Umbilical cord blood transplant from unrelated HLA-mismatched donors in children with high risk leukemia

Abstract

Summary:In the last 3 years, 14 children with high-risk leukemia (11 ALL, 2 AML and 1 CML) underwent cord blood transplantation from unrelated HLA-mismatched donors at a median of 99 days from the start of search. Eight patients were transplanted in second CR, one in accelerated phase, three at relapse and two patients in first CR. Conditioning regimen (fractionated TBI, etoposide, CY and anti-lymphocyte serum) and prophylaxis of GVHD (CsA and 6-methylprednisolone) were identical for all patients. Neutrophils > 0.5 ؋ 10 9 /l were reached at a median of 33 days from transplant, but in four cases we observed an autologous hematopoietic reconstitution (three spontaneous, one after autologous BM rescue). Acute and chronic GVHD were observed in 10/14 and 3/8 evaluable cases, respectively. Three patients died of transplant-related toxicity and three patients relapsed. The probabilities of event-free, disease-free and overall survival were 50, 53 and 64%, respectively. Cord blood transplant from HLA-mismatched unrelated donor is a valid option for the treatment of children with high-risk leukemia. With our eligibility criteria, conditioning regimen and prophylaxis of graft-versus-host disease, the main obstacles to successful transplant were represented by graft failure and fatal acute GVHD. Keywords: cord blood; leukemia; children; transplantation The majority of children and a significant proportion of adults with acute leukemia may be cured of their disease by standard treatments which do not include up-front allogeneic BMT. However, some patient categories are predicted to have a dismal outcome and may be salvaged by supralethal chemoradiotherapy followed by allogeneic BM rescue. Alternative sources of hemopoietic stem cells might be exploited in patients lacking an HLA-matched related or unrelated BM donor.Hemopoietic progenitor cells have been recognized in the umbilical cord blood (UCB) since 1974. 1 Thereafter, Correspondence: Dr W Arcese, Cattedra di Ematologia, via Benevento 6, 00161 Roma, Italy Received 11 September 1998; accepted 29 October 1998 many studies suggested that the UCB could be employed for transplantation, 2 and finally the first UCB transplant was successfully performed in a patient with Fanconi anemia in 1988. 3 The indication for a UCB transplant extended rapidly from patients with an HLA-matched or -mismatched sibling donor 4 to candidates for transplantation from unrelated donors. [5][6][7] As an alternative to international bone marrow donor registries, the expansion of UCB banks both in Europe and in North America opened new perspectives of transplantation for a significant proportion of leukemic patients lacking an HLA-matched related donor. [8][9][10] Therefore since April 1995 we adopted a policy of searching stem cell sources in UCB banks for patients with high risk leukemia. So far, 14 patients prepared with an identical regimen of conditioning and GVHD prophylaxis have been submitted to an HLA-mismatched unrelated UCB transplant. Five of these patients (UPN 300, UPN 312, UPN 324, U...

Tacrolimus for prevention of graft-versus-host disease after mismatched unrelated donor cord blood transplantation

“…The pool of potential donors has also recently expanded with the introduction of unrelated donor cord blood transplantation (CBT). [1][2][3][4][5] An unexpected advantage of CBT was the lower risk of acute graft-versus-host disease (GVHD) in comparison to marrow or mobilized peripheral blood stem cell transplantation. 6 This is thought to result from the relative immaturity of the T cells in cord blood.…”

“…7,8 However, the incidence of acute GVHD with CBT from HLA-mismatched unrelated donors remained substantial (38-73%), and the associated treatment-related mortality has limited long-term outcome. [1][2][3][4][5][6] Tacrolimus is an immunosuppressive macrolide lactone that inhibits the effects of calcineurin in the earliest steps of T cell activation, a mechanism of action similar to that of cyclosporine, but the potency of tacrolimus in vitro is more than 100 times that of cyclosporine. 9 This suggested that tacrolimus might be more effective than cyclosporine as GVHD prophylaxis in high-risk settings.…”

Pre-transplant prognostic factors for patients with high-risk leukemia undergoing an unrelated cord blood transplantation

“…Cord blood represents the most recent source of hematopoietic stem cells used in the unrelated transplant setting for patients who lack a related HLA compatible donor. [1][2][3][4][5][6][7][8][9][10][11][12] Two comparative studies have shown that, in children, unrelated cord blood transplant (CBT) is an acceptable alternative to unrelated bone marrow (BM) transplant. 13,14 Furthermore, three recent reports from either multicentric 9 or unicentric 10,12 experiences suggest that CBT could be considered a reasonable alternative also in adults provided that an adequate number of nucleated cells (NC) is infused.…”

“…6 Growth factors were not intentionally used in our patients. However, patients with neuthrophil counts o0.2 Â 10 9 /l and marrow cellularity o5% by day 25 after transplant received granulocyte colony-stimulating factor (G-CSF, Lenograstim, Aventis-Pharma) at the dose of 5 mg/kg daily.…”

“…Out of them, 14 have been previously reported. 6 Transplant procedures CB units were provided by the cord blood banks of GRACE, Italy (Milano, Roma, Torino, Firenze, Padova)…”