The primary objective of this proposal is to conduct the first-in-human randomized clinical trial evaluating prophylactic DLI-X (pro-DLI-X) for relapse prevention following matched sibling donor (MSD) or haploidentical (haplo) hematopoietic cell transplantation (HCT) in patients with hematologic malignancies. Additionally, the study aims to assess the safety and efficacy of therapeutic DLI-X (t-DLI-X) compared to t-DLI alone in patients with minimal residual disease (MRD+) or overt relapse post-alloHCT. For patients with CD19-positive lymphoid malignancies, the study will incorporate blinatumomab, while those with myeloid or CD19-negative lymphoid malignancies will receive t-DLI-X or t-DLI alone.

We hypothesize that both pro-DLI-X and t-DLI-X, with or without blinatumomab, will demonstrate safety and superior efficacy by enhancing graft-versus-leukemia (GvL) effects mediated by natural killer (NK) cells, γδ T cells, and CD8+ T cells, while maintaining manageable and treatment-responsive graft-versus-host disease (GvHD).

DLI Recipient Inclusion Criteria:

• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female, aged 0-65 years
• Diagnosis of acute leukemia (lymphoid, myeloid or undifferentiated) myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML) or non-Hodgkin's lymphoma (NHL)
• Undergoing myeloablative or reduced intensity matched sibling donor (MSD) HCT or haploidentical HCT
• Have a locally available healthy matched or haploidentical (≥5/10 HLA antigen matched) related donor between 12 and 50 years of age, consented and able to perform the exercise sessions. (see donor inclusion criteria)
• The familial donors will first complete the fitness evaluation to determine VO2max and peak cycling power and following successful completion of the donor evaluation, the patients willing to participate in the randomized trial will be enrolled.

DLI Donor Inclusion Criteria:

• Matched sibling donor or HLA-haploidentical relatives of the patient, including biological parents, siblings, or children, half-siblings, cousins or aunts and uncles
• Weight is greater than 30 kg
• Age 12 and 50 years
• Ability to undergo phlebotomy
• Cardiac, renal, pulmonary, and hepatic function within normal limits
• Complete blood count (CBC) with differential and platelet count within normal limits, and CMP within normal limits as deemed acceptable by the Principal Investigator and provider evaluating donor.
• The familial donors should be able complete the fitness evaluation to determine VO2max and peak cycling power and following successful completion of the donor evaluation, the patients willing to participate in the randomized trial will be enrolled.

DLI Recipient Exclusion Criteria:

• Acute grade III-IV aGvHD or moderate/severe chronic GvHD.
• Requiring immunosuppression therapy for treatment of GvHD.
• Co-morbidities: AST/ALT greater than 5 x ULN; Bilirubin greater than 2 x ULN; Creatinine greater than 2 x ULN for age or creatinine clearance/GFR <40 ml/min/1.73m2; Pulmonary function: DLCO less than 40% of normal or O2 Sat less than 92%; Cardiac: left ventricular ejection fraction less than 35%; active infection; HIV positive; Karnofsky score (adults) less than 60% or Lansky score less than 50% (pediatrics)
• Uncontrolled or severe bacterial, fungal or viral infection.
• Positive serum or urine pregnancy test for girls post menarche or women of childbearing age.
• Severe psychiatric illness or mental deficiency making compliance to treatment unlikely and/or informed consent impossible.
• Any reason, at the investigator's discretion, that the participation of the patient in this protocol would not be in patient's best interest, or where the patient would be unable to adhere to the study requirements.

DLI Donor Exclusion Criteria:

• Unable to perform graded exercise test
• Cardiac or pulmonary disease restricting exercise
• Positive anti-donor HLA antibody
• Pregnant or lactating
• Active infection
• Positivity for HIV, hepatitis B (HBV), hepatitis C (HCV), human T-cell lymphotropic virus (HTLV-I/II)
• Severe psychiatric illness or mental deficiency making compliance with donation unlikely and/or informed consent impossible.