CLAG-M or FLAG-Ida Chemotherapy and Reduced-Intensity Conditioning Donor Stem Cell Transplant for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelomonocytic Leukemia

Inclusion Criteria:

• Age >= 18 years with an Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) =< 5 for patients over 60 years -(Enrollment of patients >= 75 years of agewill require case presentation at the transplant Patient Care Conference (PCC) andapproval by consensus)

• Acute myeloid leukemia (AML) (2016 World Health Organization [WHO] criteria) that iseither primary refractory (as defined by failure of 2 cycles of 7+3-likechemotherapy, 1 cycle of high-dose cytarabine-based chemotherapy, or at least 2cycles of venetoclax in combination with other therapies), or is in untreated orunsuccessfully treated first or subsequent relapse. Patients in morphologicalremission (i.e. < 5% blasts in the bone marrow) but evidence of minimal residualdisease (MRD) by multiparameter flow cytometry, cytogenetics/fluorescence in situhybridization (FISH), or molecular means will be eligible for trial participation.Patients with relapsed or refractory acute leukemia of ambiguous lineage (acuteundifferentiated leukemia, mixed phenotype acute leukemia) that is either primaryrefractory or is in untreated or unsuccessfully treated first or subsequent relapseare also eligible

• Subjects with previously treated myelodysplastic syndrome (MDS) and chronicmyelomonocytic leukemia (CMML), defined as prior treatment with at least onehypomethylating agent (HMA; azacitidine and/or decitabine) whose disease progressed,relapsed, or was refractory to HMA treatment as follows: 1) patients who have failedat least 4 cycles of monotherapy with azacitidine or decitabine, 2) patients whoreceived at least 2 cycles of HMA in combination with another therapeutic agent.Subjects with MDS and CMML who failed at least 1 cycle of induction chemotherapywill be also eligible

• The use of hydroxyurea prior to initiation of study treatment is allowed. Patientswith symptoms/signs of hyperleukocytosis, WBC > 100,000/uL or with concern for othercomplications of high tumor burden (e.g. disseminated intravascular coagulation) canbe treated with leukapheresis or may receive up to 2 doses of cytarabine (up to 500mg/m^2 per dose) prior to start of study treatment

• Karnofsky score >= 70; Eastern Cooperative Oncology Group (ECOG) 0-1

• Adequate cardiac function defined as absence of decompensated congestive heartfailure and/or uncontrolled arrhythmia and left ventricular ejection fraction >= 45%

• Bilirubin =< 2.5 x institutional upper limit of normal unless elevation is thoughtto be due to hepatic infiltration by AML, Gilbert's syndrome, or hemolysis

• Adequate pulmonary function defined as absence of oxygen (O2) requirements andeither carbon monoxide diffusing capability test (DLCO) correct >= 70% mmHg or DLCOcorrected 60-69% mmHg and partial pressure of oxygen (pO2) >= 70 mmHg

• Serum creatinine =< 1.5 mg/dL

• Prior autologous HCT is permissible if relapse occurred > 3 months but =< 6 monthsafter HCT

• Prior TBI-containing allogeneic HCT up to 3 Gy is permissible if > 6 months afterHCT

• A human leukocyte antigen (HLA)-matched or near-matched related or unrelated donoror haploidentical donor for collection of stimulated peripheral blood stem cellsmust be identified and readily available

• Women of childbearing potential and men must agree to use adequate contraceptionbeginning at the signing of the consent until at least 12 months post-transplant

• Patients may have previously received chemotherapy with a mitoxantrone, idarubicin-or cladribine/fludarabine-based regimen for MDS or AML. If the patient has receivedCLAG-M or FLAG-Ida before and has been sensitive to this regimen, eligibility willbe determined on a case-by-case basis by the study principal investigator (PI)

• Ability to understand and sign a written informed consent document (or legalrepresentative)

• DONOR: Patients must have an HLA-matched related donor or an HLA-matched unrelateddonor, or haploidentical donor who meets standard FHCC and/or National Marrow DonorProgram (NMDP) or other donor center criteria for peripheral blood stem cell (PBSC)donation as follows:

• Related donor: related to the patient and genotypically or phenotypicallyidentical for HLA-A, B, C, DRB1 and DQB1. Phenotypic identity must be confirmedby high-resolution typing

• Unrelated donor:

• Matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; OR

• Mismatched for a single allele without antigen mismatching at HLA-A, B, orC as defined by high resolution typing but otherwise matched for HLA-A, B,C, DRB1 and DQB1 by high resolution typing

• Donors are excluded when preexisting immunoreactivity is identified thatwould jeopardize donor hematopoietic cell engraftment. The recommendedprocedure for patients with 10 of 10 HLA allele level (phenotypic) matchis to obtain panel reactive antibody (PRA) screens to class I and class IIantigens for all patients before HCT. If the PRA shows > 10% activity,then flow cytometric or B and T cell cytotoxic cross matches should beobtained. The donor should be excluded if any of the cytotoxic cross matchassays are positive. For those patients with an HLA class I allelemismatch, flow cytometric or B and T cell cytotoxic cross matches shouldbe obtained regardless of the PRA results. A positive anti-donor cytotoxiccrossmatch is an absolute donor exclusion

• Patient and donor pairs homozygous at a mismatched allele in the graftrejection vector are considered a two-allele mismatch, i.e., the patientis A0101 and the donor is A0102, and this type of mismatch is notallowed

• Haploidentical donor:

• Donors must be haploidentical relatives of the patients. Donor-recipientcompatibility will be tested through HLA typing at high resolution for the HLAloci (-A, -B, -C, -DRB1, -DQB1). Donor and recipient should share at least 5/10HLA loci.

• Age ≥ 12 years

• Weight ≥ 40 kg.

• Ability of donors younger than 18 years of age to undergo apheresis without useof a vascular access device. Vein check must be performed and verified by anapheresis nurse prior to arrival.

• Donor must meet the selection criteria as defined by the Foundation of theAccreditation of Cell Therapy (FACT) and will be screened per the AmericanAssociation of Blood Banks (AABB) guidelines.

• In case of more available haploidentical donors, selection criteria shouldinclude, in this order:

• For cytomegalovirus (CMV) seronegative recipients, a CMV seronegativedonor

• Red Blood Cell compatibility

• i. RBC cross match compatible

• ii. Minor ABO incompatibility

• iii. Major ABO incompatibility

Exclusion Criteria:

• Patients >= 18 years being treated at Seattle Children's Hospital

• Active central nervous system (CNS) disease

• Concomitant illness associated with a likely survival of < 1 year

• Active systemic fungal, bacterial, viral, or other infection, unless disease isunder treatment with anti-microbials and/or controlled or stable. Patients withfever thought to be likely secondary to myeloid malignancy are eligible

• Known hypersensitivity or contraindication to any study drug used in this trial

• Pregnancy or lactation

• Concurrent treatment with any other approved or investigational anti-leukemia agent

• Haploidentical donor exclusion criteria:

• Since detection of anti-donor-specific antibodies (anti-DSA) is associated withhigher graft rejection rate, patients will be screened for anti-DSApre-transplant. Patient with DSA mean fluorescent intensity (MFI) <5000 afterdesensitization treatment, will be considered eligible to participate in thestudy.