Prompt and durable engraftment in two older adult patients with high risk chronic myelogenous leukemia (CML) using ex vivo expanded and unmanipulated unrelated umbilical cord blood

203

172

Umbilical cord blood transplantation (UCBT) in adults is limited by the small number of primitive hematopoietic stem cells (HSC) in each graft, resulting in delayed engraftment post transplant, and both short-and longterm infectious complications. Initial efforts to expand UCB progenitors ex vivo have resulted in expansion of mature rather than immature HSC, confounded by the inability to accurately and reliably measure long-term reconstituting cells. Ex vivo expansion of UCB HSC has failed to improve engraftment because of resulting defects that promote apoptosis, disrupt marrow homing and initiate cell cycling. Here we discuss the future of ex vivo expansion, which we suggest will include the isolation of immature hematopoietic progenitors on the basis of function rather than surface phenotype and will employ both cytokines and stroma to maintain and expand the stem cell niche. We suggest that ex vivo expansion could be enhanced by manipulating newly discovered signaling pathways (Notch, Wnt, bone morphogenetic protein 4 and Tie2/angiopoietin-1) and intracellular mediators (phosphatase and tensin homolog and glycogen synthase kinase-3) in a manner that promotes HSC expansion with less differentiation. Improved methods for ex vivo expansion will make UCBT available to more patients, decrease engraftment times and allow more rapid immune reconstitution post transplant.

Section: Early Clinical Experience Of Hsc Ex Vivo Expansionmentioning

confidence: 98%

Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche

Hofmeister

Zhang

Knight

et al. 2006

203

172

“…15 Until now, information about the results of UD-CBT has only been available through registries, 13,16,21 in small series from single institutions, 12,14,33 or as anecdotal case reports. 19,20,[34][35][36][37] In all instances, the populations of patients and the conditioning regimens in these series have been heterogeneous. Furthermore, with just two exceptions, 21,38 all these series have pooled both child and adult cases.…”

Section: Discussionmentioning

confidence: 99%

“…18 The reported cases of UD-CBT in adults with CML are very limited. At present, only anecdotal case reports exist, 19,20 together with several cases from among three heterogeneous series of patients with different diseases, two from registries including mainly pediatric cases, 13,16 and one of adults from a single institution. 21 This deficit has been due mainly to grave concerns about the possibility of engraftment failure after UD-CBT in adults.…”

mentioning

confidence: 99%

Unrelated donor cord blood transplantation in adults with chronic myelogenous leukemia: results in nine patients from a single institution

Sanz

Saavedra

Jiménez

et al. 2001

Summary:The potential role of unrelated donor cord blood transplantation (UD-CBT) in adults is not well established. We report the results of UD-CBT in nine adult patients with chronic myeloid leukemia (CML). The median age was 27 years (range, 19-41 years), and the median weight was 62 kg (range, 45-78 kg). At transplant, six patients were in chronic phase (five in first, and one in second), two in blast crisis, and one in accelerated phase. Eight had received intensive chemotherapy, and three had undergone autologous peripheral blood hematopoietic stem cell transplantation. Four had received interferon with no cytogenetic response, and only three underwent UD-CBT within 1 year of diagnosis. After serological typing for class I antigens, and high-resolution DNA typing for DRB1, the degree of HLA match between patients and cord blood (CB) units was 4/6 in six cases and 5/6 in three cases. The median number of nucleated cells infused was 1.7 × 10 7 /kg (range, 1.2 to 4.9 × 10 7 /kg), and was above 2 × 10 7 /kg in only two cases. All patients received thiotepa, busulfan, cyclophosphamide and anti-thymocyte globulin as conditioning; cyclosporine and prednisone for graft-versushost disease (GVHD) prophylaxis; and G-CSF from day +7 until engraftment. All seven evaluable cases engrafted. The median time to reach an absolute neutrophil count у0.5 × 10 9 /l and у1 × 10 9 /l was 22 days (range, 19-52 days) and 28 days (range, 23-64 days), respectively. In the four patients evaluable for platelet recovery time to levels of у20 × 10 9 platelets/l, у50 × 10 9 platelets/l, and у100 × 10 9 platelets/l, these ranged from 50 to 128 days, 60 to 139 days, and 105 to 167 days, respectively. Three patients developed acute GVHD above grade II, and three of the five patients at risk developed extensive chronic GVHD. Four patients, all transplanted in chronic phase, remain alive in mol-

“…Attempts to increase UCB cell dose has laid the basis for laboratory 56 and phase I clinical trials [57][58][59] focused on ex vivo expansion of UCB grafts. Although early clinical trials reported thus far do not point to more rapid hematopoietic recovery in UCB recipients, there is improved day 100 survival compared with historical controls.…”

Section: Future Initiatives: Ucb Transplantationmentioning

confidence: 99%

Umbilical cord blood for allogeneic transplantation in children and adults

Laughlin

2001

Summary:Early clinical reports outlining outcomes for primarily pediatric patients undergoing UCB transplantation, point to delayed time to hematopoietic recovery, and favorable incidence and severity of graft-versus-host disease. Intensive clinical and laboratory research is ongoing focused on strategies to foster UCB allogeneic donor engraftment, thereby allowing wider application of this stem cell source for patients requiring allogeneic transplantation. Bone Marrow Transplantation (2001) 27, 1-6. Keywords: umbilical cord blood; allogeneic transplantation Allogeneic blood and bone marrow stem cell transplantation is limited by the availability of suitable HLAmatched related donors. In 1988, umbilical cord blood (UCB) hematopoietic stem cells (HSC) from a related sibling were transplanted successfully into a child with Fanconi anemia. 1 Subsequently, UCB from HLA-mismatched related 2 and unrelated donors has been shown to successfully engraft pediatric 3-8 and a few reported adult patients 6,9-11 with hematologic malignancies, immunodeficiency syndromes, inborn errors of metabolism, or marrow failure syndromes. This article will review the use of UCB as a suitable alternative for allogeneic transplantation. Tables 1 and 2 outline the advantages and disadvantages for the application of UCB as a new source of HSC for patients requiring allogeneic transplantation. UCB collection and bankingSince the first successful unrelated UCB transplant was performed by J Kurtzberg and the pediatric transplant team at Duke University in 1993, 7 clinical and laboratory studies have burgeoned and standard operating procedures have been developed for the collection, processing, and storage of UCB units. [12][13][14][15][16][17][18][19] UCB collection is performed during the final phase of labor or, more commonly, after delivery of