Thiotepa Based Conditioning for Haploidentical Stem Cell Transplantation with Post Transplant Cyclophosphamide for Pediatric Acute Leukemia Is Highly Effective

Abstract

Introduction Haploidentical family donor is universally available and is increasing being used as an alternative donor choice for treating adults with leukaemia needing hematopoietic stem cell transplant (HSCT). Thiotepa is an alkylating agent which has been used successfully as part of conditioning in adult leukemia patients undergoing haploidentical SCT with Post transplant cyclophosphamide (PTCy). But such data is lacking in children. Herein, we describe the experience of treating children with acute leuekmia with thiotepa based conditioning for haploidentical HSCT with PTCy. Methods We retrospectively analysed outcome data of 12 children with acute leukaemia (acute lymphoblastic leukemia-8, acute myeloid leuekmia-3 and Mixed phenotype acute leukemia-1) who underwent haploidentical HSCT with PTCy; median age was 6.5 years (range 1-14 years). All were in complete remission (CR) prior to HSCT (CR1-6, CR2-6). Donors were mobilized with GCSF. The conditioning was myeloablative with Thiotepa 10 mg/kg day-6, Fludarabine 40 mg/m2 day-5 to -2, Cyclophosphamide 14.5 mg/kg on day-5 and -4, Total body irradiation 2 Gray on day-1 in 8 children and Rituximab 100/m2 day-8, Thiotepa 10 mg/kg on day-7, Fludarabine 40 mg/m2 day-6 to -3, Busulfan 3.2 mg/kg day-6 to -3 (TBF) and Rabbit ATG 1.5 mg/kg day-4 to-2 in 4 children. All received PTCy 50 mg/kg on day 3 and 4 as graft vs. host disease (GVHD) prophylaxis along with tacrolimus or cyclosporine and mycophenolate mofetil. A median of 9.5 million of CD34 cells/kg was infused (range 4-20 million/kg). Results All patients engrafted. Median time of neutrophil engraftment was 18 days (range 11-29) and platelet engraftment was 18 days (range 12-26). All achieved fully donor chimerism on day+30. One child with acute myelogenous leukemia died due to steroid refractory grade IV acute gut GVHD on day+38. Child with infant leukemia died on day+330 with chronic GVHD of Lung. One child relapsed 2 years post HSCT. As he had CD20 positive B cell ALL, so he was treated with Rituximab and achieved CR3. He is alive and disease free on monthly rituximab 100 mg/m2 for more than 3 years post his relapse. Chimerism on day +100 and + 180 was fully donor in all patients. Remaining 9 patients are in continued CR. Acute GVHD was seen in 3 patients (grade III-IV in 1) but none in TBF and ATG regimen. Chronic GVHD was seen in four patients (extensive in 3) but only in 1 out of 4 in TBF regimen. Haemorrhagic cystitis with BK virus activation was seen in 4 patients (all 4 received TBF). Viral reactivation of CMV was seen in 5 patients. Overall survival was 83% and event-free survival was 75 % at a median follow-up of 930 days (range 200-1765 days). Transplant related mortality was 17%. Conclusion Thiotepa based myeloablative conditioning is highly effective in children undergoing haploidentical HSCT with PTCy for acute leukemia. Addition of ATG reduced acute and chronic GVHD.