Post-Transplant Cyclophosphamide Improved Outcomes of HLA Mismatched Hematopoietic Stem Cell Transplantation in Children with β-Thalassemia Major

Background:Hematopoietic stem cell transplantation(HSCT) is currently the only treatment shown to provide an effective, definitive cure for β-thalassemia major (TM). All over the world a major constraint is the lack of access to this therapy related to the lack of a suitable donor. Matched related donors are generally available only for a third of patients with TM.The need for alternative donors has therefore been explored in several ways-partially mismatched related donors, related haploidentical transplants,and matched or mismatched unrelated donors.Persisting concerns regarding high rejection rates and graft versus host disease (GVHD) need to be addressed through the evaluation of novel protocols in current and future studies.The effect of alloreactive clone destruction in post-transplant cyclophosphamide (Cy, PTCy) transplant resulted in low GVHD and high relapse but nice immuno-recovery and immuno-tolerance by keeping antivirus and regulatory T cells. Therefore, we developed a novel protocol for TM patients received HSCT form HLA mismatched donors.

Patients and methods:Twenty patients received HSCT form HLA mismatched donors between May 2014 and May 2017,with median follow-up time of 38 months (range: 2-65months).The median age at transplant was 8 years (rang:4-13years). Of them, 15 patients received unrelated- donor peripheral blood stem cell transplant(UD-PBSCT) consisted of 13 HLA 9/10(HLA-A loci,DRB loci and DRQ loci mismatched are 8,2and2,respectively) and 2 HLA 8/10(1 HLA-A and DRB loci mismatched and 2 HLA-DRB and DRQ loci mismatched), another 5 patients received HLA 9/10 related-donor peripheral blood stem cell transplant (RD- PBSCT) consisted of 3 HLA-A loci and 2 HLA-DRB loci mismatched.Among them,3 patients received adopting bone marrow(BM) and/or unrelated-donor cord blood(UD-CB). Conditioning regimen included Thymoglobuline on day -10 to -8, Cy on day-7, Busulfan on day-6 to -4, Fludarabine on day-6 to -2 and Thiotepa on day-3. GVHD prophylaxis consisted of Cy on day+3 to +4, Mycophenolate mofetil and Tacrolimus from day+6. BM or UCB was infused on day+1.GVHD prophylaxis consisted of Cy on day+3 to+4, Mycophenolate mofetil and Tacrolimus from day+5.

Results:The median infused total nucleated cell (TNC) dose was 24.8×108/kg (range: 9.0-40.2×108/kg). The median dose of infused CD34+ cells was 13.88×106/kg (range 2.89-38.76× 106/kg). All twenty patients had a successful engraftment with > 95% donor-derived cells by day 30 after transplantation.The median time to neutrophil recovery was 21 days (range 16-36days). The platelet and hemoglobin engraftment times were 14 days (range10-65days) and 15 days (range 8-48days), respectively.The cumulative incidences of grades Ⅱ-III acute GVHD (aGVHD) was 10.0% (2/20 patients).No patient developed grade IV aGVHD after transplantation. No extensive or limited chronic GVHD(cGVHD) was diagnosed among any patients in the group.The incidences of CMV and EBV antigenmia were 10.0% (2/20) and 0%(0/20), respectively. All of the 20 patients were alive without TM, and overall survive(OS)and thalassemia free survive (TFS) were 100% and 100%, respectively.We also compared the outcomes of PTCy protocol with fifty-two patients with β-TM received one or two locis HLA mismatched HSCT by use of the NF-08-TM protocol(see Li et al., Blood 2012).OS and TFS were higher in the PTCy group(100%vs.90.4%,p<0.05 and 100%vs.86.5%,p<0.05, respectively;).No patients in the PT Cy protocol group had GR, whereas 2 patients had GR in the NF-08-TM protocol group (0.00% vs.3.84%,p<0.05,respectively ).Of the 50 patients who had a successful in the NF-08-TM protocol group engraftment,aGVHD occurred in 8 patients and the incidence of grade Ⅱ-III and IV aGVHD were 6% and 6% (3/50 and 3/50 patients), respectively. One pulmonary cGVHD was diagnosed in the NF-08-TM protocol group and one patient died of IV GVHD.Compared to the NF-08-TM protocol group, patients in PTCy protocol group had a lower incidence of aGVHD(10.00% vs.16.00%,p<0.05), especially IV aGVHD (0.00% vs.6.00%, p<0.05).

Conclusion: PTCy protocol leaded to 100% OS and TFS with low GR and GVHD rate compared with the NF-08-TM protocol in patients with β-TM who received HSCT form HLA mismatched donors. A large-cohort study with extending follow-up time should be developed in the future.