Every patient responds differently to their cancer treatment, and some treatments work better for some patients more than others. For patients with relapsed, refractory ( R/R) AML, there may be fewer approved treatment options remaining. In this research study, the investigators are testing whether high throughput drug screening (HTS) in combination with robust molecular testing by HopeSeq (includes DNA sequencing for >500 genes and 160 gene rearrangements and RNAseq for >5,000 genes) can help doctors determine which treatment might work best for each individual patient. HTS tests how the patient's own AML cells respond to different treatment options including individual drugs and triple drug regimens and recommends for the best treatment options for an individual patient. Participants will provide extra bone marrow and/or blood at the time of routine procedure, and these extra sample(s) will be tested using the Cancer Drug Sensitivity Test ( CDST) HTS, CLIA approved in Washington state since 2014. A committee (the Functional Molecular Tumor Board) will review the HopeSeq and HTS results, past treatments, and clinical description, and give a recommendation for the best AML treatment options for each individual patient. The patient's doctor will get a copy of the recommendation and discuss treatment options with the patient. The patient and their doctor will decide on the best treatment plan for the patient, one which will be approved by insurance. Patients will not be treated with any drugs as part of this study. Then at 6 and 12 months, there will be retrospective review of medical records to determine how will the testing predicted the response, drug sensitivity or resistance, and overall and disease-free survival will be monitored.

The investigators will utilize high throughput drug screening (HTS) to assess sensitivity of patient's leukemic cells to drugs and drug combinations (~135). Bone marrow aspirate (BMA) or peripheral blood blasts, or if these are not involved, then bone marrow or tissue biopsy or involved fluids will be used for testing in the HTS and time to HTS report will be recorded. Genomics analysis (sequencing) will be utilized to additionally inform drug choice using the City of Hope HopeSeq Heme Comprehensive (HopeSeq) targeted next generation sequencing (NGS) and RNA seq assays. The turnaround time (TAT) of the above NGS assays is 8-10 business days (≈12-14 calendar days). The Cancer Drug Sensitivity Test Diagnostic (CDST) is a HTS assay with a faster TAT (5-7 calendar days) that is CLIA-approved for patient diagnostic purposes. CDST HTS will be performed in the Quellos High Throughput Core Facility at the University of Washington (UW) in Seattle, WA. These assays detect relevant genomic, and transcriptomic, and functional data events which the investigators hypothesize will provide an opportunity to rationally tailor drug selections and combinations for the treatment of patients with AML that have relapsed and/or refractory AML. HopeSeq, which includes most of the relevant genomic pathways in hematologic malignancies, will be performed on peripheral blood (PB) or bone marrow aspirate (BMA), or if insufficient cells, formalin fixed paraffin embedded (FFPE) tissues may also be analyzed. HopeSeq will be performed as conventional care ~14 days prior to, or at the time of study enrollment, or study will access the results through the Hematopoietic Tissue Biorepository (HTB) at City of Hope. Based on the molecular diagnosis report from HopeSeq and the CDST HTS report, the investigators A propose to convene a Functional Molecular Tumor Board (FMTB) will meet that will consider the data from the molecular and functional studies, as well as information from a literature review for clinical and laboratory findings for other patients with the specific clinical features and molecular/functional data that will offer patients and their physicians treatment recommendations possible treatment options based on multiomic data (HopeSeq and CDST HTS reports) as well as clinical features within 14-18 days from sample acquisition. But ultimately, the patient's treating physician will decide which regimen is best considering individual patient factors such as performance status, prior regimens, insurance authorization, and patient preferences. The retrospective correlation with patient response will enable determination of the relative predictive contribution of each of the tests, both positive and negative predictive value.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative.
• Agreement to allow the use of archival tissue from diagnostic tumor biopsies
• Age: ≥ 18 years
• ECOG ≤ 3 (Appendix A)
• Patients with histologically confirmed AML according to ICC or WHO criteria, and
• Refractory/relapsed (R/R) to prior treatment with one or more regimens if adverse risk or two or more regimens if favorable/intermediate risk (Appendix B)
• Sufficient bone marrow and/or peripheral blood sample (archival or fresh) to run the high throughput screening (HTS; Estimate sufficient if circulating blast count of 5,000 or greater or cellular marrow with greater than or equal to 20% blasts.) Otherwise,
• Sufficient cells flushed from bone marrow biopsy, if bone marrow is not aspirable, OR
• Extramedullary disease, if it is possible to obtain a fluid or biopsy sample from that location
• Expected survival is greater than 100 days.
• Fully recovered from the acute toxic effects (except alopecia) to ≤ Grade 1 to prior anti-cancer therapy

Exclusion Criteria:

• Treatment with any chemotherapeutic agent necessary to control AML burden is permitted between day -18 and -1.
• Must not have received or planning to receive live vaccine while being on study
• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (FAB class M3-AML)
• Active central nervous system (CNS) disease (OK if treated and responding)
• Active graft vs host disease (GVHD)
• Unstable cardiac disease as defined by one of the following:
• Cardiac events such as myocardial infarction (MI) within the past 6 months
• Uncontrolled atrial fibrillation or hypertension
• Clinically significant uncontrolled illness
• Uncontrolled active infection
• Females only: Pregnant or breastfeeding
• Any other condition or active malignancy that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).

Adults with relapsed/refractory acute myeloid leukemia