Reduced-Toxicity Conditioning with Haploidentical Hematopoietic Cell Transplantation for Pediatric Relapsed/Refractory Hematologic Malignancies
Authors: Yoshimi Ai , Kato Keisuke 
Published: December 2024

Objective: In Japan, the 5-year survival rate for high-risk pediatric leukemia treated with unrelated donor allogeneic bone marrow transplantation remains poor at 40-50%. Intensive conditioning regimens increase transplant-related mortality and cause severe complications, including endocrine disorders like short stature and gonadal dysfunction, as well as developmental issues and secondary cancers due to high-dose total body irradiation (TBI) or high-dose busulfan (BU). Haploidentical hematopoietic cell transplantation (haploHCT) offers a strong graft versus leukemia effect, making it a treatment option for high-risk pediatric hematologic malignancies. However, limited literature exists on combining reduced-toxicity conditioning (RTC) with haploHCT. This study aims to evaluate the efficacy and complications of combining RTC with haploHCT in children with relapsed/refractory hematologic malignancies.
Methods: We retrospectively analyzed cases at our single institution from February 2011 to July 2022 involving initial HCT with RTC for pediatric hematologic malignancies that were relapsed, non-remission, or minimal residual disease-positive after induction therapy. RTC was defined as TBI ≤ 8 Gy or half-dose BU. HaploHCT was defined as HCT with fewer than 6 HLA allele matches. We analyzed overall survival (OS), disease-free survival (DFS), incidence of acute and chronic graft versus host disease (GVHD), growth hormone-dependent short stature, secondary sexual development in post-pubertal cases, and incidence of secondary cancers.
Results: The study included 40 patients (18 boys, 22 girls) with a median age at HCT of 6.5 years (7 months to 17 years). Diseases included Acute Lymphoblastic Leukemia (ALL) in 13 cases, Acute Myeloid Leukemia (AML) in 24 cases, non-Hodgkin's Lymphoma in 2 cases, and Chronic Myeloid Leukemia in 1. At HCT, 25 cases were in remission, and 15 were not. Conditioning regimens included TBI 4-6 Gy + Fludarabine (FLU) 150-180 mg/m2 + Melphalan (MEL) 180 mg/m2 + Anti-Thymocyte Globulin (ATG) 2.5-8 mg/kg in 15 cases, half-dose BU + FLU 150-180 mg/m2 + MEL 180 mg/m2 + ATG 2.5-8 mg/kg in 14 cases, FLU+MEL+ATG in 5 cases, and other regimens in 6 cases. Donors included mother (18 cases), father (16 cases), and sibling (6 cases). Grafts were peripheral blood (26 cases) or bone marrow (14 cases) with a median infused nucleated cell count of 9.41 x 108 /kg (range 3.03-30.1 x 108 /kg). GVHD prophylaxis included Tacrolimus (TAC) + short-term Methotrexate (sMTX) + Methylprednisolone (mPSL) in 30 cases, TAC + sMTX in 6 cases, and Post-Transplant Cyclophosphamide (PTCy) in 4 cases. With a median follow-up of 1,627 days (range 29-4,690 days), the 5-year OS was 61.9 %, and the 5-year DFS was 54.5 %. There were 19 deaths (relapse in 10 cases and HCT-related complications in 9 cases, including thrombotic microangiopathy (3 cases), interstitial pneumonia (2 cases), bronchiolitis obliterans (1 case), invasive aspergillosis (1 case), sepsis (1 case), and EB virus-associated lymphoproliferative disorder (1 case)). Acute GVHD grades II-IV occurred in 23 cases (58 %), grades III-IV in 15 cases (38 %), and moderate to severe chronic GVHD in 5 cases (8 %). Among the 21 surviving patients, three had growth hormone-dependent short stature. Among the eight girls currently over ten years old, six who were under nine years old at HCT had menstruation, while two who were over nine years old at transplantation had gonadal dysfunction. None of the patients developed secondary cancer.Conclusion: Combining RTC and haploHCT improves survival rates for relapsed/refractory pediatric hematologic malignancies. The incidence of acute and chronic GVHD was comparable to traditional methods due to the use of ATG. This regimen significantly reduces late complications, particularly preserving gonadal function in prepubertal patients at the time of HCT. Furthermore, in ALL, OS was lower for non-remission transplants than for remission transplants. Relapses occurred mainly within two years post-HCT. In AML, there was no significant difference in OS between remission and non-remission transplants, with some cases of late relapse occurring after five years. Incorporating treatments such as targeted therapies before transplantation in ALL, and post-transplant chemotherapy or donor lymphocyte infusions for relapse prevention in AML, could further improve survival rates.