ALBERT

Description: Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p

Description: Introduction: Gemtuzumab ozogamicin (GO; MylotargTM) is an antibody-drug conjugate composed of an anti-CD33 monoclonal antibody covalently linked to the potent antibiotic calicheamicin. Previous studies have shown GO is generally well tolerated and can induce durable second remissions when administered as monotherapy or in combination with chemotherapy in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). We report safety data from an expanded-access protocol (EAP) that allowed compassionate use of GO in patients with R/R AML or acute promyelocytic leukemia (APL) and no access to comparable or alternative therapy. Methods: Conducted in the United States, the GO EAP (NCT02312037) was an open-label study in patients aged ≥3 months with R/R AML (including myelodysplastic syndrome) or APL who were considered to have the potential to derive clinical benefit and had exhausted other treatment options. The protocol allowed for treatment regimens tested in clinical trial settings and reported in the Mylotarg Investigators Brochure or peer-reviewed journals. Data from these trials indicated these regimens could potentially benefit a patient with R/R AML or APL. For R/R AML patients, the regimens included GO as monotherapy or in combination with anthracyclines and/or nucleoside-analogue containing regimens or hypomethylating agents. For patients with APL, these included GO as monotherapy or in combination with all-trans retinoic acid and/or arsenic trioxide. Patients were permitted to re-enroll in treatment, and their data are summarized according to each enrollment treatment. Results: A total of 331 patients received GO either as monotherapy for R/R AML (adult [aged ≥18 years]: n=118; pediatric [aged

Description: Abstract 4975 Introduction Clofarabine is a nucleoside analog approved in an intravenous form on a daily × 5 schedule to treat relapsed/refractory pediatric acute lymphoblastic leukemia. It is also active in adult acute myeloid and lymphoblastic leukemia. Clofarabine, given orally at a dose of 20 – 40 mg/m2 daily for 5 consecutive days, was shown to achieve a response rate of 43% in patients with high-risk MDS (Faderl S et al. J Clin Oncol 28:2755-60,2010). In that study the toxicity profile (mainly pancytopenia) was better with lower doses, while response rates did not differ. Animal models suggest that protracted administration of clofarabine is more efficacious and less toxic. The optimal dose and schedule of oral clofarabine for the treatment of patients with MDS is unknown. The goal of this study was to establish the safety and maximum tolerated dose (MTD) of clofarabine administered orally at a low daily dose over a protracted period for the treatment of MDS. Methods Adult patients (ECOG performance status of 0–2) with MDS and a prognostic score of INT-1 or higher according to the International Prognostic Scoring System were eligible. INT-1 patients had to be transfusion-dependent. Patients had to have failed first line therapy consisting of either a hypomethylating agent, or lenalidomide in the case of patients with the 5q- abnormality. The starting dose and schedule of oral clofarabine was 5mg (fixed dose) daily for 10 consecutive days of a 28 day cycle. This dose and schedule were modified as outlined below. Bone marrow biopsies were done after 3, 6 and 12 cycles of treatment. Patients could receive up to 12 cycles. Results A total of 7 patients (4 women and 3 men) were enrolled. The median age was 72 years (56-81). Two patients had 5q- MDS and had failed or developed disease progression after prior lenalidomide treatment. Two patients had CMML-1 and CMML-2. One patient had MDS/MPD. Two patients had RA and MDS-U. The non 5q- patients had all received treatment with either decitabine or azacitidine. Patient 1 had RA with del(5)(q13q33) and complex cytogenetics. She became transfusion independent on lenalidomide therapy but relapsed 8 months after stopping therapy due to lenalidomide toxicity. She then received 5mg of oral clofarabine daily for 10 days and developed grade IV pancytopenia. Her bone marrow at day 18 revealed complete aplasia. Her blood counts recovered by day 47 and ultimately normalized. She remained transfusion-independent off therapy for 2 months. Patient 2 had CMML-1 with grade 3 thrombocytopenia. He failed azacitidine therapy and was treated on study with oral clofarabine at a dose of 5mg daily for 10 consecutive days. He developed grade 4 thrombocytopenia which recovered to transfusion-independence 4 months after start of therapy. The protocol was then modified to start patients on 1mg orally of clofarabine daily for 10 consecutive days. Patient 3 had RA with trisomy 8. She was transfusion dependent and had failed decitabine, lenalidomide and immunosuppressive therapy. She received 2 cycles of oral clofarabine at 1mg daily for 10 days. She developed grade 4 thrombocytopenia after cycle 2. Her platelet count recovered to baseline on day 26. She continues to be transfusion-dependent. The protocol was modified again to reduce the number of treatment days to 7 if patients developed more than a 25% drop in baseline blood counts after 10 days of clofarabine at 1mg daily. All patients who were treated with 1mg oral clofarabine daily for 10 days had a greater than 25% drop from baseline blood counts with cycle 1 and received only 7 days of therapy for subsequent cycles. On the 7 day treatment cycle we did not observe any significant toxicity. One patient with a mixed MPD/MDS who was transfusion-dependent after failing 4 cycles of decitabine therapy remained transfusion-independent for 12 months while on monthly clofarabine. One patient with CMML-2 who had failed decitabine therapy remains on therapy after 7 cycles of treatment and is transfusion-independent. After 6 cycles of therapy her bone marrow blasts had dropped from a baseline of 18% to 8%. Conclusion Low dose oral clofarabine shows promise for the treatment of high-risk MDS. However, this patient population seems to be particularly sensitive to protracted treatment schedules of clofarabine. A dose of oral clofarabine of 1mg daily for 7 days on a 28 day cycle is safe in this patient population and shows promising efficacy. This dose is adopted for an ongoing Phase II study. Disclosures: Shami: Genzyme: Honoraria, Research Funding.

Description: JS-K (O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate) is a diazeniumdiolate class of prodrug which is designed to release nitric oxide (NO·) on reaction with glutathione S-transferases (GST). GST has been shown to be overexpressed in a broad spectrum of tumor cells. Therefore, JS-K can possibly turn GST overexpression to the tumor’s disadvantage by generating high intracellular concentrations of cytotoxic NO·. Multiple myeloma (MM) is currently an incurable hematological malignancy where new treatment options are urgently needed. In this study we investigated the cytotoxicity of JS-K in MM in vitro and in vivo. JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient MM cells (IC50: 0.3–2.5 mM). Importantly, no significant cytotoxic effects of JS-K at these doses were observed in normal peripheral blood mononuclear cells. JS-K treatment induced apoptosis in MM cells which was associated with PARP, caspase 8, and caspase 9 cleavage; increased cell surface expression of Fas/CD95; Mcl-1 cleavage; Bcl-2 phosphorylation; as well as mitochondrial cyt c, AIF, and EndoG release. Moreover, JS-K could overcome the survival and growth advantages conferred by exogenous IL-6 and IGF-1, or by adherence of MM cells to bone marrow stromal cells. Flow cytometry experiments revealed significant NO· generation in JS-K-treated MM cells. Since NO· is known to cause DNA double strand breaks (DSB), we hypothesized that JS-K induces DSB in MM cells and confirmed DSB formation by neutral comet assay. We further showed that JS-K also activated DNA damage response pathways as evidenced by H2AX, Chk2 and p53 phosphorylation. In addition, JNK was also activated by JS-K treatment in MM cells, and inhibition of JNK significantly decreased JS-K-induced cytotoxicity, suggesting that JS-K induced apoptosis is mediated via JNK signaling. Finally, JS-K was also significantly effective in inhibiting tumor growth and prolonging median survival (p 〈 0.01) in a human plasmacytoma xenograft mouse model. Analysis of tumors harvested from treated animals showed that JS-K induced apoptosis and decreased angiogenesis in vivo. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM.

Description: Introduction Intensive treatment of acute myeloid leukemia (AML) is associated with severe pancytopenia. Thrombopoietic agents have so far failed to mitigate treatment-associated thrombocytopenia. Platelet factor 4 (PF4) is a potent negative regulator of megakaryopoeisis and its levels correlate with platelet transfusion requirements in children treated for acute lymphoblastic leukemia. Anti-PF4 antibodies diminish chemotherapy-induced thrombocytopenia in mice. ODSH (2-O, 3-O Desulfated Heparin), a heparin derivative with low anticoagulant activity, is a potent inhibitor of PF4, mitigates heparin-induced thrombocytopenia and, like other heparins, may inhibit the CXCL12/CXCR4 axis. The purpose of this pilot study was to obtain preliminary data on the effect of ODSH when combined with intensive AML treatment. Methods Adult patients with newly diagnosed untreated AML (excluding acute promyelocytic and acute megakaryoblastic leukemia) were enrolled. Induction therapy consisted of cytarabine (100 mg/m2 as a continuous 24-hour infusion on days 1 – 7) and idarubicin (12 mg/m2 by intravenous bolus on days 1 – 3). During induction cycles, ODSH was given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 7. Patients 60 or older received further post-induction therapy off study. Patients younger than 60 received consolidation therapy with high dose cytarabine (3 g/m2 every 12 hours on days 1, 3, and 5) along with ODSH given as a bolus of 4 mg/kg on day 1 followed by a continuous infusion of 6 mg/kg/day on days 1 – 5. Patients received transfusion and antibiotic support per standard guidelines. Patients did not receive growth factor support during induction cycles. Primary endpoints were to determine the safety and tolerability of ODSH combined with intensive AML therapy, and to obtain preliminary data on the effect of ODSH on platelet count recovery. Secondary endpoints included obtaining preliminary data on the effect of ODSH on complete remission rate and tolerability of chemotherapy. Data presented here are for induction cycles. Data for consolidation cycles will be presented at the meeting. Results Ten patients were enrolled. Two patients did not complete the full induction cycle due to complications unrelated to ODSH therapy and are not included in the analysis. The median age of the 8 patients (3 women) who completed the full induction cycle and were analyzed was 55 (range: 22 – 74). There were no ODSH-associated adverse events. Based on cytogenetic, molecular, or antecedent hematologic disorder, 1, 5, and 2 patients fell into the better, intermediate, and poor risk categories, respectively. Day 14 bone marrow biopsies were obtained on all 8 patients and were aplastic without detectable leukemia in all. Seven out of 8 patients who completed induction had evidence of a morphologic complete remission upon count recovery using IWG criteria. One of the 7 patients in morphologic remission had evidence of minimal residual disease by flow cytometry and cytogenetics. It is noteworthy that the 2 patients who did not receive a full course of induction therapy (treatment discontinued on Day 3 and Day 5 of the induction cycle, respectively) achieved a complete remission upon count recovery using IWG criteria with evidence of minimal residual disease by molecular testing. All 8 patients who received a full course of induction therapy were evaluable for platelet count recovery. Among those patients, the median day to obtain a sustained platelet count above 20,000/ml without transfusion was day 20 (range: 16 – 22). Five of the 8 patients who received a full course of induction therapy were evaluable for neutrophil count recovery. Among those patients, the median day to a neutrophil count above 1,000/mL was day 23 (range: 21 – 27). Conclusion We conclude that ODSH is well tolerated when combined with aggressive therapy for the treatment of AML. Results from this pilot study show that ODSH may enhance count recovery and treatment efficacy. These results justify further study of this strategy in a randomized trial. Disclosures Kennedy: Cantex Pharmaceuticals: Equity Ownership. Bavisotto:Cantex Pharmaceuticals: Consultancy. Marcus:Cantex Pharmaceuticals: Employment, Equity Ownership. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Lone Star Thiotherapies: Equity Ownership; Cantex Pharmaceuticals: Research Funding.

Description: Background Anti-CD20 mAbs are an important element in the therapeutic armamentarium for B-cell malignancies such as chronic lymphocytic leukemia (CLL). Although new targeted drugs (Ibrutinib & Idelalisib) and recently developed anti-CD20 mAbs (obinutuzumab & ofatumumab) have significant activity, the clinical management is limited by toxicity or low sensitivity to anti-CD20 mAbs. Herein we propose Drug-Free Macromolecular Therapeutics (DFMT) as a novel class of therapeutics that amplifies CD20 crosslinking and triggers apoptosis. The unique features of DFMT include augmentation of multivalent CD20 crosslinking, immune effector independence and no cytotoxic agents. Its effectiveness has been demonstrated in vitro and in preclinical Non-Hodgkin Lymphoma (NHL) models including a CD20-deficient rituximab (RTX)-resistant model, in which DFMT combined with a long-circulating polymer-gemcitabine conjugate (2P-GEM), induced prolonged survival and tumor clearance from bone marrows.[Zhang R, et al. PNAS 2014; Li L, et al. ACS Nano 2018] Therefore, we conducted assessment of DFMT on patient samples. Methods Malignant B cells were isolated from patients diagnosed by the hematologic malignancies service at the Huntsman Cancer Institute. The majority of isolates were from CLL patients. CD20 expression of each sample was evaluated by flow cytometry. DFMT consisting of two nanoconjugates was used to treat the cells in consecutive administration: first, cells were incubated with Fab'-MORF1 (bispecific engager, Fab' fragment of RTX conjugated with a morpholino oligonucleotide); after 1 h, a crosslinking effector (CLE) containing multiple copies of complementary morpholino oligonucleotide (MORF2) was added and the cells were continually incubated for another 6-20 h (depending on assays). The CLE can be prepared by conjugation of MORF2 to either N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer precursor or human serum albumin. Crosslinking of CD20 receptors is initiated by the multiple hybridization of MORF1/MORF2 at the cell surface, and results in apoptosis (Fig. 1A). Annexin V and caspase 3 assays were used to quantify B-cell apoptosis. RTX followed by goat-anti-human (GAH) secondary antibody was used for comparison. GAH was added to imitate the function of Fcγ+ immune effector cells for crosslinking of RTX. When enough cells were available, a detailed evaluation of apoptosis induction was performed, i.e. plasma membrane rupture, genomic DNA fragmentation, mitochondrial membrane permeabilization, Bcl-2 inhibition and confocal imaging to document specific biorecognition at the cell surface. In some samples, pretreatment with GEM or 2P-GEM for 48 hours followed by DFMT or RTX/GAH was conducted, and the effect of GEM in enhancing apoptosis induction was evaluated. Results The efficacy of DFMT was assessed in 44 samples including 35 CLL along with a few other B cell lymphomas such as diffuse large B cell lymphoma (DLBCL), marginal zone lymphoma (MZL), follicular lymphoma (FL), etc. DFMT induced apoptosis in 65.9% of patient samples. High-risk mutations such as 17p13 and 11q22 deletions, usually considered as poor prognostic factors in CLL, did not hamper the therapeutic efficacy of DFMT treatment. In cases with poor responses, we noted low CD20 expression levels (Fig 1B). We previously showed that pre-treatment with GEM can enhance surface CD20 expression and restore responsiveness to anti-CD20 mAb. Therefore, we pre-treated the low CD20 patient samples with GEM followed by treatment of DFMT, which induced significantly more apoptosis than RTX/GAH control (Fig 1C). In addition to increased target expression (CD20), this superior activity is likely due to synergy between GEM and DFMT, as we have shown that CD20 crosslinking triggered by DFMT stimulates a cascade of apoptotic events that eventually lead to up-regulation of the pro-apoptotic proteins Bax and inhibition of NF-ĸB, which in turn sensitizes cells to GEM.[Li L, et al. ACS Nano 2018] Conclusion DFMT effectively increased apoptosis of tumor cells from patients with a variety of B-cell malignancies, irrespective of genomic aberrations. The apoptotic response to DFMT was significantly correlated with CD20 expression, and could be enhanced by GEM-induced upregulation of CD20. DFMT alone or in combination with 2P-GEM warrants further evaluation as a therapeutic for refractory B cell malignancies. Disclosures Yang: Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; University of Utah: Patents & Royalties: PCT/US2014/023784 and PCT/US2017/37736. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees. Kopeček:University of Utah: Patents & Royalties: PCT/US2014/023784 and PCT/US2017/37736; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Induction therapy for newly diagnosed AML pts can be classified as intensive or non-intensive. Non-intensive therapies are increasingly used in pts aged 〉65 years due to concerns about their ability to tolerate intensive chemotherapy. However, the relative benefit-risk ratios associated with intensive versus non-intensive therapies in AML pts is likely affected by age, comorbidities, and disease-related characteristics, such as cytogenetic and molecular features. Here, we examine these relationships. Methods: Data from 1295 newly diagnosed AML patients, given induction therapy between 2008 and 2012 at six participating academic centers, were retrospectively collected. We used two previously validated models to define distinct prognostic groups, and within each, compared 2-year mortality rates according to whether pts received intensive or non-intensive therapy. Non-intensive therapy principally included azacitidine, decitabine, or low-dose cytarabine, while intensive therapies primarily included the standard 7+3 regimen or "high-dose" cytarabine combinations with anthracyclines or purine analogs. The first model (Blood 2015; 126:532) was a composite of the prognostic effects of age, comorbidity index, and cytogenetic/genetics risks per European Leukemia Net (ELN) classification. The second (JCO 2011; 29(33): 4417) was a treatment related mortality (TRM) index including 8 pt- and AML-specific risk factors. Results: Age distribution of the pts were ≤49 (23%), 50-59 (20%), 60-69 (33%), and ≥70 (24%) years old. Median follow-up for currently alive pts was 41 (range, 0-99) months. Cytogenetic-molecular risks per ELN classification were favorable (18%), intermediate I and II (39%), or unfavorable (43%). Induction treatments were intensive in 77% and non-intensive in 23% of pts. The proportion of patients receiving non-intensive therapy increased with increasing age (Table 1). Almost all pts (99%) with the lowest composite scores (1-3) received intensive therapies and were therefore omitted from the comparisons with either model. Per the composite model grouping, pts had better survival rates if they received intensive therapy, although the differences were not statistically significant in pts with composite scores ≥10 (Table 2). Pts with TRM scores of 0-4 and ≥5, with a score of 5 corresponding to the median score, statistically significantly benefitted from intensive therapies (Table 2). Among all pts aged 70-79 years old (n=242), 41% received intensive therapy, while 59% received non-intensive therapy. The intensively treated pts in this age range had statistically significantly higher survival rates at 2 years (26% versus 13%, HR: 0.73, 95% CI: 0.54-0.98, P=0.04, Figure). Conclusion: After accounting for underlying prognosis using 2 validated models, we found pts with newly diagnosed AML generally had better survival if they received intensive therapy. This survival benefit was not statistically proven for pts with the highest composite scores (≥10). Early mortality was not increased in older pts given intensive versus non-intensive therapy (Figure), likely due to improvements in supportive care which allowed the greater anti AML effect of intensive therapy to become manifest over time. While we cannot exclude the effects of selection bias, absent a randomized trial our results suggest intensive therapy could be considered for most pts, up to the age of 80 years, regardless of their comorbidity burden. Although results seem better with intensive therapy, less than 50% of patients with composite scores 〉3 given such therapies were predicted to be alive at 2 years, suggesting the need for randomized clinical trials between novel intensive and non-intensive therapies to achieve better survival. Table 1 Regimen intensity per pt age groups Table 1. Regimen intensity per pt age groups Table 2 Comparisons of hazard ratios (HR) and 2-year rates of survival between intensive and non-intensive initial therapies Table 2. Comparisons of hazard ratios (HR) and 2-year rates of survival between intensive and non-intensive initial therapies Figure. Intensive versus non-intensive therapies among pts aged 70-79 years with AML Figure. Intensive versus non-intensive therapies among pts aged 70-79 years with AML Disclosures Fathi: Bexalata: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Research Funding. Shami:JSK Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: INTRODUCTION: Mutation of FLT3, a tyrosine kinase receptor, is one of the most common molecular alterations in AML. In 2017, the FDA approved midostaurin for treatment of newly diagnosed AML adult patients with FLT3 mutation. Understanding of utilization and costs associated with AML pre and post Midostaurin approval is warranted. The objectives of this study were to evaluate healthcare utilization and costs between FLT3-mutated AML patients and FLT3-wildtype AML patients, pre-midostaurin approval and among initial FLT3-mutated AML patients treated with midostaurin. METHODS: FLT3-tested AML patients treated with 7+3 induction chemotherapy prior to midostaurin approval, were identified retrospectively from 2007-2016 at Huntsman Cancer Institute. A separate sample of FLT3-mutated patients treated with midostaurin from May 2017 to June 2018 were also identified. Healthcare charges, which are the individual list prices set by the medical facility, were computed for inpatient, outpatient and emergency services in this study. Since cost data were not available, charges were converted to imputed costs by applying the 2013 CMS charge-to-cost ratio of 0.492. Health care utilization through inpatient, outpatient and emergency room visits were also evaluated for FLT3-mutated and FLT3-wildtype patients. RESULTS: Pre-midostaurin: One hundred patients (39 FLT3-mutated, 61 FLT3-wildtype) prior to the availability of midostaurin were identified with a median age of 53 years. Median number of AML related inpatient visits for the total sample was 5 (FLT3-mutated [5] vs FLT3-wildtype [6] p=0.1]. Median outpatient visits were 43 for the total sample (FLT-mutated [47] vs FLT3-wildtype [51], p=0.4). Healthcare costs were categorized as AML related and all-cause related costs. AML related costs, which included transplant costs, contributed to nearly 70% of all-cause healthcare costs on an average. Approximately 38% of total AML-related costs were attributable to induction therapy among FLT3-mutated patients, while 29% of total AML-related costs among wildtype patients were related to induction (p

Description: Introduction: Acute myeloid leukemia (AML) is most frequently diagnosed in older patients (pts), whose median survival is less than 1 year. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. However, older pts often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. To this end, we designed a prospective, multi-center, longitudinal, observational study dating from first presentation of adult pts with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We examined the effects of different variables (see methods) on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including instrumental activities of daily living (IADL) and activities of daily living (ADL); frailty including walk test; geriatric assessment (GA) including cognition; Karnofsky performance status (KPS); QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale (EQ-5D), ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. High-risk myelodysplastic syndromes (MDS) receiving AML-like therapy were included. We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time. Results: The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% of pts who received HCT did so by the 9 month mark. In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5 (HR:2.11, p