Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

A Phase I/II Study of Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL); however, human leukocyte antigen (HLA)-matched donor availability continues to be a major hurdle. Historically, HLA haploidentical donor hematopoietic cell transplantation (haplo-HCT) was associated with high incidences of graft rejection and excessive non-relapse mortality (NRM), but recent advances utilizing post-transplant cyclophosphamide (PT-Cy) have revolutionized haplo-HCT and the outcomes are now comparable to allo-HCT using more traditional HLA matched related and unrelated donors. However, graft-versus-host disease (GvHD) continues to be a problem and is associated with significant morbidity and mortality in allo-HCT patients including those who receive haplo-HCT on PT-Cy platform. The aim of this early phase study is to investigate the safety and overall efficacy of azacitidine in reducing the incidence and severity of GvHD when added to PT-Cy based haplo-HCT platform for patients with AML, ALL, or advanced MDS.

Inclusion Criteria:

• Diagnosis of acute leukemia (AML/ALL) or advanced MDS (INT-2 or high risk) in complete remission (CR/CRc/CRi) documented by bone marrow biopsy done within 30 days prior to the initiation of conditioning regimen.

• Available HLA-haploidentical donor that meets the following criteria:

  • Immediate family member (sibling, offspring, or parent)
  • At least 18 years of age
  • HLA-haploidentical donor/recipient match by class I serologic typing at the A&B locus.
  • In the treating physician's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting HSC
  • No active hepatitis (B, C), HTLV, and HIV infections
  • Not pregnant

• Karnofsky performance status ≥ 70 %

• Adequate organ function as defined below:

  • Total bilirubin ≤ 2.5 mg/dl (unless the patient has a history of Gilbert's syndrome)
  • AST(SGOT) and ALT(SGPT) ≤ 3.0 x IULN
  • Creatinine ≤ 2.0 x IULN OR estimated creatinine clearance ≥ 30 mL/min/1.73 m^2 by Cockcroft-Gault Formula
  • Oxygen saturation ≥ 90% on room air
  • LVEF ≥ 40%
  • FEV1 and FVC ≥ 50% predicted, corrected DLCO ≥ 40% predicted

• At least 18 years of age at the time of study registration

• Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)

Exclusion Criteria:

• Recipients with donor sensitive antibodies (DSA), defined by 2000 or higher MFI against one or more class I or II antigens
• Known HIV or active Hepatitis B or C infection
• Underwent a previous related or unrelated allogeneic transplant
• Known hypersensitivity to one or more of the study agents
• Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of the conditioning regimen.
• Pregnant and/or breastfeeding
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or unstable cardiac arrhythmias.
• Presence of a readily available 6/6 matched sibling donor who is a candidate for donation