Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical transplantation

A group of researchers from Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China, conducted a phase II study (NCT03395860) to evaluate a novel combination of low-dose anti-thymocyte globulin (ATG) in combination with low-dose posttransplant cyclophosphamide (PTCy) in patients undergoing haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood for the prevention of graft-versus-host disease (GvHD). The results of the study were published ahead of print in Bone Marrow Transplantation.

The primary endpoint of the study was the cumulative incidence (CI) of acute GvHD (time frame: 100 days after transplantation). Secondary endpoints included leukocyte engraftment, platelet engraftment, donor chimerism, relapse incidence (RI), chronic GvHD, non-relapse mortality (NRM) overall survival (OS), disease-free survival (DFS), CMV viremia and CMV-associated diseases, and EBV viremia.

Patients and methods:

• Study duration: June 2017 – January 2018
• N = 32 patients
• Median age = 37 years (range, 20−62)
• Diagnosis:
  • De novo acute myeloid leukemia (AML): 22 patients
  • Acute lymphocytic leukemia (ALL): 5 patients
  • Myelodysplastic syndrome with excess blasts II (MDS-EB II): 3 patients
  • Chronic myelomonocytic leukemia (CMML): 2 patients
• ECOG performance status: ≤ 2
• Conditioning regimens:
  • Myeloablative conditioning: 29 patients
  • Reduced intensity conditioning: 3 patients
• GvHD prophylaxis:
  • ATG (2.5 mg/kg/d) on days −2 and −1
  • PTCy (50 mg/kg/d) on day 3
  • Cyclosporine A (CsA) and mycophenolate mofetil (MMF) were administered on day 4
• Unrelated cord blood plus peripheral blood stem cell graft was given four hours before the stem cell graft was administered

Key findings:

• 100-day CI of grade II-IV acute GvHD: 19.4% (95% CI, 5.5–3%)
• 100-day CI of grade III-IV acute GvHD: 6.9% (95% CI, 0–3%)
• 1-year RI: 25.1% (95% CI, 7.3–9%)
• 1-year DFS: 59% (95% CI, 33.3–7%)
• 1-year OS: 78.4% (95% CI, 63–8%)
• 180-day CMV reactivation: 37.5% (n = 12; 95% CI, 19.8–2%)
• 180-day EBV reactivation: 40.6% (n = 13; 95% CI, 22.6–6%)
• Seventeen patients with active disease achieved complete remission
• With a median follow-up of seven months, six of them relapsed
• Six deaths occurred:
  • Three deaths occurred due to non-relapse causes
    • One patient with CMML died in non-remission due to CNS hemorrhage
    • One patient with AML had secondary graft failure after cytomegalovirus pneumonia and soon died
    • One patient died from aspergillus pneumonia

Taken together, this phase II study indicates that low-dose ATG plus low-dose PTCy is a promising prophylactic regimen to prevent GvHD in the haplo setting. According to the authors, this study had several limitations, including the number of patients, the limited follow-up time, and the use of haplo-transplantation with unrelated cord blood. Further prospective trials are needed to assess the efficacy of low-dose ATG plus PTCy.