Dose Study of Antithymocyteglobulin in Haploidentical Allogeneic Stem Cell Transplantation

Backgroud:Graft-versus-host diseases (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially in recipients with HLA-mismatched or unrelated donors. Antithymocyteglobulin (ATG) has been widely used to prevent acute GVHD (aGVHD) in haploidentical and unrelated donor transplantation The use of ATG may increase the risk of opportunistic infections and primary disease relapse, which is associated with the dose of ATG. Till now, the optimal dose of ATG is not known for haploidentical and unrelated donor transplantation. Here, we compared the outcome of patients undergoing haploidentical HSCT who were treated with two different doses of ATG.

Methods: Between January 2013 and June 2014, 40 consecutive patients with hematological malignancies undergoing haploidentical HSCT were enrolled in this prospective study. Of the 40 patiens, 19 received allo-HSCT from sibling donors, 18 lineal relatives donors (i.e. father, mother or child) and 3 collateral relatives donors (i.e. uncle or aunt). Five patients received 1 locus HLA-A, -B, -DRB1, -C, -DQ-mismatched donor transplantation, 6 received 2 locus mismatched, 9 received 3 locus mismatched, 6 received 4 locus mismatched and 14 received 5 locus mismatched transplantation. All the patients received GVHD prophylaxis including cyclosporine A, short-term methotrexate (on day +1, +3, and +6) and mycophenolate mofetil (0.5 g twice a day on day 0 to +28) as well as ATG ( a total dosage of 7.5mg/kg or 10mg/kg according to randomization). Epstein-Barr virus (EBV) -DNA and cytomegalovirus (CMV) -DNA levels of blood were monitored weekly for the first 3 months after transplantation, every two weeks during the 4 to 9 month after HSCT, and then once a month during 10 to 12 month. The primary endpoint was the cumulative incidence of aGVHD within day +100 after allo-HSCT.

Results:Nineteen of the 40 patients were randomized to receive a total dosage of 7.5 mg/kg ATG and 21 were randomized to receive 10 mg/kg ATG. One patient was withdrawn from transplantation because of infection during conditioning and did not receive ATG. Of the 39 evaluable patients, 38 achieved engraftment except for one died of infection on day +32. The median time to neutrophil engraftment was 13 days (range, 9 to 19 days), and the median time to platelet engraftment was 14 days (range, 10 to 73 days). Patients with 7.5 mg/kg ATG achieved neutrophil engraftment earlier than those with 10 mg/kg (P=0.011). Time to platelet engraftment was comparable in the 2 arms with different dosage of ATG (P=0.063). The cumulative incidence of aGVHD grades II to IV and III to IV within day 100 post-transplantation was 26.5±7.2% and 10.6±5.0%, respectively. Acute GVHD grade II to IV developed in 35.5±11.8% of the patients with 7.5 mg/kg ATG and 19.3±8.7% of those with 10 mg/kg ATG (P=0.273). The incidence of aGVHD grade III to IV within day 100 were 11.9±7.9% in 7.5 mg/kg arm and 9.8±6.6% in 10 mg/kg arm (P=0.831). The cumulative incidence of chronic GVHD (cGVHD) 50.0%±25.0% and 59.6%±21.1% in the patients with 7.5 mg/kg and 10mg/kg ATG, respectively (P=0.819). The 1-year cumulative incidence of CMV reactivation were similar in the two arms (7.5 mg/kg arm : 82.8±10.5% vs 10 mg/kg arm: 66.7±10.3%, P=0.600). The incidence of EBV reactivation were 49.6±12.5% in 7.5 mg/kg arm and 67.2±12.7% in 10 mg/kg arm (P=0.729).Six patients relapsed, including 3 receiving 7.5 mg/kg ATG and 3 receiving 10 mg/kg ATG. The median follow up was 247 days (range, 32 to 569 days). The 1-year cumulative overall survival were 62.8±12.6% in 7.5 mg/kg arm and 68.2±10.9% in 10 mg/kg arm (P=0.536). The 1-year cumulative non-relapse mortality (NRM) rates were 23.4±10.3% and 23.3±10.5% in 7.5 mg/kg and 10 mg/kg arm, respectively (P=0.609).

Conclusion:This trial suggests that 7.5 mg/kg ATG might have similar efficacy in preventing aGVHD after haploidentical HSCT compared with 10 mg/kg.Whether patients with 7.5 mg/kg ATG have lower risk for viral infections than those with 10 mg/kg needs further studies.