Abstract: Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events ( & gt;30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

Abstract: Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Abstract: Background: Patients with acute myeloid leukemia (AML) admitted to the ICU have high in-hospital mortality, ranging from 40-70% (Halpern A, JAMA Oncology, 2017, 3; 374 and Thakkar SG, Cancer, 2008, 112; 2233). A model that considers AML-specific as well as ICU-specific variables could be of great value to identify critically ill patients likely to survive beyond hospital discharge and would help providers frame goals of care discussions. The AML Composite Model (AML-CM) was recently developed to predict early as well as late mortality after diagnosis of AML (Sorror ML, JAMA Oncology, 2017, 3:1675). The AML-CM incorporates AML cytogenetic risk, age, and comorbidity burden. It is unknown whether the AML-CM scores calculated at diagnosis of AML could add prognostic value to variables collected at the time of admission to ICU. To this end, we investigated the predictive value of AML-CM scores at diagnosis in addition to other risk factors including traditional ICU markers of illness severity collected from the time of ICU admission for prediction of 90-day mortality in patients with AML. Methods: This is a retrospective study of 218 patients with AML admitted to an ICU at one of two affiliated referral hospitals at any time during or after the initiation of chemotherapy between 2008 and 2017. We used factors from three time points: 1) initial diagnosis: sex, race, and AML-CM; 2) time of ICU admission: age, presence of relapsed or refractory disease, history of hematopoietic stem cell transplant (HCT), presence of neutropenia with ANC 〈 500; and 3) within 24 hours of ICU admission: highest creatinine ≥2.0 mg/dl, presence of bacteremia, use of invasive mechanical ventilation (IMV), noninvasive positive pressure ventilation (NPPV), dialysis, inotropes, and vasopressors. AML-CM was dichotomized based on a median score of 7 in our population, creating high-risk and standard-risk groups. The primary outcome was survival to 90 days after ICU admission. Risks for 90-day mortality were compared using unadjusted logistic regression, and the area under the receiver-operator curve (AUC) was calculated. Variables with p-value of less than 0.05 in association with 90-day mortality in a univariate logistic regression model were tested in a multivariable logistic regression model. Lastly, mortality at 90 days was calculated for patients with 0, 1, 2, or ≥3 risk factors for mortality. Results: The final study population was 217 patients, because one patient was lost to follow-up. The median age at ICU admission was 59 (range 19-83), 58% were male, and 79% were white. Mortality was 52% at 90 days. The median AML-CM was 7 (interquartile range 5-10), with 54% having AML-CM ≥7, and 46% having AML-CM 〈 7. The results of the univariate and multivariable analyses are listed in Table 1. The following variables were independently associated with 90-day mortality in the multivariate analysis: AML-CM ≥ 7 was associated with 3.6 times the odds of dying (95% CI 1.9-6.8, p=0.0001); IMV, 4.8 times the odds of dying (95% CI 2.2-10.5, p 〈 0.0001); prior HCT, 3.2 times the odds of dying (95% CI 1.5-6.9, p=0.003); and relapsed or refractory disease, 3.4 times the odds of dying (95% CI 1.8-6.7, p=0.0003). The AUC of the multivariable model which combined the 5 variables with statistically significant association on univariate analysis was 0.77. Based on results above, we calculated 90-day mortality rates among patients with 0 (n=39), 1 (n=84), 2 (n=75), and 3-4 (n=19) of the following factors: AML-CM ≥7, history of HCT, relapsed or resistant/refractory disease at ICU admission, and use of IMV (figure 1). Mortality rates at 90 days were 10%, 48%, 68%, and 95%, respectively. Conclusions: We identified 4 risk factors that show promise in predicting 90-day mortality after ICU admission in patients with AML: the AML-CM from time of diagnosis, history of HCT prior to ICU admission, disease status at ICU admission, and use of invasive mechanical ventilation within 24 hours of admission. Collectively, these factors can provide strong rationale to consider futility of ICU care among those with 3-4 risk factors, who represent ~9% of the population and have an extremely high risk of mortality at 90 days. Further, patients with 1-2 risk factors (73% of population) could be good candidates for early palliative care consult coincident with ICU admission given relatively high mortality risk within 90 days. Disclosures Becker: GlycoMimetics: Research Funding.

Abstract: 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 〈 0.05) were used to develop multivariate models examining the association between HCT and mortality within 1) the general population as well as those with 2) intermediate vs 3) unfavorable ELN risk, and 4) vulnerable pts (age ≥60 years or HCT-CI scores ≥4). The latter group constituted the majority (76%). In these analyses, all pts were considered to be in the non-HCT group until receipt of HCT at which time they enter the HCT group. The contribution of deaths to the hazard ratio (HR) for HCT reflects the relative number and characteristics of pts remaining at risk in the two groups at the time a death occurs. Results: Median follow-up was 16.8 months (range 0.1-52.4). In the initial multivariate analyses, the following were identified as significantly associated with an increased risk of mortality (Table 2): HCT-CI scores ≥5 (p 〈 0.0001), age ≥70 years (p 〈 0.0001), intermediate (p=0.03) and high ELN risk (p 〈 0.0001), relapsed/refractory AML at enrollment (p=0.0005), relapse or refractory response to initial treatment after enrollment (p 〈 0.0001), frailty per walk test (p=0.004), impaired QOL per FACT-G scores (p=0.02), increased depression per PHQ-9 (p=0.03), and dependent status per ADL scores 〈 14 (p=0.05). Survival after HCT was 58% at 2-years. Initial unadjusted analyses showed significantly lower risks of mortality in association with receiving allogeneic HCT (p=0.0003). These findings were similar in pts with intermediate (p=0.0005) or unfavorable (p 〈 0.0001) ELN risk and in vulnerable pts (p 〈 0.0001) (Table 3). However, in the adjusted models, the advantage of HCT in reducing mortality rates was lost both in the overall population (p=0.21, see figure) as well as in the other groups (p 〉 0.54, 0.40, and 0.51, respectively, Table 3). Formal tests of interactions (Table 3) showed no statistically compelling evidence that the association of HCT and mortality varies with respect to the timing of mortality or to the underlying ELN risk. Conclusions: In a prospective observational study, adjusting for key AML-specific and pt-specific variables negated the observed benefit of HCT over non-HCT therapies in reducing mortality rates among AML pts. Our results might reflect 1) improvement in supportive care and non-HCT therapies, 2) a relatively high non-relapse mortality early after HCT and the need for longer follow-up to demonstrate an adjusted benefit of HCT, and 3) the high selectivity of the transplant eligibility process, as we accounted here for variables that are often ignored in "genetic assignment" randomized studies (i.e. comorbidities and function). New randomized trials are needed; however, these trials have to be more inclusive of vulnerable pts and measure pt-specific variables. Trials focusing on reducing burden of comorbidities, frailty and poor function are needed alongside trials to treat AML with or without HCT. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Shami: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; Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy. Rizzieri:Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: 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; Novartis: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: 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. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Alexion: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Otsuka: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.

Abstract: Patients with high-risk multiple myeloma have a median survival of 〈 3 years. Tandem autologous/allogeneic hematopoietic cell transplantation with bortezomib maintenance therapy improves survival in these patients.

Abstract: 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.

Abstract: Some autoimmune disorders are increasingly recognized as risk factors for non-Hodgkin lymphoma (NHL) overall, but large-scale systematic assessments of risk of NHL subtypes are lacking. We performed a pooled analysis of self-reported autoimmune conditions and risk of NHL and subtypes, including 29 423 participants in 12 case-control studies. We computed pooled odds ratios (OR) and 95% confidence intervals (CI) in a joint fixed-effects model. Sjögren syndrome was associated with a 6.5-fold increased risk of NHL, a 1000-fold increased risk of parotid gland marginal zone lymphoma (OR = 996; 95% CI, 216-4596), and with diffuse large B-cell and follicular lymphomas. Systemic lupus erythematosus was associated with a 2.7-fold increased risk of NHL and with diffuse large B-cell and marginal zone lymphomas. Hemolytic anemia was associated with diffuse large B-cell NHL. T-cell NHL risk was increased for patients with celiac disease and psoriasis. Results for rheumatoid arthritis were heterogeneous between studies. Inflammatory bowel disorders, type 1 diabetes, sarcoidosis, pernicious anemia, and multiple sclerosis were not associated with risk of NHL or subtypes. Thus, specific autoimmune disorders are associated with NHL risk beyond the development of rare NHL subtypes in affected organs. The pattern of associations with NHL subtypes may harbor clues to lymphomagenesis.

Abstract: We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients’ overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Abstract: Introduction: Novel agents and autologous stem cell transplant (auto-SCT) have resulted in a survival benefit among patients with multiple myeloma (MM), but almost all ultimately relapse. Allogeneic transplant (allo-SCT) provides a tumor-free graft and graft-versus-myeloma (GVM) effect, but myeloablative conditioning regimens are associated with high rates of treatment-related mortality (TRM). In contrast, reduced intensity allo-SCT conditioning regimens are associated with lower TRM, but patients receiving these regimens tend to have a higher risk of relapse. Radioimmunotherapy (RIT) offers the potential to deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When incorporated into reduced intensity allo-SCT, RIT may improve responses without the associated toxicity historically associated with myeloablative conditioning. We studied 90Yttrium conjugated to an IgG1 murine anti-CD45 monoclonal antibody (MAb) (BC8), in conjunction with a reduced intensity-conditioning regimen prior to allogeneic SCT. We used CD45 as a target due to its ubiquitous expression in hematopoietic stem cells. We used the high-energy (2.8 MeVmax) beta-emitter, 90Y to facilitate a bystander crossfire effect and eliminate malignant plasma cells. Methods: This is a single-arm, open label, dose-escalation, phase I trial designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with fludarabine (flu) and low dose total body irradiation (TBI) followed by HLA-matched, related or unrelated allo-SCT for patients with high risk MM. Inclusion required patients to have at least one high risk MM-associated disease characteristic at diagnosis (del13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), del 17 by FISH, beta-2 microglobulin & gt;3.5 mcg/mL, LDH & gt;1.5 times upper limit of normal, plasma cell leukemia or progressive disease following primary therapy), and/or disease progression after auto-SCT. To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium-BC8-DOTA followed by gamma camera imaging and bone marrow biopsy. On pre-transplant day -12, patients received 90Y-BC8-DOTA at a dose calculated from the trace-labeled 111Indium-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to growth factor mobilized donor peripheral blood stem cell infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine initiated on day 0 and day -3, respectively. The MTD was defined as the dose of 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Results: A total of 15 patients were enrolled. Patient characteristics and outcomes are summarized in Table 1. One patient was withdrawn from the study prior to receiving the therapy dose after testing positive for human anti-mouse antibodies. The remaining 14 patients went on to receive 90Y-BC8-DOTA (0.5 mg/kg antibody) at escalating 90Y dose levels of 6 to 32 Gy to the liver, which is the normal critical organ. Six patients (43%) experienced grade 3-4 toxicity, predominantly GI and metabolic/electrolyte disturbances. No DLTs were observed. Because no DLTs were seen, the MTD could not be estimated. All patients achieved platelet and neutrophil engraftment, and 13 patients (93%) were & gt;95% donor in the CD3, CD33 and CD56 compartments at day +28. Estimates of overall and progression-free survival at 2 years were 77% and 78%, respectively (Figure 1). Eleven patients who completed the study regimen are alive at 2.6 months to 4.1 years. Of these, 6 patients are in complete remission, 2 have persistent disease, and 3 have relapsed at 4 months, 6 months, and 3 years post-transplant. Three patients died: 2 due to progressive disease and 1 due to respiratory failure in the setting of liver GVHD. Conclusion: The inclusion of 90Y-BC8-DOTA into a reduced intensity allo-SCT conditioning regimen is feasible and no dose-limiting toxicities have been observed. The efficacy of this regimen is promising compared with historical control rates of conventional allo-SCT for MM and should be explored in a phase II trial. Disclosures Orozco: Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Gopal: Seattle Genetics: Consultancy, Research Funding. Becker: GlycoMimetics, Inc.: Research Funding. Press: Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Bensinger: Janssen: Membership on an entity's Board of Directors or advisory committees.

Abstract: 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 〈 0.0001), age ≥50 years with those aged ≥70 years having the highest association (HR:2.71, p 〈 0.0001), ELN intermediate (HR:2.43, p=0.0003) or unfavorable risks (HR:4.3, p 〈 0.0001), receiving low-intensity induction regimens (HR:1.42, p=0.04), relapsed/refractory disease at enrollment (HR:2.04, p 〈 0.0001), dependent status per ADL scores 〈 14 (HR:1.59, p=0.005), and depression per PHQ-9 (HR:1.56, p=0.009). Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years (HR:0.40, p=0.0001), low ELN risk (HR:0.28, p 〈 0.0001), low-intensity induction (HR:0.56, p=0.02), poor KPS (HR:0.49, p=0.0005), and relapse after initial complete remission (CR) (HR:0.41, p=0.001); while pts with high-risk MDS (HR:2.43, p 〈 0.0001), relapsed/refractory disease at enrollment (HR:2.43, p 〈 0.0001), and CR after induction (HR:4.59, p 〈 0.0001) were more likely to receive HCT. Among pts aged ≥60 years, and after considering previous factors, impaired cognition (HR:0.45, p=0.007) and impaired hearing (HR:0.71, p=0.009) were associated with lower likelihood to receive HCT. Conclusions: In a prospective, observational, multi-center study, increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT. In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens. However, the independent sharp decline in receipt of HCT in pts aged 70-80 years suggests continued bias, although pts in this age group have been shown to derive similar benefit from HCT as younger pts. Use of objective comorbidity and GA tools rather than age per se to decide on HCT is encouraged. The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes. Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Rizzieri:Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Novartis: Speakers Bureau; Abbvie: 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; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Abbvie: 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. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.