Successful Haploidentical Stem Cell Transplant with Busulfan, Fludarabine, Thiotepa Conditioning and Post Transplant Cyclophosphamide, Cyclosporine and Mycophenolate Mofetil in an Infant with Thalassemia Major

Abstract

Introduction Thalassemia major is curable by allogeneic hematopoetic stem cell transplant (HSCT). Due to lack of matched unrelated donors most children of ethnic minorities are unable to access HSCT. Recent reports of haploidentical donor HSCT with reduced intensity conditioning (RIC) with post transplant cyclophosphamide (PTCy) from family donors in hemoglobinopathies have shown encouraging results. However, rejection remains a problem in children with thalassemia undergoing RIC haploidentical HSCT. Another need is to avoid total body irradiation (TBI) during conditioning in infants due to its effects on the developing brain. Traditionally for haploidentical HSCT with PTCy, Tacrolimus and Myecophenolate Mofetil (MMF) have been used as part of graft vs. host disease (GVHD) prophylaxis. However, intravenous tacrolimus is not easily available so in very young children difficult to achieve good levels with oral tacrolimus which can increase risk of rejection. Here we describe successful haploidentical HSCT in an infant with myeloablative conditioning (free of radiotherapy) and PTCy with intravenous cyclosporine and oral MMF as GVHD prophylaxis. Methods A 10-month-old, male infant with thalassemia major (Pesaro class I) who had no matched related or unrelated donor available underwent haploidentical HSCT after taking informed consent of the parents in December 2017. Donor was his mother who was 5/10 matched. He had been transfused just twice before HSCT. The conditioning was with Rituximab 100 mg/m2 IV on day -11, rabbit anti-thymoglubulin (thymoglobulin) 1.5 mg/kg/dose daily for 3 days (Day-10 to -8) Thiotepa 10 mg/kg/dose intravenous (IV) for 1 day (Day-7), Busulfan 4 mg/kg/dose daily IV for 4 days (Day -6 to -3) and Fludarabine 40 mg/m2/dose daily IV for 4 days (Day -6 to -3). Peripheral blood stem cells (10 million/kg CD34+ cells) were harvested from mother and transfused to the patient on Day 0. GVHD prophylaxis was with PTCy 50 mg/kg on Day+3 & 4, intravenous cyclosporine from day+5 (targeting levels 150-250 ng/ml) and MMF from day+5. Results His neutrophils engrafted on day+14 and platelets on day+16. He developed high grade fever from day+2 till day+5 which disappeared after PTCy. Chimerism on day+30, 100 and 12 months was fully donor. He developed no acute or chronic GVHD. At 6 months his lymphocyte counts showed CD4-400/ul, CD8-840/ul, CD19-8/ul and CD16/56-120/ul. His viral studies by PCR for cytomegalovirus, BK virus and Ebstein-Barr virus remained negative throughout. MMF was stopped on Day+35.He is disease free and GVHD free on day+400 post HSCT and is off cyclosporine. Conclusion Busulfan, Fludarabine and Thiotepa based meyeloablative conditioning is a radiotherapy free option for infants undergoing haploidentical HSCT with PTCy for thalassemia major. For GVHD prophylaxis in haploidentical HSCT with PTCy intravenous cyclosporine can be an alternative to oral tacrolimus.