RESUMEN
We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40-65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Busulfano , Ciclofosfamida , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vidarabina , Humanos , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Persona de Mediana Edad , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Femenino , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Anciano , Acondicionamiento Pretrasplante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de SeguimientoRESUMEN
Hematopoietic stem cell transplants for inherited metabolic disorders performed at Tokai University Hospital between June 5, 1986, and May 28, 2021, were analyzed and compared between the period before 2007 and the period from 2007 onward based on availability of medical resources. Transplants were performed for 38 patients with mucopolysaccharidosis, 33 with adrenoleukodystrophy, and 16 with another disorder. Before 2007, oral busulfan-based regimens were mainly used. From 2007 onward, intravenous busulfan-based regimens or 4 Gy of thoracoabdominal irradiation (TAI), fludarabine, and melphalan (Mel)/treosulfan were adopted. Between 2002 and 2010, adrenoleukodystrophy was treated with 12 Gy of TAI and Mel. HLA-identical sibling bone marrow was used in 43% of cases before 2007 and 15% from 2007 onward, while alternative donors were selected for other transplants. Overall survival and event-free survival (EFS) before 2007 and from 2007 onward were 76% and 62%, and 97% and 85%, respectively (P = 0.006 and 0.017). Transplant era predicted superior overall survival and EFS, while myeloablative conditioning also predicted EFS. The incidence of primary graft failure decreased from 2007 onward, especially in cord blood transplant when 4 Gy of TAI with 150 mg/m2 fludarabine and 180 mg/m2 Mel or 42 g/m2 treosulfan were used as conditioning.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Humanos , Masculino , Femenino , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Busulfano/análogos & derivados , Preescolar , Niño , Lactante , Adolescente , Trasplante Homólogo , Melfalán/uso terapéutico , Melfalán/administración & dosificación , Adulto , Errores Innatos del Metabolismo/terapia , Errores Innatos del Metabolismo/mortalidad , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Adrenoleucodistrofia/terapia , Estudios Retrospectivos , Adulto JovenRESUMEN
INTRODUCTION: Ewing sarcoma (ES), is a rare cancer affecting children, adolescents and adults. After VIDE (vincristine-ifosfamide-doxorobucin-etoposide) induction chemotherapy, Busulfan-Melphalan (BuMel) high-dose chemotherapy followed by autologous hematopoietic stem cells transplantation improved outcomes in unfavourable localized ES, but with more toxicities than conventional chemotherapy (VAI: Vincristine-dactinomycin-Ifosfamide). We evaluated whether the risk of acute toxicity associated with BuMel compared to VAI varied according to age in patients recruited in the R2Loc and R2Pulm randomised trials of the Euro-E.W.I.N.G.99 and Ewing-2008 trials. METHODS: We included patients with a localized high-risk disease, or pulmonary or pleural metastasis. We analysed the risk of severe toxicity according to randomised treatment group (VAI versus BuMel) and age group (<12 years, 12-17 years, 18-24 years, ≥25 years). We evaluated the heterogeneity of treatment effects by age group using interaction terms in logistic multivariable models. RESULTS: The analysis included 243 patients treated with VAI and 205 with BuMel. Overall, BuMel was associated with a higher risk of severe acute toxicity than VAI particularly haematological, gastrointestinal, liver, sinusoidal occlusive syndrome, and infections. Severe haematological toxicity and lower general condition were significantly more frequent in younger patients, whatever treatment. We did not observe any significant heterogeneity in terms of the excess risk of severe toxicities associated with BuMel compared to VAI according to age group. CONCLUSION: The excess of acute toxicity associated with BuMel compared to VAI does not vary significantly with age, suggesting the feasibility of BuMel across all age groups.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Busulfano , Trasplante de Células Madre Hematopoyéticas , Melfalán , Sarcoma de Ewing , Trasplante Autólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/terapia , Busulfano/administración & dosificación , Busulfano/efectos adversos , Niño , Adolescente , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melfalán/administración & dosificación , Melfalán/efectos adversos , Melfalán/uso terapéutico , Masculino , Femenino , Factores de Edad , Adulto , Etopósido/administración & dosificación , Etopósido/efectos adversos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Vincristina/efectos adversos , Vincristina/administración & dosificación , Vincristina/uso terapéutico , Preescolar , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Resultado del TratamientoRESUMEN
This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08-0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11-1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.
Asunto(s)
Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Ciclofosfamida , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Acondicionamiento Pretrasplante , Humanos , Masculino , Femenino , Acondicionamiento Pretrasplante/métodos , Adulto , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Adolescente , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Tasa de Supervivencia , Trasplante Homólogo , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/mortalidad , Supervivencia sin Enfermedad , Estudios Retrospectivos , AloinjertosRESUMEN
Reduced-intensity conditioning (RIC) regimens allogeneic hematopoietic stem cell transplantation (HSCT) was developed for older patients or those with poor functional status. Haploidentical donor was appropriate alternative donor for patients without matched donors or patients with emergency disease state. However, there was few studies report the outcomes of RIC regimen of anti-thymocyte globulin (ATG) based haploidentical HSCT. The selection of the appropriate RIC regimen based on age and comorbidities in ATG-based haploidentical HSCT remains poorly described. To investigate the safety and efficacy of RIC regimen ATG-based haploidentical HSCT in older or unfit patients. Additionally, to explore the potential factors that impact the prognosis of RIC regimen of ATG-based haploidentical HSCT. We included a retrospective cohort of 63 patients with hematologic malignant diseases who underwent their first RIC haploidentical HSCT from November 2016 to June 2022 at our institutions. The conditioning regimen involved fludarabine (Flu) 30 mg/m²/kg 6 days combined with busulfan 3.2 mg/kg 2 days (Bu2) or 3 days (Bu3). ATG-Fresenius (ATG-F) was administered 10 mg/kg in total, ATG-thymoglobulin (ATG-T) was administered 6 mg/kg in total. The median age of patients in the entire cohort was 60 (32-67) years with a median follow-up of 496 (83-2182) days. There were 29 patients with AML, 20 patients with MDS, and 14 patients with ALL. A total of 32 patients underwent Bu2 RIC haplo-HSCT and 31 patients were treated with Bu3 RIC haplo-HSCT. The 2-year overall survival (OS) and 2-year disease-free survival (DFS) in whole cohort were 67.7% (95% confidence interval [CI], 53.8 - 85.1%) and 61.4% (95% CI, 48.8 - 77.3%) respectively. The cumulative incidence rates of grades II to IV and grades III to IV acute graft-versus-host disease (aGVHD) in whole cohort were 15.8% (95% CI, 4.8 - 19.6%) and 9.7% (95% CI, 0.0 - 11.8%) respectively. The 2-year cumulative incidence of chronic GVHD was 34.0% (95% CI, 18.9 - 46.3%). The 2-year cumulative incidence rates of relapse (IR) and non-relapse mortality (NRM) rates in whole cohort were 27.5% (95% CI, 14.5 - 33.7%) and 11.6% (95% CI, 2.2 - 21.9%) respectively. The probability of 2-year OS were 60.2% (95% CI:42.5-85.3%) in Bu2 and 85.5%(95% CI:73.0-100%) in Bu3 group respectively(P = 0.150). The probability of 2-year DFS were 49.7% (95% CI:33.0-74.8%) in Bu2 and 72.6% (95% CI:55.5-95.5%) in Bu3 group respectively (P = 0.045). The 2-year IR of Bu2 group was significantly higher than Bu3 group (P = 0.045). However, the 2-year NRM were not significantly different between Bu2 and Bu3 group(P > 0.05). In multivariable analysis, RIC regimen of Bu3 had superior OS and DFS than Bu2 group respectively [HR 0.42, 95% CI 0.18-0.98; P = 0.044; HR 0.34, 95% CI 0.14-0.86; P = 0.022]. Besides, RIC regimen of Bu3 had lower IR than Bu2 group [HR 0.34, 95% CI 0.13-0.89; P = 0.029]. The RIC regimen of ATG-based haploidentical HSCT is a safe and effective treatment option for patients who are older or have poor functional status. In particular, a relatively high-intensity pre-treatment regimen consisting of Bu achieves significant improvements in OS and DFS, thus providing more favorable post-transplantation clinical outcomes.
Asunto(s)
Suero Antilinfocítico , Busulfano , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Vidarabina , Humanos , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Masculino , Persona de Mediana Edad , Femenino , Suero Antilinfocítico/administración & dosificación , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Estudios Retrospectivos , Anciano , Trasplante de Células Madre Hematopoyéticas/métodos , Adulto , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/mortalidad , Trasplante Haploidéntico/métodos , Tasa de SupervivenciaAsunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Vidarabina , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Persona de Mediana Edad , Acondicionamiento Pretrasplante/métodos , Femenino , Adulto , Anciano , Recurrencia , Trasplante Homólogo/métodos , Aloinjertos , Tasa de Supervivencia , Estudios RetrospectivosRESUMEN
Generation of transgenic birds can be achieved by temporal suppression of endogenous spermatogenesis in males prior to primordial germ cell implantation. One of many established methods to induce male sterility is the intraperitoneal injection of busulfan, an alkylating agent. Nevertheless, the use of busulfan injections, which may also affect hematopoietic stem cells, carries the risk of potential lethality in animals. Given their safety and non-toxic nature, it has been demonstrated that intratesticular busulfan injections in mammals are less effective than intraperitoneal injections. This study aimed to compare, for the first time, the sterility and toxicity effects of intraperitoneal vs. intratesticular busulfan injections in quail and chickens. Our experimental design involved a previously established single intraperitoneal busulfan injection of 40 mg/kg of body weight (BW). In quail, busulfan was then administered intratesticularly at 3 different concentrations (6, 12, and 20 mg/kg BW), while in chickens, the working concentration was 20 mg/kg BW. We found that a single intraperitoneal busulfan injection of 40 mg/kg of BW resulted in 100% mortality in the treated roosters. In quails, however, this concentration only caused a temporary suppression of fertility for a 15-d period. Moreover, we found that a higher dose of intratesticular injection of busulfan is required to suppress spermatogenesis in quail (20 mg/kg BW) compared to mammals (4 mg/kg BW). Following these findings, we further confirmed that intratesticular injection of 20 mg/kg BW busulfan into roosters did not affect their overall viability. However, it induced a temporary state of male sterility, consistent with the effects observed with intraperitoneal injections. Hence, our data demonstrate that quail and chicken respond differently to busulfan administration. Furthermore, the present study provides evidence that direct injection into the rooster testes causes less physiological stress than intraperitoneal injection.
Asunto(s)
Busulfano , Pollos , Coturnix , Espermatogénesis , Testículo , Animales , Busulfano/administración & dosificación , Masculino , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos , Inyecciones Intraperitoneales/veterinaria , Pollos/fisiología , Coturnix/fisiología , Inyecciones/veterinaria , Infertilidad Masculina/veterinaria , Infertilidad Masculina/inducido químicamenteRESUMEN
One key aspect of allogeneic hematopoietic cell transplantation (HCT) is pretransplant conditioning, balancing risk for relapse versus non-relapse mortality. Conditioning regimens with different alkylators at different doses can influence outcome, but data are missing for myelofibrosis, a challenging cohort of patients usually presenting at older age and with comorbidities. We evaluated in a multicenter retrospective study the comparative efficacy and safety of busulfan versus treosulfan in combination with fludarabine for myelofibrosis patients undergoing HCT. This study included 1115 patients (busulfan, n = 902; treosulfan, n = 213) receiving first HCT between 2005 and 2021. Patients were generally balanced for key patient characteristics. Overall survival at 4 years was 62% for the busulfan group versus 58% for the treosulfan group (p = .22). Impact on outcome was dose-dependent. Overall survival was 65% (95% CI, 61%-69%) for reduced intensity busulfan versus 69% (95% CI, 54%-84%) for reduced intensity treosulfan, 53% (95% CI, 44%-63%) for higher intensity busulfan, and 55% (95% CI, 46%-63%) for higher intensity treosulfan. Incidence of relapse was similar across intensity groups. In multivariable analysis, the hazard for death (with reduced intensity busulfan as reference) was 0.88 (95% CI, 0.39-2.01) for reduced intensity treosulfan (p = .77), 1.42 (95% CI, 0.96-2.10) for higher intensity busulfan (0.08), and 1.61 (95% CI, 1.14-2.26) for higher intensity treosulfan (p = .006). In terms of non-relapse mortality, comparison was not significantly different, while the hazard ratio for higher intensity treosulfan was 1.48 (95% CI, 0.98-2.23; p = .06). Here, we showed comparable outcomes and improved survival in myelofibrosis undergoing HCT with reduced intensity busulfan or treosulfan.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Mielofibrosis Primaria , Acondicionamiento Pretrasplante , Vidarabina , Busulfano/análogos & derivados , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Humanos , Mielofibrosis Primaria/terapia , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/tratamiento farmacológico , Persona de Mediana Edad , Masculino , Femenino , Acondicionamiento Pretrasplante/métodos , Estudios Retrospectivos , Anciano , Adulto , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/administración & dosificación , Adulto JovenRESUMEN
INTRODUCTION: Type of conditioning regimen impacts the outcome of patients who undergo allogeneic HSCT since graft versus host disease (GVHD), infections, regimen related toxicities (RRT) are important causes of post-transplant mortality. Despite the RRT profile of busulfan, it is frequently used worldwide. Treosulfan has advantages in terms of dose of administration, lower incidence of sinusoidal obstruction syndrome and lower neurotoxicity. We retrospectively investigated outcomes of patients who underwent allogeneic HSCT with treosulfan or busulfan based conditioning regimens in our institution. METHODS: Treosulfan was administered to 94 patients while 85 patients received busulfan. Our outcomes were RRT, chronic and acute GVHD, relapse related mortality (RRM), non-relapse mortality, and fungal infection. The clinical follow up data, regarding the primary and secondary endpoints of our study, of the patients who received treosulfan or busulfan based conditioning regimens were statistically analyzed. RESULTS: The median follow-up was 14 months for the treosulfan group while it was 11 months for the busulfan group (p = 0.16). RRT was 11.7% and 7.1% for treosulfan and busulfan respectively. The incidence of extensive chronic GVHD was less frequent in the treosulfan group compared to the busulfan group (15.7% vs. 32.1%) (p < 0.001). The incidence of acute GVHD (Grade 3 or higher) was 32.2% in the treosulfan group while it was 31.6% in the busulfan group. The RRM was 17% in the treosulfan group while it was 34% in the busulfan group. The non-relapse mortality was 35.5% and 29.4% in the treosulfan group and in the busulfan group respectively (p = 0.962). CONCLUSION: Treosulfan, with a lower RRM, lower chronic GVHD incidence and with a similar RRT profile appears to be a safe alternative to busulfan.
Asunto(s)
Busulfano , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Trasplante Homólogo , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/efectos adversos , Busulfano/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Femenino , Masculino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Adulto , Persona de Mediana Edad , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/epidemiología , Estudios Retrospectivos , Adulto Joven , Adolescente , Resultado del Tratamiento , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/efectos adversosRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a standard treatment for patients with AML and MDS. The combination of fractionated total body irradiation(8GyTBI/Flu) with fludarabine is an established conditioning regimen, but fludarabine/treosulfan(Flu/Treo) constitutes an alternative in older/comorbid patients. We conducted a retrospective analysis of 215 AML(in CR) and 96 MDS patients undergoing their first allo-HCT between 2011 and 2022, identifying 53 matched Flu/Treo and 8GyTBI/Flu patients through propensity score matching. Median follow-up of survivors was 3.3 years and 4.1 years. For the Flu/Treo group, 1-year non-relapse mortality (2% vs. 10%, p = 0.03) was lower, while 1-year relapse incidence (16% vs. 13%, p = 0.81) was similar. Three-year outcomes, including relapse-free survival and graft-versus-host disease incidence, were comparable (OS: 81% vs. 74%, p = 0.70; RFS: 78% vs. 66%, p = 0.28; chronic GvHD: 34% vs. 36%, p = 0.97; acute GvHD (100 days): 11% vs. 23%, p = 0.11). Multivariable analysis, considering age, ECOG, HCT-CI, and MRD status, revealed no associations with main outcomes. Dose-reduced conditioning with Flu/Treo or 8GyTBI/Flu demonstrated favorable and comparable survival rates exceeding 70% at 3 years with 1-year NRM rates below 10% and low relapse rates in the matched cohort. These data underline the need for further evaluation of TBI and Treo-based conditionings in prospective trials.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Irradiación Corporal Total/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Femenino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/mortalidad , Adulto , Anciano , Estudios Retrospectivos , Trasplante Homólogo/métodos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/etiología , Adulto Joven , Aloinjertos , Tasa de SupervivenciaRESUMEN
Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Tiotepa , Acondicionamiento Pretrasplante , Irradiación Corporal Total , Humanos , Irradiación Corporal Total/métodos , Acondicionamiento Pretrasplante/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Adulto , Tiotepa/administración & dosificación , Tiotepa/uso terapéutico , Femenino , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Adolescente , Adulto Joven , Trasplante Homólogo/métodosRESUMEN
BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/farmacocinética , Busulfano/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Femenino , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Resultado del Tratamiento , Estudios Retrospectivos , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Tiotepa/uso terapéutico , Tiotepa/administración & dosificación , Tiotepa/farmacocinética , Supervivencia sin Enfermedad , Estudios de Seguimiento , Enfermedades Hematológicas/terapia , Antineoplásicos Alquilantes/uso terapéutico , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/administración & dosificaciónRESUMEN
BACKGROUND: Hematopoietic cell transplantation (HCT) is an established curative therapy for transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD). The latest American Society of Hematology guidelines recommend myeloablative preparative regimen in patients under 18 years of age. PROCEDURE: The objective was to demonstrate safety and efficacy of a reduced intensity conditioning (RIC) regimen including high-dose fludarabine, anti-thymocyte globulin, and targeted busulfan as a single alkylator to sub-myeloablative exposures. RESULTS: Between 2012 and 2021, 11 patients with SCD and five patients with TDT and matched related donor (MRD) HCT were included. The median age at transplantation was 8.3 years (range: 3.7-18.8 years). The median administered busulfan AUC was 67.4 mg/L×h (range: 60.7-80 mg/L×h). Overall survival was 93.8% and event-free survival 87.5% with one engrafted SCD patient with pre-existing moyamoya disease succumbing after drainage of a subdural hematoma. One SCD patient developed a secondary graft failure and was treated with a second HCT. Myeloid chimerism was full in all other patients with a median follow-up time of 4.1 years (range: 2.0-11.1 years), whereas T-cell donor chimerism was frequently mixed. CONCLUSION: This RIC conditioning followed by MRD HCT is sufficiently myeloablative to cure pediatric patients with hemoglobinopathies without the need for additional total body irradiation or thiotepa.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Hemoglobinopatías , Acondicionamiento Pretrasplante , Humanos , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Preescolar , Niño , Masculino , Femenino , Adolescente , Hemoglobinopatías/terapia , Estudios de Seguimiento , Tasa de Supervivencia , Enfermedad Injerto contra Huésped/etiología , Supervivencia de Injerto , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Anemia de Células Falciformes/terapia , Donantes de Tejidos , Pronóstico , Talasemia/terapiaAsunto(s)
Busulfano , Ciclofosfamida , Trasplante de Células Madre Hematopoyéticas , Puntaje de Propensión , Irradiación Corporal Total , Humanos , Ciclofosfamida/uso terapéutico , Ciclofosfamida/administración & dosificación , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Masculino , Trasplante de Células Madre Hematopoyéticas/métodos , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Acondicionamiento Pretrasplante/métodos , Estudios Retrospectivos , Trasplante Homólogo/métodos , Aloinjertos , Adulto Joven , NiñoRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.
Asunto(s)
Busulfano , Células Dendríticas , Trasplante de Células Madre Hematopoyéticas , Tiotepa , Acondicionamiento Pretrasplante , Vidarabina , Humanos , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Células Dendríticas/patología , Tiotepa/administración & dosificación , Tiotepa/uso terapéutico , Masculino , Busulfano/administración & dosificación , Busulfano/uso terapéutico , Persona de Mediana Edad , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/patología , Femenino , Trasplante Homólogo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , AloinjertosRESUMEN
Short-term outcome of myeloablative (MAC) and reduced intensity (RIC) conditioning in the prospective randomized international EBMT RICMAC study in patients with myelodyplastic syndrome (MDS) was comparable but longer follow up is lacking. Patients with MDS aged 18-65 years were randomized to receive MAC (N = 64) with busulfan/cyclophosphamide or RIC (n = 65) with busulfan/fludarabine followed by stem cell transplantation -(HCT) from HLA matched or mismatched donor. After a median follow-up of 6.2 (0.4-12.5) years, 10-year OS and RFS were 54.0% and 43.9% for RIC and 44.4% and 44.2% for MAC (p = 0.15 and p = 0.78), respectively. Since the first report, 6 patients died on NRM, 4 after RIC, and 2 after MAC. Similarly, 8 patients relapsed (4 in each arm), increasing the number of relapsed patients to 28. The second HCT was performed in 18 pts, 8 in the MAC, and 10 in the RIC arm. In a multivariate analysis, ECOG status and chemotherapy prior to HCT were independent risk factors for OS and RFS, ECOG and low cytogenetic risk for NRM and chemotherapy prior to HCT for RI. Patients with low cytogenetic risk had better OS [p = 0.002], RFS [p = 0.02], and NRM (p = 0.015) after RIC as compared to MAC.
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Síndromes Mielodisplásicos , Acondicionamiento Pretrasplante , Humanos , Acondicionamiento Pretrasplante/métodos , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/mortalidad , Persona de Mediana Edad , Adulto , Masculino , Femenino , Anciano , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Ciclofosfamida/uso terapéutico , Agonistas Mieloablativos/uso terapéutico , Adulto Joven , Estudios de Seguimiento , Estudios ProspectivosRESUMEN
Treosulfan has shown promise in allogeneic hematopoietic cell transplantation (HCT) for its myeloablative properties and low toxicity. In this single-center retrospective propensity score-matched cohort study we compared treosulfan- and busulfan-based conditioning in allogeneic HCT for patients with myelodysplastic syndrome (MDS). This study included 138 adults who underwent allogeneic HCT for MDS or chronic myelomonocytic leukemia at Princess Margaret Hospital, Toronto, from 2015 to 2022. Using propensity score matching, we compared transplant outcomes between 2 well-matched cohorts who received conditioning with either fludarabine-treosulfan (FT) (n = 46) or fludarabine-busulfan with total body irradiation (FBT200) (n = 92). A scoring system based on patient age, Karnofsky performance score, and hematopoietic cell transplant comorbidity index was used to assign patients based on fitness to low-dose (30 g/m2) or high-dose (42 g/m2) treosulfan: 32 (69.6%) received high-dose treosulfan. The racial composition of the 2 groups was similar, with 27.2% and 21.7% of FBT200 and FT recipients, respectively, identifying as non-Caucasian (P = .61). Primary outcomes were analyzed at a median follow-up of 747 days. Of all participants, 116 (84.0%) received graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) and antithymocyte globulin (ATG). Patients who received FT had a superior 2-year overall survival (OS) compared to those who received FBT200: 66.9% (95% confidence interval (CI): 46.1 to 81.2) versus 44.5% (95% CI: 34 to 54.4), hazard ratio (HR): 0.43, 95% CI: 0.22 to 0.84 (P = .013). In multivariate analysis (MVA), only the use of fresh grafts (P = .02) and FT (P = .01) were associated with improved OS. FT was associated with superior 2-year relapse-free survival (RFS) compared to FBT200: 63.1% (95% CI: 42.6 to 77.9) versus 39.1% (95% CI: 29.1 to 49.1), HR: 0.44 (95% CI: 0.24 to 0.81), P = .008. In MVA, the use of fresh grafts (P = .03) and FT (P = .009) were associated with improved RFS. Recipients of FT demonstrated superior 2-year graft-versus-host disease relapse-free survival (GRFS) compared to those who received FBT200: 57.4% (95% CI: 37.8 to 72.8) versus 35.1% (95% CI: 25.5 to 45). In MVA, only FT was associated with superior GRFS (P = .02). FT recipients exhibited markedly superior 1-year event-free survival compared to recipients of FBT200 in univariate analysis (40.3% (95% CI: 25.9 to 54.2) versus 9.2% (95% CI: 4.4 to 16.3), HR: 0.47 (95% CI: 0.30 to 0.72), P < .001) and MVA (P = .004). FT was associated with lower 1-year nonrelapse mortality compared to FBT200 in univariate analysis (9.9% (95% CI: 3.0 to 21.8) versus 29.7% (95% CI: 20.6 to 39.3), HR: 0.41 (95% CI: 0.17 to 0.96), P = .04) and MVA (P = .04). Our study utilized propensity score matching to demonstrate superiority of treosulfan- over busulfan-based conditioning in stem cell transplantation of patients with MDS and is the first to evaluate the performance of treosulfan-based conditioning in combination with ATG and PTCY. As such, it contributes to the increasing body of evidence supporting the safety of treosulfan, even at the dose of 42 g/m2.
Asunto(s)
Busulfano , Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Puntaje de Propensión , Acondicionamiento Pretrasplante , Trasplante Homólogo , Humanos , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Busulfano/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/mortalidad , Adulto , Trasplante Homólogo/métodos , Anciano , Enfermedad Injerto contra Huésped , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Vidarabina/administración & dosificación , Irradiación Corporal TotalRESUMEN
OBJECTIVES: Based on a previous phase 1 study, total marrow irradiation (TMI) at 9Gy was added to a myeloablative FluBu4 conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for myeloid malignancies. Here, we report on the long-term toxicity of TMI combined with FluBu4 and compare it to patients who received only FluBu4. METHODS: We retrospectively analyzed 38 consecutive patients conditioned with FluBu4/TMI (n = 15) or FluBu4 (n = 23, control group) who had at least 1 year follow-up post-transplant. The rate of long-term adverse events that have been previously associated with total body irradiation (TBI) was analyzed in the two groups. RESULTS: The baseline characteristics did not differ between the two groups. The control group had a longer median follow-up (71.2 mo) than the TMI group (38.5 mo) (p = .004). The most common adverse events were xerostomia, dental complications, cataracts, or osteopenia and did not differ between the two groups. Cognitive dysfunction or noninfectious pneumonitis, often detected after high dose TBI, were also not different in the two groups (p = .12 and p = .7, respectively). There was no grade 4 adverse event. CONCLUSION: Our results suggest that a conditioning regimen with TMI 9Gy and FluBu4 does not increase long-term adverse events after allogeneic HSCT.
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Busulfano , Trasplante de Células Madre Hematopoyéticas , Agonistas Mieloablativos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vidarabina , Humanos , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Vidarabina/análogos & derivados , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Busulfano/efectos adversos , Busulfano/administración & dosificación , Estudios Retrospectivos , Agonistas Mieloablativos/efectos adversos , Agonistas Mieloablativos/uso terapéutico , Agonistas Mieloablativos/administración & dosificación , Irradiación Corporal Total/efectos adversos , Adulto Joven , Estudios de Seguimiento , Médula Ósea/efectos de la radiación , Médula Ósea/efectos de los fármacos , Anciano , AdolescenteRESUMEN
BACKGROUND: Cladribine, an analogue of deoxyadenosine, is used for therapy of hematological malignancies. Cladribine-containing regimen has been recommended as a rescue therapy for relapsed or refractory (R/R) acute myeloid leukemia (AML). Its combination with busulfan plus cyclophosphamide (BuCy), as an intensive conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT), requires more clinical evidence. This study aimed to explore the efficacy and safety of cladribine plus BuCy administered as an intensive conditioning regimen before allo-HSCT in R/R AML patients. METHODS: Twenty-three R/R AML patients, who underwent cladribine plus BuCy intensive conditioning regimen before allo-HSCT, were retrospectively analyzed. The median (range) follow-up duration time of observation was 0.73 (0.08-2.69) years. RESULTS: The median (range) returned levels of mononuclear cells were 11.5 (6.1-18.5) x 108/kg and CD34+ cells were 5.5 (3.5-9.3) x 106/kg. The median (range) time of platelet reconstitution was 13.0 (9.0-21.0) days and neutrophil reconstitution was 14.0 (11.0-26.0) days. The incidence of conditioning regimen related toxicity (CRRT) affected 69.6% of patients; all CRRT-affected patients had grade I-II symptoms, including gastrointestinal tract (39.1%), oral cavity (26.1%), liver (8.7%), and kidney (4.3%) CRRTs. The incidence of acute graft-versus-host disease (GVDH) included 30.4% among all patients with 4.3% of grade III-IV acute GVHD, and 34.8% of chronic GVHD. During the follow-up period, 4 (17.4%) patients relapsed, and 6 (26.1%) patients died (cause of death: disease relapse, n = 3; infection, n = 2; GVHD, n = 1). The 1-year and 2-year accumulating event-free survival rates were 66.3% and 53.1%, respectively. The 1-year accumulating overall survival rate was 74.7% and 2-year survival rate was 64.0%. CONCLUSION: Cladribine plus BuCy intensive conditioning regimen before allo-HSCT exhibits favorable treatment efficacy with acceptable toxicity in R/R AML patients.