Canadian multicenter pilot trial of haploidentical donor transplantation

Background: Canadian multicenter pilot study of haploidentical donor. Aims: To assess (1) ability to collect suitable graft (CD34+ ≥5 × 106/kg and CD3 <1 × 105/kg recipient body weight), (2) toxicity, (3) survival to day +100. Eligibility: All hematological malignancies and ages; accrual to end after 20 transplants of patients with AML in remission and age less than 55 years. Methods: Preparation: Modified Perugia regimen, chemotherapy alone; melphalan 140 mg/m2 day −9, thiotepa 10 mg/kg day −7, fludarabine 40 mg/m2 days −7 to −3, and ATG (Thymoglobulin, Sangstat) days −6 to −2 (total 10.5 mg/kg). Infection prophylaxis: Ganciclovir (GC) 5 mg/kg days 5–20 then ×5/week until day +100 then ×3/week until 210 (subjects 1–3), foscarnet (FC) 90 mg/kg days 4–21 then short course pre-emptive GC or FC (subjects 4–11); fluconazole; cotrimoxazole. Donors: G-CSF 16 μg/kg daily ×5 until second pheresis day. T-cell depletion: CliniMACS (MiltenyiBiotec). Results: Eleven patients with AML have been transplanted from four centers, eight female, three male, median age 34 (range 19–60). Disease status, first CR 1/11, second CR 4/11, third CR1/11, relapse 5/11. Graft CD34+ ≥5 × 106/kg was achieved in all cases, median 13.72 × 106/kg (Q1, Q3: 8.26,17.72; min 5.59, max 22.22), and CD3+ was <1 × 105/kg in all cases, median of 0.49 × 104/kg (Q1, Q3: 0.30, 2.20; min 0.22, max 4.10). Ten of the 11 patients have died, median survival 103.5 days (Q1, Q3: 61.0, 151.0; min 0, max 290.0). Survival to day +100 6/11 (55%). Four patients died of leukemic relapse, six of infection. Of six patients dying of infection, CMV was a definite cause in four. Of four dying with relapse, CMV was significant in one. Engraftment was assessed in 10 patients who survived >0 days. Granulocyte engraftment (>0.5 × 109/l) was achieved in all patients, median 11.5 days (Q1, Q3: 10, 17; min 8, max 70). Platelet engraftment (>20 × 109/l) was achieved in 8 of 10 patients, median 15 days (Q1, Q3: 9, 16; min 9, max 97). The two platelet non-engrafters died on days +45 and +61. Toxicity was low, with one toxic death (day 0), and the Bearman organ toxicity gradings were ≤ grade 2 in all other patients. There were no instances of graft-vs.-host disease or graft rejection. Conclusions: The problems of graft-vs.-host disease and graft rejection have been removed as barriers to haploidentical transplantation but the slow immune reconstitution limits its general application. Late referrals contribute to a high relapse rate and have delayed an optimal evaluation of the procedure.