DR-18 for the Treatment of Relapsed or Persistent Acute Myeloid Leukemia or Myelodysplastic Syndrome After Hematopoietic Cell Transplantation, the DR. DREAM Trial

Inclusion Criteria:

• ≥ 18 years of age (no upper age limit)

• Documented persistent or recurrent AML or MDS after HCT (including measurableresidual disease [MRD] or overt leukemia). Nota bene (NB): MRD (< 5% malignantblasts) must be detected with flow cytometry testing at University of WashingtonMedical Center (UWMC)/Fred Hutchinson Cancer Center (Fred Hutch) clinical laboratory

• No Food and Drug Administration (FDA)-approved targeted therapy for the subject'sAML or MDS is available, or if such therapy is available, that class of drugspreviously failed for the subject or the subject was intolerant of the therapy

• No history of grade 3 or 4 acute GvHD after the most recent HCT

• No history of moderate or severe chronic GvHD after the most recent HCT

• No active acute or chronic GvHD or other immunologic phenomenon (e.g., immunecytopenias, cryptogenic immunologic pneumonia) in last month requiring systemictherapy (Hydrocortisone or prednisone for adrenal insufficiency at ≤ 10 mg/dayprednisone-equivalent is permitted.)

• Stable or reducing immune suppression in the preceding 4 weeks without GvHD flares

• The most recent HCT was from a 10/10 human leukocyte antigen (HLA)-matched relatedor unrelated donor (assessed at HLA-A, B, C, DR, DQ)

• Evidence of blood count recovery at any time post-HCT defined as absolute neutrophilcount (ANC) ≥ 0.5 x 10^9/L for ≥ 3 consecutive days and platelets ≥ 30 x 10^9/L (independent of granulocyte colony-stimulating factor [G-CSF] or platelettransfusions for 5 days). (Blood count recovery may not be sustained.)

• No cellular immunotherapy or new targeted therapy in the 4 weeks prior to enrollment

• Karnofsky performance status (KPS) ≥ 80%

• Not pregnant/breastfeeding

• Agrees to use a suitable method of contraception for 4 months after the last dose ofDR-18

• Capable of providing informed consent

• At least 60 days have elapsed since the HCT donor cell infusion (HCT day 0). (Thereis no upper limit to the time elapsed since HCT.)

Exclusion Criteria:

• Active moderate-severe thrombotic microangiopathy (TMA) as evidenced by any of thefollowing: > 10 schistocytes per high-power field, or required anti-C5 or otheranti-complement therapy for TMA in the prior 4 weeks, any of the followingmanifestations if attributed to TMA in the prior 4 weeks: hypertension, worsening ornew renal insufficiency, ≥ 2+ proteinuria, hematochezia, seizure, transient orongoing neurologic deficits

• Renal insufficiency: Estimated glomerular filtration rate (eGFR) (calculated per theperforming laboratory's standard formula) or measured 24 hour (hr.) creatinineclearance < 30 mL/min

• Hemodialysis in the prior 4 weeks

• Major cardiac event requiring evaluation in the emergency room (ER) orhospitalization in the past 4 weeks

• New York Heart Association (NYHA) class II or higher congestive heart failure (CHF)in the past 4 weeks

• Uncontrolled cardiac arrhythmias, including atrial fibrillation

• Left ventricular ejection fraction (LVEF) < 35%. LVEF may be established withechocardiogram or MUGA scan, and left ejection fraction must be ≥ 35%

• Liver dysfunction: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 x upper limit of normal (ULN) or bilirubin > 3 x ULN

• Active uncontrolled infection. NB: Examples of controlled infections:

• Bacterial infection may be still requiring antibiotics at the time ofenrollment, but clinical signs and symptoms of the infection should beimproving. If the subject had bloodstream infection, negative blood culturesoff antibiotics must be documented prior to initiating DR-18 treatment. Forurinary tract infection, a repeat urine culture must be sterile prior toinitiating DR-18. Radiographic improvement of bacterial pneumonia may lagbehind clinical improvement so is not mandatory prior to DR-18 initiation

• Fungal infection may be still requiring antifungal medication at the time ofenrollment, but evidence of clinical response to antifungal medication (such asregression of lesions on chest CT) must be available at the time of enrollment

• Asymptomatic shedding of respiratory viruses after cessation of antiviraltherapy, or if not specifically treated with antiviral therapy, is permitted

• Cytomegalovirus (CMV) viremia or organ infection meeting institutional criteriafor CMV treatment with antiviral therapy such as ganciclovir, valganciclovir orfoscarnet must be on maintenance phase of treatment or must have completedtreatment and must not be in the induction treatment phase at the time ofenrollment. Low-level CMV viremia not meeting institutional criteria forantiviral therapy is permitted, including low-level viremia in patientsreceiving CMV prophylaxis with letermovir

• Any of the following: Pulmonary dysfunction requiring supplemental oxygen, evenintermittently, in the past 2 weeks; corrected diffusion capacity of the lung forcarbon monoxide (DLCO) or forced expiratory volume in 1 second (FEV1) < 60%predicted; bronchiolitis obliterans syndrome; prior diagnosis of idiopathicpulmonary fibrosis; prior diagnosis of drug-induced pneumonitis; cryptogenicorganizing pneumonia under active treatment

• Seizure in the past 4 weeks or significant underlying neurologic disease: Studyparticipants must not have significant active underlying neurologic disease, such asParkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy,prior symptomatic ischemic or hemorrhagic stroke, or transient ischemic attack,unless approved by principal investigator (PI). Peripheral neuropathy related todiabetes or prior chemotherapy is acceptable

• Other medical, social, or psychiatric factor that interferes with medicalappropriateness and/or ability to comply with study, as determined by the PI

• Known allergic reactions to any of the components of study treatments

• Concurrent use of other investigational anti-cancer agents

• Peripheral blood T cell chimerism < 40%