AbstractBackgroundLow‐intensity regimens have been increasingly used to treat older patients with acute myeloid leukemia (AML). Recent studies, however, suggest older patients can tolerate and potentially benefit from intensive chemotherapeutic regimens. The ability to compare the utility of varying regimen intensities in AML is hindered by the lack of a standardized definition of “regimen intensity.”MethodsWe conducted a survey asking AML physicians which of 38 regimens they would consider intensive vs less‐intensive. Electronic medical records of 592 patients receiving many of these regimens were used to design a model characterizing regimens as intensive vs less‐intensive as identified by ≥75% physician consensus. Variables included frequency and length of hospitalizations, intensive care unit admissions, severe gastrointestinal toxicities, time to nadir, and recovery of neutrophil/platelet count.ResultsPhysicians agreed at a rate of 75%‐100% on the assignment of degree of intensity to the majority (n = 28) of these regimens, while the level of agreement was <75% for the remaining 10 regimens (26%). Logistic regression analyses identified number and length of hospitalizations to be significantly associated with intensive regimens and count recovery with less‐intensive regimens. We created the “regimen‐intensity per count‐recovery and hospitalization” (RICH) index with an AUC of 0.87. Independent model validation yielded an AUC of 0.75.ConclusionsWe were able to generate a novel model that defines regimen intensity for many therapies used to treat AML. Results facilitate a future randomized study comparing intensive vs less‐intensive regimens.

BACKGROUND: The current recommendation against the need for bone marrow aspiration (BMA) in routine follow-of persons with acute myeloid leukemia (AML) in remission preceded the recognition that multiparameter flow cytometry (MFC) is a sensitive and specific means to detect imminent morphologic relapse. Given this recognition, we wondered whether BMA is now necessary, or if concordance between MFC results in peripheral blood (PB) and BMA is such as to make BMA unnecessary, at least for evaluation of measurable residual disease (MRD) by MFC. Previous studies have demonstrated a strong correlation between disease detection by MFC in PB and BMA. Here we examined 724 paired PB and BMA samples from 482 patients to further examine the concordance between PB and BMA blast detection by MFC, particularly among patients in morphologic remission. PATIENTS AND METHODS: We included adults in our institutional AML database, covering 2008-2018. Our Hematopathology database was queried to identify PB and BMA MFC sample pairs with samples considered "paired" if measured within one week of each other. If an individual had multiple pairs, all were included unless otherwise specified. Ten-color MFC was performed routinely on BMA aspirates with a panel of three antibody combinations, with the same antibody combinations applied to PB samples. When identified, the abnormal population was quantified as a percentage of the total CD45+ white cell events. Any level of residual disease was considered positive. Complete remission (CR) and relapse were defined according to the European LeukemiaNet 2017 classification. Relationship between PB and BMA blast % was measured using Spearman's Rank-Order Correlation. Relationship between PB and BMA samples identified as positive or negative is illustrated using 2 X 2 tables (Table 1). RESULTS: Considering all 724 sample pairs, the Spearman correlation coefficient between PB and BMA blast percentage was 0.93, and was 0.91 considering only the first sample pair for each individual patient (n= 482). 315 sample pairs were positive by PB, 97% of which were also positive by BMA while 95% of 409 pairs negative by PB were also negative by BMA. Similar results were seen considering only a patient's first pair. Restricting analysis to patients with pairs obtained between the dates of CR and relapse, the Spearman correlation coefficient was 0.82 with 91% of 35 cases positive in PB also positive in BMA; 93% of 114 pairs negative in PB were also negative in marrow. As a complementary means to compare pairs when AML burden was low, we examined only pairs where the BMA MFC showed <5% blasts. Here, the Spearman correlation coefficient between PB and BMA blasts was 0.83. 90% of 70 positive PB cases were also positive by BMA while 95% of 295 negative PB cases were also negative by BMA. Examining pairs taken from patients in morphologic remission immediately prior to undergoing hematopoietic cell transplant yielded a Spearman correlation coefficient of 0.92, with all 9 PB positive cases also being positive in BMA and 96% of PB negative cases being negative in BMA. CONCLUSIONS: This is the largest cohort of AML PB and BMA sample pairs analyzed by MFC to-date. The percentages of blasts measured in PB and BMA are strongly correlated. In the 365 pairs from patients with MRD-level disease, the predictive value of PB MFC positivity for BMA positivity was 90% (63/70) while the predictive value PB MFC negativity for BMA negativity was 95%. Disclosures Othus: Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gardner:Abbvie: Speakers Bureau. Walter:BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Argenx BVBA: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership.

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<0.001), higher treatment-related mortality score (p<0.001), and intensity of treatment (p<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.

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 ≥76kg in both arms (days 0-5), and mitoxantrone 6 or 18 mg/m2/day (days 1-3). CLAG at identical doses was used for post-remission therapy for up to 4 (regular-dose CLAG) or 12 (mini-CLAG) cycles. The primary endpoint was feasibility of randomization, defined as ≥26/50 of patient-physician pairs agreeing to randomization. Secondary outcomes included rate of complete remission (CR) negative for measurable ("minimal") residual disease (MRD), rate of CR plus CR with incomplete hematologic recovery (CR+CRi), and overall survival (OS). Results: This trial enrolled 33 patients. Only 3 (9%) patient/physician pairs agreed to randomization and thus randomization was deemed infeasible (primary endpoint). Eighteen pairs chose mini-CLAG-M and 12 regular-dose CLAG-M for a total of 19 subjects in the lower dose and 14 subjects in the higher dose arms. The decision favoring lower dose treatment was made largely by the physician in 5/18 (28%) cases, the patient in 11/18 (61%) cases and both in 2/18 (11%). The decision favoring the higher dose arm was made by the patient in most cases 9/12 (75%), both physician and patient in 2/12 (16%) and the physician in only 1/12 (8%) cases. Despite the limitations of lack of randomization, patients' baseline characteristics were well balanced with regard to age, performance status, TRM score, lab values and cytogenetic/mutational risk categories (Table 1). One patient was not yet evaluable for response or TRM at data cutoff. Rates of MRDneg CR were comparable: 6/19 (32%) in the lower and 3/14 (21%) in the higher dose groups (p=0.70). CR+CRi rates were also similar in both arms (43% vs. 56% in lower vs. higher dose arms; p=0.47). Three (16%) patients experienced early death in the lower dose arm vs. 1 (7%) in the higher dose arm (p=0.43). With a median follow up of 4.2 months, there was no survival difference between the two groups (median OS of 6.1 months in the lower vs. 4.7 months in the higher dose arm; p=0.81; Figure 1). Conclusions: Randomization of medically unfit patients to lower- vs. higher-intensity therapy was not feasible, and physicians rarely chose higher intensity therapy in this patient group. Acknowledging the limitation of short follow-up time and small sample size, our trial did not identify significant differences in outcomes between intensive and non-intensive chemotherapy. Analysis of differences in QOL and healthcare resource utilization between groups is ongoing. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Celgene: Other: Data Safety and Monitoring Committee. Gardner:Abbvie: Speakers Bureau. Percival:Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Becker:AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy; The France Foundation: Honoraria. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy. Walter:BioLineRx: Consultancy; Astellas: Consultancy; Argenx BVBA: Consultancy; BiVictriX: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Research Funding; Race Oncology: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding. OffLabel Disclosure: Cladribine is FDA-approved for Hairy Cell Leukemia. Here we describe its use for AML, where is is also widely used with prior publications supporting its use

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 <72 hours from completing chemotherapy (as done in our phase 2 study); the remaining patients were considered inpatient "controls". The study period began on the day of discharge (EHD group) or at the completion of chemotherapy (control group) and ended with count recovery, hospital discharge (control group), death, receipt of more chemotherapy, or at 42 days. Table 1 describes baseline variables collected. Outcomes of interest were organism and site of infections, days of IV antimicrobial use, days in intensive care unit (ICU), and survival. Bacterial infections were either culture-documented or probable based on clinical exam/imaging. Fungal infections were proven or probable based on EORTC/MSG Working Group Criteria. Microbiological documentation was required for viral infections. Results: We identified 354 inductions that met our criteria: 215 (61%) in the EHD group and 139 (39%) in the control group (baseline characteristics in Table 1). For antimicrobial prophylaxis, more EHD patients than controls used levofloxacin vs. other agents (98% vs. 93%; p=0.03) and controls more likely used posaconazole vs. EHD patients (64% vs. 52%; p<0.001). EHD patients more likely had a tunneled central venous catheter (42% vs. 32%; p=0.03) than a peripherally inserted central catheter (53% vs 67%; p=0.03). 53% of EHD patients vs. 39% of controls developed ≥1 infection during the study period (p=0.01). There were no differences between groups in type of organism identified. We then assessed whether the higher infection rate in EHD patients led to inferior outcomes (Table 2). There were no differences in ICU admission (7% vs. 10%; p=0.44) or early death (4% vs. 7%; p=0.24) between EHD and controls. Despite a higher rate of infections, EHD patients spent fewer days on IV antimicrobials. For the whole cohort, however, patients with ≥1 infection more likely required ICU care than those without infection (14% vs 4%, p<0.001) but there was no difference in early death rates between patients who developed an infection and those who did not. Development of gram positive bacteremia was associated with risk of ICU admission, a trend towards early death and a longer hospital stay. Development of fungal infection was also associated with a longer hospital stay (12.7 vs 6.4 days) but not risk of ICU admission or early death. There was no association between type of prophylactic antifungal agent and subsequent diagnosis of fungal infection, between catheter type and risk of bacteremia, or between housing distance to our institution and infection risk (EHD group). Conclusion: An EHD care strategy following AML-like induction chemotherapy is associated with a higher rate of infection but not an increased risk for ICU stay or early death. Central catheter type, specifics of antimicrobial prophylaxis, and distance to our institution were not associated with infection risk in the EHD group. Further investigation to elucidate the risk factors for the increased rate of infection in the EHD group is warranted. Disclosures Halpern: Pfizer Pharmaceuticals: Research Funding; Bayer Pharmaceuticals: Research Funding. Othus:Glycomimetics: Other: Data Safety and Monitoring Committee; Celgene: Other: Data Safety and Monitoring Committee. Buckley:CTI Biopharma: Employment. Percival:Pfizer Inc.: Research Funding; Nohla Therapeutics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Becker:The France Foundation: Honoraria; Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding. Scott:Incyte: Consultancy; Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy. Oehler:Pfizer Inc.: Research Funding; Blueprint Medicines: Consultancy; NCCN: Consultancy. Gernsheimer:Bioverativ: Consultancy; Novartis: Honoraria; Dova pharmaceuticals: Consultancy; Shionogi: Consultancy; Rigel: Consultancy; Fuji film: Consultancy; Amgen: Consultancy, Honoraria; Cellphire: Consultancy. Orozco:Actinium Pharmaceuticals: Research Funding. Cassaday:Seattle Genetics: Other: Spouse's disclosure: employment, stock and other ownership interests; Amgen: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. Hartley:Pfizer Inc.: Employment, Equity Ownership. Welch:Pfizer Inc: Employment, Equity Ownership. Walter:Seattle Genetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Agios: Consultancy; Amgen: Consultancy; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Kite Pharma: Consultancy; Covagen: Consultancy; Boston Biomedical: Consultancy; Race Oncology: Consultancy.

Purpose of review Patients with acute myeloid leukemia (AML) are almost invariably kept in the hospital until resolution of cytopenias following intensive induction chemotherapy. This care approach is costly and may further contribute to the reduced qualify of life of these patients. This has raised interest in moving at least part of this care to the outpatient setting. Reimbursement challenges for inpatient administration of some of the new drugs approved for AML in the last 2 years adds to this interest. Recent findings Retrospective and smaller prospective studies have shown that outpatient management following intensive induction chemotherapy ('Early Hospital Discharge') is feasible and may be well tolerated and cost-effective. Reported experience is more limited regarding administration of intensive chemotherapy in the outpatient setting. Summary Although of interest, barriers to the successful implementation of outpatient care models, such as limited outpatient infrastructure or geographical limitations, will have to be overcome in many cancer centers. Importantly, before wide-spread introduction, the safety and 'efficacy' (e.g. reduction in medical resources and/or cost and improvement in quality of life) of outpatient care strategies will need to be further evaluated in a prospective - and ideally randomized - manner across more heterogeneous types of oncology and geographical settings.

Abstract INTRODUCTION: Gemtuzumab ozogamicin (GO, MylotargTM) was re-approved by the FDA and has been commercially available since September 2017. Prior to re-approval, adults and children with relapsed/refractory AML or APL were treated with GO obtained through an expanded access program under an institutional IND at our Cancer Consortium: Fred Hutchinson Cancer Research Center (FHCRC), the University of Washington Medical Center (UWMC), Seattle Children's Hospital (SCH), and the Seattle Cancer Care Alliance (SCCA). METHODS: Between 2014-2017, we enrolled 44 patients (median age 40); patient characteristics are summarized in Table 1. Twelve were children treated at SCH and 32 adults at SCCA/UWMC. Forty had AML, 3 mixed phenotype acute leukemia and 1 APL. Forty-two had relapsed disease and 2 were primary refractory. Median duration of CR1 was 11.2 months (range 0-104). Median number of prior induction attempts was 2 (range 1-8). Eligibility initially required intermediate or "good" risk cytogenetics, though subsequently patients whose blasts were CD33 positive were included regardless of cytogenetics. Additional inclusion criteria were ECOG performance status (PS) ≤3, bilirubin ≤2.0 mg/dl, and ALT/AST ≤5 fold the institutional upper limit of normal. RESULTS: Two patients received single-agent GO (9mg/m2 day 1), 1 patient with APL received GO + ATRA + Aza, and the remainder typically received 3mg/m2 with chemotherapy for a single dose or on days 1, 4, and 7 (Table 2). Patients received a median of 2 cycles (range 1-6) of GO (the APL patient received 6 cycles). Timing of GO around hematopoietic stem cell transplant (HCT) is also noted in Table 2. Table 3 shows the grade 3-4 toxicities occurring within 60 days of receipt of GO per number of patients, rather than number of events. Two children developed sinusoidal obstructive syndrome (SOS) >60 days post GO. Both incidences were post an allogeneic hematopoietic cell transplant (HCT), one at 15 days post HCT and the other 28 days post HCT. The first patient had complete resolution of SOS and remains alive 2 years later, the second patient developed SOS day 28 post HCT then died of an invasive mucormycosis infection in the setting of immunosuppression on day 37 of the HCT. Six deaths occurred within 60 days of beginning GO: 1 from cardiogenic shock, 1 from multiorgan failure post aspiration event, 2 from pneumonia/sepsis, and 2 from disease progression. No deaths were attributed to GO. Thirteen of the 44 patients (29%; 95% CI:18-44%) achieved complete remission (CR), 3 with measurable residual disease (MRD 7%) (Table 4). The MRD was detected by flow cytometry in 2 patients, and PCR for inversion 16 in 1 patient. Sixteen had CR with incomplete hematologic recovery (CRi) and 15 were resistant or died before assessment. Eight remain alive in CR with a median event free survival (EFS) of 31 months (range 7-47). Thirty-six patients have died, with a median survival of 17.2 months (range 0.5-9.4). Table 4 outlines response by "more" or "less" intense regimens (intensity is defined in Table 2) and by adult vs. pediatric populations. We found higher response rates in patients who received GO combined with more intensive [78% CR+CRi] rather than less intensive therapy [44% CR+CRi] and in those with fewer prior regimens [100% CR+CRi in patients with 1 prior regimen compared to 48% with ≥2 prior regimens]. In addition, responses were obtained in patients with intermediate risk cytogenetics (11 out of 19 total intermediate = 58%) or unfavorable (3 out of 8 total unfavorable = 37%), although a higher fraction of responses were seen with favorable cytogenetics [t(8;21, inv16, t(15;17)] (15 out of 17 total favorable = 88%). CONCLUSION: GO was safe and well tolerated. Based on CR1 duration and number of salvage regimens, the observed 9/28 CR rate with GO + intense therapy compares with a rate of expected 7/28 had the same patients received prior intense salvage therapy without GO (Estey E, Blood [1996/88:756]). GO combinations are a reasonable option for relapsed/refractory AML, but might be of more value in patients with only measurable residual disease. ACKNOWLEDGEMENTS: The GO team wishes to acknowledge Pfizer Inc. for their commitment to patients by supplying drug, and our Investigational Pharmacy, the Institutional Review Board, and the FDA for supporting the efforts of this expanded access program in making gemtuzumab ozogamicin accessible to people with relapsed or refractory AML. Disclosures Walter: Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Amgen Inc.: Other: Clinical trial support, Research Funding; Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding; Pfizer: Consultancy. Scott:Celgene: Consultancy, Research Funding; Agios: Consultancy; Alexion: Consultancy; Novartis: Research Funding. Cassaday:Adaptive Biotechnologies: Consultancy; Merck: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Seattle Genetics: Other: Spouse Employment, Research Funding; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Research Funding; Incyte: Research Funding. Becker:GlycoMimetics: Research Funding.

Randomized trials are the best way to avoid bias. However the proportion of patients who are considered for randomization, but are not randomized, is rarely reported. Without this knowledge the ability to generalize results of a randomized trial to a larger population is limited.

The National Comprehensive Cancer Network (NCCN) recommends that a repeat bone marrow evaluation is carried out seven to ten days following completion of induction therapy so that if a patient's day 14 bone marrow shows residual blast cell counts of >10%, the patient would proceed early to a second cycle of induction therapy. Although blast cell counts of <5% on day 14 bone marrow is sensitive in predicting remission on day 28, various studies have found that day 14 bone marrow is highly nonspecific because a large proportion of patients with blast cell counts of >5% on day 14 bone marrow would still attain a complete remission of the disease without any further chemotherapy. Clinical decision based on day 14 bone marrow will result in some of these patients being given a second induction therapy unnecessarily. A second cycle of chemotherapy is associated with not only higher risk for treatment-related mortality but also increased use of hospital resources such as increased intravenous antimicrobials use, longer hospital stay, and higher demand for blood products. In this article, we examined the utility, discussed the shortfalls, and re-appraised the values of day 14 bone marrow in the management of patients with AML. On the basis of our review, we suggest that the practice of day 14 bone marrow examination should be re-evaluated and should probably only be carried out in the setting of clinical trials with clear questions to address its role in predicting outcome of the therapeutic intervention.

Assuming a person with acute myeloid leukemia (AML) wishes to receive AML-specific treatment, physicians must choose between conventional therapy, for example azacitidine, decitabine or “7+3”, and investigational therapy. Although results with most investigational therapies have not been superior to those seen with conventional therapies, the results of any relatively new trial are unknown; few patients have typically been enrolled, the enrolled patients are heterogeneous, and follow-up is short. Hence the decision between conventional and investigational therapy must rest on likely results with the latter. In particular, the reason to elect a trial is not a “promising” pre-clinical rationale or “encouraging” early results but dissatisfaction with the predicted results of conventional therapy, with the patient concluding outcome with the trial cannot really be much worse than outcome with conventional therapy.

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).

Evidence suggest that even patients aged 70 or above benefit from specific AML therapy. The fundamental decision in AML then becomes whether to recommend standard or investigational treatment. This decision must rest on the likely outcome of standard treatment. Hence we review factors that predict treatment related mortality and resistance to therapy, the latter the principal cause of failure even in patients aged 70 or above. We emphasize the limitations of prediction of resistance based only on pre- treatment factors and stress the need to incorporate post-treatment factors, for example indicators of minimal residual disease. We review various newer therapeutic options and considerations that underlie the decision to recommend allogeneic hematopoietic cell transplant. Am. J. Hematol. 91:825-846, 2016. (c) 2016 Wiley Periodicals, Inc.

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.

Background The intensive chemotherapy regimens used to treat acute myeloid leukaemia routinely result in serious infections, largely due to prolonged neutropenia. We investigated the use of non-HLA-matched ex-vivo expanded cord blood progenitor cells to accelerate haemopoietic recovery and reduce infections after chemotherapy.Methods We enrolled patients with a diagnosis of acute myeloid leukaemia by WHO criteria and aged 18-70 years inclusive at our institution (Fred Hutchinson Cancer Research Center) into this phase 1 trial. The primary endpoint of the study was safety of infusion of non-HLA-matched expanded cord blood progenitor cells after administration of clofarabine, cytarabine, and granulocyte-colony stimulating factor priming. The protocol is closed to accrual and analysis was performed per protocol. The trial is registered with ClinicalTrials.gov, NCT01031368.Findings Between June 29, 2010, and June 26, 2012, 29 patients with acute myeloid leukaemia (19 newly diagnosed, ten relapsed or refractory) were enrolled. The most common adverse events were fever (27 [93%] of 29 patients) and infections (25 [86%] of 29 patients). We observed one case of acute infusional toxicity (attributed to an allergic reaction to dimethyl sulfoxide) in the 29 patients enrolled, who received 42 infusions of expanded progenitor cells. The following additional serious but expected adverse events were observed (each in one patient): grade 4 atrial fibrillation, grade 4 febrile neutropenia, lung infection with grade 4 absolute neutrophil count, colon infection with grade 4 absolute neutrophil count, grade 4 changed mental status, and one death from liver failure. No unexpected toxicity or graft-versus-host disease was observed. There was no evidence of in-vivo persistence of the expanded progenitor cell product in any patient beyond 14 days or induced alloimmunisation.Interpretation Infusion of the expanded progenitor cell product seemed safe and might provide a promising treatment method for patients with acute myeloid leukaemia.

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disorder such that each patient exhibits a unique pattern of mutations. Nevertheless, standard treatment approaches are largely used for all patients with the exception of those with the PML-RARA translocation or FLT3 mutations. We are conducting a feasibility study, "Individualized Treatment for Relapsed/Refractory Acute Leukemia Based on Chemosensitivity and Genomics/Gene Expression Data" (NCT02551718). This abstract summarizes the results in the AML patients.

Abstract 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.

Fewer patients with primary refractory AML ("PREF") are entered into phase 3 trials than are patients with relapsed AML. This is particularly noteworthy because data from phase 3 trials for newly diagnosed AML indicated PREF and relapse are equally common. Here I discuss three possible reasons for this discrepancy. First, there is disagreement whether the criterion for PREF AML should be failure of one or two courses of initial induction therapy. Second, there may be an impression that PREF AML is qualitatively worse than relapsed AML. Third, there may be a general unwillingness to randomize patients with such poor prognoses.