Modified Memory-Like NK Cells and TCRαβ T-cell Depleted Half-Matched Related Donor Transplant for the Treatment of High-Risk Acute Myeloid Leukemia (ABCD NK trial)

Inclusion Criteria

• COHORT 1 INCLUSION CRITERIA:
• High risk acute myeloid leukemia (AML) in either: * Complete remission (CR) per European LeukemiaNet (ELN) criteria, as defined by < 5% marrow blasts by morphology in the context of hematological recovery (absolute neutrophil count [ANC] ≥ 0.5× 10^9/L, platelet count ≥ 50 × 10^9/L). * Morphological leukemia free state (MLFS) defined by the absence of hematological recovery and < 5% marrow blasts by morphology.
• Patients must further meet one of the below for inclusion into the study: * De novo AML in first complete remission (CR1) with any of the following high-risk features: ** Measurable residual disease (MRD) ≥ 1% after first induction course ** MRD ≥ 0.1% after second induction course ** RPN1-MECOM ** RUNX1-MECOM ** NPM1-MLF1 ** DEK-NUP214 ** KAT6A-CREBBP (if ≥ 90 days at diagnosis) ** FUS-ERG ** KMT2A-AFF1 ** KMT2A-AFDN ** KMT2A-ABI1 ** KMT2A-MLLT1 ** 11p15 rearrangement (NUP98 – any partner gene) ** 12p13.2 rearrangement (ETV6 – any partner gene) ** Deletion 12p to include 12p13.2 (loss of ETV6) ** Monosomy 5/Del(5q) to include 5q31 (loss of EGR1) ** Monosomy 7 ** 10p12.3 rearrangement (MLLT10b – any partner gene) ** FLT3/ITD with allelic ratio > 0.1%, without bZIP CEBPA or NPM1 ** RAM phenotype as evidenced by flow cytometry ** Other high-risk features not explicitly stated here, after discussion/approval with protocol principal investigator (PI). * De novo AML in ≥ second complete remission (CR2) * Therapy-related AML in CR1 * AML evolving from myelodysplastic syndrome (MDS)
• One prior hematopoietic cell transplant is allowed, provided remission criteria as defined above are met.
• COHORT 2 INCLUSION CRITERIA:
• High risk acute myeloid leukemia (AML) defined by either of the following: * Treatment refractory disease: AML that is not in complete remission despite prior standard of salvage therapies. * Multiple relapsed disease: AML that has relapsed after 2 or more hematopoietic cell transplantations.
• Bone marrow (BM) disease burden: Less than 25% bone marrow blasts by morphology must be present (M2 marrow), irrespective of peripheral hematological recovery.
• BOTH COHORTS INCLUSION CRITERIA:
• Less than or equal to 40 years of age
• Lansky (< 16 years) or Karnofsky (≥ 16 years) performance status of > 60%
• Total bilirubin ≤ 3 x institutional upper limit of normal (IULN) for age
• Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) ≤ 5 x IULN for age
• Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73m^2 as estimated by (1) updated Schwartz formula for ages 1-17 years or Cockcroft-Gault formula for ages ≥ 18 years, (2) 24-hour creatinine clearance, or (3) renal scintigraphy. If GFR is abnormal for age based on updated Schwartz or Cockcroft-Gault formula, accurate measurement should be obtained by either 24-hour creatinine clearance or renal scintigraphy.
• Renal function may also be estimated by serum creatinine based on age/gender. A serum creatinine < 2 x IULN for age/gender is required for inclusion on this protocol.
• Adequate cardiac function, defined by left ventricular ejection fraction (LVEF) at rest ≥ 50% or shortening fraction (SF) ≥ 27% (via echocardiogram or multigated acquisition scan [MUGA]).
• Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capability (DLCO) ≥ 50% of predicted.
• Oxygen (O2) saturation ≥ 92% on room air by pulse oximetry and no supplemental O2 at rest for children < 8 years of age or those unable to perform pulmonary function testing (PFT). For children unable to perform PFT, a high-resolution computed tomography (CT) chest should be obtained.
• The effects of these treatments on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry, for the duration of study participation, and for 24 months following transplant. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an institutional review board (IRB) approved written informed consent document, or patient has a guardian who has the ability to understand and willingness to sign an IRB approved written informed consent document.
• Available familial haploidentical donor. The HCT donor must be available and willing to undergo 2 leukapheresis procedures: (I) one mobilized collection for the hematopoietic progenitor cell (HPC) graft and (II) one non-mobilized leukapheresis collection for the manufacturing of ML NK cells.
• Donor and recipient must be identical at a minimum of one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum of 5/10 match is required and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.
• DONORS FOR BOTH COHORTS INCLUSION CRITERIA:
• Donor must be at least 18 years of age.
• Donor must be HLA haploidentical (≥ 5/10 and ≤ 9/10 allele match at the -A, -B, -C, DRB1 and DQ loci) by high resolution typing and related to the patient.
• Donor must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).
• Donor must be available and willing to undergo one mobilized and one non-mobilized leukapheresis procedure.
• Donor may not be pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days prior to initiation of recipient's conditioning regimen, within 7 days of donor stem cell mobilization regimen and prior to second non-mobilized leukapheresis.
• Donor must be able to understand and willing to sign an IRB-approved written informed consent document.
• Prioritization Schema: * Note: An unrelated donor search is not required prior to enrollment on this protocol. The availability of an HLA matched related or unrelated donor does not make the subject ineligible for study participation. * The following criteria (in no particular order) should be considered for haploidentical donor selection: ** ABO compatibility. ** Cytomegalovirus (CMV) serostatus: prioritize a CMV negative donor for a CMV negative recipient. Prioritize a CMV positive donor for a CMV positive recipient. ** Younger adults and non-obese donors should be preferred. ** If all else is equal, male donors may be preferred over nulliparous female donors who may be preferred over multiparous female donors.

Exclusion Criteria

• BOTH COHORTS EXCLUSION CRITERIA:
• Active GvHD. If patient had prior GvHD, patient must be off immunosuppression for at least 3 months prior to starting study treatment.
• Active non-hematologic malignancy. History of other malignancy is acceptable as long as therapy has been completed and there is no current evidence of disease.
• Currently receiving any other investigational agents at the time of transplant.
• Active central nervous system (CNS) or extramedullary disease. History of CNS or extramedullary disease currently in remission is acceptable.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study.
• Inability to discontinue medications that are likely to interfere with ML NK cell activity, i.e., glucocorticoids and other immunosuppressants.
• Presence of significant anti-donor HLA antibodies per institutional standards. Anti-donor HLA antibody testing is defined as a positive crossmatch test of any titer (by complement dependent cytotoxicity or flow cytometric testing) or the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay > 3000.
• Presence of a second major disorder deemed a contraindication for HCT.
• Patients with Fanconi Anemia or Down Syndrome
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (bacterial, viral with clinical instability, or fungal), symptomatic congestive heart failure, or unstable cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of the start of conditioning.