ALBERT

Description: Background: Standard chemotherapies for relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) are often unsuccessful. Pre-treatment ("priming") with hypomethylating agents such as decitabine has been shown to sensitize AML cells to chemotherapeutics, prompting a phase 1/2 study (NCT01729845) of MEC preceded by decitabine priming (d/MEC) in relapsed/refractory AML/MDS. Methods: Patients ≥18 years with relapsed/refractory AML or high-risk MDS (〉10% blasts) requiring first or subsequent salvage therapy were eligible if they had adequate organ function and a treatment-related mortality (TRM) score of

Description: Background: Because infections are a major cause of morbidity and mortality after AML induction chemotherapy, patients typically remain hospitalized for monitoring and rapid antimicrobial therapy until hematopoietic recovery. With declining early mortality and improved oral antimicrobials, interest in moving post-induction care to the outpatient setting has emerged. In the 5-year period since completing a prospective phase 2 trial evaluating an Early Hospital Discharge (EHD) strategy, EHD following AML-like induction chemotherapy has become routine at our institution. In recent retrospective analyses, we found 〉80% of EHD patients required hospital readmission, primarily for neutropenic fever. Still, the EHD strategy was safe and reduced healthcare resource utilization, and EHD patients spent 〉70% of their post-chemotherapy time as outpatients. Here, we investigated differences in the pattern of infectious complications between patients managed as outpatients following induction chemotherapy and those who remain hospitalized until hematopoietic recovery. Methods: We retrospectively identified all adults ≥18 years with untreated AML/high-grade myeloid neoplasms (≥10% blasts in blood/ bone marrow) who started intensive induction chemotherapy ("7+3" or a regimen of similar/higher intensity) at our institution from 8/1/2014-7/31/2018. Patients were considered "EHD" if they were discharged from the hospital

Description: Human tumors contain large numbers of clonal, subclonal and random mutations. Clonal mutations, present in 30% or more of the cells, are classified as either drivers that promote proliferation or passengers of unknown or to be determined function. Subclonal and random mutations that are present in a small subset of tumor cells, prior to chemotherapy, could serve as a reservoir for the emergence of drug resistance. Even in the presence of clinical complete remissions in AML, subclonal mutations could be present in a small number of cells that selectively expand during chemotherapy and result in relapse and death. Next-generation DNA sequencing now makes it feasible to monitor the frequency of different subclonal mutations in patients as tumors evolve over time, raising the possibility of personalizing treatment by anticipating the mutations that signal relapse in time to prevent clinical recurrence of AML. We have used Duplex DNA Sequencing (DS) to detect very low-frequency subclonal and random mutations in AML during relapse and prior to treatment. While whole genome sequencing (WGS) provides extensive data on the clonal distribution of mutations in AML, it lacks sufficient accuracy to identify subclonal mutations when they are present at frequencies less than 5%. In contrast, DS focuses on a limited number of target genes at the level of single DNA molecules. Mutations are scored only if they are present at the same position in both strands of the same DNA molecule and are complementary, resulting in sequencing accuracy that is more than 1000-fold greater than that of routine next-generation DNA sequencing. Using DNA from 12 treatment-naïve AML samples and 2 normal bone marrow samples, we first targeted the exons that encode the catalytic domains of the five major human replicative polymerases. We detected both synonymous and non-synonymous mutations in most of the targeted genes. Mutations in the two major human replicative DNA polymerases have been recently identified in adenocarcinomas of the colon, and mutations in the proof-reading domain of DNA polymerase epsilon result in the highest reported point mutation frequencies so far reported in any cancer. Until now, mutations in DNA polymerases have not been described in AML. Presumably a similar or higher subclonal mutation load exists in the coding regions of other genes in AML and in genes found in other tumors. In order to follow the course of mutation accumulation in AML after treatment and leading to relapse, we used capture hybridization that was designed to enrich for 15 genes previously reported to be mutated in AML. We identified multiple subclonal and random mutations in many of these genes. In one relapse sample, we identified a mutation in NRAS that was present in 32% of the cells. The same mutation was detected by DS in 1% of the cells from the same patient prior to treatment, which is well below the signal threshold of WGS. These initial studies demonstrate the feasibility of using DS to define the changes that occur during and after treatment, and suggest the use of DS to determine mutations that impart drug resistance. The findings from the DNA polymerase capture offers evidence that abundant non-synonymous mutations are present in treatment-naïve AML, implying that the seeds of treatment resistance may already have taken root by the time of diagnosis. Disclosures No relevant conflicts of interest to declare.

Description: Background: We have previously shown that the survival of patients with AML who fail to achieve complete remission (CR) with 7+3 has improved since the 1980s. However, although CR rates with 7+3 have improved over the last four decades, we have not previously evaluated how outcomes for patients who achieve a CR1 with 7+3 has changed over time. Here we evaluate if either length of first CR (CR1) after 7+3 or of survival after relapse from CR1 has changed over the last four decades. Patients and Methods:We analyzed 1247 patients randomized to 7+3 arms from 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocols gave 7+3 per existing standard, which changed over time. In S8600, S9031, and S9033 the ara-C and daunorubicin doses were 200mg/m2and 45mg/m2, in S0106 100mg/m2and 60mg/m2, and in S1203 200mg/m2and 90mg/m2. CR was defined morphologically. To account for censoring in the dataset, we used landmark analyses. To evaluate patterns in length of CR1, among patients achieving CR1 and alive at 2 and 3 years, we calculated the proportion of 2 (or 3) years spent in CR1. To evaluate survival after relapse, among patients who achieved CR1 but who relapsed in next 2 (or 3) years we calculated the proportion of patients alive at least 1 year after relapse. To account for changing patient characteristics over time, multivariate linear and logistic regression models were fit. Results:Overall survival has improved dramatically over the last 4 decades (Figure 1). Additionally, among patients who achieved CR1 and were alive 2 years later, the proportion of those 2 years spent in CR1 has significantly improved over the last 4 decades (Figure 2) from a median of 58% to a median of 96% (p

Description: Abstract 2191 Background: Treatment protocols for newly diagnosed AML typically use age (often 60 years) alone to restrict eligibility to either younger or older patients. Implied in this practice is the assumption that age is the principal predictor of therapeutic failure in AML due to either early treatment-related mortality (TRM) or resistance to therapy in patients who do not incur TRM. Yet, clinical observation and previous studies indicate that other prognostic factors modulate the effect of age on TRM and resistance, suggesting that age as sole or primary criterion for treatment allocation may be suboptimal. Methods: To test this hypothesis in newly-diagnosed non-APL AML, we quantified the relative effects of age and other covariates using 1,127 patients (median age: 57 years) treated on Southwest Oncology Group (SWOG) trials from 1986–2009 and 1,604 patients (median age: 61 years) treated on various protocols at M.D. Anderson Cancer Center (MDA) from 2000–2008. We calculated weekly hazard rates (the probability of death in week × given that the patient was alive at the beginning of the week) for both cohorts overall and in various age subgroups. We used the area under the receiver operator characteristic curve (AUC) to quantify the effects of covariates for prediction of TRM and resistance (no TRM but patient does not enter CR or relapses within 1 year of CR), where an AUC of 1 indicates that a covariate is perfect at prediction while an AUC of 0.5 indicates no prediction (i.e. it is no better than flipping a coin). Results: Despite the use of different treatment protocols, survival in the SWOG and MDA cohorts was virtually superimposable. In both cohorts, the maximum weekly hazard occurred at weeks 3 and 4 from start of treatment, after which it decreased. The maximum hazard was relatively independent of age and remained between weeks 3 and 5 in patients age 70 years, respectively. The existence of such a discrete cut-point suggested that patients who die early are qualitatively distinct and prompted us to examine the relative effect of age and other covariates in patients who (a) died within the first 30 days of treatment (our empirically-based definition of TRM, 9% of MDA and 12 % of SWOG patients, respectively) and (b) survived at least 30 days but did not enter complete remission or relapsed within 1 year (“resistant”, 43% of MDA and 59% of SWOG patients, respectively). A model including age alone to predict early mortality had an AUC of 0.67, while a model including performance status (PS) alone had an AUC of 0.72. By comparison, a more refined model hat included PS, age, platelet count, cytogenetics, secondary AML, albumin, white blood cell count, peripheral blood blast count, and LDH yielded an AUC of 0.86. Elimination of age resulted in a model with an AUC that was only minimally lower (0.85). Prediction of resistance was more difficult with a model including age, secondary AML, cytogenetics, peripheral blood blasts, race, hemoglobin, and marrow neutrophils giving an AUC of only 0.70. Elimination of age had little effect (AUC 0.67) while age alone gave an AUC of 0.64. Conclusion: Age alone appears inadequate in predicting resistance and particularly TRM. The use of models based on several covariates improves predictive ability, but the ability to predict resistance is still limited, suggesting the value of randomized trials to assess treatment designed to reduce resistance. The observation that elimination of age has little effect on the predictive ability of such models, suggests that age is primarily a surrogate for other covariates. Disclosures: No relevant conflicts of interest to declare.

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

Description: Background: Optimal treatment for medically less fit adults with acute myeloid leukemia (AML) remains uncertain. Retrospective data suggest intensive therapy may lead to better outcomes in these patients. However, these findings must be interpreted cautiously because of the possibility of selection bias and other confounders. Ideally, the optimal treatment intensity is defined via randomized trial but whether patients and their physicians are amenable to such a study is unknown. We therefore designed a trial (NCT03012672) to 1) evaluate the feasibility of randomization between intensive and non-intensive therapy in this population and 2) examine the impact of treatment intensity on response rate and survival. We used CLAG-M as high-dose cytarabine-based intensive induction therapy. Rather than selecting different classes of drugs in the 2 treatment arms- which may have different modes of action and therefore confound the question of treatment intensity - we used reduced-dose ("mini") CLAG-M as the non-intensive comparator. Methods: Adults ≥18 years were eligible if they had untreated AML or high-grade myeloid neoplasms (≥10% blasts in blood or marrow) and were medically less fit as defined by having a "treatment related mortality" (TRM) score of ≥13.1, corresponding to a 〉10-15% 28-day mortality with intensive chemotherapy. Left ventricular ejection fraction ≤45% was the only organ function exclusion. Patient-physician pairs were first asked if they were amenable to randomized treatment allocation. If so, they were randomized 1:1 to mini- vs. regular-dose CLAG-M. If not, in order to evaluate our secondary endpoints, the patient or physician could choose the treatment arm and still enroll on study. Patients and physicians then completed surveys elucidating their decision-making processes. Up to 2 induction courses were given with mini- vs. regular-dose CLAG-M: cladribine 2 or 5 mg/m2/day (days 1-5), cytarabine 100 or 2,000 mg/m2/day (days 1-5), G-CSF 300 or 480µcg/day for weight

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: Many patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome with 10-19% blasts (MDS-EB2) do not enter complete remission (CR) following initial induction chemotherapy. At an academic referral center, such patients often stay to receive additional treatment, or return to their home communities for further care. For patients and providers alike, the decision about whether to stay or go after initial treatment failure is often fraught. To better inform such decision-making, in this retrospective single-center analysis, we compared covariate-adjusted survival for patients who elected to stay for further treatment at our center and those who returned to their home communities for subsequent care. Methods: We included adults ≥ age 18 years of age with newly-diagnosed AML or MDS-EB2 treated at our institution between January 2012 and May 2018 who failed to enter CR (〈 5% morphologic bone marrow blasts) or CR with incomplete hematologic recovery (CRi) after their first cycle of induction chemotherapy. We excluded patients who died before they could begin re-induction therapy. Patients who stayed at our institution for additional treatment are referred to as the "stay" group (n=86); patients who left are considered the "go" group (n=35). Multivariable Cox regression analysis was used to account for other measured covariates possibly influencing survival. Results: The go group was older and had a higher median treatment-related mortality (TRM) score (Table 1), the latter predictive of the probability of death within the first 28 days of initial induction therapy. Forty-seven percent of stay patients received high-intensity re-induction (containing cytarabine at individual doses ≥1g/m2) while 50% received low-intensity treatment (e.g. azacitidine, decitabine, or low-dose cytarabine). Twenty-nine percent of go patients received treatment (mostly low-intensity) in the community setting, while 63% received supportive care only. The stay patients had a median of 2 subsequent hospitalizations (range 0-12) and spent a median of 27 days hospitalized after initial treatment failure (range 0-124). Survival was longer in the stay group compared to the go group (median 8.3 vs. 1.8 months, p