RESUMO
Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.
Assuntos
Mastocitose Sistêmica/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Estaurosporina/análogos & derivados , Adulto , Idoso , Feminino , Seguimentos , Humanos , Leucemia de Mastócitos/tratamento farmacológico , Leucemia de Mastócitos/patologia , Masculino , Mastocitose Sistêmica/patologia , Pessoa de Meia-Idade , Estaurosporina/efeitos adversos , Estaurosporina/uso terapêutico , Adulto JovemRESUMO
Donor-lymphocyte infusion (DLI) for relapse following haploidentical hematopoietic cell transplantation (haploHCT) with post-transplant cyclophosphamide (PTCy) has been described in recipients of bone marrow grafts, but not recipients of G-CSF mobilized peripheral blood (PB) grafts. We retrospectively identified patients who underwent DLI following PB-haploHCT with PTCy for relapse, or loss of chimerism (LOC). Twelve patients (57%) received DLI for hematologic relapse/persistent disease, seven (33%) for extramedullary relapse and two (10%) for LOC. Sixteen (76%) received chemotherapy prior to DLI, which did not correlate with response. The most common first dose was 1 × 106 CD3+ cells/kg. Two patients developed grade I aGvHD post DLI, one had grade II and two had grade III. One developed mild skin cGvHD 1361 days post DLI. Pre-DLI aGvHD predicted post-DLI aGvHD (P=0.025). Six patients achieved CR after DLI for overt relapse, one achieved full donor chimerism after LOC. Patients with LOC or EM relapse had superior relapse-free survival following DLI (P=0.029). DLI following PB-haploHCT with PTCy is a viable salvage therapy for overt relapse or LOC without a substantial increase in GvHD, and donor lymphocytes may be collected simultaneously with graft collection to facilitate availability in patients at high risk of relapse.
Assuntos
Ciclofosfamida/uso terapêutico , Transfusão de Linfócitos , Transplante de Células-Tronco de Sangue Periférico/métodos , Terapia de Salvação/métodos , Idoso , Intervalo Livre de Doença , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de Tecidos , Transplante Haploidêntico , Resultado do TratamentoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/administração & dosagem , Leucemia Mieloide Aguda/terapia , Transplante de Células-Tronco , Adolescente , Adulto , Idoso , Autoenxertos , Benzilaminas , Ciclamos , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagemAssuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Depleção Linfocítica , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco de Sangue Periférico , Adolescente , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante , Adulto , Idoso , Aloenxertos , Clofarabina , Intervalo Livre de Doença , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Clonal/genética , Epigênese Genética/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Exoma , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Polimorfismo de Nucleotídeo Único , Indução de Remissão , Resultado do Tratamento , Carga TumoralRESUMO
Post-transplant cyclophosphamide (PT-Cy) is the backbone of GvHD prophylaxis following haploidentical hematopoietic cell transplantation (haplo-HCT). PT-Cy has also been used in matched related (MRD) and unrelated (MUD) settings. It is not known whether outcomes are similar between haplo-HCT and MRD/MUD HCT when PT-Cy is used. We performed a retrospective analysis of 83 patients with AML who underwent HCT (using PT-Cy-based GvHD prophylaxis) from MRD, MUD or haploidentical donors. The groups were similar in baseline characteristics with the exception of older age in the MRD/MUD group (P=0.012). In multivariate analysis, the effect of donor type (MRD/MUD vs haploidentical) on transplant outcomes was not significant in any of the models except for faster neutrophil recovery after MRD/MUD transplants (hazard ratio: 2.21; 95% confidence interval: 1.31-3.72, P=0.002). In conclusion, we showed similar outcomes in MRD/MUD vs haploidentical HCT (except slower count recovery following haplo-HCT) when PT-Cy is used for GvHD prophylaxis. Although slower count recovery following haplo-HCT (compared with MRD/MUD transplants without PT-Cy) has been attributed to using PT-Cy, our results suggest that HLA disparity is the primary cause of this difference. Furthermore, our analysis supports PT-Cy as a viable option for GvHD prophylaxis after MRD/MUD transplants.
Assuntos
Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Idoso , Doadores de Sangue , Feminino , Sobrevivência de Enxerto , Haplótipos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Histocompatibilidade , Humanos , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Pré-Medicação , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Histocompatibilidade , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante Haploidêntico/métodos , Adulto , Idoso , Feminino , Antígenos HLA/análise , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Linfócitos T , Transplante Haploidêntico/mortalidade , Adulto JovemRESUMO
High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ácidos Borônicos , Mieloma Múltiplo , Pirazinas , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Podofilotoxina/administração & dosagem , Podofilotoxina/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodosAssuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Neoplasias Hematológicas , Mobilização de Células-Tronco Hematopoéticas , Depleção Linfocítica , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Fatores de TempoRESUMO
Recent studies suggest that most cases of myelodysplastic syndrome (MDS) are clonally heterogeneous, with a founding clone and multiple subclones. It is not known whether specific gene mutations typically occur in founding clones or subclones. We screened a panel of 94 candidate genes in a cohort of 157 patients with MDS or secondary acute myeloid leukemia (sAML). This included 150 cases with samples obtained at MDS diagnosis and 15 cases with samples obtained at sAML transformation (8 were also analyzed at the MDS stage). We performed whole-genome sequencing (WGS) to define the clonal architecture in eight sAML genomes and identified the range of variant allele frequencies (VAFs) for founding clone mutations. At least one mutation or cytogenetic abnormality was detected in 83% of the 150 MDS patients and 17 genes were significantly mutated (false discovery rate ≤0.05). Individual genes and patient samples displayed a wide range of VAFs for recurrently mutated genes, indicating that no single gene is exclusively mutated in the founding clone. The VAFs of recurrently mutated genes did not fully recapitulate the clonal architecture defined by WGS, suggesting that comprehensive sequencing may be required to accurately assess the clonal status of recurrently mutated genes in MDS.
Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Feminino , Frequência do Gene , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , RecidivaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Lenalidomida , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Indução de Remissão , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Adulto JovemRESUMO
BACKGROUND: Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). This pilot prospective randomized clinical trial compares valganciclovir (VGV) to ganciclovir (GCV) as pre-emptive therapy for CMV viremia in the post-allogeneic HSCT population. METHODS: Patients undergoing allogeneic HSCT who were at risk for CMV viremia were monitored post HSCT by weekly quantitative whole blood polymerase chain reaction. Pre-emptive therapy was delayed until the viral load (VL) was >10,000 copies/mL once, or >5000 copies/mL twice. Patients were randomized to either GCV 5 mg/kg twice a day (b.i.d.) for 7 days followed by daily GCV 5 mg/kg for up to 21 days, or VGV 900 mg b.i.d. for 7 days followed by 900 mg daily for up to 21 days. The primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy. RESULT: In total, 37 patients were enrolled; 19 patients received treatment with VGV and 18 patients received treatment with GCV. The VGV was not inferior in efficacy to GCV as pre-emptive therapy, with rates of viral clearance at 28 days of 89.5% and 83%, respectively (P-value for non-inferiority = 0.030). Toxicities were similar between the 2 arms. No patients developed CMV disease. CONCLUSIONS: In this trial, the rates of clearance of viremia appear to be similar with VGV and GCV.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Ganciclovir/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Viremia/prevenção & controle , Administração Oral , Adolescente , Adulto , Antivirais/administração & dosagem , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Relação Dose-Resposta a Droga , Feminino , Ganciclovir/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Estudos Prospectivos , Transplante Homólogo , Valganciclovir , Carga Viral/efeitos dos fármacos , Viremia/virologia , Adulto JovemRESUMO
Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. In this study, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of myeloblast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared with patients without DNMT3A mutations (P=0.005) and more rapid progression to AML (P=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.
Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Mutação , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Códon/genética , Ilhas de CpG/genética , Metilação de DNA/genética , DNA Metiltransferase 3A , DNA de Neoplasias/genética , Progressão da Doença , Éxons/genética , Feminino , Células Precursoras de Granulócitos/enzimologia , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/enzimologia , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Análise de Sequência de DNA , Adulto JovemRESUMO
The application of myeloablative Allo-SCT is limited by its associated morbidity and mortality. Reduced-intensity conditioning regimens attempt to diminish these, but are associated with a higher risk of disease relapse. Given the evidence of activity of clofarabine and cytarabine in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), we explored a novel reduced-intensity conditioning regimen based on this backbone. Patients received clofarabine 40 mg/m(2) i.v. on days -6 to -2, cytarabine 1 g/m(2) i.v. on days -6 to -2 and anti-thymocyte globulin (ATG) 1 mg/kg on day -4 and 2.5 mg/kg x 2 days on days -3 and -2. Seven patients were enrolled. Their median age was 54 years; three were with MDS and four with AML. The median duration of neutropenia was 14 days and that of thrombocytopenia was 22 days. Toxicities included hand-foot syndrome (57% grade 2), elevated alanine aminotransferase (ALT) (57% grade 3), elevated aspartate aminotransferase (AST) (86% grade 3) and hyperbilirubinemia (29% grade 3-5). No acute GVHD was observed. Enrollment to the trial was halted after three of the first seven patients expired on days +15, +26 and +32. Three of the four surviving patients have relapsed with a median TTP of 152 days. This regimen was not sufficiently immunosuppressive to ensure engraftment, and was associated with substantial morbidity and mortality.
Assuntos
Nucleotídeos de Adenina/administração & dosagem , Soro Antilinfocitário/administração & dosagem , Antimetabólitos Antineoplásicos/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Citarabina/administração & dosagem , Imunossupressores/administração & dosagem , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante/métodos , Nucleotídeos de Adenina/efeitos adversos , Adulto , Idoso , Soro Antilinfocitário/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Arabinonucleosídeos/efeitos adversos , Clofarabina , Citarabina/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Taxa de Sobrevida , Fatores de Tempo , Transplante HomólogoRESUMO
Allogeneic stem cell transplantation (SCT) has been shown to be a curative therapy for some patients with non-Hodgkin's lymphoma (NHL). Total-body irradiation and high-dose cyclophosphamide combinations are the most established conditioning regimens used in this setting. We examined the efficacy and toxicity of cyclophosphamide, BCNU, and VP-16 (CBV) as a suitable chemotherapy-only regimen for NHL patients. In total, 18 patients, median age 42 years, with NHL were treated with CBV followed by allotransplant. Patients had received a median of two prior chemotherapy regimens. Median times to neutrophil and platelet recovery were 19 and 15 days, respectively. Interstitial pneumonitis occurred in one patient. There have been four relapses after a median follow-up of 39 months. Overall, there were four deaths, one because of relapse. The 2-year estimates of relapse-free and overall survival are 56 and 76%, respectively. CBV is a safe and an effective alternative to TBI-containing regimens before allogeneic SCT for NHL.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Carmustina/administração & dosagem , Ciclofosfamida/administração & dosagem , Etoposídeo/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Linfoma não Hodgkin/tratamento farmacológico , Adolescente , Adulto , Plaquetas/citologia , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Infecções/mortalidade , Hepatopatias/mortalidade , Pneumopatias/mortalidade , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Recidiva , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do TratamentoRESUMO
On the basis of observations of dog models and from earlier studies with humans, we hypothesized that a low-dose (550 cGy) TBI-based conditioning regimen would result in sustained engraftment of HLA-matched sibling peripheral blood stem cells (PBSC) with low treatment-related mortality (TRM) and low serious organ toxicity if the TBI was given as a single dose and at a high dose rate. The regimen included 550 cGy TBI administered as a single dose at 30 cGy/min and cyclophosphamide. Cyclosporine was given as GVHD prophylaxis. Twenty-seven good-risk (acute leukemia in first remission and chronic-phase chronic myelogenous leukemia) and 53 poor-risk (other) patients were accrued. Complete donor engraftment occurred in 93% to 100% of evaluable patients at each scheduled assessment and was durable through 4 years. Mixed chimerism (50% to 98% donor) was observed in 9 patients (11%). Without further intervention, all patients had complete donor engraftment on subsequent assessments. Graft failure did not occur. TRM through at least 2 years was 7% in the good-risk and 19% in the poor-risk diagnostic groups. Grade 4 (fatal) organ toxicity occurred in only 2 patients (2.5%). Other causes of TRM included infection and GVHD. Median follow-up for the surviving patients was 1234 days (range, 780-1632 days). Current status includes 39 patients (49%) alive and in complete remission, 2 alive in relapse, and 39 dead. Relapse occurred in 15% of the good-risk group and 45% of the poor-risk group. The Kaplan-Meier estimates of 3-year disease-free and overall survival of the good-risk group were 77% and 85%, respectively, and of the poor-risk group were 34% and 36%, respectively. Low-dose (550 cGy), single-exposure TBI given at a high dose rate with cyclophosphamide resulted in consistent durable engraftment of HLA-matched sibling PBSC with a low risk of fatal organ toxicity and TRM.