We prospectively studied immune reconstitution in 102 children who underwent T-lymphocyte depleted bone marrow transplants using either closely matched unrelated donors or partially matched familial donors by assaying total lymphocyte counts (TLC), T-cell subsets, B cells, and natural killer cells. TLC, CD3+, and CD4+ T-cell counts remained depressed until 2 to 3 years posttransplant, whereas CD8+ T-cell counts normalized by 18 months, resulting in an inverted CD4:CD8 ratio until 12 months posttransplant. Although the percentage of NK cells was elevated early posttransplant, their absolute numbers remained normal. CD20+ B cells were depressed until 12 to 18 months posttransplant. Factors affecting immunophenotypic recovery were analyzed by nonparametric statistics. Younger patients tended to have higher TLC posttransplant. Higher marrow cell doses were not associated with hastened immunophenotypic recovery. Graft-versus-host disease (GVHD) and/or its treatment significantly delayed the immune reconstitution of CD3+, CD4+, and CD20+ cells. The presence of cytomegalovirus was associated with increased CD8+ counts and a decrease in the percentages of CD4+ and CD20+ cells.

Severe hemorrhagic cystitis developed in 6 children after marrow transplantation, 3 of whom had a viral etiology. All 6 patients received instillations of prostaglandin E1 directly into the bladder and 5 of the 6 had complete resolution of hematuria. This finding contrasts with our previous experience with severe hemorrhagic cystitis, particularly the type due to a viral infection, persisting in the face of numerous bladder manipulations. We encourage the use of this nontoxic treatment to gain further information regarding its effect on the bladder epithelium. The mechanism of action remains completely unknown.

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Relapse after allogeneic hematopoietic SCT (HSCT) carries a poor prognosis and is a common cause of death. Outcomes of children who relapse post HSCT are not well known. In this retrospective multicenter study we included 532 patients who underwent allogeneic HSCT and examined the outcomes of 160 patients (30%) who relapsed. Treatment options after relapse included (i) palliative therapy with non-curative intent (n ¼ 43), (ii) salvage chemotherapy (without a second HSCT, n ¼ 55) or (iii) salvage chemotherapy followed by a second HSCT (n ¼ 62). Sixty two patients underwent a second HSCT. The 1-year disease-free survival (DFS) for those given palliative therapy, chemotherapy alone and who underwent a second transplant was o1%, 9% and 50% (P ¼ o0.0001), respectively. The DFS at 1 and 2 year was 50% and 35%, respectively, among the patients who received a second transplant versus 9% and 2% in those who did not (P ¼ o0.0001). In multivariable analysis longer time to relapse (P ¼ 0.04) and undergoing a second HSCT (Po0.001) were associated with improved outcome. Withdrawal of immunosuppressive therapy, followed by curative intent chemotherapy should be offered to all patients who relapse after an allogeneic HSCT. A second HSCT should be considered, especially in patients who respond to salvage chemotherapy. INTRODUCTIONRelapse of the primary malignancy after HSCT is a common cause of transplant failure. According to the Center for International Blood and Marrow Transplantation and Research data, relapse accounts for 41% of deaths after matched-sibling donor HSCT and 34% of deaths after unrelated-donor HSCT. 1 In the recent European Bone Marrow transplantation report on behalf of the acute leukemia working party, the 5-year OS was 8 ± 1% for adults who experience relapse post-transplant. 2 Similarly, patients who experience relapse after reduced intensity conditioning (RIC) HSCT, have a 2-year OS of 29%. 3 Second allogeneic HSCT has always been considered a potential treatment option for patients who relapse following their first transplant. In a retrospective study of 150 adult patients who underwent a second HSCT, the reported 5-year OS and disease-free survival (DFS) were 32% and 30%, respectively; the risks of relapse and a non-relapse mortality (NRM) were 44% and 45%, respectively. 4 Kurosawa et al. 5 from Japan reported that the 1-year OS after post-transplant relapse was significantly better at 58% in patients who had a second HSCT as compared with 14% in the cohorts who got chemotherapy or no intervention with curative intent. They concluded that for patients who relapse after transplant, successful re-induction chemotherapy and a second HSCT may be effective for prolonging survival without excessive NRM. While the overall prognosis of patients relapsing after a RIC HSCT is poor, interventions such as the combined use of immunotherapy and chemotherapy can improve patient

Summary:The utility of bone marrow transplantation for childhood leukemia in patients unable to achieve a remission prior to transplant is controversial. To address this issue, we analyzed a subset of patients with advanced leukemia entered on prospective transplant trials at our hospital. Fifty-eight patients with ALL or AML (age 1-19) were identified. They had failed standard chemotherapy and were in relapse (22 in 1st, 27 in 2nd, three in 3rd, and three in 4th) or had never achieved an initial remission (three) at the time of transplant. Fifty-two patients received marrow from mismatched family members (haplo or DR-identical), while six received marrow from matched siblings. Most patients received myeloablative therapy consisting of total body irradiation, etoposide, cyclophosphamide, and cytosine arabinoside. Marrow from mismatched donors was T cell depleted. Only one of 52 patients transplanted with a mismatched donor survived long-term while three of six patients transplanted in relapse with a fully matched sibling donor are alive 6-10 years post BMT. The major causes of death were infection (39%) and relapse (28%). Acute GVHD grade III-IV was noted in 7% of patients. A comparable group of patients with leukemia transplanted at our center in remission using similarly mismatched family member donors (haplo or DR-identical) had an event-free survival of 28%. In conclusion, our data suggest that BMT utilizing mismatched family member donors is a poor option for patients in relapse at the time of transplant. New treatment strategies need to be developed to effectively manage these patients. Bone Marrow Transplantation (2000) 25, 943-948. Keywords: relapsed leukemia; BMT; mismatched donors Bone marrow transplantation (BMT) is increasingly utilized as an aggressive therapeutic option in children with relapsed or high-risk leukemia, although there is significant