lupus model, a single dose of CB Tregs results in significant decrease in circulating effector T cells (Fig 1E) up to 8 weeks. Furthermore, under stressful conditions of continued culture in the presence of inflammatory cytokines including IL15 and IL23, CB Tregs do not secrete IL-17 or express RORγt, a concern of plasticity that plagues PB Tregs (Fig 1F). In fact, CB Tregs increase their secretion of the suppressor cytokine, IL-10 in response to inflammatory stress, which supports our hypothesis, that CB Tregs based adoptive therapy can have wide application and can be used to treat inflammatory disorders. Therefore, we hypothesized that adoptive therapy with CB Tregs can be utilized as treatment for the inflammatory bone marrow failure (BMF) disorders including aplastic anemia, hypoplastic myelodysplasia and primary myelofibrosis. Study Design and Methods: We have now launched a phase I clinical trial examining the role of single infusion of CK0801, an allogeneic, fresh CB Treg product, utilizing novel process development that consist of well-defined qualification criteria for the starting material (cord blood units), parameters for manufacturing and culture-expansion; and well-defined analytic testing and lot release criteria, for the treatment of BMF, where 3 doses are examined: i) dose level I: 1x106 cells/kg; ii) dose level II: 3x106 cells/kg and iii) dose level III: 10x106 cells/kg (NCT03773393). The study follows 3+3 phase I design where 3 patients will be treated at dose level I. If no DLT is observed, then the dose will be escalated to dose level II and if no DLT is observed, then the dose will be escalated to dose level III. If 1 DLT is observed at a dose level, then 3 additional patients will be treated at that level. If no additional DLTs, then that dose level will be defined as MTD. If ≥2DLTs are observed at dose level II or III, then prior dose level is defined as MTD. If ≥2DLTs at dose level I, then DSMB will review and evaluate for study continuation. MTD will be decided when 6 patients are treated at a dose level with < 2 DLTs. The eligibility criteria include: i) diagnosis of aplastic anemia, myelodysplastic syndrome or myelofibrosis, ii) Age > 18 years, iii) cord blood unit matched at HLA 3 out of 6 with the patient for generation of CK0801. The primary endpoint includes dose limiting toxicity (DLT) as defined by i) severe (grade 3 or 4) infusion toxicity within 24 hours; ii) regimen related death within 30 days or iii) severe (grade 3 or 4) cytokine release syndrome within 30 days. The secondary endpoints include i) disease-specific response including complete remission, transfusion independence and hematologic improvement and ii) duration of response. The exploratory endpoints include assessment of PB and BM immune reconstitution and inflammatory cytokines at baseline and scheduled follow ups of Days 0, +1, +3, +7, +14, +21, +30, +60, +90, +180 and +365 in the post-treatment setting. These studies will include T cell compartment analysis: Treg, Effector T cells, T-cell anti-viral activity. Serum will be analyzed for inflammatory cytokines: IL1, IL2, IL4, IL6, IL7, IL8, IL10, IL17, IFN-gamma, ST2, REG3a, OPN, Follistatin, Elafin, TGF-beta. Optional exploratory cytokines: SCF, G-CSF, GM-CSF, HGF, VEGF, SDF1a, MCP1, MCP2, TARC, MIP3a, TECK, CTACK, CCL28, FGF, PDGF, EGF, TGF-α, TLR. The first patient is already consented with a planned total of 9 patients.

Landmark Response and Survival Analyses from 102 MDS and CMML Patients Treated with Guadecitabine in a Phase 2 Study Showing That Maximum Response and Survival Is Best Achieved with Adequate Treatment Duration

Landmark Response and Survival Analyses from 102 MDS and CMML Patients Treated with Guadecitabine in a Phase 2 Study Showing That Maximum Response and Survival Is Best Achieved with Adequate Treatment Duration

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Preliminary Results from a Phase II Study of the Combination of Pevonedistat and Azacitidine in the Treatment of MDS and MDS/MPN after Failure of DNA Methyltransferase Inhibition

Extended Experience with a Very Low Dose, Metronomic, Subcutaneous Decitabine Regimen Intended to Deplete DNMT1 without Cytotoxicity

Rationale: Dose-reduction of a nucleoside analog reduces cytotoxicity and hence can increase safety, but with less cytotoxicity-driven efficacy as a trade-off. Such an efficacy trade-off, however, may not apply to the nucleoside analog decitabine, because it has a molecular-targeted action of depleting DNA methyltransferase 1 (DNMT1) separable from cytotoxicity, and that occurs and is saturated at low concentrations. In fact, higher decitabine doses/concentrations, by causing cytotoxicity, limit feasible exposure times for this molecular effect that can cytoreduce p53-null, chemorefractory myeloid malignancies via terminal-differentiation instead of apoptosis, simultaneously sparing normal hematopoiesis. Hence, we designed decitabine application to avoid cytotoxicity and increase DNMT1-targeting and describe here results in 69 patients (25 of whom were previously described with shorter follow-up (NCT01165996)(J Clin Invest 2015; 125(3):1043-55]). Methods: IRB approved Myeloid Malignancy Registry (16-020) and Sample Repository protocols (5024) curated demographic, laboratory, intervention, outcome, and mutational data in myeloid malignancy patients after written informed consent; 69 of 1694 patients in the Registry received the alternative decitabine regimen: (i) Dose: 0.1-0.2 mg/kg (~3.5-5 mg/m2), verified to deplete DNMT1 without cytotoxicity in primate and human studies; (ii) Schedule: 1-2X/week, frequent and distributed, to increase S-phase dependent DNMT1-depletion; (iii) Route: subcutaneous, to avoid high peak concentrations.A standard starting dose of 0.2 mg/kg was reduced to 0.15 mg/kg if infection risk was high (e.g., ANC<500). Frequency of administration was dictated by disease aggression and response: e.g., 2X/week on consecutive days for myeloblasts >10% or for lack of response to 1X/week. Neutropenia from treatment was managed by interruption then resumption upon neutrophil recovery (same dose or lower by 0.05 mg/kg). Routine anti-emetic prophylaxis was not required. Results: Non-cytotoxic DNMT1-depletion was confirmed by bone marrow gH2AX and DNMT1 measurements (published for 1st25 patients). The 69 patients had MDS 54%, MDS/MPN 14%, MPN 17% and AML 15%. Their median age was 69 years (range 45-89). Prior therapies (77%) were 5-azacytidine 29%, lenalidomide 19%, erythropoietin 26%, hydroxyurea 7%, ruxolitinib 7%, cytarabine 4%. The side-effect was neutropenia (non-cytotoxic DNMT1-depletion skews myeloid differentiation away from GMP and to EMK), complicated by fever/infection in 31 patients (45%), with 1 septic death. Eight of these 31 patients (25%) had fever/infection before treatment. Blood count improvements meeting IWG criteria for response (hematologic improvement [HI]/complete remission [CR]) occurred in 30 patients (43%; CR 14%) (Fig 1A) and were durable(median treatment duration in HI/CR 82 weeks [range 14-347]). Treatment decreased bone marrow myeloblasts, even in cases without HI/CR (Fig 1B). HI/CR was achieved in MDS/AML containing monosomy 7, trisomy 8, complex cytogenetic abnormalities and/or multiple mutations (Fig 1C). Cytogenetics were normalized in 10/36 (28%) (Fig 1C). Patients with HI/CR had better overall survival (median 31 vs18 months) (p=0.036) (Fig 1D). Predictors of HI/CR were higher baseline neutrophils (median 3.04 vs 1.23 x109/L; p=0.002)and higher marrow cellularity (median 70 vs48%; p=0.044)(Fig 1E, F). Conclusion: Myeloid malignancies containing diverse genetic abnormalities responded sustainably (up to 6.5 years follow-up) to a decitabine regimen designed and demonstrated to be non-cytotoxic yet DNMT1-targeting, consistent with scientific data validating DNMT1 as a mutation-agnostic target that operates in a final common pathway of myeloid transformation. Although this single-agent regimen is non-curative, we postulate that avoidance of cytotoxicity, combined with target-validity, enabled sustained disease control/transfusion-freedom in several patients. Reported links between some mutations, e.g., in TET2, and decitabine response could be via higher neutrophils that in turn enable frequent decitabine exposures, a basic requirement for response. Also fundamental, HI/CR requires not just suppression of malignant clones but marrow capacity to support and recover functional hematopoiesis, suggesting why low baseline marrow cellularity predicted non-response. Disclosures Maciejewski: Novartis: Consultancy; Alexion: Consultancy. Saunthararajah:Novo Nordisk: Consultancy; EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties. OffLabel Disclosure: Alternative dose and scheduling of Decitabine for myeloid neoplasms