Double Unrelated Reduced-Intensity Umbilical Cord Blood Transplantation in Adults

Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Biology of Blood and Marrow Transplantation (Impact Factor: 3.4). 02/2007; 13(1):82-9. DOI: 10.1016/j.bbmt.2006.08.041
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Umbilical cord blood (UBC) stem cells are a useful stem cell source for patients without matched related or unrelated donors. Adult transplantation with single UBC units is associated with high transplantation-related mortality (TRM). In most cases, mortality is due to infection related to slow engraftment and immunoincompetence. In this study, we used a reduced-intensity conditioning regimen of fludarabine, melphalan, and antithymocyte globulin followed by 2 partially matched UBC units. The UBC units were a 4/6 HLA match or better with each other and with the patient and achieved a minimum precryopreservation cell dose of 3.7 x 10(7) nucleated cells/kg. A total of 21 patients (median age, 49 years) were treated. The median time to an absolute neutrophil count > 0.5 x 10(9)/L was 20 days, and the median time to an unsupported platelet count > 20 x 10(9)/L was 41 days. Two patients experienced primary graft failure and underwent a second UBC transplantation. One patient had a late graft failure. Acute graft-versus-host disease (GVHD) grade II-IV occurred in 40% of patients. The 100-day TRM was 14%, and the 1-year disease-free survival was 67%. Mixed chimerism was associated with a higher risk of chronic GVHD. Our findings indicate that adult patients can tolerate double UBC transplantation well and achieve sustained antitumor responses using this reduced-intensity conditioning regimen.

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    • "Cell dose titration of co-injected donor cells revealed that relative initial CD34 + cell content was strongly predictive of BM graft dominance (Fig. 2, B and C), reflecting clinical observations made in the context of human transplantation with mixed CB cells from two combined donors (Ballen et al., 2007). Furthermore , earlier transplantation provided a competitive repopulation advantage if donor cells were instead transplanted in a successive fashion (unpublished data), again recapitulating clinical reports (Ballen et al., 2007; Avery et al., 2011). In no instance did we observe evidence of immune recognition between donor cells (Yahata et al., 2004), as assured by the use of lineage-depleted (Lin  ) CB samples lacking CD2 + T cells (Fig. 2 B), and the application of the NOD SCID recipient background, which precludes terminal maturation of immune competent lymphocytes (Shultz et al., 2005). "
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    ABSTRACT: Allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) is currently the leading strategy to manage acute myeloid leukemia (AML). However, treatment-related morbidity limits the patient generalizability of HSCT use, and the survival of leukemic stem cells (LSCs) within protective areas of the bone marrow (BM) continues to lead to high relapse rates. Despite growing appreciation for the significance of the LSC microenvironment, it has remained unresolved whether LSCs preferentially situate within normal HSC niches or whether their niche requirements are more promiscuous. Here, we provide functional evidence that the spatial localization of phenotypically primitive human AML cells is restricted to niche elements shared with their normal counterparts, and that their intrinsic ability to initiate and retain occupancy of these niches can be rivaled by healthy hematopoietic stem and progenitor cells (HSPCs). When challenged in competitive BM repopulation assays, primary human leukemia-initiating cells (L-ICs) can be consistently outperformed by HSPCs for BM niche occupancy in a cell dose-dependent manner that ultimately compromises long-term L-IC renewal and subsequent leukemia-initiating capacity. The effectiveness of this approach could be demonstrated using cytokine-induced mobilization of established leukemia from the BM that facilitated the replacement of BM niches with transplanted HSPCs. These findings identify a functional vulnerability of primitive leukemia cells, and suggest that clinical development of these novel transplantation techniques should focus on the dissociation of L-IC-niche interactions to improve competitive replacement with healthy HSPCs during HSCT toward increased survival of patients.
    Journal of Experimental Medicine 09/2014; 211(10). DOI:10.1084/jem.20140131 · 12.52 Impact Factor
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    • "However, treatment-related mortality (TRM) or chronic GVHD were not higher but a higher graft-versus-leukemia effect was anticipated17,18,19,20,21,22). When 2 units of CB were transplanted, very interesting engraftment kinetics were revealed: early after double CBT (day +21) both CB units contributed to hematopoiesis in 40%-50% of patients, but by day +100 one unit predominated in the vast majority of the patients17,23). The unit predominance may be influenced by postthaw viability24), length of time interval between the infusion of the two CB units25) and ex vivo expansion26,27). The importance of T cells to establish chimerism and to ensure stem cell engraftment has been widely documented28,29,30,31,32,33). "
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    ABSTRACT: Cord blood (CB) has been used as an important and ethical source for hematopoietic stem cell transplantation (SCT) as well as cell therapy by manufacturing mesenchymal stem cell, induced pleuripotential stem cell or just isolating mononuclear cell from CB. Recently, the application of cell-based therapy using CB has expanded its clinical utility, particularly, by using autologous CB in children with refractory diseases. For these purposes, CB has been stored worldwide since mid-1990. In this review, I would like to briefly present the historical development of clinical uses of CB in the fields of SCT and cell therapy, particularly to review the experiences in Korea. Furthermore, I would touch the recent banking status of CB.
    Korean Journal of Pediatrics 03/2014; 57(3):110-116. DOI:10.3345/kjp.2014.57.3.110
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    • "However, use of UCB as a stem cell source has been limited until recently by the delayed engraftment and relatively high rate of primary graft failures due to the low volume and low CD34+ cell content. Use of double, instead of single, UCB has partially overcome these issues [36,37]. "
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    ABSTRACT: Haploidentical related donors are alternative stem cell sources for patients without human leukocyte antigen (HLA)-matched related or unrelated donors. Immediate access to the donor, availability for patients with rare haplotypes, ease of stem cell procurement, and lack of a requirement for a physical cord blood bank or an extensive HLA database render this type of hematopoietic stem cell transplantation particularly attractive despite the high histoincompatibility barrier between the recipient and the haploidentical graft. In this review, we answer the following questions: 1) What are the current transplant strategies used to overcome the histoincompatibility barrier in haploidentical stem cell transplantation and their clinical results? 2) How should we choose the donor when there is more than one available haploidentical donor? 3) How does transplantation from haploidentical donors compare to that from umbilical cord blood? Conflict of interest:None declared.
    Turkish Journal of Haematology 12/2013; 30(4):342-350. DOI:10.4274/Tjh.2013.0054 · 0.36 Impact Factor
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