Kurzfassung: 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).

Kurzfassung: 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.

Kurzfassung: 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.

Kurzfassung: 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.

Kurzfassung: 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.

Kurzfassung: Purpose. Several studies have shown that allogeneic hematopoietic cell transplant (HCT) in first complete remission (CR1) reduces risk of relapse and improves relapse-free survival in patients with intermediate- and poor-risk AML. Benefits in overall survival (OS) are less obvious. One possible explanation is that once relapse occurs previous receipt of allogeneic HCT in CR1 is associated with shorter survival, with a lower CR rate following salvage therapy for relapse being a possible contributing factor. The aims of our study were to analyze the specific effect of allogeneic HCT in CR1 on (a) second CR rate and (b) OS from first salvage therapy. Patients and Methods. We identified 166 consecutive patients with AML (APL excepted, but including MDS with 10-19% blasts) who after achieving CR1 with initial treatment relapsed and subsequently received first salvage therapy between 2005 and 2013 at our institution. We used chart reviews to collect data on: (1) age, (2) CR1 duration, (3) ECOG performance status at relapse, (4) cytogenetic category (ELN criteria for adverse, intermediate, "favorable", and "missing") at relapse, (5) allogeneic HCT in CR1 (yes vs. no, and then myeloablative vs. reduced intensity vs. no) and (6) intensity of salvage therapy: with high-dose cytarabine containing therapy or myeloablative HCT considered "high intensity", 3+7 +/- other drugs as average intensity, and other salvage treatments as low intensity. CR was defined using conventional criteria. OS was measured from date of first salvage therapy to death from any causes analyzed using the Kaplan-Meier method. Multivariable regression analysis was performed using logistic and Cox models, adjusted for the 6 covariates noted in the preceding paragraph. Results. The median age of the 166 patients was 53.5 years (20 - 80 years). The three groups differed regarding this variable (p 〈 0.001): a median of 47 years (22 - 66) in the 27 patient myeloablative group, 61 years (21 - 75) in the 20 patient reduced intensity group and 54 years (20 - 82) in the 119 patient no-HCT group. The median CR1 duration was 7.9 months, and CR1 duration did not differ statistically (p = 0.46) in the three groups: 11.5 months myeloablative group, 8.8 months reduced intensity group, and 6.4 months no-HCT group. Cytogenetic data were missing in 22 patients; in the remaining 144, 8% had "favorable", 67% intermediate, and 25% adverse risk cytogenetics with no statistically significant differences in distribution between the three groups (p = 0.27 considering all patients). The median PS was 1, with 19% of patients having PS ≥ 2. Patients in the reduced intensity group more often had PS ≥ 2 (40% vs. 19% for myeloablative and 16% for no-HCT) (p = 0.07). 52% received high intensity salvage therapy (including 4 who received myeloablative allogeneic HCT), 18% received average intensity, and 30% received low intensity. The three groups differed regarding intensity of salvage therapy (p = 0.04). 25% of reduced intensity patients received high intensity salvage vs. 44% of myeloablative and 59% of no-HCT. In contrast, 26% of no-HCT patients received low intensity salvage vs. 37% myeloablative group and 40% reduced intensity group. The CR2 rate was 37.9%. The median survival after first salvage was 7.8 months. A multivariable analysis showed that HCT in CR1 had no significant effect on CR2 rate (OR 1.33, p = 0.50) or OS (HR 0.87, p = 0.55). In contrast, shorter CR1 duration and low intensity salvage were independently associated with a lower CR2 rate with favorable cytogenetic at relapse associated with a higher CR2 rate, while PS ≥ 2, low intensity salvage, and, to a lesser extent, shorter CR1 duration were similarly associated with poorer survival with favorable cytogenetic at relapse associated with better survival. An analysis of myeloablative vs. reduced intensity vs. no-HCT led to similar conclusions: myeloablative HCT p = 0.98 and reduced intensity HCT p = 0.29. Together with the Kaplan-Meier plots (Figure 1, log rank p = 0.90) the data suggest that neither myeloablative nor reduced intensity HCT in CR1 has an adverse effect on OS after first salvage. Conclusion.There was no evidence that preceding allogeneic HCT in CR1 was associated with lower probabilities of CR2 or OS after first salvage therapy. We believe our results should encourage use of allogeneic HCT in CR1 with some confidence that this will not unfavorably affect CR2 rate and OS should post HCT relapse occur. Disclosures No relevant conflicts of interest to declare.

Kurzfassung: Background Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand, on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Higher expression of E-sel ligand is associated with relapse and poor survival. Uproleselan (GMI-1271), a novel E-selectin antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity such as mucositis with improved survival in vivo. Preclinical data support combination of uproleselan with chemotherapy improves response without additional toxicity. A phase 1/2 study (NCT02306291) of uproleselan added to chemotherapy (mitoxantrone, etoposide, cytarabine, MEC) in R/R AML showed promising outcomes at the recommended phase 2 dose (RP2D), including a CR/CRi rate of 41% and median OS of 8.8 m (95% CI 5.7-11.4). 11/16 (69%) evaluable patients were MRD negative (DeAngelo et al ASH 2018). Patients with sufficient expression of the appropriate E-selectin ligand (the target of the E-selectin inhibitor) exhibited higher CR/CRi rate and longer survival. Median OS for Leukemic blasts/E-sel ligand ≥10% vs leukemic blasts/E-sel ligand 〈 10% was 12.7m and 5.2 m, respectively (report in progress). Collectively, these data indicate that high E-sel ligand expression may contribute to clinical chemotherapy resistance, particularly increasing the risk of relapse, which can be reversed with E-sel inhibition. In addition, chemotherapy is well known to cause severe mucositis, with resultant infections, prolongation of hospital stay, morbidity and mortality, and a dramatic reduction in the expected incidence and severity of mucositis was seen with uproleselan in combination with MEC. At the RP2D, Grade 3/4 mucositis was 2%. Breakthrough Therapy Designation was granted by FDA for treatment of patients with R/R AML. A pivotal phase 3 study (NCT03616470) is underway. The aims of this phase 3, double-blind, placebo controlled study are to assess the efficacy and safety of uproleselan with standard salvage chemotherapy in R/R AML, evaluate the incidence of MRD, and assess for correlation of E-sel ligand expression on blasts with outcomes in R/R AML. Study Design and Methods This study is a global, randomized, double-blind, placebo-controlled phase 3 registration trial. Major Eligibility Criteria ≥18 to ≤75 years old Primary refractory AML, first or second relapse of AML Prior transplant (HSCT) is allowed Must be medically eligible for chemotherapy ECOG performance status ≤2 Study treatment and endpoints Treatment is MEC or FAI (fludarabine, cytarabine, idarubicin) induction with blinded study drug (uproleselan/placebo at 1:1 ratio) administered 1 day prior (sentinel dose) and then BID through 2 days post chemotherapy. Consolidation (HiDAC/IDAC) with uproleselan/placebo (same assignment) up to 3 cycles is allowed. The primary endpoint is overall survival; key secondary endpoints include the incidence of severe oral mucositis during induction and CR/CRh rate. Measurable residual disease, event free survival, safety, and pharmacokinetics will also be evaluated. In addition, the relationship between E-sel ligand expression on leukemic cells in the bone marrow and clinical outcomes in AML will be determined. Statistical methods The phase III primary endpoint will compare overall survival between the treatment arms using a stratified log-rank test. Stratification factors will be age group, disease status, backbone chemotherapy and prior transplant status. Median time to event values will be estimated using the Kaplan-Meier method. The study is powered to detect an improvement in median OS using a log-rank test (HR= 0.68, one-sided 0.025 type I error rate). A hierarchical testing procedure will be used to assess the statistical significance of the key secondary analyses, incidence of severe oral mucositis and remission rate (CR/CRh, CR). Study status This trial is expected to enroll 380 patients across approximately 9 countries in North America, Europe, and Australia. The first patient was enrolled in November 2018. Disclosures DeAngelo: Novartis: Consultancy, Patents & Royalties: Royalty, Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Abbvie: Research Funding; GlycoMimetics: Research Funding; Celgene: Consultancy; Blue Print Medicines: Consultancy, Research Funding; Shire: Consultancy. Erba:Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding. Jonas:AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. O'Dwyer:AbbVie: Consultancy; GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Bhatnagar:Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support; Karyopharm Therapeutics: Other: Research support. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Cull:Amgen: Other: Travel, accommodation ; AbbVie: Other: Travel, accommodation; Glycomimetics: Other: Travel, accommodation. Armstrong:GlycoMimetics: Consultancy. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Chen:GlycoMimetics: Employment. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Thackray:GlycoMimetics Inc: Employment. Feldman:GlycoMimetics Inc: Employment. Advani:Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Becker:Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria.

Kurzfassung: Abstract 4332 Allogeneic SCT is widely considered the therapy most likely to prolong survival in pts with AML in first CR(CR1) or relapse (REL). Questions have arisen regarding the frequency with which the procedure is undertaken in a defined population of pts presenting with newly-diagnosed AML and subsequently followed through REL and after, or in pts presenting in REL. We first analyzed 26 consecutive UW pts age 〈 70 who did not have CBF AML, who were not NPM1+/FLT3,- and who achieved CR1 with at least 4 months have elapsing from presentation date. These patients would typically be considered candidates for SCT in CR1 Eleven of the 26(42%, 95% CI 23-63%) received SCT at a median of 3.5 months (range 0.5-9.0) from CR date. Rates of SCT were 42% both in pts age 〈 60(8/19) and in pts ≥ 60 (3/ 7). In contrast to a report from another institute in which 14/99 pts age ≥50 received SCT in CR1 7/16 of the current pts did so (p=0.01). Rates of SCT were 6/13 in pts at highest risk based on cytogenetics and FLT3 status and 3/11 in pts at lower (i.e. “intermediate” risk; risk status not known in 2) Three of the 15 pts who did not receive SCT had available donors, but 12 were not HLA –typed. Age distribution was similar (p=0.31) in pts who were and were not HLA-typed and in only 2 non-typed pts were financial considerations or pt refusal an issue. Rather, notes suggested that physicians felt that pts were doing well and might not need SCT. We also examined our 21 consecutive pts who were under age 70, did not receive SCT in CR1, and were given first salvage therapy (S1) for relapse, again with at least 4 months follow-up from relapse date. These 21 included patients referred to us at initial diagnosis or only at time of S1. The frequency with which they were transplanted (8/21; 38% 95%CI 18-62%) did not differ from the frequency with which SCT was done in CR1. However SCT was most commonly done as 2nd salvage therapy (4 cases), with 3 pts transplanted in CR2 or CR and only 1 given SCT as S1.10 of the 13 S1 pts never given SCT had available donors (3 related, 3 unrelated, 4 cord) with SCT not done because of high blasts and/or poor performance status. We conclude that although older and younger pts may be equally likely to receive SCT in CR1, failure to HLA type may be a major impediment to increasing rates of SCT in CR1. Although relapsed pts are transplanted as often as pts in CR1, such transplants are only rarely used as initial therapy of relapse. Disclosures: No relevant conflicts of interest to declare.

Kurzfassung: Background: MRD is an established prognostic/predictive factor in ALL. Achieving MRD negativity (MRDNeg) early during treatment is associated with superior outcomes with pediatric regimens. However, little is known about how to use MRD assessments with hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine), one of the most commonly used regimens in adults with ALL. MRDNeg at 3 months has been shown to be predictive of outcome with hyperCVAD + tyrosine kinase inhibitor (TKI) in Philadelphia chromosome (Ph)+ ALL (Ravandi, Blood, 2013, p. 1214), but this is relatively late in the treatment course. We hypothesized that achieving MRDNeg earlyduring treatment would be associated withbetter outcomes with hyperCVAD. Methods: We performed a retrospective analysis of our center's experience since 2005 under an IRB-approved protocol. We included pts with ALL (excluding Burkitt and mixed-phenotype) age 〉 18 years (yrs) who received hyperCVAD as initial therapy. MRD was assessed primarily by either multiparameter flow cytometry or BCR-ABL quantitative PCR on bone marrow, though other techniques (e.g., cytogenetics [CG]) were considered if obtained. Timing and nature of assessments were left to treating physicians. Pts were not defined as MRDNeg until all assays performed were unable to detect any disease. Clinical risk at diagnosis was defined by age ( 〉 35 yrs), white blood cells (WBC; 〉 30 for B-ALL, 〉 100 for T-ALL), and CG (Ph+, MLL rearranged, -7, +8, complex, low hypodiploid, and near triploid). Events included morphologic or MRD recurrence, change in treatment due to inadequate response, death from any cause, or secondary malignancy. Frequencies of characteristics between groups were compared using a Fisher exact test. Cox proportional hazards (PH) models were used to investigate associations between variables. A test of PH was used to assess the impact of time on the association between MRD and outcome, in which MRD was modeled as a time-dependent covariate with left-truncation. Clinical follow-up was updated as of June 2015. Results: We identified 142 pts for this analysis: 18% T-ALL, 73% 〉 35 yrs, 24% had high WBC (6 unknown), and 48% had high-risk CG, 71% of which (34% of total) were Ph+ (11 unknown). Sixty-five pts (46%) underwent hematopoietic cell transplantation (HCT) in first remission (CR1): 32% with reduced-intensity and 68% with myeloablative conditioning. All Ph+ pts received TKI with hyperCVAD: 23 (48%) received imatinib and 25 (52%) received dasatinib. Median time of 1st MRD assessment (relative to start of treatment) was 37 days, with 27% occurring by 21 days and 85% by 90 days; 42% were MRDNeg at 1stassessment, 26% became MRDNeg later, and 32% did not become MRDNeg during treatment with hyperCVAD. Incidences of age 〉 35 yrs (P = 1), high-risk CG (P = 0.08), Ph+ (P = 0.72), and high WBC (P = 0.38) were not significantly different in MRDNeg pts. HCT in CR1 was more common in MRDNeg pts (P = 0.05). In Cox PH models adjusted for HCT in CR1, CG, and WBC, MRDNeg pts had significantly better overall survival (OS; hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.81; P = 0.01; 48 events) and event-free survival (EFS; HR 0.27, 95% CI 0.16-0.46; P 〈 0.01; 84 events). Through an exploratory landmark analysis, the benefit of MRDNeg on EFS became more pronounced after 8 weeks: pts who were MRDNeg by 8 weeks had significantly better EFS (HR 0.53, 95% CI 0.32-0.89; P = 0.02) than those who were not. Further, achieving MRDNeg earlier during treatment was associated with better EFS. In a test of PH on the time-dependent Cox PH model, time to MRDNeg had a significant impact on the association between MRD status and EFS (P = 0.02) but not OS (P = 0.19). This is depicted in Fig 1, where being MRDNeg earlier after treatment initiation is associated with a smaller beta (i.e., significantly less hazard for an event). Conclusions: MRDNeg is an independent predictor of superior OS and EFS in adults receiving hyperCVAD for ALL. Further, achieving MRDNeg earlier during treatment was associated with better EFS. When considering the time-dependent nature of MRD status relative to EFS, 8 weeks after initiation of hyperCVAD may represent an important prognostic time point. If confirmed in an independent dataset, this may prove to be a useful surrogate in both routine clinical practice and future clinical trials with this regimen. Disclosures Cassaday: Pfizer: Research Funding; Seattle Genetics: Research Funding.

Kurzfassung: 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.