Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study.
ABSTRACT Cord-blood transplants are associated with delayed or failed engraftment in about 20% of adult patients. The aim of this phase I/II study was to establish the safety and efficacy of a new administration route (intrabone) for cord-blood cells, measured by the donor-derived neutrophil and platelet engraftment.
Adult patients with acute leukaemia, for whom an unrelated stem-cell transplantation was indicated and no suitable unrelated human leucocyte antigen (HLA)-matched donor had been identified, were included in the study and underwent a cord-blood transplant in San Martino Hospital, Genoa, Italy. Eight patients were in first complete remission, ten in second complete remission, and 14 had advanced-stage, refractory disease. HLA matching was 5/6, 4/6, and 3/6 for 9, 22, and one patient, respectively. Cord-blood cells were concentrated in four 5-mL syringes, and were infused in the superior-posterior iliac crest under rapid general anaesthesia. Median transplanted cell dose was 2.6 x 10(7)/kg (range 1.4-4.2). The primary endpoint was the probability of neutrophil and platelet recovery after intrabone cord-blood transplantantion. Secondary endpoints included the incidence of acute graft-versus-host disease, relapse, and overall survival. This trial is registered on the ClinicalTrials.gov website, number NCT 00696046.
Between March 31, 2006, and Jan 25, 2008, 32 consecutive patients with acute myeloid leukaemia (n=20) or acute lymphoblastic leukaemia (n=12) underwent a cord-blood transplant (median age 36 years [range 18-66]). No complications occurred during or after the intrabone infusion of cells. Four patients with advanced-stage disease died within 12 days of the procedure. Median time to recovery of neutrophils in 28 patients (>/=0.5 x 10(9)/L) was 23 days (range 14-44) and median time to recovery of platelets in 27 patients (>/=20 x 10(9)/L) was 36 days (range 16-64). All patients were fully chimeric from 30 days after transplantation to the last follow-up visit, suggesting an early complete donor engraftment. No patient developed grade III-IV acute graft-versus-host disease. Causes of death were transplant related (n=5), infection (n=7), and relapse (n=4). 16 patients were alive and in haematological remission at a median follow-up of 13 months (range 3-23).
Our preliminary data suggest that direct intrabone cord-blood transplantation overcomes the problem of graft failure even when low numbers of HLA-mismatched cord-blood cells are transplanted, thus leading to the possibility of use of this technique in a large number of adult patients.
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ABSTRACT: Autologous cord blood transplantations are rarely applied in patients with hematologic as well as metastatic solid cancers since contamination of malignant clones is a concern.We report a case of therapy-related myelodysplasia after metastatic neuroblastoma who suffered from graft rejection and life-threatening infections after a myeloablative unrelated cord blood transplantation.The patient experiences long-term survival, free from leukemia/neuroblastoma after infusion of autologous cord blood cells.It suggests that autologous cord blood transplantation after high dose therapy might be a curative strategy for certain hematologic or metastatic solid cancers.Medicine 02/2015; 94(5):e438. DOI:10.1097/MD.0000000000000438 · 4.87 Impact Factor
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ABSTRACT: A prospective phase II multicentric trial was performed to obtain less than 25% non-relapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using reduced intensity conditioning regimen (RIC) consisting of total body irradiation (TBI 2Gy), cyclophosphamide (50mg/kg) and fludarabine (200mg/m2) (TCF). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients transplanted in first complete remission (CR1) (n=48) had a higher frequency of unfavorable cytogenetics, secondary AML and greater number of induction courses of chemotherapy to achieve CR1 compared to the others. The median infused total nucleated cells (TNC) was 3.4 x107/kg; 60% received double UCBT; 77% were HLA mismatched (4/6) and 40% had major ABO-incompatibility. Cumulative incidence (CI) of neutrophil recovery at day-60 was 87% and CI of 100-day acute-GVHD (II-IV) was 50%. At 2-years, CI of NRM and relapse incidence were 20% and 46%, respectively. In a multivariate analysis, major ABO incompatibility (p=0.001) and TNC (<3.4x107/kg; p=0.001) were associated with increased NRM and use of 2 or more induction courses to obtain CR1 with increased relapse incidence (p=0.04). Leukemia-free survival (LFS) at 2-years was 35%, and the only factor associated with decreased LFS was secondary AML (p=0.04). In conclusion, despite the decreased NRM observed, other RIC regimens with higher myelosuppression should be evaluated to decrease relapse in high risk AML. (EUDRACT 2006-005901-67). Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2014; DOI:10.1016/j.bbmt.2014.11.009 · 3.35 Impact Factor
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ABSTRACT: Intrabone (IB) hematopoietic cell transplantation (HCT) of umbilical cord blood in humans remains experimental and the technique has not been optimized. It is unknown whether hematopoietic progenitor cells (HPCs) injected IB are initially retained in the marrow or rapidly enter into the venous circulation before homing to the marrow. To develop an IB-injection technique that maximizes HPC marrow-retention, we tracked radiolabeled human HPCs following IB-injection into swine. We developed a method to radionuclide-label HPCs using a long-lived positron emitter (89) Zr and protamine sulfate that resulted in cellular-retention of low-dose radioactivity. This approach achieved radioactivity levels sufficient for detection by positron emission tomography with both high sensitivity and spatial resolution when fused with computed tomography. We found that conditions utilized in pilot IB-HCT clinical trials conducted by others led to both rapid drainage into the central venous circulation and cellular extravasation into surrounding muscle and soft tissues. By optimizing the needle design, using continuous real-time intra-marrow pressure monitoring, and by reducing the infusion-volume and infusion-rate, we overcame this limitation and achieved high retention of HPCs in the marrow. This method of IB cellular delivery is readily applicable in the clinic and could be utilized in future investigational IB-HCT trials aimed at maximizing marrow retention of HPCs. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.American Journal of Transplantation 02/2015; 15(3). DOI:10.1111/ajt.13007 · 6.19 Impact Factor