Intrabone Transplantation of a Single Cord Blood Unit Using Non-Irradiated Reduced-Intensity Conditioning
Authors: Murata Makoto , Maeda Yoshinobu , Masuko Masayoshi , Onishi Yasushi , Endo Tomoyuki , Terakura Seitaro , Ishikawa Yuichi , Iriyama Chisako , Ushijima Yoko , Goto Tatsunori , Fujii Nobuharu , Tanimoto Mitsune , Kobayashi Hironori , Shibasaki Yasuhiko , Fukuhara Noriko , Inamoto Yoshihiro , Suzuki Ritsuro , Matsushita Tadashi , Kodera Yoshihisa , Kiyoi Hitoshi , Naoe Tomoki , Nishida Tetsuya 
Published: October 2019

Introduction: Cord blood transplantation (CBT) is a treatment option for patients with hematological disorder. Recent development of reduced-intensity conditioning (RIC) allows elderly patients and those with comorbidities to benefit from CBT. However, RIC-CBT has not been optimized in part due to graft failure or delayed engraftment. Intrabone infusion of cord blood cells has the potential to ensure engraftment and shorten the time of hematological recovery (Lancet Oncol 2008;9:831-9). The aim of this phase II study was to examine the efficacy and safety of intrabone transplantation of a single cord blood unit using non-irradiated RIC.

Patients and Methods: Patients were eligible for the study if they had hematological malignancy, needed CBT, were ≥55 years or 16 to 54 years with hematopoietic stem cell transplantation-specific comorbidity index ≥1, and had an available cord blood unit with serological HLA-A, B, and DR ≥4/6 match and with cryopreserved total nucleated cells (TNCs) at least 2×107/kg. Cord blood units were thawed, washed with a saline solution plus dextran and human albumin, resuspended in approximately 10 ml of the solution, and aliquoted in two to four syringes. After local anesthesia, standard bone marrow aspiration needles were inserted into iliac bone. Approximately 5 ml of cord blood cell suspension was gently infused. This procedure was repeated for all the remaining aliquots across the iliac crest. All patients received tacrolimus and short-term methotrexate as graft-versus-host disease (GVHD) prophylaxis and granulocyte colony-stimulating factor after transplantation. The primary endpoint was the probability of survival with neutrophil engraftment on day 60 after transplantation. This study was approved by the ethical committee of each institute.

Results: Of the 22 enrolled patients, one was not assessable because the patient did not receive intrabone CBT due to the worsening of general condition after the enrollment. The age of 21 evaluable patients ranged 38 to 66 years (median, 57 years). The diagnosis included leukemia (n = 14), lymphoma (n = 6), and myelodysplastic syndromes (n = 1). All patients received fludarabine 150 to 180 mg/m2 and cyclophosphamide 60 to 120 mg/kg with the exception of a patient who received fludarabine 125 mg/m2 and melphalan 140 mg/m2. The number of cryopreserved TNCs ranged 2.0 to 4.9×107/kg (median, 2.7×107/kg), and the number of cryopreserved CD34 positive cells ranged 0.44 to 3.14×105/kg (median, 0.92×105/kg). Mild swelling of skin at the injection site was observed in one patient, however it resolved spontaneously. No other complications occurred during or after the intrabone infusion of cells. The cumulative incidences of neutrophil (≥0.5×109/L), reticulocyte (≥1%), platelet (≥20×109/L) recoveries were 76.2%, 71.4%, and 76.2%, respectively. For those who achieved hematopoietic recovery, the median time to neutrophil, reticulocyte, and platelet recoveries were 17 days, 28 days, and 32 days, respectively. One patient died of veno-occlusive disease on day 42 with achievement of neutrophil recovery. Accordingly, the probability of survival with neutrophil engraftment on day 60 after transplantation (primary endpoint) was 71.4% (95%CI, 51.8 to 88.3%). Of evaluable 16 patients, seven (43.8%) and three (18.8%) developed grade II-IV and III-IV acute GVHD, respectively. No patients developed chronic GVHD. There was a significant difference in the incidence of neutrophil recovery between patients receiving ≤2.7×107/kg TNCs (n = 11) and those receiving >2.7×107/kg TNCs (n = 10) (55% vs. 100%, P = 0.035). Meanwhile, there was a significant difference in the time to neutrophil recovery between patients receiving ≤0.92×105/kg CD34 positive cells (n = 11) and those receiving >0.92×105/kg CD34 positive cells (n = 10) (median, 18 days vs. 16 days; range, 16 to 25 days vs. 14 to 19 days; P= 0.014). Overall survival at 1 year after transplantation was 52.4% (95%CI, 29.7 to 70.9%).

Conclusion: The present data suggest that intrabone transplantation of a single cord blood unit using non-irradiated RIC provides an opportunity for patients who are unable to be exposed to irradiation at the time of pre-transplant conditioning for several reasons, including preservation of fertility, and exposure to the upper limit of irradiation before transplantation, to receive RIC-CBT. Further studies in a larger series of patients are required.

Disclosures

Maeda: Mundipharma KK: Research Funding. Onishi:SymBio Pharmaceuticals: Research Funding. Matsushita:KaketsuKen: Honoraria, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; JB: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kiyoi:Yakult Honsha Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Phizer Japan Inc.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Celgene Corporation: Consultancy; Chugai Pharmaceutical Co. LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; MSD K.K.: Research Funding. Naoe:TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Pfizer Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Celgene K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; CMIC Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Astellas Pharma Inc.: Research Funding.