Comparison of Haploidentical Transplantation with Post-Transplantation Cyclophosphamide and Umbilical Cord Blood Transplantation in Children and Adolescents with Hematologic Malignancies after Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring

Introduction: Haploidentical related donor (Haplo) and umbilical cord blood (UCB) stem cell sources represent common alternative donor strategies used when a matched sibling donor or matched unrelated donor is not available for hematopoietic stem cell transplantation (HSCT). The aim of this study was to compare the results of graft source on outcome of children and adolescents with hematologic malignancies after Haplo and UCB transplantation in the setting of targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic (PK) monitoring.

Patients and methods: We retrospectively analyzed outcomes in 140 pediatric patients with hematologic malignancies who received allogeneic HSCT from Haplo donors (n=36), UCB (n=24), and unrelated donors (n=80) in Seoul National University Children's Hospital from January 2009 to February 2018. Because UCB transplantation had been conducted until 2016 while Haplo transplantation using posttransplantation cyclophosphamide (PTCy) was started from 2014 in our institution, differences over time of HSCT must be considered to compare them. Therefore, unrelated HSCT group was divided into Unrelated A group (n=51) who received HSCT from 2009 to 2013 and Unrelated B group (n=29) from 2014, which were compared first with the purpose of using them as a control to compare Haplo and UCB groups. Patients who received the first allogenic HSCT using an intensive PK monitoring, targeted busulfan-based myeloablative conditioning were included. The majority of UCB and unrelated groups received busulfan, fludarabine ± etoposide regimen with antithymocyte globulin. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and mycophenolate mofetil were used in UCB group while tacrolimus and methotrexate in unrelated groups. Busulfan, fludarabine and cyclophosphamide with PTCy, tacrolimus and methotrexate for GVHD prophylaxis were used in Haplo group.

Results: First of all, Unrelated A group was compared to Unrelated B group. The median follow-up time were 5.7 years (0.2-9.5) and 1.8 years (0.3-4.5) in the Unrelated A and Unrelated B groups, respectively. The event-free survival (EFS) rates at 2 years (78.1±5.8% versus 72.3±9.1%, P=0.917) and overall survival (OS) rates at 2 years (83.7±5.3% versus 77.8±9.1%, P=0.874) in Unrelated A and B groups were similar. Under the assumption that there was no significant survival difference over time of HSCT from 2009 to 2013 and that from 2014 in our institution, the outcomes of Haplo and UCB groups were compared subsequently. The median follow-up time were 4.8 years (0.1-9.3) and 1.8 years (0.3-4.5), respectively. The median time to neutrophil and platelet recovery were 15 days (13-21) versus 14 days (12-40) (P=0.059), and 27 days (13-71) versus 46 days (21-77) (P<0.001) in Haplo and UCB groups, respectively. Engraftment failure occurred in 1 patient of UCB group. The cumulative incidence (CI) rates of acute GVHD grade II-IV, grade III-IV, and extensive chronic GVHD in Haplo and UCB groups were 38.9% versus 54.2% (P=0.479), 2.8% versus 29.2% (P=0.004), and 11.7% versus 12.5% (P=0.906), respectively. The CI rates of nonrelapse mortality were significantly lower in Haplo group (0% versus 33.6%, P<0.001), while the relapse incidences were not different (18.3% versus 8.6%, P=0.272). The event-free survival (EFS) rates at 2 years (79.3±7.0% versus 54.2±10.2% %, P=0.034) and overall survival (OS) rates at 2 years (85.8±6.7% versus 65.7±9.9%, P=0.029) in Haplo and UCB groups were significantly different.

Conclusion: In this study, the CI rates of nonrelapse mortality and acute GVHD III-IV was lower in Haplo group than in UCB transplants, which translates into a better EFS and OS rate in Haplo group. Our results suggest that haploidentical HSCT with PTCy using intensive PK monitoring, targeted busulfan-based myeloablative conditioning regimen is a safe and promising alternative option for patients with hematological malignancies who lack an HLA-matched donor.