No abstract

Importance Adults with acute myeloid leukemia (AML) typically remain hospitalized after induction or salvage chemotherapy until blood count recovery, with resulting prolonged inpatient stays being a primary driver of healthcare cost. Pilot studies suggest that outpatient management following chemotherapy might be safe and could reduce cost for these patients. Objective To compare safety, resource utilization, infections and cost between adults discharged early following AML induction or salvage chemotherapy and inpatient controls. Design Non-randomized phase 2 study. Setting Single center study conducted at the University of Washington Medical Center in Seattle, WA. Participants Over a 43-month period (January 1, 2011 – July 31, 2014), 178 adults receiving intensive AML chemotherapy were enrolled. After completion of chemotherapy, 107 met pre-designated medical and logistical criteria for early discharge (ED), while 29 met medical criteria only and served as inpatient controls. Interventions for Clinical Trials ED patients were discharged from the hospital at the completion of chemotherapy, and supportive care was provided in the outpatient setting until count recovery (median 21 days, range 2–45 days). Controls received inpatient supportive care (median 16 days, range 3–42 days). Main Outcome Measures 1) differences in early mortality 2) differences in resource utilization (ICU days, transfusions/study-day and IV antibiotics/study-day) 3) numbers of infections and 3) total and inpatient charges/study-day between early discharge patients and controls. Results Four patients discharged early (4%) but no controls died within 30 days of enrollment (p=0.58). Nine patients discharged early (8%) but no controls required intensive care unit-level care (p=0.20). No differences were noted in the average daily number of red blood cell (p=0.55) or platelet (p=0.31) transfusions. Patients discharged early did have more positive blood cultures (p=0.04) but required fewer days of IV antibiotics (p=0.007). Overall, daily charges among discharged patients were significantly lower (median $3,840 vs. $5,852; p<0.001) despite increased charges per inpatient day when readmitted (median $7,405 vs. $6,267; p<0.001). Conclusions and Relevance Early dischargefollowing intensive AML chemotherapy can reduce cost and use of IV antibiotics, but attention should be paid to complications that may occur in the outpatient setting. This study was registered at www.ClinicalTrials.gov (NCT01235572).

Proteins created from recurrent fusion genes like CBFB-MYH11 are prevalent in acute myeloid leukemia (AML), often necessary for leukemogenesis, persistent throughout the disease course, and highly leukemia specific, making them attractive neoantigen targets for immunotherapy. A nonameric peptide derived from a prevalent CBFB-MYH11 fusion protein was found to be immunogenic in HLA-B*40:01 + donors. High-avidity CD8 + T cell clones isolated from healthy donors killed CBFB-MYH11 + HLA-B*40:01 + AML cell lines and primary human AML samples in vitro. CBFB-MYH11-specific T cells also controlled CBFB-MYH11 + HLA-B*40:01 + AML in vivo in a patient-derived murine xenograft model. High-avidity CBFB-MYH11 epitope-specific T cell receptors (TCRs) transduced into CD8 + T cells conferred antileukemic activity in vitro. Our data indicate that the CBFB-MYH11 fusion neoantigen is naturally presented on AML blasts and enables T cell recognition and killing of AML. We provide proof of principle for immunologically targeting AML-initiating fusions and demonstrate that targeting neoantigens has clinical relevance even in low-mutational frequency cancers like fusion-driven AML. This work also represents a first critical step toward the development of TCR T cell immunotherapy targeting fusion gene-driven AML.

Outcomes with “7+3” are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. 121 patients, median age 60 (range: 21–81) years, were enrolled. In phase 1, cohorts of 6–12 patients were assigned to 12–18mg/m2/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18mg/m2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRDneg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRDneg) for a CR/CRi rate of 81/94 (86%). 4-week mortality was 2%. After adjustment, the MRDneg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7+3 at our center and 245 matched patients treated with 7+3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18mg/m2/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.