Chemotherapy-induced nausea and vomiting: antiemetic trials that impacted clinical practice.

OBJECTIVE: to review the scientific evidence related to serotonin and substance P and the clinical impact targeting these two neurotransmitters have had managing chemotherapy-induced nausea and vomiting (CINV). DATA SOURCE: a PubMed search (January 1968 to December 2008), restricted to English-language publications, was conducted using the key words antiemetics, cancer chemotherapy, cisplatin, serotonin, substance P, NK(1), and 5-HT(3). Abstracts emanating from the meetings of the American Society of Clinical Oncology and Multinational Association of Supportive Care in Cancer during the period May 2000 to June 2008 were also reviewed. DATA SYNTHESIS: two important outcomes emanated from well-conducted antiemetic clinical trials (Table 1): first, evidence that serotonin and substance P are major mediators of acute and delayed symptoms and second, improved, though not complete, control of CINV. CONCLUSION: serotonin-type 3 and neurokinin-1 receptor antagonists are the most effective agents currently available. In most cases, these agents are used in conjunction with glucocorticoids. The use of these three types of agents is incorporated into current clinical practice guidelines. Further understanding of the biological and biochemical basis of nausea and vomiting may enhance management of this potentially debilitating adverse effect.

Intensification of therapy for children with lower-risk acute lymphoblastic leukemia: long-term follow-up of patients treated on Children's Cancer Group Trial 1881.

PURPOSE: From December 1988 through December 1992, the Children's Cancer Group (CCG) conducted a randomized trial (CCG-1881) designed to evaluate the impact of adding a single delayed intensification phase of therapy to standard therapy for patients with newly diagnosed low-risk acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients (n = 778) with newly diagnosed ALL, 2 to 9 years of age at diagnosis with an initial WBC count less than 10,000/microL, were eligible for this protocol. All patients received induction, consolidation, and interim maintenance phases of therapy over the first 16 weeks. At week 16, patients remaining in remission were randomly assigned to receive or not receive a single 7-week delayed intensification (DI) phase of therapy. Maintenance therapy was given in lieu of or after DI, with total duration of therapy approximately 3 years for boys and 2 years for girls. RESULTS: Patients randomized to receive DI experienced fewer relapse events in all categories. Kaplan-Meier life-table estimates for continuous complete remission (CCR) at 7 years for the randomized regimens were 77% (SE, 2.4%) for the standard regimen and 83% (SE, 2.7%) for the DI regimen (P =.072). The only prognostic factor of significance post-randomization in this selected low-risk population was the day 14 marrow response (P =.0001). CONCLUSION: The addition of a single DI phase of therapy was well tolerated and augmented 7-year CCR by 6% (SE of the difference, 3.3%), resulting in 26% fewer adverse events. Overall survival for eligible patients at 7 years is 90% (SE, 1.2%).

Human granulocyte colony-stimulating factor in children with high-risk acute lymphoblastic leukemia: a Children's Cancer Group Study.

PURPOSE: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on hematopoietic toxicities, supportive care requirements, time to complete intensive therapy, and event-free survival (EFS) and overall survival (OS) in children with high-risk acute lymphoblastic leukemia (HR-ALL). PATIENTS AND METHODS: A total of 287 children with HR-ALL were randomly assigned to intensive chemotherapy regimens (New York I [NY I] or NY II) as part of the Children's Cancer Group (CCG)-1901 protocol. The induction phases consisted of five drugs (vincristine, prednisone, l-asparaginase, daunorubicin, and cyclophosphamide). Initial consolidation comprised six-agent chemotherapy combined with 18 Gy of total-brain irradiation. Patients were randomly assigned to receive G-CSF (5 microg/kg/day) during either induction or initial consolidation. A crossover study analysis was done on the 259 patients who completed both phases of therapy. RESULTS: The mean time to neutrophil recovery (>/= 0.5 x 109/L) was reduced with G-CSF (16.7 v 19.1 days, P =.0003); however, patients who received G-CSF did not have significantly reduced episodes of febrile neutropenia (149 v 164, P =.41), positive blood cultures (57 v 61, P =.66), or serious infections (75 v 79, P =.62). Hospitalization (14.0 v 13.9 days, P =.87) and induction therapy completion times (NY I, 30.3 v 31.3 days, P =.11; NY II, 33.4 v 32.3 days, P =.40) were not significantly altered. There were no differences in 6-year EFS (P =.24) or OS (P =.54) between patients receiving or not receiving G-CSF on CCG-1901, NY I and NY II. CONCLUSION: Children with high-risk ALL do not appear to benefit from prophylactic G-CSF.

Diagnostic X-rays and ultrasound exposure and risk of childhood acute lymphoblastic leukemia by immunophenotype.

The objective of this study was to evaluate the association between in utero diagnostic X-rays and childhood acute lymphoblastic leukemia (ALL) and the less well-studied relationship of this malignancy to preconception and postnatal diagnostic X-rays or fetal ultrasound exposures. The Children's Cancer Group conducted a case-control study including interviews with parents of 1842 ALL cases diagnosed under the age of 15 years and 1986 individually matched controls. Associations of self-reported parental preconception, in utero, and postnatal X-ray exposure with risk of childhood ALL were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs) obtained from logistic regression models among the overall group of ALL cases as well as immunophenotypic and age-specific subgroups. Overall, in utero pelvimetric diagnostic X-rays were not associated with the risk of pediatric ALL (OR, 1.2; 95% CI, 0.8-1.7). Childhood ALL, all types combined (OR, 1.1; 95% CI, 0.9-1.2) and specific types were also not linked with postnatal diagnostic X-ray exposures. Neither maternal (OR, 0.9; 95% CI, 0.8-1.2) nor paternal (OR, 1.1; 95% CI, 0.8-1.4) lower abdominal preconception diagnostic X-rays were associated with risk of childhood ALL. Among the multiple comparisons for age-, sex-, and subtype-specific subgroups, we observed an elevated risk of total ALL among children ages 11-14 at diagnosis (OR, 2.4; 95% CI, 1.1-5.0) in relation to in utero pelvimetric diagnostic X-ray exposures and a small increase in pre-B ALL for all ages combined (OR, 1.7; 95% CI, 1.1-2.7) in relation to postnatal diagnostic X-rays. In utero diagnostic ultrasound tests were not linked with risk of childhood ALL. We found little consistent evidence that in utero diagnostic ultrasound tests or X-rays were linked with an increased risk of childhood ALL. Small increases in total or pre-B ALL risks for children in selected age groups to very low ionizing radiation exposures from postnatal or preconception diagnostic X-ray exposures may represent chance findings or biases. Future studies of diagnostic X-rays and childhood leukemia in the United States will require extensive additional efforts and resources to quantify risk because of declining in utero exposures in the general population (thus necessitating large numbers of subjects, particularly cases) and the difficulty in validating reported exposures.

Effects of an inadvertent dose of cytarabine in a child with Fanconi's anemia: reducing medication errors.

We report the case of a 7-year-old boy with Fanconi's anemia, who underwent a bone marrow transplant using an unrelated donor, and who received an inadvertent dose of cytarabine (cytosine arabinoside). The cytarabine was given by mistake 6 months following transplant. This caused excessive toxicity to many systems, including the pulmonary and renal systems. The patient recovered from the episode, but this article further highlights the acute adverse effects of cytarabine. Furthermore, it is the first report of excessive toxicity to cytarabine in a child with Fanconi's anemia. The article also highlights the problems of medication administration errors, particularly in those exquisitely sensitive to the effects of toxic drugs.

Severe aplastic anemia associated with hepatitis and complicated by pulmonary aspergillosis: response to immune suppression and antifungal therapy.

The true etiology of severe aplastic anemia is unknown; however, autoimmune activation of T-lymphocytes is one of the potential causes. Stem cell transplantation is regarded as a first line therapy if a fully matched sibling is available. Immunosuppressive therapy is reserved for those who have no matched sibling available for transplant, or for those individuals who fall outside the age range eligible for stem cell transplantation. This case describes a child with a hepatitis-associated severe aplastic anemia for whom a fully matched sibling was available but a transplant was postponed due to active hepatitis. While awaiting bone marrow transplantation, the child acquired a life-threatening aspergillosis infection treated with amphotericin B, granulocyte infusions, and surgical resection of the involved lung. A decision was made to proceed with immunosuppressive therapy while waiting for successful treatment of the fungal infection. Following administration of equine anti-thymocyte globulin (ATG), high dose granulocyte colony stimulating factor (G-CSF), cyclosporine, and steroids, the child had partial hematopoietic reconstitution and is now followed in our clinic. This case demonstrates the extraordinary multidisciplinary care required during the early phases of treating severe aplastic anemia. With such care, recovery is a possibility.

Ten-year survival of children with acute lymphoblastic leukemia: a report from the Children's Oncology Group.

The Children's Cancer Group initiated risk-based allocation for childhood acute lymphoblastic leukemia 3 decades ago. Long-term survival data (minimum follow-up >10 years) is now available. About 3711 eligible children were enrolled in risk-adjusted treatment protocols (1983-1989). Ten-year event-free survival (EFS) and overall survival were 62% (standard deviation [SD] = 1%) and 73% (SD = 1%). These data showed a significant improvement (P < 0.0001) compared with the predecessor studies. Since 11% of patients with initial relapses survived without second events, these data predicted a cure rate of 73%. Ten-year EFS and survival were improved significantly for patients with intermediate risk (P < 0.0001), high risk (P < 0.0001) and lymphomatous features (P < 0.0001). Key components of therapies included delayed intensification and substitution of intrathecal chemotherapy for prophylactic/preventive cranial radiation in low- and intermediate-risk patients. This is the largest series of children on concurrent studies who were observed more than 10 years.

Bone marrow transplantation versus prolonged intensive chemotherapy for children with acute lymphoblastic leukemia and an initial bone marrow relapse within 12 months of the completion of primary therapy: Children's Oncology Group study CCG-1941.

PURPOSE: To compare conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with acute lymphoblastic leukemia (ALL) and an early first marrow relapse. PATIENTS AND METHODS: After informed consent, 214 patients with ALL and early marrow relapse began multiagent induction therapy. One hundred sixty-three patients with fewer than 25% marrow blasts and count recovery at the end of induction (second remission [CR2]) were allocated by donor availability. Fifty patients with sibling donors were allocated to CBMT. Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation. RESULTS: Overall, 3-year event free survival from entry is 19% +/- 3%. Thirty-two of 50 CBMT patients (64%) and 19 of 37 ABMT patients (51%) underwent transplantation in CR2 with 3-year disease-free survival of 42% +/- 7% and 29% +/- 7%. The 3-year DFS is 29% +/- 7%, 21% +/- 7%, and 27% +/- 8% for patients allocated to CBMT, ABMT, and CT, respectively. Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2. Of these, five patients died after BMT and 5 patients relapsed. CONCLUSION: More than one half of patients died, failed reinduction, or relapsed again before 3 months after CR2 (median time to BMT). Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, 0.8 with P values of .56, .80, and .36, respectively. Outcomes remain similar and poor for children with ALL and early marrow relapse. BMT is not a complete answer to the challenge of ALL and early marrow relapse.

A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission.

We compared the outcomes of 298 patients with acute lymphoblastic leukemia in first or second complete remission (CR1 or CR2) receiving HLA-matched sibling allografts after cyclophosphamide and total body irradiation (Cy-TBI) conditioning with 204 patients receiving etoposide and TBI. Consequently, 4 groups were compared: Cy-TBI <13 Gy (n = 217), Cy-TBI > or =13 Gy (n = 81), etoposide-TBI <13 Gy (n = 53), and etoposide-TBI > or =13 Gy (n = 151). Analyses of relapse, leukemia-free survival (LFS), and survival were performed separately for CR1 and CR2 transplantations. Transplant-related mortality did not differ by conditioning regimen. In CR1, there were also no significant differences in relapse, LFS, or survival by conditioning regimen. In CR2, these outcomes differed among conditioning groups. In comparison with Cy-TBI <13 Gy, the risks of relapse, treatment failure (inverse of LFS), and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses > or =13 Gy. For both CR1 and CR2 transplantations, causes of death were similar among the groups; disease recurrence accounted for 47% of deaths. We conclude that for HLA-identical sibling allografts for acute lymphoblastic leukemia in CR2, there is an advantage in substituting etoposide for Cy or, when Cy is used, in increasing the TBI dose to > or =13 Gy.

Hematopoietic stem cells.

The hematopoietic system of the young child acquires, through time, the ability to cope with exposure to a number of environmental toxins and infectious agents. Occasionally, severe aplastic anemia occurs secondary to exposure to some of these toxins or infectious agents. The occurrence of severe aplastic anemia provides an opportunity to study the maturation of the hematopoietic system because often the immune system is partially intact. Hematopoietic stem cell transplants permit the study of the complete reconstitution of the hematopoietic and immunologic system. Stem cell transplants are often used to treat severe aplastic anemia or, alternatively, may be part of the treatment for an underlying malignant disease or a genetic disease. Sources of stem cells and the age of the recipient and donor have an impact on the success of the stem cell transplant. A stem cell transplantation provides a window of opportunity to study and observe the normal maturation of the immune system and the sensitivity. Very clearly, children recover from severe aplastic anemia and stem cell transplantations more readily with fewer problems and complications than adults. The environmental risks that a child who received a stem cell transplantation faces are related primarily to the deficiencies of the hematopoietic system and immune system during the recovery phase. Therefore, diminished resistance to infectious agents, primarily viruses and other opportunistic organisms, are the primary risk that children who are recovering from these transplantations face. There are few data on the susceptibility of these children to the toxic effects of other environmental toxicants during the recovery period, which may take years before complete recovery.

Milestones in the development of pediatric hematopoietic stem cell transplantation--50 years of progress.

In the 1950s, the first infusions of hematopoietic stem cells were given as a form of treatment for childhood leukemia. This heralded the beginning of a field that has expanded to include the treatment of immune deficiencies, a variety of leukemias and solid tumors, and then genetic diseases. A number of milestones are highlighted, particularly in regard to the use of alternative sources of hematopoietic stem cells such as unrelated donors, peripheral blood stem cells and umbilical cord stem cells. In addition, newer techniques of using non-myeloablative preparative regimens helped to reduce the toxicity and long-term consequences of hematopoietic stem cell transplant. Many diseases now benefit from the replacement of the marrow stem cells and the provision of a new immune system and improved immune surveillance.

Preparative therapies used for those with Fanconi's anemia undergoing stem cell transplants and subsequent engraftment rates.

Fanconi anemia patients are often treated with stem cell transplants to prevent myelodysplastic changes or leukemic progression. A variety of preparative regimens have been utilized. A case of a 13-year-old child with Fanconi's anemia is presented to highlight the preparative therapy utilized, engraftment rates which have been seen and the incidence of graft-vs.-host disease (GvHD). A review of the literature suggests the most successful preparative therapies with the highest engraftment rates and also suggests the best GvHD regimens.

Persistent questions about the treatment of severe aplastic anemia in children as illustrated by five cases.

We present our recent experience treating five children with severe aplastic anemia (SAA). One patient was transplanted and the remaining 4 patients were treated with immunosuppression of various types and duration. These five cases illustrate the many outstanding points which remain to be clarified regarding the care of children with SAA. We have outlined the treatment options available to each of these patients and the path that we followed along with their outcomes. Additional research and consideration is necessary to arrive at definitive answers to the questions posed by these five cases.

Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983.

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

Racial and ethnic differences in survival of children with acute lymphoblastic leukemia.

Black children with acute lymphoblastic leukemia (ALL) have poor outcomes, but limited information is available for children from other racial and ethnic backgrounds, such as Hispanic and Asian. We undertook a retrospective cohort study of children with ALL treated on Children's Cancer Group therapeutic protocols to determine outcomes by racial and ethnic backgrounds of patients treated with contemporary risk-based therapy. In total, 8447 children (white, n = 6703; Hispanic, n = 1071; black, n = 506; and Asian, n = 167) with newly diagnosed ALL between 1983 and 1995 were observed for a median of 6.5 years. Analysis of disease outcome was measured as overall survival (OS) and event-free survival (EFS) and was adjusted for known predictors of outcome including clinical features, disease biology, socioeconomic status, and treatment era (1983-1989 vs 1989-1995). There was a statistically significant difference in survival by ethnicity (P <.001). Five-year EFS rates were: Asian, 75.1% +/- 3.5%; white, 72.8% +/- 0.6%; Hispanic, 65.9% +/- 1.5%; and black, 61.5% +/- 2.2%. Multivariate analysis revealed that when compared with white children, black and Hispanic children had worse outcomes and Asian children had better outcomes after adjusting for known risk factors. The poorer outcomes among black children were most apparent among patients with standard-risk features (relative risk [RR], 2.0; 95% confidence interval [CI], 1.6-2.5), whereas poorer outcomes in Hispanic children (RR, 1.4; 95% CI, 1.2-1.6) were most evident among patients with high-risk features. Asian children had better outcomes than all racial and ethnic groups among high-risk patients, particularly in the recent era (5-year EFS, 90.9% +/- 6.1%). Racial and ethnic differences in OS and EFS persist among children with ALL who receive contemporary risk-based therapy. Future studies should focus on reasons-perhaps compliance or pharmacogenetics-for those differences.

Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 x 2 factorial design to receive dexamethasone (6 mg/m(2)/d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m(2)/d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m(2)/d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous system-directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system-relapse rate of 3.7% +/- 0.8%, compared with 7.1% +/- 1.1% for prednisone (P =.01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% +/- 2% for dexamethasone and 77% +/- 2% for prednisone (P =.002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse.

Double-delayed intensification improves event-free survival for children with intermediate-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Addition of a delayed-intensification (DI) phase after standard induction/consolidation therapy was previously shown to improve outcome for patients younger than 10 years of age with intermediate-risk acute lymphoblastic leukemia (ALL). The current trial randomized 1204 patients to regimens containing a single DI phase (405 patients), 2 DI phases (DDI) (402 patients), or a single DI phase in conjunction with increased vincristine and prednisone pulses during maintenance (DIVPI) (397 patients). Estimates of event-free survival (EFS) and survival at 6 years are 79% +/- 1% and 89% +/- 1%, respectively. EFS was improved on DDI compared with either DI (log-rank P =.04; Kaplan-Meier [KM] P =.04; relative risk [RR] = 1.38) or DIVPI (log-rank P =.04; KM P =.01; RR = 1.39). There was no difference in EFS for the DI and DIVPI regimens (log-rank P =.96; KM P =.75). Survival estimates at 6 years were 87% (SD = 2%) for DI; 91% (SD = 2%) for DDI; and 90% (SD = 2%) for DIVPI (P =.17). Significant univariate risk factors for the overall cohort included poor day-7 marrow response, black race, and age of at least 5 years. These data demonstrate that DDI improves EFS of patients younger than 10 years of age with intermediate-risk ALL.

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission.

We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML.