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: To prospectively assess the applicability of reduced-intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT), we wrote a protocol in which all untreated patients 50 years or older with acute myeloid leukemia (AML) and unfavorable cytogenetics would be evaluated during induction for a possible RIC-HSCT in first complete remission (CR1). Ninety-nine of 259 patients entered CR. Fifty-three of the 99 were seen by the Transplant Service with the remainder not seen because of illness, lack/unavailability of siblings, refusal, or, primarily, unclear reasons (21 patients). A donor was identified for 26 patients (21 sibling, 5 unrelated) with RIC-HSCT performed in 14 (13 sibling). Results in consulted patients suggested that 50% or fewer of the 85 patients who did not undergo transplantation were potential transplant candidates. We attempted to find one or more chemotherapy pair-mates for each patient who underwent transplantation based on cytogenetics, age, and a relapse-free survival (RFS) time that was more than or equal to the time from CR1 to RIC-HSCT in the patient who underwent transplantation. Thirty-two of the 39 matches favored (longer RFS) RIC-HSCT and 7, chemotherapy. The probability that the corresponding beta distribution was different than expected (ie, that RIC-HSCT was superior) was 0.99 (P = .004). Results were similar with respect to survival. While RIC-HSCT thus seems of interest, methods are needed to extend its applicability.

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.