Outcome following unrelated cord blood transplant in 136 patients with malignant and non-malignant diseases: a report from the Australian and New Zealand children's haematology and oncology group.

Unrelated umbilical cord blood (UCB) is an alternative stem cell source for paediatric patients lacking a matched related or unrelated marrow donor. We report the results of all paediatric unrelated UCB transplants performed in Australia and New Zealand over a 10-year period. A total of 135 patients were transplanted, 100 for malignant disease (74%) and 35 for non-malignant disorders. The majority (88%) of patients received an HLA-mismatched graft. The median infused total nucleated cell dose was 4.7 x 10(7)/kg and CD34+ count 1.9 x 10(5)/kg. Neutrophil engraftment occurred in 83% of patients by day 42 (median 23 days) and platelet engraftment in 55% by day 60 (median 56 days). Grades II-IV and III-IV acute GVHD occurred in 41 and 18% of patients, respectively. TRM and overall survival 1-year post transplant were 32 and 61%, respectively. A higher probability of neutrophil recovery (P=0.004) and faster time to recovery (median 18 days vs 26 days, P=0.008) were observed in recipients of a cord unit with a CD34 cell dose >or=1.7 x 10(5)/kg. Our results support selection of cord units with CD34 cell doses >or=1.7 x 10(5)/kg to promote faster engraftment, improve survival and lower TRM.

Long-term outcomes in children with high-risk neuroblastoma treated with autologous stem cell transplantation.

We retrospectively analysed the outcomes of children transplanted for high-risk neuroblastoma (NB) at a single institution predominantly transplanted with total body irradiation and chemotherapy. The aims of this study were to determine the prognostic impact of clinical and biological features and to document long-term health outcomes. Forty patients were transplanted with a single unpurged autograft. Fourteen patients died from disease progression and two from late complications of treatment. Twenty-three patients are alive at a median of 4.6 years from diagnosis. Kaplan-Meier estimates of overall survival at 2, 5 and 10 years are 76+/-7.0, 60.2+/-8.4 and 54.7+/-9.3% following transplant. Response to induction therapy was significantly associated with survival (P<0.01). Long-term complications included growth (100%) and pubertal failure (83%), hearing impairment (73%), orthopaedic complications (63%), renal impairment (47%) and thyroid abnormalities (36%). Intrinsic and acquired resistance to chemotherapy remains the major obstacle to improving outcomes in high-risk NB. Although patients with chemo-sensitive disease are less likely to experience a relapse, substantial therapy-related toxicities result in poor long-term health outcomes for survivors.

Allogeneic bone marrow transplant improves outcome for juvenile myelomonocytic leukaemia.

OBJECTIVE: To correlate clinical presentation and therapeutic outcomes in children with a diagnosis of juvenile myelomonocytic leukaemia. METHODS: The medical records of 14 children who fulfilled the International Juvenile Myelomonocytic Leukaemia Working Group Criteria for a diagnosis of juvenile myelomonocytic leukaemia (JMML) presenting to a single institution were reviewed, and their clinical status at September 2000 was documented. RESULTS: The most common presenting features were hepatosplenomegaly and lymphadenopathy. Fifty per cent of cases presented in the first year of life. Nine of 14 patients initially received chemotherapy otherwise used in the treatment of acute myeloid or lymphoblastic leukaemia with no apparent benefit. All six patients who received conditioning therapy with chemotherapy alone, followed by allogeneic bone marrow transplant (BMT), are in complete remission at a median follow-up duration of 12 months (range 5-91 months). Five of six patients surviving post-allogeneic BMT received marrow from an unrelated donor. Only one of seven patients who did not receive BMT survived long-term. CONCLUSION: Children with a diagnosis of JMML should be treated with allogeneic BMT as soon as a suitable donor is found. The role of anti-leukaemic therapy in this disease, prior to BMT, requires further investigation in the context of a multicentre clinical trial.

Prolonged ex vivo culture of cord blood CD34(+) cells facilitates myeloid and megakaryocytic engraftment in the non-obese diabetic severe combined immunodeficient mouse model.

A clinical goal for ex vivo expansion of cord blood (CB) CD34(+) cells is to shorten the period of neutropenia and thrombocytopenia following myeloablative therapy and transplantation. Prolongation of cytokine expansion leads to the production of greater numbers of cells, and should have an impact on neutrophil and platelet recovery. Furthermore, expansion of CD34(+) cells should support the continued production of neutrophils and platelets in the 6-week period following transplantation. We tested these hypotheses by characterization of the kinetics (human CD45(+) cells in the blood) and phenotype (CD45, CD34, CD61, CD33, CD19 and CD3) of human engraftment in the non-obese diabetic severe combined immunodeficient mouse (NOD-SCID) following 7 or 14 d of ex vivo expansion of CB CD34(+) cells. Mice transplanted with 14 d cells showed greater percentages of human CD45(+) cells in the blood, bone marrow and spleen than mice transplanted with unexpanded cells or 7 d cells. Prolonging cytokine exposure of CD34(+) cells and transplantation with increasing numbers of input cells facilitated the production of absolute numbers of CD34(+), CD33(+), CD61(+) and CD19(+) cells in vivo. Furthermore, analysis of SCID engrafting potential showed that prolongation of culture duration facilitates in vivo expansion of CD45(+), CD34(+) and CD19(+) cells after transplantation. It is anticipated that prolonged (2 weeks) ex vivo culture of CB will have a beneficial clinical effect.

Prior cryopreservation of ex vivo-expanded cord blood cells is not detrimental to engraftment as measured in the NOD-SCID mouse model.

Cytokine-mediated expansion has been proposed and successfully used to facilitate engraftment post transplantation. This study examined whether cryopreservation following expansion has a detrimental effect on the ability of cells to engraft, using the NOD-SCID mouse model. Cord blood (CB) CD34(+) cells were incubated for 7 days with stem cell factor (SCF), flt-3 ligand (FL), and megakaryocyte growth and development factor (MGDF). Expanded CD34(+) cells were transplanted into NOD-SCID mice either fresh or following cryopreservation and thawing. After thawing, recovery of nucleated cells was 94%, of CD34 cells was 63%, and of day-14 progenitors was 17%. The loss of day-14 progenitor cells among the thawed expanded cells did not influence the kinetics of human engraftment in the mouse. Bone marrow (BM) of mice transplanted with thawed expanded CD34(+) cells (14 +/- 3.9%) showed significantly higher levels of human engraftment than mice transplanted with fresh expanded CD34(+) cells (1.5 +/- 0.5%, p = 0.0064). Thawed expanded CD34(+) cells had significantly higher SCID Engrafting Potential (SEP) than freshly expanded CD34(+) cells (p < 0.001). Results suggest that prior cryopreservation does not prevent expanded cells engrafting in NOD-SCID mice.

Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission.

Allogeneic bone marrow transplantation is an effective postremission strategy for patients with acute myelogenous leukemia (AML) in first complete remission (CR). The value of administering consolidation chemotherapy before human leukocyte antigen (HLA)-identical sibling transplantation is not established. Outcomes of patients with AML in first CR receiving no consolidation therapy, standard-dose cytarabine consolidation therapy, and high-dose cytarabine consolidation therapy before HLA-identical sibling transplantation were compared. Five-year treatment-related mortality rates were 30% (95% confidence interval [CI], 18% to 42%) in patients receiving no consolidation chemotherapy, 22% (95% CI, 17% to 28%) in those receiving standard-dose cytarabine consolidation, and 24% (95% CI, 17% to 31%) in those receiving high-dose cytarabine (P = NS). Five-year cumulative incidences of relapse were 19% (10% to 30%), 21% (16% to 27%), and 17% (11% to 24%), respectively (P = NS). Five-year probabilities of leukemia-free survival were 50% (36% to 63%), 56% (49% to 63%), and 59% (50% to 66%), respectively (P = NS). Five-year probabilities of overall survival were 60% (46% to 71%), 56% (49% to 63%), and 60% (51% to 67%), respectively (P = NS). The data indicate that postremission consolidation with cytarabine before allogeneic transplantation for AML in first CR is not associated with improved outcome compared to proceeding directly to transplantation after successful induction. (Blood. 2000;96:1254-1258)

Conditions that enable human hematopoietic stem cell engraftment in all NOD-SCID mice.

BACKGROUND: Transplantation of human hematopoietic stem cells is the only true test of their long-term repopulation potential. Models are readily available to evaluate murine hematopoietic stem cells, but few exist that allow reliable quantification of human stem cells. The non-obese diabetic-severe combined immunodeficient (NOD-SCID) mouse model enables quantification of human hematopoietic stem cells, but the conditions that permit human engraftment in all animals have yet to be defined. The aims of the project were, therefore, to describe the variables that allow human engraftment in the NOD-SCID mouse model and the techniques that accurately quantify this engraftment. METHODS: NOD-SCID mice that had or had not received 250, 325, or 400 cGy irradiation received cord blood (CB) mononuclear or CD34+ cells i.v. or i.p. Mice were killed 6 weeks after transplantation, and the bone marrow, spleen, and thymus were harvested. Four-color flow cytometric analysis, semi-quantitative PCR, myeloid and erythroid progenitor, and stem cell assays were used to monitor human engraftment. RESULTS: A 250 or 325 cGy and i.v. injection of CB mononuclear or CD34+ cells is required to detect multilineage human engraftment in the bone marrow, spleen, or thymus of NOD-SCID mice. Four-color flow cytometric analysis and semi-quantitative PCR enable accurate detection of 0.1% human cells. Progenitor and stem cell assays provide functional information about the engrafted cells. CONCLUSIONS: Successful development of the NOD-SCID mouse model and techniques to assess human engraftment now allow it to be used reliably to analyze the effects of short-term cytokine exposure on the long-term repopulating capacity of CB stem cells.

Haemophagocytic lymphohistiocytosis in children.

OBJECTIVE: To evaluate the clinical and diagnostic features of children presenting with haemophagocytic lymphohistiocytosis (HLH), evolution of the disease and outcomes in response to treatment. METHODOLOGY: The medical records of 12 children, aged 5 weeks to 13 years at diagnosis, with HLH managed at a single institution were reviewed. RESULTS: Presenting features were fever, hepatosplenomegaly, pancytopenia and hypertriglyceridemia or hypofibrinogenemia. Nine patients (75%) developed central nervous system (CNS) disease. Only one child with CNS disease survived. Five children had complete responses to therapy (42%), but all relapsed at a median of 1.5 months after starting treatment (range 2 weeks to 5 months). Two of the children treated are long-term survivors (17%), both after allogeneic bone marrow transplantation. All deaths occurred in the context of active disease. CONCLUSIONS: Haemophagocytic lymphohistiocytosis is a disease with a poor prognosis. Central nervous system complications are common and response to treatment usually is transient. This study provides support for the use of immunomodulatory therapy for remission introduction followed by consideration of allogeneic bone marrow transplantation.

Acquired autoimmune thrombocytopenia post-bone marrow transplantation for severe combined immunodeficiency.

Children with severe combined immunodeficiency (SCID) have profoundly diminished humoral and cellular immunity resulting in death during infancy unless immune reconstitution occurs by bone marrow transplantation (BMT). Thrombocytopenia post-bone marrow transplantation can be seen in relation to infection, graft-versus-host disease (GVHD) and rarely, as an autoimmune phenomenon due to immune dysregulation. We report two cases of severe AITP following BMT for SCID. Both cases developed large intracerebral hemorrhages from which one died. Autoimmune thrombocytopenia in this setting can be life-threatening and we recommend early and active intervention.

Graft-versus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia.

T and B lineage ALL cells express different levels of HLA-class II antigens, which may serve as targets for graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). The object of this study was to determine whether GVL effects after HLA-identical sibling bone marrow transplantation differed in T and B lineage ALL. We studied 1132 patients with ALL of T lineage (n = 416) or of B lineage (cALLa+) (n = 716) transplanted in first (n = 605) or second (n = 527) remission with bone marrow from an HLA-identical sibling donor, between 1982 and 1992, and reported to the IBMTR by 165 teams. Cox proportional hazards regression models were used to determine the relative risk (RR) of relapse in patients with acute (grades II-IV) or chronic GVHD vs patients without GVHD. Acute and chronic GVHD were considered as time-dependent covariates. Patients transplanted in first and second remission were analyzed separately. GVHD decreased relapse risks to a similar extent in T and B lineage ALL. For first remission transplants, relative risks of relapse for patients with vs those without GVHD was 0.34 for T lineage ALL and 0.44 for B lineage ALL. Corresponding relative risks in second remission transplants were 0.54 and 0.61. This study confirms earlier findings of an antileukemia effect of GVHD in ALL. This effect was similar in T lineage and B lineage ALL, despite probable differences in HLA-class II antigen expression.

Cytokine-mediated expansion does not deplete cord blood cells with stem cell characteristics.

Cord blood (CB) has been successfully used to regenerate the hematopoietic system after myeloablative therapy. We investigated whether cytokine mediated expansion depletes CB of cells with stem cell characteristics. CB mononuclear cells (MNC) were enriched for quiescent (primitive) stem cells by incubation with 25 micrograms/ml 5-Fluorouracil (5-FU) and control CB MNC were incubated with media alone. Cells were then incubated for 7 days with Interleukin-1 (IL1)+IL3+Stem Cell Factor (SCF) and progenitor content, cell cycle status, nucleated cell count, immunophenotype and resistance to 25 micrograms/ml 5-FU (primitive stem cells) were evaluated before and after cytokine exposure. Incubation with IL1+IL3+SCF caused an increase (fold expansion) in committed (28.6 +/- 8.1), immature (5.8 +/- 1.8), and primitive progenitors (4.1 +/- 0.8) among control CB MNC compared to a decrease in committed progenitors (0 +/- 0) but an increase in both immature (8.4 +/- 4.8) and primitive progenitors (7 +/- 2.9) among 5-FU resistant CB MNC. An increase in the proportion of CD34+ cells occurred in both fractions. Expanded control CB MNC showed a significant increase in numbers of 5-FU resistant committed (p = 0.024), immature (p = 0.014) and primitive progenitors (p = 0.01) as compared with fresh CB MNC. Re-exposure of 5-FU resistant expanded CB MNC to 5-FU shows growth of some immature and primitive progenitors. Cytokine-mediated expansion of untreated and quiescent CB cells is possible and cytokine-mediated expansion does not deplete CB cells with stem cell characteristics.

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings.

PURPOSE: To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS: A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS: Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION: Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia conditioned with busulfan, cyclophosphamide and melphalan.

Children with acute lymphoblastic leukemia (ALL) undergoing allogeneic bone marrow transplantation (BMT) using total body irradiation (TBI)-containing conditioning regimens are at risk of substantial late sequelae affecting growth and endocrine functions. This has lead to the use of non-TBI or chemotherapy conditioning regimens for ALL patients in many centers. However, it is unknown whether chemotherapy conditioning results in improved antileukemic efficacy or reduced transplant-related toxicity. We report our experience using a chemotherapy conditioning regimen (busulfan (Bu), cyclophosphamide (CY) and melphalan (Mel)) in 26 consecutively enrolled children with ALL (group I). At a median follow-up of 58 months, event-free survival (EFS) for Bu/CY/Mel-treated patients was 27% (+/- 8.7), while the leukemic relapse rate was 49% (+/- 13). Regimen-related toxicity was severe in these patients: overall treatment-related mortality was 42%, while 50% of patients had interstitial pneumonitis and 35% of patients had severe hemorrhagic cystitis. A historical control group of 25 consecutively enrolled patients, mostly treated with TBI-containing regimens (group II), had an EFS of 36% (+/- 9.6%) and a leukaemic relapse rate of 45% (+/- 11) at a median follow-up of 117 months. We conclude that the Bu/CY/Mel conditioning regimen leads to severe transplant-related toxicity and did not significantly improve leukemic relapse rates.

Successful bone marrow transplantation in a child with X-linked chronic granulomatous disease.

A 16-month-old Aboriginal boy was diagnosed with chronic granulomatous disease (CGD) when he presented with frequent significant infections from the age of 12 months. BMT was performed from a HLA-matched sibling after conditioning with busulphan, cyclophosphamide, etoposide and antithymocyte globulin. A small bowel obstruction developed in the first week and settled with conservative treatment. VOD occurred in the third week, resolving after treatment with tissue plasminogen activator. Sustained engraftment has occurred, as indicated by return of the nitroblue tetrazolium (NBT) test to normal when performed at 11 weeks and 7 months post-BMT. No further infections have occurred. BMT can be successfully performed for CGD. Complications occurring post-BMT may be related to the underlying disease (CGD). BMT remains an attractive option for CGD in children who have a matched sibling donor.

Late diagnosis and correction of purine nucleoside phosphorylase deficiency with allogeneic bone marrow transplantation.

A 5-year-old boy with spastic quadriplegia, T cell immunodeficiency, hypouricemia and immune cytopenias from age 8 months, was found to have purine nucleoside phosphorylase (PNP) deficiency, and developed chronic lung disease. Successful matched sibling BMT for PNP deficiency has not previously been reported. BMT using marrow from an HLA-identical sibling donor was performed after conditioning with busulfan (16 mg/kg), cyclophosphamide (200 mg/kg), melphalan (90 mg/m2) and anti-thymocyte globulin (36 mg/kg). T lymphocyte numbers, PNP activity and uric acid levels rapidly improved and he remains well 12 months after transplant.

Autologous bone marrow transplantation for advanced neuroblastoma using teniposide, doxorubicin, melphalan, cisplatin, and total-body irradiation.

BACKGROUND: Disseminated neuroblastoma after infancy has a dismal prognosis; long-term survival with conventional therapy occurs in approximately 10% of cases. PATIENTS AND METHODS: Between 1985 and 1992, we followed a strategy aimed to achieve remission with an induction combination of intensive chemotherapy, primary resection, and tumor-bed radiotherapy (TBRT). Patients who achieved remission proceeded to myeloablative chemoradiotherapy and unpurged autologous bone marrow transplant (ABMT). Twenty-eight patients older than 1 year presented with stage IV disease during the study period; six died of progressive disease and three died of complications of therapy. Nineteen patients achieved remission, two of whom did not receive ABMT. Seventeen patients proceeded to ABMT. Conditioning was with teniposide 130 mg/m2, doxorubicin 30 mg/m2, melphalan 120 mg/m2, cisplatin 80 mg/m2, and total-body irradiation 12 Gy in six fractions (modified VAMP-TBI). RESULTS: Principal nonhematologic toxicities were mucositis and diarrhea. There were no ABMT-related deaths. Two patients relapsed at 8 and 26 months post-ABMT, respectively. Fifteen patients remain in complete remission (CR) at 24 to 102 months (median, 71) from ABMT and 30 to 114 months (median, 78) from diagnosis. Survival rates of all 28 patients are 61% and 50% at 2 and 5 years, respectively, and the disease-free survival (DFS) of the ABMT group is 94% and 87% at 2 and 5 years, respectively. CONCLUSION: Modified VAMP-TBI appears to be an effective conditioning regimen, with 15 of 17 patients remaining disease-free, with no toxic deaths. This result compares favorably with that of other groups. Larger numbers of patients need to be treated to confirm the efficacy of this therapy.

Bone marrow transplantation for Fanconi anemia.

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Common presentations and management of leukaemia in childhood.

The curability of childhood leukaemia (acute lymphoblastic, acute non lymphoblastic and chronic myeloid) has improved dramatically over the past 25 years. The author reviews the clinical presentations and current therapeutic approaches in broad principle. The importance of supportive care (both at the time of diagnosis and during therapy) and the potential for long-term side effects relevant to adult life are discussed.

Allogeneic and autologous bone marrow transplantation for acute non-lymphoblastic leukaemia.

Bone marrow transplantation (BMT) has had an increasing role in the treatment of acute nonlymphoblastic leukaemia (ANLL). A review of patients transplanted between May 1975 and August 1991 was undertaken in order to evaluate problems and outcome, and examine the role of both autologous and allogeneic BMT at various stages in the treatment of ANLL. Forty-seven patients received either an allogeneic (n = 24) if a suitable donor was identified or autologous (n = 23) BMT if there was no allogeneic donor. Conditioning therapy consisted of total body irradiation (TBI) and cyclophosphamide (n = 14) or busulfan and cyclophosphamide (n = 33) with or without melphalan. Graft-versus-host disease prevention was with methotrexate (n = 9), methotrexate and cyclosporin (n = 10) or T cell depletion (n = 5). Minimum follow-up for surviving patients was 24 months (median 65 months). For patients transplanted in first remission there was a 0% and 9 +/- 6% transplant-related mortality, a 37 +/- 11% and 33 +/- 12% relapse risk and a 63 +/- 11% and 63 +/- 12% event-free survival for autologous and allogeneic BMT, respectively. In second remission, there was a 14% mortality, 50 +/- 20% relapse risk and 43 +/- 19% event-free survival for allogeneic BMT. No patient transplanted in relapse survived. In patients who survived greater than 24 months, late side effects were noted in all 8 (100%) patients given TBI and in 2 of 19 (10.5%) given busulfan.(ABSTRACT TRUNCATED AT 250 WORDS)