Treatment-related Mortality Score Research Articles

Impact of Socioeconomic Disparities on Outcomes in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Introduction: It is increasingly recognized that racial and socioeconomic disparities play an important prognostic role and contribute to differences in outcomes in adults receiving chemotherapy for acute myeloid leukemia (AML). Structural racism has also been implicated in limiting access to allogeneic hematopoietic cell transplantation (HCT). However, it is unclear to what degree racial and socioeconomic disparities impact post-HCT outcomes of patients with AML in contemporary practice. To address this uncertainty, we investigated the impact of socioeconomic, racial, and non-biologic disparities on outcomes in a large cohort of adults with AML undergoing allogeneic HCT while in first or second morphologic remission. Methods: We identified 1,004 adults with AML (2022 ICC criteria) who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Data was collected on each patient's individual socioeconomic status (SES), including occupation, insurance type, and education attainment. Distance traveled, marital status, household size, country of birth, and religious affiliation were also recorded. Each occupation was classified by the International Socio-Economic Index (ISEI), a standard index of occupational status. Area-level SES was analyzed through the Area Deprivation Index (ADI), a validated measure of socioeconomic disadvantage which corresponds to U.S. census tract measurements. Collected HCT variables include the AML treatment-related mortality score (TRM), pre-HCT flow cytometric MRD status, HLA donor status, cytogenetic risk, conditioning regimen intensity, and incidence of severe acute and chronic graft-vs-host disease. Measured outcomes include non-relapse mortality (NRM), overall survival (OS), relapse, and relapse free survival (RFS). Cause-specific hazard models were used for univariate and multivariable regression analysis and C-statistics were calculated to quantify each model's ability to predict outcomes. Results: In univariate analysis, none of the socioeconomic or non-biologic factors were significantly associated with NRM, and all had poor predictive performance, with C-statistics not exceeding 0.53 for: marital status, larger household size (i.e., patients with children), distance traveled, ISEI, ADI, insurance status, educational attainment, or country of birth. TRM score (P<0.001), non-myeloablative conditioning (P<0.001), reduced intensity conditioning (P<0.001), CR2 (P=0.017) and marital status (P=0.014) were significantly associated with NRM in a multivariable model, but predictive performance of this model was only fair (C=0.69; Table 1). Marital status was only associated with NRM after multivariable adjustment but not on univariate evaluation, possibly because married patients were, on average, older (P<0.001), more likely to be male (P<0.001), and have higher occupational status/ISEI (P<0.001) and TRM scores (P<0.001), with age and sex as likely confounders (Table 2). African American patients (n=14) were found to have worse NRM in both univariate (P=0.036) and multivariate (P=0.024) models, consistent with previously identified racial/ethnic disparities in AML cohorts. Similar results were found for SES and non-biologic variables in regards to OS, relapse, and RFS. Notable exceptions after multivariable adjustment include: ADI was significantly associated with OS (P=0.036) and RFS (P=0.044) and marital status was not significantly associated with OS or relapse. Additional analyses demonstrated that ISEI and ADI were not associated with increased TRM or HLA donor status. Finally, distance traveled decreased in HCT recipients post-2013 (P<0.003), though the number of AML-related transplants remained unchanged. Conclusion: In this retrospective, single center analysis, socioeconomic and non-biologic factors had very limited impact on outcomes following allografting for adults with AML. While reassuring, patients able to undergo allogeneic HCT are highly selected (e.g. need for caregiver, insurance, etc.) possibly accounting for this finding, as could integrated, multidisciplinary cancer care networks and longitudinal care coordination post-HCT. Further research is needed to investigate disparities among HCT-eligible patients and improve access to HCT with a focus on reducing racial/ethnic disparities.

Addition of Sorafenib to Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone (CLAG-M) in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) and High-Grade Myeloid Neoplasms Independent of FLT3-Mutation Status: Final Results of a Phase 1/2 Study

BACKGROUND: We previously showed that cladribine, cytarabine, G-CSF and dose-escalated mitoxantrone (CLAG-M) led to a higher rate of complete remissions without measurable residual disease (MRDneg CR) than 7+3. Recently, a randomized trial demonstrated addition of the multikinase inhibitor sorafenib to 7+3 improved event free survival (EFS) irrespective of FLT3 mutation status. Here, we report the results of a phase 1/2 study (NCT02728050) evaluating addition of sorafenib to CLAG-M (CLAGM+S) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms (≥10% blasts). Phase 1 results were reported previously. METHODS: Patients aged 18-60 years were eligible if they had a treatment-related mortality score (TRM) of ≤13.1 (corresponding to a predicted <13.1% risk of death by day 28 following intensive induction chemotherapy) and adequate organ function. Patients with uncontrolled infection or concomitant illness with expected survival <1 year were excluded. Cohorts of 6-12 patients were assigned to 1 of 6 dose levels of mitoxantrone (10, 12, 15, or 18 mg/m2/day, days(d) 1-3) and sorafenib (200 to 400 mg twice daily [BID] on d10-20 with induction and 8-27 with consolidation). G-CSF dose was 300 or 480 μg/day (weight-based, d0-5), cladribine 5 mg/m2/day (d1-5), and cytarabine 2 g/m2/day (d1-5). Up to 4 cycles of post-remission therapy with CLAG+S (mitoxantrone omitted) were allowed, followed by 12 months of maintenance sorafenib. Patients were taken off trial if they underwent allogeneic transplant. As primary endpoint in Phase 2, the rate of MRDneg CR following CLAGM+S was compared to a matched historical control population who received CLAG-M alone. Secondary endpoints included rate of CR, overall response rate (ORR defined as CR+CR with incomplete hematologic recovery [CRi]), overall survival (OS), EFS and the toxicity profile. EFS and OS were estimated using the Kaplan-Meier method and compared using Cox regression models. RESULTS: 84 patients were enrolled from 12/8/2016-10/7/2021. In Phase 1, CLAG-M with mitoxantrone at 18 mg/m2/day and sorafenib 400 mg BID was established as the recommended phase 2 dose (RP2D). Sixty-one patients with a median age of 50 [range: 21-60] years were treated at the RP2D. ELN2017 risk category was favorable in 28%, intermediate in 36%, and adverse in 34%. FLT3-ITD and TKD mutations were present in 28% and 7% respectively. Mortality within 28 days was 2%. At the RP2D, a response of MRDneg CR occurred in 49/61 patients (80%, 95% CI: 68-89%). Additional responses of MRDpos CR and CRi (3 patients each) led to an ORR of 90%. The MRDneg CR rate in patients with and without FLT3-mutations was similar (90% vs. 83%, p=0.30). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 29 and 25 days. Besides infections/neutropenic fever, rash was the most common grade ≥3 adverse event. With a median follow up of 35 months, median OS was not reached; 12-month OS was 82%. There was no difference in OS and EFS in the FLT3-mutated and FLT3-wild type patients. We next compared CLAGM-S to a historical cohort of 71 newly diagnosed patients treated with CLAG-M alone, matched for mitoxantrone dose, age and TRM score (Table 1). In univariate analysis, rates of MRDneg CR, OS and EFS were similar (p=0.83, 0.16, and 0.37 respectively). Likewise, there was no difference in OS (p=0.54) or EFS (p=0.63) in FLT3-mutated patients who received CLAGM+S vs CLAG-M. In subgroup analysis, we observed a benefit favoring CLAGM+S for both OS (p<0.01) and EFS (p=0.03) among ELN2017 intermediate risk patients (Figure 1). No benefit of CLAGM+S vs CLAG-M alone in either OS or EFS was observed among adverse risk patients. Analysis of the favorable-risk cohort was limited by small sample size. Multivariate models comparing CLAGM-S to CLAG-M alone (reference) and controlling for age, secondary disease, FLT3 status and cytogenetic risk showed improved OS (HR=0.38, 95%CI 0.17-0.84, p= 0.02) and EFS (HR= 0.43, 95% CI 0.22-0.85 p=0.02) following CLAGM-S; MRDneg CR was also more likely with CLAGM-S though not statistically significant (OR= 2.56, 95% CI 0.68-9.61, p= 0.16). CONCLUSION: Addition of sorafenib to CLAG-M produces high rates of MRDneg CR in newly diagnosed AML patients ≤60 and prolongs OS and EFS in multivariate analysis compared to historical, matched control cohort receiving GLAG-M alone, a benefit that was particularly evident in patients with intermediate-risk disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Utility of theTreatment-Related Mortality (TRM)score to predict outcomes of adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.

There is long-standing interest in estimating non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) for AML, but existing tools have limited discriminative capacity. Using single institution data from 861 adults with AML, we retrospectively examined the treatment-related mortality (TRM) score, originally developed to predict early mortality following induction chemotherapy, as a predictor of post-HCT outcome. NRM risks increased stepwise across the 4 TRM score quartiles (at 3 years: 9% [95% confidence interval: 5–13%] in Q1 vs. 28% [22–34%] in Q4). The 3-year risk of relapse was lower in patients with lower TRM score (26% [20–32%] in Q1 vs. 37% [30–43%] in Q4). Consequently, relapse-free survival (RFS) and overall survival (OS) estimates progressively decreased (RFS at 3 years: 66% [59–72%] in Q1 vs. 36% [29–42%] in Q4; OS at 3 years: 72% [66–78%] in Q1 vs. 39% [33–46%] in Q4). With a C-statistic of 0.661 (continuous variable) or 0.642 (categorized by quartile), the TRM score predicted NRM better than the Pretransplantation Assessment of Mortality (PAM) score (0.603) or the HCT-CI/age composite score (0.576). While post-HCT outcome prediction remains challenging, these findings suggest that the TRM score may be useful for risk stratification for adults with AML undergoing allogeneic HCT.

A Phase 1/2 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

A Phase 1/2 Trial of Cladribine, High-Dose Cytarabine, G-CSF, and Dose-Escalated Mitoxantrone (CLAG-M) Plus Gemtuzumab Ozogamicin in Adults with Newly-Diagnosed Acute Myeloid Leukemia (AML) or Other High-Grade Myeloid Neoplasm

G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (GCLAM) in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Grade Myeloid Neoplasms: Final Results from a Phase 1/2 Trial

▪Background: Outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission (CR) rates often not exceeding 15-20%. Results from a previous 2 study in poor-risk relapsed/refractory acute myeloid leukemia (AML) suggested encouraging activity of a combination of G-CSF, cladribine, cytarabine, and mitoxantrone (GCLAM). Given data suggesting benefit of escalated doses of anthracyclines in AML, we conducted a phase 1/2 study (NCT02044796) of GCLAM using escalated doses of mitoxantrone for patients with relapsed/refractory AML or high-risk myeloid neoplasms (≥10% blasts).Patients and Methods: Patients≥18 years were eligible if they had a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a predicted 28 day mortality of ≤6.9% with standard induction chemotherapy) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤3.25 mg/dL). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in previous trials). Other drugs doses were G-CSF (days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second course of GCLAM was given if CR was not achieved in cycle 1. Up to 4 cycles of consolidation with GCLA (mitoxantrone omitted) were allowed if CR or CR with incomplete blood count recovery (CRi) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the next treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding infection or constitutional symptoms.Results: Among 26 patients treated in phase 1, 2 DLTs occurred at dose level 4 (encephalopathy and cardiogenic shock), establishing GCLAM with mitoxantrone at 16 mg/m2/day as the MTD. Forty patients, median age 63 [range: 33-77] years, median TRM score 2.0 [0.2-6.39], with AML (n=34) or high-grade myelodysplastic syndrome (n=6) received GCLAM at MTD; 28% had secondary disease. Nineteen were primary refractory and 21 had relapsed disease (median duration of CR1: 12 months). Cytogenetics were favorable in 1, intermediate in 21, and adverse in 18; 6 patients had NPM1 and 1 had FLT3 mutations. Ten patients achieved CR (25%, 95% confidence interval [CI]: 13-41%) and 13 a CRi (32%, 95% CI: 19-49%) with 1-2 induction cycles, for an overall response rate (ORR) of 58% (95% CI: 40-73%). Nine of the 10 CR patients (90%) were negative for minimal residual disease by flow cytometry. One further patient had a morphologic leukemia free state, 11 had resistant disease, 2 were not evaluable, and 2 died in aplasia within 28 days of therapy for a TRM rate of 5%. The median overall survival (OS) was 11.5 months. Besides infections/fever, the most common grade ≥3 adverse events were rash and hypoxia (fluid overload/infection-related). Median times to an absolute neutrophil count ≥500/μL and platelet count ≥50,000/μL were 29 days each. In multivariable analysis controlling for baseline prognostic features, compared to 41 patients treated with GCLAM outside this study with mitoxantrone at 10mg/m2/day, GCLAM with mitoxantrone at 16mg/m2 was associated with better OS (hazard ratio [HR]=0.45, 95% CI: 0.24-0.85, p=.01) and a nonsignificantly higher ORR (odds ratio [OR]=1.87; 95% CI: 0.69-5.10, p=.22). Further, compared to patient treated with other salvage regimens used at our institution (GCLAC [G-CSF, clofarabine and high-dose cytarabine], n=61; d/MEC [decitabine priming, mitoxantrone, etoposide, and cytarabine], n=52), GCLAM with mitoxantrone at 16mg/m2 was associated with better ORR and OS than d/MEC (OR=3.33, p=.012; HR for death= 0.50, p=.01) and a similar ORR compared to GCLAC (OR=1.69, p=.25) after multivariable adjustment with a HR for death of 0.68 (95% CI: 0.39-1.18, p=.17).Conclusion GCLAM with mitoxantrone at 16 mg/m2/day is well tolerated with a low TRM rate, and has potent anti-leukemia activity in relapsed/refractory myeloid neoplasms. Survival for this regimen appears better than when the regimen is used with mitoxantrone at 10 mg/m2/day and compared to other salvage regimens such as d/MEC. DisclosuresScott:Alexion: Consultancy, Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Acceleron: Other: Data and Safety Monitoring Board; Agios Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Becker:GlycoMimetics, Inc.: Research Funding. Walter:Aptevo Therapeutics: Research Funding; ADC Therapeutics: Research Funding.

Accuracy of SIE/SIES/GITMO Consensus Criteria for Unfitness to Predict Early Mortality After Intensive Chemotherapy in Adults With AML or Other High-Grade Myeloid Neoplasm.

With increasing therapeutic alternatives available, there is growing interest in tools that accurately identify patients most suitable for intensive acute myeloid leukemia (AML) chemotherapy. Nowadays, conceptual criteria proposed by an Italian panel of experts are widely used for this purpose. How accurately these Ferrara criteria predict fitness for intensive chemotherapy is unknown. We assessed the fitness of adults undergoing intensive AML therapy based on Ferrara criteria and determined the accuracy of this assessment for early mortality and survival prediction. Among 655 adults who received curative-intent induction or reinduction chemotherapy with 7 days of standard-dose cytarabine and 3 days of an anthracycline ("7+3") CLAG-M (cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone), or reduced-dose CLAG-M, 197 (30%) met at least one of the criteria defining unfitness for intensive chemotherapy (F-unfit). Compared with F-fit patients, the overall survival of F-unfit patients was significantly shorter (median, 4.8 months; 95% CI, 3.6 to 6.5 months v 36.8 months; 95% CI, 27.4 to 73.0 months; P < .001). When used alone, the Ferrara unfitness assessment was more accurate in predicting day 28 and day 100 mortality than the treatment-related mortality score we developed previously (used binary, ≤ 13.1 v > 13.1), as indicated by area under the receiver operating characteristic curve (AUC) values of 0.76 and 0.79 versus 0.66 and 0.62. The predictive accuracy of the Ferrara unfitness assessment could be significantly improved by including additional covariates such as performance status and albumin, yielding AUCs as high as 0.84-0.85 for the prediction of day 28 or day 100 mortality. Prediction of overall survival was less accurate, yielding a c-statistic value as high as 0.75 in multivariable models. Ferrara unfitness criteria provide a good prediction tool for shorter-term mortality after intensive AML chemotherapy. Our data may serve as a benchmark for expected outcomes with intensive chemotherapy in F-fit and F-unfit patients.

Covariates Associated with Receipt of High, Intermediate, or Low Intensity Initial Induction in AML or High Risk MDS

Background Age and fitness typically enter into decisions regarding "intensity" of initial induction therapy for newly-diagnosed AML or its prognostic equivalent myelodysplastic syndrome with 10-20% blasts (hrMDS); patients with either are eligible for most of our institution's AML studies. However, "fitness" is a non-specific term. Here we examined the relation between specific covariates and intensity of initial induction. The primary goal was to examine the ability of multivariate models to identify objective characteristics associated with choice of intensity of induction: high + intermediate vs. low, and of high vs. intermediate + low. Patients and Methods We reviewed 1,346 newly diagnosed AML/hrMDS patients seen at our center from January 2008 through May 2018. We excluded 226 patients who received palliative care only or unknown treatment outside our center and 188 patients given uncommon regimens, generally on a clinical trial. High-intensity treatment consisted of ara-C in single doses ³ 1g/m2, intermediate intensity was 7+3 +/- other drugs, and low intensity was azacitidine or decitabine +/- other drugs. Pre-treatment characteristics examined in the 932 analyzed patients (29% with 10-20% blasts) for potential inclusion in multivariate models were year of treatment, age, gender, de novo or secondary disease, performance status (PS), white blood cell count, treatment related mortality score (TRM, predicting death by day 28 after receipt of intermediate or intense induction), blast percentage, ELN 2017 risk, and distance from home to our center (Table 1). P-values &lt; 0.01 were considered "significant" in the multivariate models with values for area under receiver operating characteristic (AUC) curves of 0.6-0.7, 0.7-0.8, and 0.8-0.9 considered, as commonly understood, to respectively denote "poor", "fair", and "good" predictive ability. Results 57% of the 932 patients received high intensity treatment, 21% intermediate intensity, and 23% low intensity. Covariates significantly associated with receipt of high vs. intermediate/low intensity on multivariable analysis were younger age, (surprisingly) PS 3-4 (OR 1.4, 95% CI 1.1, 1.8), lower TRM score, and &gt; 20% blasts. The model's AUC was 0.69. Older age, higher TRM score and blasts 10-20% were associated with receipt of low rather than high or intermediate intensity induction. This model's AUC was 0.85. With the marginal exception that patients with ELN 2017 adverse risk were more likely to receive high intensity induction (OR 1.1, 95%CI 1.0-1.2) neither ELN 2017 risk nor secondary vs. de novo AML were associated with decisions regarding intensity. Although rates of CR without MRD and of induction failure (neither CR nor CRi) were better following high (56%, 20% respectively) or intermediate (58%, 28%) than low intensity induction (16%, 58%), after accounting for age, PS (2 rather than 0-1), TRM score and ELN risk, overall survival was similar in high vs. low intensity [OR 0.95, 95%CI 0.8-1.2], high vs. intermediate (0.99, 95%CI 0.8-1.3) and intermediate vs. low (0.96, 95%CI 0.7-1.3) groups. Conclusion A multivariable model provided reasonably accurate prediction of which patients with newly-diagnosed AML or hrMDS will receive low intensity induction at our institution, but a poor prediction of which patients will receive high intensity. Other, perhaps less objective, covariates subsumed under "fitness" may play an important role, particularly in the latter decision. Disclosures Gardner: Abbvie: Speakers Bureau. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Scott:Agios: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Walter:Argenx BVBA: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Agios: Consultancy; BiVictriX: Consultancy; BioLineRx: Consultancy; Seattle Genetics: Research Funding; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Astellas: Consultancy.

AML Clinical Trial Decision Making: How Often Do Physicians Follow a Consensus-Derived Assignment Scheme?

AML Clinical Trial Decision Making: How Often Do Physicians Follow a Consensus-Derived Assignment Scheme?

Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML)

Additional Cytotoxic Chemotherapy Is Unlikely to Eliminate Measurable Residual Acute Myeloid Leukemia (AML)

Frequency, and Effect on Survival, of Ineligibility for Clinical Trials in Newly Diagnosed Acute Myeloid Leukemia and High-Grade Myeloid Neoplasms

Introduction: Although National Comprehensive Cancer Network guidelines state "the best management of any patient with cancer is in a clinical trial," few adults with cancer participate in clinical trials. Consequently, ASCO and similar organizations have suggested modifications to eligibility criteria with the goal of increasing participation in clinical trials without a major increase in toxicity. Here we examine the effect of standard exclusion criteria on the ability to enroll patients with newly-diagnosed acute myeloid leukemia (AML) or high-grade myeloid neoplasms (≥10% blasts) on clinical trials. We compare survival outcomes of patients according to eligibility defined based on standard exclusion criteria. Methods: We identified 442 consecutive patients diagnosed with AML or high-grade myeloid neoplasms at the University of Washington/Fred Hutchinson Cancer Research Center between January 1, 2014 and December 31, 2016 after approval by our Institutional Review Board. Pre-treatment characteristics were collected from our institutional database and medical records. Patients were considered "eligible" if they were ≥ 75 years of age, had performance status (PS) 0-2, GFR ≤ 60 ml/min, ALT ≤ twice the upper limit of normal, bilirubin ≤1.5mg/dl, no solid tumor diagnosed within two years preceding the diagnosis of AML/MDS, LVEF ≥ 49%, and no history of congestive heart failure or myocardial infarction. Patients were classified as "ineligible" if they failed to meet at least one of these criteria. Results: 272 of our 442 patients (62%) received induction with intermediate or high intensity regimens, 23% received low intensity therapy, and 10% palliative care alone; treatment status was unknown in 6%. 207 patients (52% of those not electing palliative care) received treatment on a clinical trial. The same proportion were considered eligible, as defined above. Characteristics commonly associated with ineligibility were increased age (17%), decreased GFR (15%), and solid tumor within prior two years (14%). Univariate analysis demonstrated significant associations between ineligibility and male sex (p=0.013), secondary disease (p&lt;0.001), higher treatment-related mortality score (p&lt;0.001), and intensity of treatment (p&lt;0.001). Multivariate analyses accounting for baseline covariates such as cytogenetics and age indicated the presence of one or more ineligibility factors was associated with significantly decreased overall survival [HR 1.75 (95% CI 1.32, 2.32)]. Discussion: Like observations in solid tumor patients (Lichtman et al, JCO 2017), we observed a high percentage (approximately half) of patients with newly diagnosed AML and high-grade myeloid neoplasms who had at least one characteristic that would make them ineligible to participate in typical clinical trials. Ineligibility was associated with decreased overall survival. Although this finding may have reflected the inability to enroll on clinical trials, it is at least equally plausible shorter survival would have been seen on trials compared to patients who were eligible and enrolled. The effects of exclusion criteria should be borne in mind when analyzing the results of clinical trials. Further clinical trials are needed for ineligible patients. One mechanism to ensure that ineligible patients would be studied would be the requirement by the FDA for a post-marketing study that would enroll patients not represented in the trials leading to approval, since these patients typically have few good options. Disclosures Percival: Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Othus:Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Gardner:AbbVie: Speakers Bureau. Halpern:Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Sorror:Advisory board participation and honorarium from JAZZ pharmaceuticals: Other: Mohamed Sorror, MD MSc Fred Hutchinson Cancer Research Center University of Washington . Walter:Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding.

A Comparison of Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Treated On versus Off Study

Abstract Introduction: Despite decades of research, acute myeloid leukemia (AML) remains difficult to treat, and clinical trials are recommended as first line therapy by the NCCN. Although many new drugs show promise in early trials, further experience often does not confirm these results. One possible explanation is that patients on trials are not broadly representative. Here, we retrospectively compared characteristics, response, and survival in patients given the same investigational regimens according to whether treatment was given on versus off study. Methods: Patients treated for AML or high-risk MDS at FHCRC/UW between 2008 and 2015 were included. Investigator-initiated protocols for newly diagnosed (ND) and relapsed / refractory (RR) disease were included if ≥15 patients were treated off study. Analyses used Fisher’s exact test, Wilcoxon rank sum test, the Kaplan-Meier method, and Cox multivariate models. Results: 165 ND patients received either escalating doses of G-CLAM or idarubicin, cytarabine, and pravastatin while 243 RR patients received G-CLAM, decitabine-primed MEC or G-CLAC. Overall, 216 were treated on study and 192 were treated off study; reasons for the latter were: protocol not open (n=64), high treatment-related mortality score (n=21), poor health / organ function (n=26), physician or patient preference (n=25), lack of insurance (n=6), and not identified (n=50). No significant differences were found in age, gender, cytogenetic risk, or primary vs. secondary leukemia, but those treated on study in dose escalation protocols were more likely to receive higher doses. RR patients treated off study had typically received more salvage regimens. The 86 ND patients treated on study had higher rates of CR/CRi (90% vs. 64%, P Despite having higher remission rates, ND patients treated on vs. off study had comparable OS, and, among patients achieving remission, RFS (Figure 1a and 1b). After multivariate adjustment, there remained no association with OS (HR 0.87 [0.52-1.47]) or RFS (HR 0.96 [0.53-1.75]). Survival outcomes were also similar regardless of study assignment among RR patients (Figure 1c and 1d), in both univariate and multivariate analysis (OS, HR 0.82 [0.58-1.17]; RFS HR 0.72 [0.39-1.34]). Patients treated on or off dose escalation protocols at the maximum tolerated dose were no more likely to achieve remission or have longer survival, and incorporating subsequent allogeneic transplant as a time-varying covariate did not significantly affect outcomes. Conclusions: The higher response rates in ND patients treated on vs. off study suggests a measure of selection bias unrelated to readily assessable covariates, while the fundamental determinant of response in RR patients and survival in all patients appears to be unfavorable disease features (adverse cytogenetics, number of prior salvages, duration of CR1). Routine reporting of off study data for investigator-initiated studies could provide a clearer picture of regimen response rates and would grant further insight into the effects of selection bias. Download : Download high-res image (94KB) Download : Download full-size image Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Shadman: Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding.

Decitabine Plus Cytarabine for Induction of Remission in Newly Diagnosed Elderly AML or High Risk MDS Patients

Introduction:Acute myeloid leukemia (AML) primarily affects older adults. Treating these patients requires balancing risk of toxicity with risk of ineffective therapy. Here we examine the ability of decitabine combined with cytarabine (DecitAC) to strike such a balance. Our objectives were to 1) examine the likelihood DecitAC would improve 6-month survival probability from historical 60% (poor risk)-65% (good risk) in older patients treated with azacitidine + gemtuzumab on SWOG study - S0703 (Nand S et al Blood. 2013;122(20);3432-3439) to 80% in patients age ≥60 with newly diagnosed AML or high risk MDS (10-19% blasts); 2) determine response rate in this population; and 3) evaluate the effect of cytarabine dose escalation in patients who had a response short of CR after the first 2 cycles of the combination.Patients and Methods:In addition to age ≥ 60, patients needed a treatment related mortality (TRM) score <22.9 corresponding to <25% chance of death within 28 days of beginning 7+3 or high dose cytarabine-containing induction (Walter et al. JCO 2011). Prior use of azacitidine, lenalidomide, or decitabine, but not more intense therapy, was permitted. Doses were: decitabine 20mg/m2 once daily days 1 through 10, and cytarabine 100mg/m2once daily days 1 through 7. Two courses were planned to be given 28-35 days apart, regardless of blood counts. Bone marrow evaluation was planned after DecitAC course 2. The protocol allowed for cytarabine dose escalation after course to 1gm/m2 daily x 5 days for patients with ≥ 20% blasts by flow cytometry and if non-hematologic toxicities were < grade 3. If blasts were 5-19% by flow after two cycles, the doctor would choose between the original dose of cytarabine or the dose escalated dose. For patients that had ≥ grade 3 non-hematologic toxicities, the number of DecitAC dosed days were shortened if <5% blasts by flow after 2 cycles, or the patient was taken off study if marrow had ≥5% blasts by flow. Treatment was given outpatient or inpatient and patients were often managed by their referring physicians.Results:12 newly diagnosed patients (10 AML, 2 MDS) were treated on protocol at our academic center. 18 others (16 AML, 2 MDS) were treated off study because of higher TRM scores or by community oncologists, with chart review on an IRB approved protocol. TRM scores ranged from 0.5 - 61 with a median of 10. Ages ranged from 46-92 with a median of 73. Fourteen of the 26 AML patients had an antecedent hematological disorder. Two AML patients had ELN favorable risk disease, 12 had intermediate, and 12 adverse.DecitAC produced CR in 14/30 patients (47%; 95% CI 28-65%), CRi was seen in 7 other patients. No patients died within the first 28 days (95% CI 0-11%, i.e. up to 3 patients) contrasted with 5 expected deaths based on TRM score. Dose escalation of cytarabine to 1 gm/m2 on course 3 was conducted in 2 patients (TRM scores 14.2 and 9.8), each of whom died on this couse.Median survival in the 30 patients was 8 months and is 19 months in the 9 patients still alive as of August 2016. At 6 months survival probability was 57% in this group considered poor risk by definition in the comparison group vs. 60% in the controls. Results were not affected by whether patients were managed here or by their local physicians. Grade 3 adverse events included infections, diarrhea, hepatic dysfunction, and others, as expected with other regimens treating newly diagnosed AML and MDS patients.Conclusion:DecitAC resulted in a CR+Cri rate of 21/30 (70%) caused less TRM than expected. Whether this reflects the general decline in TRM or a specific effect of DecitAC is unknown. DecitAC can be given equally well in the community as at an academic center. However pending multivariate analysis it does not appear to improve survival relative to that seen previously. DisclosuresBecker:GlycoMimetics: Research Funding.

Mitoxantrone, Etoposide, and Cytarabine (MEC) Following Epigenetic Priming with Decitabine in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS): Final Results from a Phase 1/2 Study

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 <9.2 (corresponding to an expected TRM of <9.2% with standard induction chemotherapy). Prior treatment with hypomethylating agents or MEC (but not combined) was allowed. Patients with prior hematopoietic stem cell transplant (HCT) were eligible. Excluded were patients with concomitant illness with expected survival <1 year and uncontrolled infection. In phase 1, cohorts of 6-12 patients were assigned to 1 of 3 dose levels of decitabine (20mg/m2 for 5, 7, or 10 days) followed 5 days later by MEC (mitoxantrone 8mg/m2/day x 5 days; etoposide 100 mg/m2/day x 5 days; cytarabine 1 g/m2/day x 5 days). Patients with persistent AML were eligible for re-induction. Patients achieving a CR or CR with incomplete platelet recovery (CRp) could receive 2 more cycles of similarly dosed d/MEC. Dose-limiting toxicity (DLT) was defined as: 1) a grade 3 non-hematologic toxicity lasting >48 hours resulting in a >7-day delay of the subsequent treatment cycle; 2) a grade ≥4 non-hematologic toxicity, if recovery to grade ≤2 within 14 days. Both excluded febrile neutropenia/infection and constitutional symptoms. During phase 2, a Simon minimax 2-stage design was used to monitor whether a response rate of 0.25 was reached, with 80% power and a 1-sided alpha of 7%, assuming a historical CR rate of 10-15%.Results: Fifty-two patients, median age 55 (range: 19-72) years, with primary refractory (n=19) or relapsed disease (n=33; median duration of prior CR: 5 [1-19] months) and a median TRM score of 3.15 (range: 0.07-9.05) were enrolled. They received a median of 2 (1-7) prior therapies; 14 had prior HCT. During dose escalation, 1 DLT occurred at each the 2nd and 3rd dose level, identifying a 10-day course of decitabine with MEC as MTD. Since no differences in response rates were noted between the 7 and 10-day course of decitabine, a 7-day course of decitabine was used in phase 2 for logistical reasons. Overall, 11/51 evaluable patients achieved a CR (21.6%; 95% confidence interval [CI]: 11.3-35.3%) of whom 9 had no measurable residual disease (MRD) by flow cytometry. This CR rate compared favorably to a historic control population with patient matching based on duration of prior remission and number of prior salvage therapies (Estey et al. Blood 1996; 88:756), with an observed/expected CR ratio of 1.77. Seven further patients achieved a CRp, and 2 had a CR with incomplete count recovery (CRi) for an overall response rate (ORR) of 20/51 (39.2%; 95% CI: 25.8-53.9%). Among the 45 evaluable patients treated with a 7 or 10-day course of d/MEC, the ORR was 37.8% (95% CI: 23.8-53.5%). Five patients achieved a morphologic leukemia-free state, 21 had resistant disease, and 5 died before response assessment. Median response duration (CR, CRi or CRp) was 130 (15-1,229) days, with 3 of these responses ongoing. Overall survival of these 20 patients was longer (median of 332 [62-1,000 days]) than that for patients who failed to achieve remission but did not experience TRM (median 119 [45-530] days). Inclusion of 6 eligible patients that were treated with this regimen outside the clinical trial did not change these results. Nine patients died within 28 days of treatment initiation for a TRM rate of 17.6% due to infection/septic shock (5), intracranial hemorrhage (1), respiratory failure (2), and progressive disease (1). Besides grade 3-4 cytopenias, infection/neutropenic fever, nausea, and mucositis were the most common adverse events.Conclusion: D/MEC is feasible and has anti-leukemic activity in heavily pretreated relapsed/refractory AML and high-risk MDS. A comparative analysis of these results with other contemporary intensive salvage regimens is ongoing. A follow-up study is also being done to explore the relative value of pre-treatment vs. concomitant use of decitabine with intensive salvage chemotherapy. DisclosuresOthus:Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts).Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms.Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%).Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. DisclosuresOthus:Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

A Comparison of Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome Treated on Versus Off Study

Introduction: Despite decades of research, acute myeloid leukemia (AML) remains difficult to treat, and clinical trials are recommended as first line therapy by the NCCN. Although many new drugs show promise in early trials, further experience often does not confirm these results. One possible explanation is that patients on trials are not broadly representative. Here, we retrospectively compared characteristics, response, and survival in patients given the same investigational regimens according to whether treatment was given on versus off study.Methods: Patients treated for AML or high-risk MDS at FHCRC/UW between 2008 and 2015 were included. Investigator-initiated protocols for newly diagnosed (ND) and relapsed / refractory (RR) disease were included if ≥15 patients were treated off study. Analyses used Fisher’s exact test, Wilcoxon rank sum test, the Kaplan-Meier method, and Cox multivariate models.Results: 165 ND patients received either escalating doses of G-CLAM or idarubicin, cytarabine, and pravastatin while 243 RR patients received G-CLAM, decitabine-primed MEC or G-CLAC. Overall, 216 were treated on study and 192 were treated off study; reasons for the latter were: protocol not open (n=64), high treatment-related mortality score (n=21), poor health / organ function (n=26), physician or patient preference (n=25), lack of insurance (n=6), and not identified (n=50). No significant differences were found in age, gender, cytogenetic risk, or primary vs. secondary leukemia, but those treated on study in dose escalation protocols were more likely to receive higher doses. RR patients treated off study had typically received more salvage regimens.The 86 ND patients treated on study had higher rates of CR/CRi (90% vs. 64%, P<0.001) and CR without MRD (67% vs. 36%, P<0.001) than the 79 treated off study. These associations remained after adjusting for treatment date, age, gender, secondary leukemia, adverse cytogenetics, and regimen type (OR 3.99 [95% CI: 1.60-9.97] and OR 2.93 [1.39-6.17] respectively). In contrast, neither CR/CRi nor CR without MRD rates differed for RR patients treated on (n=130) or off (n=113) protocol: 52% vs. 41%, P=0.07 and 28% vs. 19%, P=0.14. The same applied after adjusting for the above factors as well as duration of first remission and salvage number: OR 1.79 [0.95-3.40] and OR 1.73 [0.80-3.71].Despite having higher remission rates, ND patients treated on vs. off study had comparable OS, and, among patients achieving remission, RFS (Figure 1a and 1b). After multivariate adjustment, there remained no association with OS (HR 0.87 [0.52-1.47]) or RFS (HR 0.96 [0.53-1.75]). Survival outcomes were also similar regardless of study assignment among RR patients (Figure 1c and 1d), in both univariate and multivariate analysis (OS, HR 0.82 [0.58-1.17]; RFS HR 0.72 [0.39-1.34]). Patients treated on or off dose escalation protocols at the maximum tolerated dose were no more likely to achieve remission or have longer survival, and incorporating subsequent allogeneic transplant as a time-varying covariate did not significantly affect outcomes.Conclusions: The higher response rates in ND patients treated on vs. off study suggests a measure of selection bias unrelated to readily assessable covariates, while the fundamental determinant of response in RR patients and survival in all patients appears to be unfavorable disease features (adverse cytogenetics, number of prior salvages, duration of CR1). Routine reporting of off study data for investigator-initiated studies could provide a clearer picture of regimen response rates and would grant further insight into the effects of selection bias. [Display omitted] DisclosuresOthus:Glycomimetics: Consultancy; Celgene: Consultancy. Shadman:Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Emergent: Research Funding; Acerta: Research Funding.

Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo Plus Cytarabine in the Phase 3 VALOR Study

Baseline Predictors of Mortality in Patients with Relapsed or Refractory Acute Myeloid Leukemia Treated with Vosaroxin Plus Cytarabine or Placebo Plus Cytarabine in the Phase 3 VALOR Study

Oncology Providers Ability to Prognosticate Patient Outcomes: An Analysis of the Survey on Provider Assessment of Risk (SPAR) Study

Background: Prognostic judgment plays a critical role in the practice of oncology. These predictions help providers determine appropriate treatment options and advise patients about the future. There is, however, little known about how accurate oncology providers are in making such predictions. In this study, we aimed to determine the accuracy of oncology providers in predicting serious medical events in adults admitted to oncology services at the University of Washington.Patients and Methods: Surveys were collected from oncology providers, including physicians, advanced practice providers (APPs), and nurses for patients within 24 hours of being admitted to our inpatient oncology services. Surveys assessed provider characteristics and their predictions about 30-day outcomes (death, ICU transfer, and transition to comfort care). Estimates of these outcomes were compared with actual outcomes by evaluating area under the receiver operating characteristic curve (AUC). For patients with newly diagnosed AML, the treatment-related mortality (TRM) score was calculated as previously described [Walter et al, J Clin Oncol 2011]. Analyses accounted for clustering within patient encounter, as more than one provider may have answered a survey (e.g., a physician and a nurse).Results: Between May 2014 and April 2015, 727 surveys were collected representing 490 individual patient encounters. Among all surveys, median patient age was 54 years (range: 20-94). The primary diagnosis was leukemia in 49%, lymphoma in 22%, solid tumor in 25%, and benign hematologic problem in 4%. Respondents were 29% internal medicine house-staff, 26% oncology attendings or fellows, 21% APPs, 19% nurses, and 4% other physicians. Overall, providers overestimated the likelihood of ICU transfer (11% [9-13%] actual vs. 19% [17-20%] predicted, p<0.0001), were realistic regarding transition to comfort care (13% [11-15%] actual vs. 15% [13-16%] predicted, p=0.22), and minimally overestimated the likelihood of death (10% [8-12%] actual vs. 13% [11-14%] predicted, p=0.027). The AUCs for provider predictions of ICU transfer, transition to comfort care, and mortality were 0.60 (0.53-0.67), 0.80 (0.74-0.84), and 0.76 (0.70-0.82) respectively. We stratified responses based on provider and patient characteristics and describe our results in Table 1. Notably, providers appeared to prognosticate mortality more accurately for patients admitted for planned chemotherapy than for unplanned events (AUC 0.79 [0.71-0.86] vs 0.68 [0.59-0.78]), though the difference was not statistically significant. In the subset of patients with newly diagnosed AML receiving curative-intent induction chemotherapy, the 30-day mortality rate was 10%, and the AUC for provider prediction of mortality was 0.83 (0.71-0.95), which was very similar to the accuracy of predictions based on calculated TRM score for these patients with AUC 0.82 (0.68-0.95). Respondents reported basing their estimates on the TRM score in 5 of 63 cases.Respondents reported making predictions based on many patient factors, but the three most commonly cited were the underlying malignancy, presence of comorbidities, and performance status; these reasons did not differ between respondents who were more versus less accurate in their ability to predict mortality.Conclusions: The SPAR study suggests that providers predict early mortality with fair accuracy, ICU transfer with poor accuracy, and transition to comfort care with good accuracy. Inaccuracies in prediction of mortality and ICU transfer veer in the direction of pessimism. While sample size limits detailed subgroup analysis, our results do not suggest large differences in prediction ability by provider type, years of experience, or patient type. The TRM score, which has been shown to predict 28-day mortality in patients with newly diagnosed AML undergoing intensive induction chemotherapy, appears to be roughly as accurate as providers' predictions. [Display omitted] DisclosuresWalter:Pfizer, Inc.: Consultancy; AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Amgen, Inc.: Research Funding.

The Treatment Related Mortality Score Predicts Early Adverse Events during Intensive Induction Chemotherapy for Acute Myeloid Leukemia (AML)

Background: Despite improvements in supportive care, treatment of AML remains associated with complications. We have developed a multivariate model – the Treatment-Related Mortality (TRM) score – which includes age, performance status, and 6 other covariates to predict 28-day mortality with c-statistic = 0.82 (1.0 = perfect prediction, 0.5 = no prediction) (Walter et al. J Clin Oncol 2011). We investigated associations between TRM score and complications developing during AML treatment.Patients and Methods: 179 adults (median age 53 [range: 18-77] years) with newly diagnosed AML treated at our institution from 2002-2012 with 7 + 3 or similar therapy were included. Documented infections, ICU transfer, and death until the earlier of day 28 or administration of additional chemotherapy were recorded. Patients were categorized by quartiles of TRM score. All outcomes were treated as time-to-event endpoints. The survival probabilities in the absence of infection or ICU transfer were estimated using the Kaplan-Meier method; the 10 patients in the ICU at the start of chemotherapy were excluded from analysis of ICU transfer as an adverse event. Outcomes between TRM scores by quartile were assessed using log-rank test for trend; scores above and below the median were compared using Cox regression. Multivariate models were adjusted for gender, cytogenetic risk, baseline absolute neutrophil count, and year of treatment.Results: The median TRM score was 4.6 (quartiles 2.3 and 10.5). Documented infections occurred in 72 patients (40%), ICU transfer in 14 (8%), and death in 4 (2%) within 28 days of induction. Patients with higher ranges of TRM scores were more likely to develop infections (Ptrend=0.006; Fig 1a) and require ICU transfer (Ptrend=0.003; Fig 1b). In particular, TRM scores above the median were associated with increased risk of infection (P=0.02; Fig 1c) and ICU transfer P=0.0004; Fig 1d). After multivariable adjustment, the risk of documented infection was 1.72 (95% CI: 1.06-2.81)-fold higher for patients with TRM >4.5. Consistent with our recent analysis, baseline grade 4 neutropenia was also independently associated with infection (HR 2.2 [95% CI: 1.38-3.52]) (Buckley et al. Am J Hematol 2014). There was only one ICU transfer, and there were no deaths among the 92 patients with TRM score less than the median. Although supportive care measures have improved in recent years, a high TRM score was still associated with ICU transfer in the subset of patients treated from 2007-2012 (P=0.001).Conclusions: The TRM score is associated not only with death, but also with other early adverse events. A cut-point of 4.5, which will need to be confirmed in an independent study cohort, may separate low- from high-risk patients in terms of susceptibility to infection and likelihood of requiring an ICU transfer. The TRM score may thus improve assessment of the risks of intensive induction chemotherapy and help allocate health care resources. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prediction of Treatment-Related Mortality in Patients with Relapsed and Refractory Acute Myeloid Leukemia

IntroductionDespite improvements in supportive care, treatment-related mortality (TRM) remains a significant problem for patients with acute myeloid leukemia (AML). In order to quantify fitness for intensive AML therapies, we recently developed a multivariate model for predicting TRM, defined as death within 28 days of treatment initiation in patients undergoing intensive induction chemotherapy for newly-diagnosed AML. Here, we examine the performance of this TRM model in patients with relapsed or refractory AML and assess whether the model can be improved for this population.MethodsUsing a database of patients treated for AML at our institution since 2003, we identified patients with relapsed or refractory disease treated with intensive chemotherapy, defined as regimens that were at least as intense as typical “7+3” regimens; patients who received treatment protocols with cytarabine <100 mg/m2/day or demethylating agents alone were excluded. We collected the following variables required to calculate the TRM score: ECOG performance status, age, platelet count, albumin, presence or absence of secondary AML, WBC, peripheral blood blast percentage, and creatinine. TRM scores were then calculated as described in J Clin Oncol 2011;29:4417. For a subset of these patients, the following additional variables were collected: duration of prior complete remission, number of prior chemotherapy regimens, number of prior hematopoietic cell transplants, and the number of antibiotics prescribed for treatment of presumed or documented infections at the time of chemotherapy initiation. For this smaller subset, we used a logistic regression model to create a preliminary updated TRM model that included these clinical variables in addition to the variables in the original TRM score. Finally, we used the area under the receiver operator characteristic curve (AUC) to quantify the ability of a model to predict TRM; in this approach, an AUC of 1 indicates perfect prediction of TRM while an AUC of 0.5 indicates no prediction; AUC values of 0.6-0.7, 0.7-0.8, and 0.8-0.9 are commonly considered as poor, fair, and good, respectively.ResultsA total of 270 patients met our study inclusion criteria. Fifteen (5.6%) died within 28 days of starting chemotherapy, i.e. experienced TRM. The AUC for the previously published TRM score in predicting early death in this population was 0.66. For comparison, in our original study of 2,238 patients with newly-diagnosed AML, we obtained an AUC of 0.82. Expanding the definition of TRM to include those patients who died within 60 (N = 47, 17.4%) or 90 days (N = 75, 27.8%) of starting chemotherapy did not improve the original model’s performance in our cohort (AUCs of 0.62 and 0.59, respectively). The additional variables described above were available for 133 of the 270 patients in our cohort. Within this subset, the AUC for the original TRM score was 0.65 in predicting death within 28 days. Incorporation of these new covariates in a preliminary TRM model yielded an improved AUC of 0.81 for this smaller subset.ConclusionsOur data indicate that the TRM score, originally developed for patients with newly-diagnosed AML, only has a fair ability to predict TRM in patients with relapsed and refractory AML. However, with inclusion of additional covariates, such as prior CR duration and number of prior chemotherapies, TRM can be predicted quite well, to a degree similar to the accuracy demonstrated by the original model in newly-diagnosed patients. While our findings need to be confirmed in larger, independent cohorts of patients, they suggest the possibility of developing an objective measure to determine fitness for intensive salvage chemotherapy in AML. DisclosuresNo relevant conflicts of interest to declare.

Randomized Study of Liposomal Cytarabine and Daunorubicin (CPX-351) for Adults with Untreated High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) at High Risk of Treatment-Related Mortality

Background: Because of the concern for therapeutic resistance and excessive toxicity or even treatment-related mortality (TRM), many medically unfit patients do not receive AML-directed therapy, although evidence suggests that outcomes are improved if essentially all of these patients are offered some form of chemotherapy rather than given supportive care only. Here, we evaluated the potential value of attenuated doses of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in medically unfit patients with newly diagnosed AML or high-risk MDS (≥10% blasts). In earlier trials, CPX-351 appeared to afford superior outcomes in high-risk AML patients with a wide therapeutic window suggesting that reduced dose treatment may be helpful in this population.Methods: Patients aged ≥18 years with untreated AML or high-risk MDS were eligible if they had a TRM score of ≥13.1, corresponding to an expected TRM (i.e. death within 28 days of treatment initiation) of 31% with standard induction chemotherapy. Bilirubin was to be <2.0 mg/ml because of hepatic excretion of CPX-351, and active infection was an exclusion criterion. Patients were randomly assigned 1:1 to receive CPX-351 at either 32 or 64 units/m2 per dose (previous phase 1 investigations established a maximum tolerated dose of 101 units/m2 per dose) on days 1, 3, and 5 for up to 4 identical induction/re-induction courses. Patients achieving either complete remission (CR) or CR with incomplete platelet count recovery (CRp) could receive up to 4 courses of post-remission treatment with CPX-351 using the same dose on days 1 and 3 only. The primary goal of the study was to estimate whether either the 32 or 64 units/m2 doses were likely to improve TRM rates while keeping the CR rate comparable to historic controls. Specifically, a Bayesian design was used to monitor both response (CR) and toxicity (TRM), with early stopping if the posterior probability was <0.10 that the true TRM rate was <15% (vs. the historical = 31%) or if the posterior probability was >0.90 that the true CR rate with CPX-351 was <30% (historical = 30%).Results: 23 patients, median age 71.1 (range: 53.1-91.1) years, with a median TRM score of 25.7 (range: 13.7-90.0) and a median ECOG performance status of 2 (range: 1-3), were enrolled. Cytogenetic risk was favorable in 1, intermediate in 8, and adverse in 14 (including 3 with insufficient culture growth for analysis), with 9 patients having a monosomal karyotype. 13 patients had secondary disease. Overall, study patients received a median of 1 (range, 1-3) cycles of induction therapy. Among the first 9 patients randomized to 64 unit/m2, 1 CR, 1CRp, and 3 deaths by day 28 occurred. The deaths were due to overwhelming infection in patients presenting with TRM scores of 14.5, 44.4, and 57.9. Because of these 3 deaths, accrual to the 64 units/m2 arm stopped. The 9 patients given 64 units/m2 might have, by chance, been more unfavorable than the large number of historical pts. (n =2,238) used to derive the TRM score. We addressed this possibility by summing the TRM scores in these 9 patients, thus calculating the number of expected deaths by day 28 had these patients received historical treatments, principally 3+7 or higher doses of cytarabine. The number of expected deaths was 3.0, the same as the number observed. Because it met neither the early stopping bound for TRM or lack of CR, the 32 units/m2arm has continued accrual. 14 patients have been enrolled (including 3 who were enrolled without randomization after the higher-dose arm closed). 2 CRs (14.3%) were observed, and 4 patients died early; deaths were related to overwhelming infection in 1 (TRM score of 23.7), and early disease progression in 3 (TRM scores of 23.7, 33.3, and 90.0).Conclusion: This study illustrates the challenge of balancing therapeutic resistance and disease/treatment-related complications in medically unfit adults with AML. Within the constraints of historical controls and an experience limited to 9 patients at the higher dose level, our data suggest that at 64 units/m2, CPX 351 is relatively unlikely to decrease TRM to 15% (from ~30% historically) and increase CR rate to 40% (from ~30% historically) in patients at high risk of TRM. These results present the first attempt at identifying and treating medically unfit patients with CPX-351 and suggest that further adjustments in eligibility and CPX-351 dosing to maximize efficacy and reduce early leukemia-related deaths are needed. DisclosuresOff Label Use: CPX-351 currently has investigational drug status. Louie:Celator Pharmaceuticals, Inc: Employment.