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This phase I/II trial studies the side effects and best dose of donor lymphocyte infusions when given together with daratumumab and to see how well they work in treating participants with acute myeloid leukemia that has come back after a stem cell transplant. A donor lymphocyte infusion is a type of therapy in which lymphocytes (white blood cells) from the blood of a donor are given to a participant who has already received a stem cell transplant from the same donor. The donor lymphocytes may kill remaining cancer cells. Monoclonal antibodies, such as daratumumab, may interfere with the ability of cancer cells to grow and spread. Giving daratumumab and donor white blood cells may work better in treating participants with acute myeloid leukemia.

PRIMARY OBJECTIVES:

I. To evaluate safety and tolerability of daratumumab and escalating doses of donor lymphocyte infusions (DLI) in post-hematopoietic cell transplantation (HCT) patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) transformed to AML (phase I).

II. To evaluate overall response rate to daratumumab and DLI in patients with post-HCT relapsed AML and MDS (phase II).

SECONDARY OBJECTIVES:

I. To assess overall response rates in minimal residual disease (MRD) positive patients and in patients with overt morphological relapse.

II. To assess MRD conversion rates from MRD positive to MRD negative. III. To determine the post-relapse 6-month overall response (OS) rates of patients with relapsed AML and MDS following allogeneic hematopoietic stem cell transplantation (allo-HSCT) who are treated with daratumumab.

IV. To determine the rates of graft-versus-host disease (GVHD) (both grades II-IV and III-IV) and autoimmune side effects of daratumumab.

V. To determine the post-relapse 6-month progression-free survival (PFS) rates of patients with relapsed AML and MDS following allo-HSCT who are treated with daratumumab.

EXPLORATORY OBJECTIVES:

I. To compare CD38 expression levels in myeloid blasts and interferon gamma (IFN-y) levels in plasma at the time of relapse before starting daratumumab and at progression or relapse after daratumumab.

II. To compare peripheral blood T cell number and subsets (CD3, CD4, CD8, (CD38 expression on regulatory T cells [T-regs], CD4 and CD8), T regs, B-regulatory cells, natural killer (NK) cell numbers and bone marrow T cell subsets at the time of relapse before starting daratumumab, at the time of partial/complete response to daratumumab, and at the time of progression or relapse after daratumumab.

III. To evaluate whether daratumumab has (i) direct anti-leukemia effects (ii) antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and (III) immune modulation of autologous immune system (NK cells, T cells, T-regs, B-regulatory cells [B-regs], and myeloid-derived suppressor cells [MDSCS]) in AML.

IV. To evaluate the effect of daratumumab on exosome content and clearance along with other soluble factors in AML.

V. To evaluate serum interferon (IFN) levels pre-daratumumab, during and post-daratumumab.

VI. To evaluate whether fratricide occurs in patients treated with daratumumab.

OUTLINE: This is a phase I, dose escalation study of donor lymphocyte infusions followed by a phase II study.

Participants receive daratumumab intravenously once a week for 8 weeks and donor lymphocyte infusion in weeks 3 or 4 in the absence of disease progression or unacceptable toxicity. Participants found to be in complete response (CR) at the end of 8 weeks may receive daratumumab IV once every 2 weeks for 8 weeks, and then once monthly for 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 1 year.

Inclusion Criteria:

• AML relapse following Allo-HSCT (Morphological relapse, or MRD positive verified by flow cytometry, cytogenetics, and molecular mutations)

• Relapsed/Refractory AML must not be candidates for available therapies known to be effective for treatment of their AML.

• MDS transformed to AML following Allo-HCT

• Patients who received a 10/10 HLA-matched allogeneic HCT either from sibling donors or unrelated donors or atleast a 5/10 haploidentical transplant.

• Engraftment must have occurred as defined by platelet (PLT) count > 20,000/µL and ANC

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• Eastern Cooperative Oncology Group (ECOG) performance status < 3

• Creatinine clearance > 40 ml/min (calculated or measured)

• Aspartate aminotransferase (AST) < 3 x upper limit of normal (ULN), alanine aminotransferase (ALT) < 3 x ULN

• Total bilirubin < 1.5 x ULN

• Off calcineurin inhibitors for at least 2 weeks

• Prednisone dose ≤ 20 mg/day

• Patients with proliferative disease can be cytoreduced with cytotoxic chemotherapy at Investigator discretion, but there should be at least a 14 day window between start of cytoreductive therapy and start of daratumumab

• Blast count ˂20K/day (hydrea use is allowed)

Exclusion Criteria:

• No demonstrable evidence of donor chimerism (˂ 55% donor CD3 or CD33 chimerism)
• Patients with a molecular mutation without chromosomal abnormalities or declining chimerisms (MRD status must be verified by surface marker and mutational analyses)
• Active graft-versus-host disease (GvHD) grades II-IV; prior acute GVHD could have occurred but resolved at time of initiation of daratumumab
• Extensive chronic GvHD requiring ongoing immunosuppression with calcineurin inhibitors
• Patients with FLT3+ AML or blast crisis CML who have not yet received post-transplant TKI therapy
• Active central nervous system (CNS) disease testicular disease

EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.; seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy).

• Patients must not have moderate or severe persistent asthma within the past 2 years and must not have currently uncontrolled asthma of any classification.
• History of grade IV anaphylactic reaction to monoclonal antibody therapy
• Active autoimmune disease prior to transplant
• Concurrent use of any other investigational drugs