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1.
J Clin Oncol ; 37(7): 589-597, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653422

RESUMO

PURPOSE: Single-cycle melphalan 200 mg/m2 and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free survival (PFS) and overall survival (OS) for transplantation-eligible patients with multiple myeloma (MM). We designed a prospective, randomized, phase III study to test additional interventions to improve PFS by comparing AHCT, tandem AHCT (AHCT/AHCT), and AHCT and four subsequent cycles of len, bortezomib, and dexamethasone (RVD; AHCT + RVD), all followed by len until disease progression. PATIENTS AND METHODS: Patients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS. RESULTS: The study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms. CONCLUSION: Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Lenalidomida/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Quimioterapia de Consolidação , Dexametasona/efeitos adversos , Progressão da Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Agonistas Mieloablativos/administração & dosagem , Intervalo Livre de Progressão , Estudos Prospectivos , Indução de Remissão , Reoperação , Fatores de Tempo , Transplante Autólogo , Estados Unidos , Adulto Jovem
2.
Support Care Cancer ; 27(3): 839-848, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30109488

RESUMO

Busulfan is a major component of chemotherapy conditioning in hematopoietic cell transplantation (HCT). This alkylating agent is highly toxic at myeloablative doses, exposing HCT patients to risks of mortality. Non-myeloablative (NMA) and reduced-intensity conditioning (RIC) using busulfan have shown impaired toxicity. However, the toxicity of NMA/RIC in the digestive tract is poorly described. This study aimed to characterize the mucositis in the oral cavity (OM), oropharynx/esophagus, and gastrointestinal tract derived from conditionings with myeloablative and non-myeloablative doses of busulfan. We retrospectively retrieved clinical data of HCT patients (n = 100) who underwent myeloablative conditioning (MAC) or NMA/RIC with busulfan. Frequency and time duration of mucositis in the oral cavity and oropharynx/esophagus, diarrhea, and prescription of total parenteral nutrition (TPN) and opioids were also collected. OM severity (p = 0.009) and time duration of mucositis in oropharynx/esophagus (p = 0.022) were frequently higher in MAC than NMA/RIC. A myeloablative dose of busulfan was a risk factor for OM grade ≥ 2 (OR = 4.8, p = 0.002) and for mucositis in oropharynx/esophagus ≥ 5 days (OR = 2.64, p = 0.035). A longer duration of mucositis in the oropharynx/esophagus was also associated with an increase in the prescription of opioids (OR = 7.10, p < 0.001).Overall survival (OS) in MAC was significantly higher than that in NMA/RIC (p = 0.017). No variables related to mucositis interfere significantly in OS. In conclusion, myelosuppression in busulfan-based regimens are predisposed to a high risk for severe OM and to prolonged mucositis in the oropharynx/esophagus.


Assuntos
Bussulfano/efeitos adversos , Doenças do Sistema Digestório/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/efeitos adversos , Mucosite/induzido quimicamente , Agonistas Mieloablativos/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Adulto , Idoso , Bussulfano/administração & dosagem , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mucosite/etiologia , Agonistas Mieloablativos/administração & dosagem , Estudos Retrospectivos
3.
Bone Marrow Transplant ; 54(2): 218-225, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29884851

RESUMO

Weight-based dosing of intravenous busulfan is widely used in hematopoietic cell transplantation. However, a variety of dosing weights have been described. The objective of this retrospective study was to determine the pharmacokinetic impact of using ideal body weight as the initial dosing weight in obese as compared to non-obese transplant recipients. The secondary objectives were to describe the use of alternative dosing weights, the impact on survival, and the rates of toxicities. The mean steady-state concentration was 779.3 ng/mL (n = 82) in the non-obese cohort and 673.7 ng/mL (n = 63) in the obese cohort (p < 0.001). A smaller proportion of concentrations were below goal in the non-obese cohort (10% vs. 41%, p < 0.001). Ideal body weight and adjusted body weights with a 25 and 40% correction factor are appropriate in non-obese patients; adjusted body weights with a 25 and 40% correction factor are appropriate in obese patients. There was no difference in overall survival (p = 0.18); there was a difference in median progression-free survival (1078 vs. 500 days, p = 0.045) in the non-obese compared to obese cohorts. The use of ideal body weight to dose busulfan resulted in lower steady-state concentrations, a larger proportion of subtherapeutic concentrations, and worse progression-free survival in obese patients.


Assuntos
Bussulfano/administração & dosagem , Cálculos da Dosagem de Medicamento , Transplante de Células-Tronco Hematopoéticas/métodos , Peso Corporal Ideal , Adolescente , Adulto , Idoso , Peso Corporal , Bussulfano/farmacocinética , Bussulfano/toxicidade , Intervalo Livre de Doença , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/farmacocinética , Obesidade , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
4.
Leuk Lymphoma ; 60(1): 19-28, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29966474

RESUMO

Hemophagocytic lymphohistiocytosis (HLH), a rare but life-threatening condition characterized by uncontrolled inflammation, is increasingly recognized in adults. The management of adult onset HLH is challenging, in part due to gaps in current state of knowledge on etiology, clinical presentation, diagnosis, and management. HLH secondary to triggers such as infections, autoimmune disorders, and malignancy are more commonly seen in adults although cases of familial form have also been reported. Underlying conditions such as sepsis, or malignancy could pose as major confounders while applying universal diagnostic criteria, and therefore could lead to delay in diagnosis. Despite advent of newer therapeutic agents, outcomes of adults continue to remain poor. Future efforts need to be orchestrated to develop evidence-based tailored therapies to improve outcomes of this under recognized heterogeneous entity.


Assuntos
Anti-Infecciosos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/uso terapêutico , Linfo-Histiocitose Hemofagocítica/terapia , Recidiva Local de Neoplasia/terapia , Adulto , Idade de Início , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Quimioterapia Combinada , Medicina Baseada em Evidências/métodos , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/mortalidade , Agonistas Mieloablativos/administração & dosagem , Recidiva Local de Neoplasia/mortalidade , Prognóstico , Indução de Remissão/métodos , Terapia de Salvação/métodos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos
5.
Biol Blood Marrow Transplant ; 25(2): 391-397, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30244102

RESUMO

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUCpred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUCfirst from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUCfirst being within the ±10% target range (P = .04 for both associations). There was no significant association between AUCfirst and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.


Assuntos
Bussulfano , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos , Condicionamento Pré-Transplante , Adulto , Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/farmacocinética
6.
Exp Clin Transplant ; 17(2): 243-250, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30295587

RESUMO

OBJECTIVES: Allogeneic hematopoietic stem cell transplantation has been used for several decades to treat patients with acute lymphoblastic leukemia. Total body irradiation has been promoted as an important component of conditioning regimens for this process; however, recent reports of chemotherapy-based conditioning regimens have shown comparable outcomes. MATERIALS AND METHODS: We report our experience with radiation-free conditioning using busulfan and cyclophosphamide in 127 pediatric patients with acute lymphoblastic leukemia who were treated between 1997 and 2014. The median age was 11 years (range, < 1 to 15 y), 70% of patients were male, 81.1% received transplants from HLA-matched siblings, 83% received peripheral blood stem cells, 41% were in second complete remission at the time of transplant, and 83% had B-lineage immunophenotype. RESULTS: In patients who were in complete remission at the time of transplant, 5-year overall survival, leukemia-free survival, and relapse rates were 62.48% (95% confidence interval, 52.29-71.09%), 49.43% (95% confidence interval, 39.57-58.53%), and 45.64% (95% confidence interval, 35.85-54.88%), respectively. We observed significant differences between outcomes in patients by time of transplant, presence of chronic graft-versus-host disease, and remission status. CONCLUSIONS: Our relapse rates were comparable to those shown in recent studies, although the transplant-related mortality rate was lower. The results of our study showed that a busulfan/cyclophosphamide conditioning regimen has acceptable outcomes without the undesirable adverse effects of total body irradiation, particularly in pediatric patients. Large multicenter studies are needed to assess less toxic conditioning regimens with fewer adverse effects in these patients.


Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Condicionamento Pré-Transplante/métodos , Adolescente , Fatores Etários , Bussulfano/efeitos adversos , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Progressão da Doença , Quimioterapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Irã (Geográfico) , Masculino , Agonistas Mieloablativos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Intervalo Livre de Progressão , Recidiva , Indução de Remissão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Irradiação Corporal Total/efeitos adversos
7.
Exp Clin Transplant ; 17(1): 93-96, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-27855592

RESUMO

OBJECTIVES: The only known curative therapy for primary myelofibrosis is allogeneic hematopoietic stem cell transplant. MATERIALS AND METHODS: We retrospectively evaluated 11 transplant procedures involving 10 patients (5 men and 5 women) diagnosed with primary myelofibrosis between 2005 and 2014. RESULTS: The median age at the time of transplant was 60.5 years (range, 22-62 years). Stem cell sources were unrelated (n=1) and related (n=11) peripheral blood stem cells. Conditioning regimen was myeloablative for 8 and reduced intensity for 3 transplants. The median number of infused CD34+ cells was 6.8 × 106 cells/kg (range, 3.2-10.4 × 106 cells/kg). Neutrophil and platelet engraftment occurred at median of 22 days (range, 12-31 days) and 19.5 days (range, 13-56 days). Acute and chronic graft-versus-host disease was seen in 4 of 11 allografts. Relapse and nonrelapse mortality rates were 20%. Six patients (60%) were still alive without disease after median follow-up of 68.5 months (range, 17-120 months). Median progression-free survival and overall survival were 61 months (range, 2-120 months) and 65 months (range, 2-120 months). CONCLUSIONS: Our results suggest that allogeneic hematopoietic stem cell transplant may provide a curative treatment for primary myelofibrosis patients. A myeloablative regimen seems to be effective and safe, especially for younger primary myelofibrosis patients.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária/cirurgia , Doença Aguda , Adulto , Células Alógenas/imunologia , Antígenos CD34/imunologia , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Intervalo Livre de Progressão , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
8.
PLoS One ; 13(11): e0206980, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30496309

RESUMO

In this study we utilized a large animal model to identify a dose of intravenous busulfan that can cause reversible myelosuppression. Nine baboons (Papio anubis) were treated with IV busulfan at 6.4 (Group A), 8 (Group B), or 9.6 mg/kg (Group C). Peripheral blood counts were measured up to 90 days after treatment and serial bone marrow samples were obtained to analyze CD34+ cell content and colony forming units. Overall, the highest grade of peripheral blood cytopenia was observed 15 days after treatment in all three groups (n = 3/group). In particular, we observed a notable reduction of neutrophil and platelet counts in the blood and the number of marrow CD34+ cells and colony forming units. In contrast, the effect of busulfan on hemoglobin levels was mild. Baboons who received the highest dose of busulfan showed only a 25-35% recovery of marrow CD34+ cells and colony forming units after 90 days of busulfan administration. However, all three groups of animals showed a full recovery of peripheral blood counts and normal marrow cellularity and tri-lineage hematopoiesis after treatment. Notably, all three doses of busulfan were tolerated well without significant extra-medullary toxicity. These results validate the hierarchy of blood cells likely targeted by busulfan, and based on these findings, clinical trials using myelotoxic but not myeloablative doses of intravenous busulfan will be designed for patients with myeloid malignancies.


Assuntos
Bussulfano/administração & dosagem , Hematopoese/efeitos dos fármacos , Agonistas Mieloablativos/administração & dosagem , Administração Intravenosa , Animais , Contagem de Células Sanguíneas , Medula Óssea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Contagem de Leucócitos , Modelos Animais , Papio , Primatas , Células-Tronco/metabolismo
9.
Am J Hematol ; 93(10): 1211-1219, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30033639

RESUMO

Busulfan plus cyclophosphamide (BuCy) is the traditional conditioning regimen for allogeneic stem cell transplant (allo-SCT) for young, fit patients with acute myeloid leukemia (AML). The thiotepa-busulfan-fludarabine (TBF) protocol has recently demonstrated promising outcome in cord blood and haploidentical SCT; however, there is limited evidence about this regimen in transplant from matched siblings (MSD) and unrelated donors (UD). We retrospectively compared outcomes of 2523 patients aged 18-50 with AML in remission, undergoing transplant from MSD or UD prepared with either TBF or BuCy conditioning. A 1:3 pair-matched analysis was performed: 146 patients receiving TBF were compared with 438 patients receiving BuCy. Relapse risk was significantly lower in the TBF when compared with BuCy group (HR 0.6, P = .02), while NRM did not differ. No significant difference was observed in LFS and OS between the two regimens. TBF was associated with a trend towards higher risk of grades III-IV aGVHD (HR 1.8, P = .06) and inferior cGVHD (HR 0.7, P = .04) when compared with BuCy. In patients undergoing transplant in first remission, the advantage for TBF in terms of relapse was more evident (HR 0.4, P = .02), leading to a trend for better LFS in favor of TBF (HR 0.7, P = .10), while OS did not differ between the two cohorts. In conclusion, TBF represents a valid myeloablative conditioning regimen providing significantly lower relapse and similar survival when compared with BuCy. Patients in first remission appear to gain the most from this protocol, as in this subgroup a tendency for better LFS was observed when compared with BuCy.


Assuntos
Transplante de Medula Óssea , Bussulfano/uso terapêutico , Ciclofosfamida/uso terapêutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico , Tiotepa/uso terapêutico , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Terapia Combinada , Intervalos de Confiança , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Avaliação de Medicamentos , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/efeitos adversos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Tiotepa/administração & dosagem , Tiotepa/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/uso terapêutico , Adulto Jovem
10.
Blood Adv ; 2(11): 1198-1206, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29844205

RESUMO

Busulfan combined with cyclophosphamide (BuCy) has long been considered a standard myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (HCT), including both nonmalignant conditions and myeloid diseases. Substituting fludarabine for cyclophosphamide (BuFlu) to reduce toxicity without an increase in relapse has been increasingly performed in children, but without comparison with BuCy. We retrospectively analyzed 1781 children transplanted from 2008 to 2014 to compare the effectiveness of BuCy with BuFlu. Nonmalignant and malignant disease populations were analyzed separately. Overall mortality was comparable for children with nonmalignant conditions who received BuFlu or BuCy (relative risk [RR], 1.14, P = .52). Lower incidences of sinusoidal obstruction syndrome (P = .04), hemorrhagic cystitis (P = .04), and chronic graft-versus-host disease (P = .02) were observed after BuFlu, but the influence of the conditioning regimen could not be assessed by multivariate analysis because of the low frequency of these complications. Children transplanted for malignancies were more likely to receive BuFlu if they had higher hematopoietic cell transplantation-comorbidity index scores (P < .001) or their donor was unrelated and HLA-mismatched (P = .004). Nevertheless, there were no differences in transplant toxicities and comparable transplant-related mortality (RR, 1.2; P = .46), relapse (RR, 1.2; P = .15), and treatment failure (RR, 1.2; P = .12). BuFlu was associated with higher overall mortality (RR, 1.4; P = .008) related to inferior postrelapse survival (P = .001). Our findings demonstrated that outcomes after BuFlu are similar to those for BuCy for children, but for unclear reasons, those receiving BuFlu for malignancy may be at risk for shorter postrelapse survival.


Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/efeitos adversos , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adolescente , Adulto , Aloenxertos , Bussulfano/efeitos adversos , Criança , Pré-Escolar , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Agonistas Mieloablativos/administração & dosagem , Estudos Retrospectivos , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos
11.
Exp Clin Transplant ; 16(6): 736-744, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29790457

RESUMO

OBJECTIVES: We evaluated the safety and efficacy of 2 conditioning regimens (busulfan/fludarabine vs modified busulfan/cyclophosphamide) in patients with acute myeloid leukemia undergoing haploidentical hematopoietic stem cell transplant. MATERAILS AND METHODS: Twenty patients with primary acute myeloid leukemia had been randomized into busulfan/fludarabine and modified busulfan/cyclophosphamide groups. We retrospectively compared hematopoietic engraftment, regimen-related toxicity, graft-versus-host disease, transplant-related mortality, leukemia-free survival, and overall survival between the groups. RESULTS: All patients achieved engraftment with 100% donor chimerism. The median times for the neutrophil and platelet engraftment in the busulfan/fludarabine and modified busulfan/cyclophosphamide groups were 14.1 versus 14.3 days and 12.7 versus 12.2 days, respectively. Significantly lower incidences of pretreatment toxicity, blood transfusion, and virus activation were observed in the busulfan/fludarabine group. Acute grade 1 graft-versus-host-disease developed in all patients, which was successfully controlled with methylprednisolone. There were no significant differences in engraftment, graft-versus-host disease, leukemia-free survival, and overall survival between groups. Both of these conditioning regimens achieved stable engraftment. Regimen-related toxicity in the busulfan/fludarabine group was well tolerated compared with that in the modified busulfan/cyclophosphamide group, without an increase in relapse rate. CONCLUSIONS: Our results demonstrated that myeloablative busulfan/fludarabine might be a highly effective and low-toxicity alternative for patients with acute myeloid leukemia.


Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/administração & dosagem , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Bussulfano/efeitos adversos , China , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Quimioterapia Combinada , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Haploidêntico , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Adulto Jovem
12.
Clin Cancer Res ; 24(17): 4098-4109, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29769208

RESUMO

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution.Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells.Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098-109. ©2018 AACR.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia/terapia , Linfócitos/imunologia , Síndromes Mielodisplásicas/terapia , Linfócitos T/imunologia , Adulto , Antígenos CD34/imunologia , Linfócitos T CD4-Positivos/imunologia , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunidade Inata/imunologia , Leucemia/imunologia , Leucemia/patologia , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Linfócitos T/patologia , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante Haploidêntico , Transplante Homólogo
13.
Leuk Res ; 69: 60-65, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29660493

RESUMO

Peripheral monocytes have recently been evaluated as a prognostic factor in different types of hematological malignancies. This study assessed the prognostic value of absolute monocyte count (AMC) post-transplant on the clinical outcomes of 59 patients with acute myeloid leukemia (AML) who had undergone myeloablative conditioning (MAC) allogeneic hematopoietic stem cell transplant (allo-HSCT) with busulfan and cyclophosphamide (Bu/Cy). Kaplan-Meier analysis showed that patients with a high AMC (≥ 0.57 × 109/L) on post-transplant day (PTD) 15 had a significantly worse overall survival (OS) compared to patients with a low AMC (< 0.57 × 109/L) on PTD 15 (P = .0049). Univariate Cox proportional hazard analyses revealed that only high AMC on PTD 15 was a poor prognostic factor for OS (P = .008) and post-relapse survival (P = .030). We conclude that AMC ≥ 0.57 × 109/L on PTD 15 is associated with more deaths in patients with AML who have undergone MAC allo-HSCT with Bu/Cy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Monócitos/citologia , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
14.
Eur J Pharm Sci ; 120: 1-9, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29705215

RESUMO

Treosulfan (TREO), a structural analog of busulfan, is currently studied as a myeloablative agent in conditioning regimens before hematopoietic stem cell transplantation in pediatric patients. High exposure to TREO (>1650 mg∗h/mL) might be related to early toxicity, especially skin toxicity and mucositis. The aim of the present study was to investigate a potential relationship between exposure to TREO and its monoepoxytransformer (S,S-EBDM), as well as variability of the pharmacokinetics of these entities by means of a population pharmacokinetic approach with a non-linear mixed-effects analysis. The study included data from 14 children with malignant and non-malignant diseases treated with TREO in daily doses 10-14 g/m2. The parent-metabolite population pharmacokinetic model was developed in NONMEM 7.3 software. Upon the constructed model, an extensive simulation was performed to assess the correlation between exposure to TREO and S,S-EBDM. It was found that TREO and S,S-EBDM pharmacokinetics was best described with 2-compartmental and 1-compartmental linear models, respectively. The vast majority (>65%) of TREO was transformed to S,S-EBDM. Overall, a considerable interpatient variability of pharmacokinetic parameters was observed, especially the clearance of S,S-EBDM. A weak correlation was found between the exposure to TREO and S,S-EBDM (r = 0.1681, p < 0.0001). Also, patients with an exposure to TREO above 1650 mg∗h/mL were most likely to have also a high exposure to S,S-EBDM (35.38 µM∗h vs. 43.14 µM∗h, p < 0.0001). In summary, a parent-metabolite population pharmacokinetic model for TREO and S,S-EBDM was developed for the first time. It was shown that there is a weak correlation between exposure to TREO and S,S-EBDM. Therefore therapeutic drug monitoring of not only prodrug but also its active epoxide might be needed.


Assuntos
Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Modelos Biológicos , Agonistas Mieloablativos/farmacocinética , Pró-Fármacos/farmacocinética , Condicionamento Pré-Transplante/métodos , Ativação Metabólica , Adolescente , Fatores Etários , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Bussulfano/farmacocinética , Criança , Pré-Escolar , Simulação por Computador , Feminino , Humanos , Lactente , Masculino , Agonistas Mieloablativos/administração & dosagem , Dinâmica não Linear , Polônia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Software , Condicionamento Pré-Transplante/efeitos adversos
15.
Clin Lymphoma Myeloma Leuk ; 18(5): 368-374, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625929

RESUMO

INTRODUCTION: The optimal intensity of myeloablation with a reduced-toxicity conditioning regimen to decrease relapse rate after allogeneic stem-cell transplantation without increasing transplant-related mortality (TRM) has not been well established. MATERIALS AND METHODS: We compared outcomes between 5 mg/kg (T5) and 10 mg/kg (T10) thiotepa-based conditioning regimens in 29 adults who underwent allogeneic stem-cell transplantation for hematologic malignancies. RESULTS: After a median follow-up of 11 months, TRM was 0% and 14% at 100 days and 1 year, respectively, with TRM observed only in the T5 group (P = .016). The relapse incidence at 1 year was 20%. No patient had disease in first complete remission at the time of transplantation. At 1 year, progression-free and overall survival were 30% versus 87% (P = .012) and 46% versus 87% (P = .008) in the T5 and T10 groups, respectively. In univariate and multivariate analysis, only age at transplantation and total dose of thiotepa had a significant impact on TRM, overall, and progression-free survival. CONCLUSION: Patients deemed fit to receive T10-based conditioning for allogeneic stem-cell transplantation to treat high-risk hematologic malignancies had better overall and progression-free survival than those who received T5 with no additional toxicities. Patients should be stratified before conditioning, and those judged fit should receive T10, while the others should consider alternative reduced-intensity conditioning regimens.


Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/administração & dosagem , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante/métodos , Adulto , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Adulto Jovem
16.
Leuk Lymphoma ; 59(12): 2836-2841, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29616863

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Recidiva Local de Neoplasia/prevenção & controle , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Quimioterapia de Manutenção/efeitos adversos , Quimioterapia de Manutenção/métodos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Síndromes Mielodisplásicas/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Adulto Jovem
17.
Pediatr Blood Cancer ; 65(7): e27034, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29528181

RESUMO

BACKGROUND: Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan-cyclophosphamide-melphalan (Bu-Cy-Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less-toxic myeloablative conditioning regimen containing busulfan-fludarabine (Bu-Flu) would be associated with equivalent outcomes. PROCEDURE: Twenty-seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre- and post-HCT (starting Day +30) mutant allele burden was measured in all and pre-HCT therapy was administered according to physician discretion. RESULTS: Fifteen patients were randomized (six to Bu-Cy-Mel and nine to Bu-Flu) after meeting diagnostic criteria for JMML. Pre-HCT low-dose chemotherapy did not appear to reduce pre-HCT disease burden. Two patients, however, received aggressive chemotherapy pre-HCT and achieved low disease-burden state; both are long-term survivors. All four patients with detectable mutant allele burden at Day +30 post-HCT eventually progressed compared to two of nine patients with unmeasurable allele burden (P = 0.04). The 18-month event-free survival of the entire cohort was 47% (95% CI, 21-69%), and was 83% (95% CI, 27-97%) and 22% (95% CI, 03-51%) for Bu-Cy-Mel and Bu-Flu, respectively (P = 0.04). ASCT1221 was terminated early due to concerns that the Bu-Flu arm had inferior outcomes. CONCLUSIONS: The regimen of Bu-Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre-HCT responses to chemotherapy, and post-HCT management.


Assuntos
Rejeição de Enxerto/tratamento farmacológico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mielomonocítica Juvenil/terapia , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante , Bussulfano/administração & dosagem , Criança , Pré-Escolar , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Recém-Nascido , Leucemia Mielomonocítica Juvenil/complicações , Masculino , Prognóstico , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
18.
JCI Insight ; 3(5)2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29515031

RESUMO

Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy.


Assuntos
Evolução Clonal/imunologia , Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/terapia , Recidiva Local de Neoplasia/genética , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Evolução Clonal/efeitos dos fármacos , Células Clonais/efeitos dos fármacos , Células Clonais/imunologia , Análise Mutacional de DNA , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/efeitos adversos , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento
19.
Pediatr Blood Cancer ; 65(6): e27010, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29469225

RESUMO

BACKGROUND: Infantile malignant osteopetrosis (IMO) is an autosomal recessive condition characterized by defective osteoclast activity, with hematopoietic bone marrow transplant being the only available cure. Over the past several years, new conditioning regimes and donor options have emerged, thus extending the possibility of cure to a greater number of patients and improving the outcomes of bone marrow transplant. Here we detail the outcomes of bone marrow transplant in a cohort of 31 patients treated with a combination of fludarabine, treosulphan, thiotepa, and antithymocyte globulin. PROCEDURES: Thirty-one patients with IMO who underwent hematopoietic stem cell transplantation with fludarabine, treosulphan, thiotepa, and antithymocyte globulin at our center from 2012 to 2017 are retrospectively reviewed in this study. Twenty-six patients were transplanted from 10/10 matched donors (13 from siblings, 11 from unrelated, and two from extended family donors), four from 9/10 matched unrelated donors, and one from a 9/10 matched family donor. RESULTS: Overall survival was 100% with a median follow-up of 363 days (range 74-1891). There were 12 cases of acute graft versus host disease (GvHD) (38.7%), no cases of veno-occlusive disease, and eight cases of hypercalcemia (25.8%). Almost 80% of patients suffered viral reactivations with two cases of Epstein-Barr-virus-driven post-transplant lymphoproliferative disease. All cases of GvHD and viral reactivation were successfully treated. CONCLUSIONS: We conclude that transplantation in children with IMO using fludarabine, treosulphan, thiotepa, and antithymocyte globulin is safe and effective and should be performed as early as possible following diagnosis, prior to the development of severe disease sequelae.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Agonistas Mieloablativos/administração & dosagem , Osteopetrose/terapia , Condicionamento Pré-Transplante , Adolescente , Adulto , Soro Antilinfocitário/administração & dosagem , Bussulfano/administração & dosagem , Bussulfano/análogos & derivados , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Melfalan/administração & dosagem , Prognóstico , Estudos Retrospectivos , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto Jovem
20.
Cancer ; 124(8): 1733-1742, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29424927

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the only potentially curative treatment option for relapsed follicular lymphoma (FL), yet questions remain about the optimal timing. This study analyzed long-term outcomes and associated factors among recipients of allo-HCT with FL. METHODS: Patients with relapsed FL who underwent allo-HCT from 2001 to 2011 with a human leukocyte antigen (HLA)-matched donor were included. Outcome analyses for overall survival (OS), progression-free survival (PFS), transplant-related mortality (TRM), and disease relapse/progression were calculated. A multivariate analysis was performed to determine factors associated with outcomes, and a prognostic score for treatment failure was developed in a subset analysis of patients. RESULTS: In all, 1567 patients with relapsed FL were included; the median follow-up was 55 months. The 5-year probabilities of OS and PFS were 61% and 52%, respectively. The 5-year cumulative incidences of disease progression/relapse and TRM were 29% and 19%, respectively. Chemoresistant disease, older age, heavy pretreatment, poor performance status (PS), and myeloablative protocols were predictors for worse survival. The prognostic score, using age, lines of prior therapy, disease status, and PS, stratified patients into 3 groups-low, intermediate, and high risk-with 5-year PFS rates of 68%, 53%, and 46%, respectively, and 5-year OS rates of 80%, 62%, and 50%, respectively. CONCLUSIONS: Allo-HCT should be considered for patients with relapsed FL and available HLA-matched donors. Outcomes are better in earlier phases of the disease, and reduced-intensity conditioning should be preferred. The prognostic score presented here can assist in counseling patients and determining the time to proceed to transplantation. Cancer 2018;124:1733-42. © 2018 American Cancer Society.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfoma Folicular/terapia , Recidiva Local de Neoplasia/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Progressão da Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/imunologia , Humanos , Incidência , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Linfoma Folicular/diagnóstico , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/efeitos adversos , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Prognóstico , Intervalo Livre de Progressão , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Doadores de Tecidos , Condicionamento Pré-Transplante/efeitos adversos , Transplante Homólogo/efeitos adversos , Falha de Tratamento , Adulto Jovem
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