Patients with acute myeloid leukemia (AML) who are in morphologic complete remission are typically considered separately from patients with active disease (ie, $ 5% marrow blasts by morphology) in treatment algorithms for allogeneic hematopoietic cell transplantation (HCT), which implies distinct outcomes for these two groups. It is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcome for those patients in morphologic remission. This effect of pre-HCT MRD prompted us to compare outcomes in consecutive patients in MRD-positive remission with patients with active AML who underwent myeloablative allogeneic HCT at our institution. Patients and MethodsWe retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry on bone marrow aspirates in all patients. Any level of residual disease was considered to be MRD positive. ResultsThree-year relapse estimates were 67% in 76 patients in MRD-positive morphologic remission and 65% in 48 patients with active AML compared with 22% in 235 patients in MRD-negative remission. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment, MRD-negative remission status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared with MRD-positive morphologic remission status or having active disease, with similar outcomes between the latter two groups. ConclusionThe similarities in outcomes between patients in MRD-positive morphologic remission and those with active disease at the time of HCT support the use of treatment algorithms that use MRD-rather than morphology-based disease assessments.

Measurable (“minimal”) residual disease (MRD) before or after hematopoietic cell transplantation (HCT) identifies adults with AML at risk of poor outcomes. Here, we studied whether peri-transplant MRD dynamics can refine risk assessment. We analyzed 279 adults receiving myeloablative allogeneic HCT in first or second remission who survived at least 35 days and underwent 10-color multiparametric flow cytometry (MFC) analyses of marrow aspirates before and 28±7 days after transplantation. MFC-detectable MRD before (n=63) or after (n=16) transplantation identified patients with high relapse risk and poor survival. Forty-nine patients cleared MRD with HCT conditioning, whereas 2 patients developed new evidence of disease. The 214 MRDneg/MRDneg patients had excellent outcomes, whereas both MRDneg/MRDpos patients died within 100 days following transplantation. For patients with pre-HCT MRD, outcomes were poor regardless of post-HCT MRD status, although survival beyond 3 years was observed among the 58 patients with decreasing but not the 7 patients with increasing peri-HCT MRD levels. In multivariable models, pre-HCT but not post-HCT MRD was independently associated with OS and RR. These data indicate that MRDpos patients before transplantation have a high relapse risk regardless of whether or not they clear MFC-detectable disease with conditioning and should be considered for pre-emptive therapeutic strategies.

Background: Treatment algorithms for allogeneic hematopoietic cell transplantation (HCT) typically consider patients with acute myeloid leukemia (AML) in morphologic complete remission (CR) separately from those with active disease (i.e. ≥5% marrow blasts by morphology), implying distinct outcomes for these two groups. However, it is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcomes for patients in morphologic CR. This well established effect of pre-HCT MRD prompted us to compare outcomes in patients in MRDpos CR to those with active AML who underwent myeloablative allogeneic HCT at our institution. Patients and Methods: We retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry (MFC) on bone marrow aspirates in all patients. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Results: Three hundred and eleven patients (87%) were in morphologic CR at the time of transplantation, with 76 (21%) in MRDpos CR and 235 (66%) in MRDneg CR. 48 patients (13%) had active disease (7 untreated newly diagnosed AML, 16 untreated relapsed AML, and 25 refractory or relapsed AML who failed salvage therapies). Patients with MRDpos CR or active AML more often had adverse-risk cytogenetics (P=0.001) and secondary leukemias (P<0.001) than MRDneg CR patients. Patients with active AML also more often had incomplete blood count recovery before HCT than patients in morphologic CR (P<0.001). Three-year relapse estimates were 67% in MRDpos morphologic CR patients and 65% in patients with active AML, contrasted to 22% in MRDneg CR patients. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment for age, cytogenetic risk, type of AML (de novo vs. secondary AML), pre-HCT karyotype (normalized vs. not), and pre-HCT peripheral blood counts (recovered vs. not), MRDneg CR status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared to being in MRDpos morphologic CR or having active disease, with very similar outcomes between the latter two groups. Specifically, compared to MRDneg CR patients, the hazard ratios (95% confidence interval) for MRDpos CR patients and those with active disease were 3.68 (2.51-5.40) and 4.39 (2.56-7.53) (both P <0.001) for overall survival; for progression-free survival, corresponding hazard ratios were 4.37 (3.02-6.30) and 5.29 (3.18-8.80) (both P <0.001), whereas for risk of relapse, these estimates were 4.16 (2.68-6.44) and 4.86 (2.49-9.49) (both P <0.001), respectively. Conclusion: Outcomes for adults transplanted with morphologically detectable disease closely resemble those of MRDpos CR patients, with a cumulative relapse risk of ~65% and survival estimates of 20-25% at 3 years. This similarity held up after accounting for numerous other prognostic covariates. The resemblance in outcomes between patients with MRDpos morphologic CR and those with active disease at the time of HCT support the use of treatment algorithms that use MRD-based rather than morphology-based disease assessments. Disclosures Radich: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Gilliad: Consultancy; Ariad: Consultancy. Walter:AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Pfizer, Inc.: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

IMPORTANCE-Adults with acute myeloid leukemia (AML) commonly require intensive care unit (ICU) support, but risk factors for ICU admission and adverse outcomes remain poorly defined.OBJECTIVE-We utilized the University HealthSystem Consortium (UHC) database to examine risk factors, mortality, length of stay (LOS), and cost associated with ICU admission for AML patients. DESIGN-The UHC is a hospitalization database that contains demographic, clinical, and cost variables prospectively abstracted by certified coders from discharge summaries and cost charges generated by UHC institutions from 2004-2012. We extracted information from AML patients were responsible for the conception and design of this article and contributed to the literature search, data analysis and interpretation, and wrote and critically revised the manuscript. G.H.L was responsible for conception and design, acquisition of data, data interpretation, and critically revised the manuscript. E.C contributed to the conception and design, acquisition of data, data analysis and interpretation, statistical analysis, drafting of the manuscript, and critically revised the manuscript. All authors had final approval of the manuscript. A.B.H. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Disclosures: E.C. and G.H.L receive salary support from a research grant from Amgen for their institution. R.B.W. has a consulting/ advisory role for Amphivena Therapeutics, Covagen AG, AstraZeneca, Seattle Genetics and Pfizer and receives research funding from Seattle Genetics, Amgen, Celator, CSL Behring, Seattle Genetics, Amphivena Therapeutics, and Abbvie. PARTICIPANTS-We identified 43,249 patients with AML ≥18 years of age with active AML hospitalized for any cause at UHC hospitals during the timeframe. We excluded patients who had previously undergone hematopoietic cell transplantation. HHS Public AccessMAIN OUTCOME MEASURES-Primary outcomes were ICU admission and inpatient mortality among ICU patients. Secondary outcomes included ICU and total hospitalization LOS and cost.RESULTS-26.1% of identified AML patients required ICU admission. Independent risk factors for ICU admission included age <80 years (odds ratio [OR] =1.56), hospitalization in the South (OR=1.81), hospitalization at a small/medium hospital (OR=1.25), ≥1 comorbidity (OR=10.64 for 5 comorbidities), sepsis (OR=4.61), fungal infection (OR=1.24) and pneumonia (OR=1.73). Inhospital mortality was higher for patients requiring ICU care (43.1% vs. 9.3%), with independent risk factors for death in those patients including age ≥60 (OR=1.16), non-white ethnicity (OR=1.18), hospitalization on the West Coast (OR=1.19), comorbidity burden (OR 18.76 for 5 comorbidities), sepsis (OR=2.94), fungal infection (OR=1.20), and pneumonia (OR=1.13). Mean hospitalization costs were higher for patients requiring ICU care ($83,354 vs. $41,973) and increased with each comorbidity from $50,543 to $124,820 for those with 0 vs. ≥5 ...