RESUMEN
The role of hypomethylating agent therapy (HMT) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) in patients with myelodysplastic syndrome (MDS) remains undetermined. We investigated the feasibility of HMT followed by alloHCT in patients with MDS. In all, 19 patients who received HMT followed by alloHCT were analyzed. A total of 7 patients were classified as low-risk and 12 as high-risk, based on World Health Organization (WHO) classification at the time of HMT. HMT consisted of decitabine in 9 patients and azacitidine in 10. After HMT, two patients achieved CR, six mCR, three hematologic improvement alone, and six SD in terms of best response. HMT did not alter WHO classification in 15 patients (79%), whereas 1 patient (5%) improved and 3 (16%) progressed to AML. Most patients (95%) received a non-myeloablative conditioning regimen based on fludarabine/BU/anti-thymocyte globulin, and peripheral blood-mobilized stem cells. Neutrophil and platelet engraftments were achieved in 95 and 79% of patients, respectively. The incidences of acute and chronic GVHD were 42 and 26%, respectively. In all, 2-year OS rates were 68%, and the overall outcomes of those who achieved CR/mCR with HMT tended to be superior to those without CR/mCR. HMT followed by alloHCT was a feasible and effective treatment strategy for patients with MDS.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/terapia , Trasplante Homólogo/métodos , Adulto , Anciano , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Metilación de ADN , Decitabina , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Enfermedad Injerto contra Huésped/terapia , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Neutrófilos/citología , Riesgo , Acondicionamiento Pretrasplante/métodos , Resultado del TratamientoRESUMEN
We analyzed the clinical significance of pre-transplant International Prognostic Scoring System (IPSS) score and comorbidity in 68 patients who underwent allogeneic hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS) (n=48) or acute myeloid leukemia evolved from MDS (n=20) between December 1995 and January 2008 in a single institute. During a median follow-up period of 41.0 months (range, 3.2-132.0 months), 27 patients died, and 7 relapsed. The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 60.0 and 57.4%, respectively, and the 5-year cumulative incidences of non-relapse mortality (CINRM) and relapse were 32.7 and 9.9%, respectively. OS, EFS, and CINRM were significantly different according to pre-transplant IPSS score and presence of pre-transplant comorbidity, which were independent risk factors along with Karnofsky performance score in multivariate analyses. In conclusion, pre-transplant IPSS score and comorbidity may stratify the risk of post transplant outcomes in MDS.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos/terapia , Adulto , Comorbilidad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Post transplant infusion of donor-type natural killer (NK) cells has been shown to have an anti-leukemia-enhancing effect without evoking GVHD in murine hematopoietic cell transplantation (HCT) models. Here, we tested 14 patients (age, 23-65 years), 12 with acute leukemia and 2 with myelodysplastic syndrome, who underwent HLA-mismatched HCT and subsequently received donor NK cell infusions. Cell donors (age, 16-51 years), comprising seven siblings, five offspring, and two mothers of the patients, underwent growth factor-mobilized leukapheresis for 3-5 days. Cells collected on the first 2-4 days were used for HCT, whereas those collected on the last day were CD34 selected by magnetic-activated cell sorting (median, 2.22 x 10(6) cells/kg; range, 0.29-5.66). Donor NK cells were generated from the CD34(+) cells by ex vivo cell culture over a 6-week period (median, 9.28 x 10(6) cells/kg; range, 0.33-24.50; CD122/CD56(+) 64%; CD3(+) 1.0%; and viability 88%). There were no signs of acute toxicity in patients infused with these cells 6-7 weeks post transplant. Overall, one and five patients developed acute and chronic GVHD during post transplant period, respectively. These results showed that clinical-grade donor NK cell production from CD34(+) cells is feasible.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/citología , Células Asesinas Naturales/trasplante , Transfusión de Linfocitos/métodos , Adulto , Antígenos CD34 , Técnicas de Cultivo de Célula , Estudios de Factibilidad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Células Asesinas Naturales/citología , Leucemia/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Donantes de Tejidos , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
We used the National Institutes of Health (NIH) criteria for the diagnosis, classification and scoring of chronic GVHD (cGVHD) to reevaluate patients with cGVHD originally diagnosed using classic criteria. We retrieved data from 236 patients diagnosed with cGVHD on the basis of classic criteria. Excluding 20 'liver-alone' patients, we re-categorized 216 patients in keeping with the NIH criteria. Twenty patients were reclassified as having acute GVHD and 196 patients as having cGVHD (170 'classic chronic' (Cl-Ch) and 26 'overlap chronic' (Ov-Ch)). The 5-year GVHD-specific survival (GSS) was significantly different between the two cGVHD subtypes, specifically 87.3% for Cl-Ch vs 70.2% for Ov-Ch (P=0.006). The NIH severity criteria were effective in expecting 5-year GSS rates at both the onset (93.5, 81.3 and 79.7% (P=0.047)) and peak intensity of the disease (100, 89.7 and 78.7% (P=0.004) for the mild, moderate and severe grade, respectively). Multivariate analysis showed that NIH severity criteria were independently significant prognostic factors for GSS (mild vs moderate, HR 4.35, P=0.036; mild vs severe, HR 5.25, P=0.020). Our results support the role of the NIH criteria in classifying cGVHD and in assessing the severity of the disease to predict patient prognosis of cGVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/clasificación , Enfermedad Injerto contra Huésped/diagnóstico , National Institutes of Health (U.S.)/normas , Guías de Práctica Clínica como Asunto/normas , Enfermedad Crónica , Clasificación , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Pronóstico , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Estados UnidosRESUMEN
To build a risk score (RS) model of fatal intracranial hemorrhage (FICH) in patients with acute leukemia, we retrospectively assessed risk factors in 792 patients newly diagnosed with acute leukemia, 41 of whom had analyzable FICH. We found that female gender (relative risk (RR) = 5.234, P<0.001), acute promyelocytic leukemia (RR = 4.057, P = 0.003), leukocytosis (RR = 3.301, P = 0.004), thrombocytopenia (RR = 3.283, P = 0.005) and prolonged prothrombin time (RR = 3.291, P = 0.016) were significantly associated with occurrence of FICH in multivariate analysis. To calculate RS for FICH, one point was assigned for each risk factor, making the RS between 0 and 5. The RS model segregated patients into three prognostic groups: a low-risk group (LRG) for RS of 0 or 1; an intermediate-risk group (IRG) for RS of 2 or 3; and a high-risk group (HRG) for RS of 4 or 5. Expectation of FICH was well correlated with risk groups (all P-values < 0.001). Overall survival was significantly shorter in the HRG compared with the LRG. The RS model we constructed to predict the occurrence of FICH will be verified through prospective studies.
Asunto(s)
Hemorragias Intracraneales/epidemiología , Leucemia Mieloide/epidemiología , Leucemia Promielocítica Aguda/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Índice de Severidad de la Enfermedad , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Hemorragias Intracraneales/diagnóstico , Corea (Geográfico)/epidemiología , Leucemia Mieloide/diagnóstico , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Clinical impact of imatinib was evaluated in 20 patients (median age, 37 years; range, 15-67 years) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who were administered with induction chemotherapy of daunorubicin, vincristine, prednisolone, and L-asparaginase, along with imatinib 600 mg/day during remission induction and 400 mg/day during consolidation courses. One patient died on day 14 from septic shock, while the remaining 19 achieved complete remission (CR). In total, 15 patients underwent allogeneic hematopoietic cell transplantation (HCT) during first CR. After median follow-up period of 799 days, six patients experienced recurrence; two with early recurrence within 100 days, one with leptomeningeal recurrence at 11 month, and three with post-HCT recurrence. Eight patients died. Median CR duration (821 days) and median patient survival (894 days) in the study were significantly longer by 2.9- and 2.3-fold, respectively, when compared to those of 18 historical patients treated with same regimen of combination chemotherapy without imatinib. Toxicities of the combined treatment were manageable and included grade 4 myelosuppression (n = 20) and reversible > or = grade 3 hyperbilirubinemia (n = 4). Beneficial clinical effects were observed when imatinib was added to combination chemotherapy in patients with newly diagnosed Ph+ ALL. Further studies with larger number of patients are necessary.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Piperazinas/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pirimidinas/administración & dosificación , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Piperazinas/efectos adversos , Estudios Prospectivos , Pirimidinas/efectos adversos , Inducción de Remisión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Donor leukocyte infusion (DLI) alone has very limited efficacy for patients with acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic bone marrow transplantation (BMT). We, therefore, prospectively tested the efficacy of cytoreductive chemotherapy (intermediate-dose cytarabine+idarubicin+etoposide) followed immediately by G-CSF-primed DLI (Chemo-DLI) in 10 relapsed ALL patients after allogeneic BMT. Seven achieved complete remission (CR) at a median of 25 days (19-73 days) after DLI. Of these seven CR patients, only one remains alive in CR 907 days after DLI. Two CR patients died in CR of graft-versus-host disease. The remaining four CR patients relapsed at a median of 153 days (120-991 days) after DLI. One is alive with leukemia at post-DLI day 1217. The median survival duration after DLI was 175 days (15-1217 days). In summary, although Chemo-DLI for relapsed ALL after allogeneic BMT induced a relatively high CR rate, durable remissions were rare. Although our data should be interpreted cautiously considering the small number of patients, these results suggest that poor outcome of DLI in relapsed ALL may be primarily due to intrinsic resistance to graft-versus-leukemia effect rather than to the rapid pace of the disease.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Médula Ósea , Transfusión de Leucocitos , Leucemia-Linfoma Linfoblástico de Células Precursoras/prevención & control , Donantes de Tejidos , Adulto , Antineoplásicos/administración & dosificación , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Idarrubicina/administración & dosificación , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Estudios Prospectivos , Recurrencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Using non-total body irradiation (TBI) containing preparative regimens, 13 patients with severe aplastic anemia (SAA) were transplanted from an alternative donor in a single institute. In total, 12 donors were unrelated volunteers and one was an HLA one-locus mismatched sibling. Median time from diagnosis of SAA to bone marrow transplantation (BMT) was 10.1 months (range, 1.6-180.1). Nine patients had received immunosuppressive treatment with ATG before BMT, while four had not. Preparative regimens consisted of cyclophosphamide plus ATG in nine patients, cyclophosphamide plus fludarabine in two patients, and cyclophosphamide plus fludarabine plus ATG in two patients. All patients received non-T-cell depleted bone marrow from the donor. Cyclosporine plus methotrexate were given for GVHD prophylaxis. All patients engrafted on a median of day 21 (range, 15-27). Grade III-IV acute GVHD developed in three (23%) of 13 patients and extensive chronic GVHD in four (31%) of 12 evaluable patients. With a median follow-up duration of 1138 days (range, 118-1553), 10 patients are alive with durable engraftment showing 74.6% (95% confidence interval, 49.5-99.7%) of survival rate. Cause of the deaths was CNS bleeding in one and chronic GVHD in two. In conclusion, non-TBI containing preparative regimen could ensure durable engraftment in alternative donor BMT for SAA and showed promising results.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea/métodos , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adolescente , Adulto , Transfusión Sanguínea , Ciclofosfamida/farmacología , Ciclosporina/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/etiología , Histocompatibilidad , Prueba de Histocompatibilidad , Humanos , Inmunosupresores/farmacología , Masculino , Metotrexato/farmacología , Metotrexato/uso terapéutico , Linfocitos T/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Vidarabina/farmacología , Irradiación Corporal TotalRESUMEN
Severe metabolic abnormalities occurring within 100 days after allogeneic hematopoietic cell transplantation (HCT) were investigated in 311 patients. The metabolic abnormalities included hyper- and hypocalcemia, hypophosphatemia, hyper- and hypokalemia, hyper- and hyponatremia, hyper- and hypomagnesemia, hypercholesterolemia, hyper- and hypoglycemia, and hyperuricemia. Severe abnormalities, defined as grades III-V by NCI CTCAE v3.0, occurred in 269 patients (86.5%). Multivariate analysis revealed that patients with moderate-to-severe hepatic veno-occlusive disease had significantly higher risk for the occurrence of severe metabolic abnormalities. Grades III-IV acute graft-versus-host disease was the most frequently associated with individual metabolic abnormalities. Patients with at least one severe metabolic abnormality had significantly higher day 100 nonrelapse mortality (P=0.015) and lower 5-year overall survival (P=0.002) than those without severe abnormalities. The number of metabolic abnormalities also stratified the patients with different clinical outcomes. In conclusion, severe metabolic abnormalities occurring within 100 days after allogeneic HCT were common, and their occurrence was significantly associated with inferior clinical outcomes. These results indicate that metabolic parameters should be monitored in patients undergoing allogeneic HCT and that the occurrence of severe metabolic abnormalities should be considered an important toxicity parameter in prospective clinical trials regarding allogeneic HCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades Metabólicas/etiología , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Ensayos Clínicos como Asunto , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas/terapia , Enfermedad Veno-Oclusiva Hepática/etiología , Humanos , Masculino , Enfermedades Metabólicas/mortalidad , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Riesgo , Factores de Riesgo , Factores Sexuales , Trasplante de Células Madre , Factores de Tiempo , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
For patients with acute myeloid leukemia (AML) relapsed after allogeneic bone marrow transplantation (BMT), donor leukocyte infusion (DLI) as sole therapy has very limited efficacy. We tested the effects of cytoreductive chemotherapy, followed immediately by G-CSF-primed DLI (chemotherapy followed by DLI, Chemo-DLI), in 16 AML patients who relapsed after allogeneic BMT. In all, 10 of these patients achieved complete remission (CR), four of whom remain alive in CR at a median follow-up of 1488 days after DLI. The 2-year overall survival (OS) for the entire cohort was 31%. The 1-year OS for patients with post-BMT remission of 6 months or longer was 55%, compared with 0% for patients with post-BMT remission of less than 6 months, making post-BMT remission duration the only significant prognostic factor for OS (P=0.015). These findings suggest that Chemo-DLI could induce durable remissions in a proportion of relapsed AML patients with relatively long post-BMT remission duration. All five patients who relapsed after achieving CR with Chemo-DLI relapsed at extramedullary sites in the presence of continuous bone marrow remission, suggesting uneven graft-versus-leukemia effects in different parts of the body. Although our data should be interpreted cautiously considering the limited number of patients, isolated extramedullary relapse seems to be common after Chemo-DLI.
Asunto(s)
Trasplante de Médula Ósea , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Leucemia Mieloide/terapia , Recurrencia Local de Neoplasia/terapia , Donantes de Tejidos , Enfermedad Aguda , Adolescente , Adulto , Enfermedad Injerto contra Huésped , Humanos , Incidencia , Transfusión de Leucocitos , Persona de Mediana Edad , Inducción de Remisión , Tasa de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The role of methotrexate (MTX), given with cyclosporine (CS), after HLA-identical sibling bone marrow transplantation needs to be defined. In all, 80 patients with hematologic malignancies were enrolled in a prospective randomized trial. All were given BuCy conditioning. The 40 patients in the CS arm received CS 3 mg/kg/day intravenously, with subsequent oral dosing. Patients in the CS + MTX arm received, in addition to CS, MTX intravenously, 15 mg/m2 on day 1, and 10 mg/m2 on days 3, 6, and 11. Transplantation-related mortality was low in both groups of patients (13 vs 11% for CS vs CS + MTX groups, P = 0.94). The CS group had a significantly higher frequency of chronic graft-versus-host disease (56 vs 32%, P = 0.05). After a median follow-up of 22.1 months (5.1-47.8 months), three of 30 vs 10 of 28 patients with acute leukemia/myelodysplastic syndrome (MDS) in CS group vs CS + MTX group relapsed (P = 0.01) yielding better overall survival for patients with acute leukemia/MDS treated with CS (P = 0.02). After HLA-identical sibling bone marrow transplantation, immunosuppression with CS, with or without MTX, resulted in similarly low transplantation-related mortality. In acute leukemia/MDS, decreased relapse with patient survival prolongation was observed in the CS group.
Asunto(s)
Trasplante de Médula Ósea , Ciclosporina/administración & dosificación , Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Leucemia Mieloide/terapia , Metotrexato/administración & dosificación , Enfermedad Aguda , Adolescente , Adulto , Enfermedad Crónica , Quimioterapia Combinada , Femenino , Antígenos HLA/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mieloide/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Prospectivos , Recurrencia , Hermanos , Tasa de Supervivencia , Donantes de TejidosRESUMEN
The outcomes of patients who experience the failure to reconstitute a trilineage of blood cells after initial neutrophil engraftment were evaluated in 178 patients with hematologic disorders, who underwent allogeneic HCT. Of 165 qualified patients (five with primary engraftment failure; eight deaths before day 60 of HCT), 43 (26%) satisfied the criteria for the initial (n=22; failure of platelet >20 000/microl or red blood cell transfusion independence/reticulocyte count >/=1.0% by day 60) or subsequent (n=21, ANC <500/microl for >/=3 days, platelet <20 000/microl for >/=7 days, or red blood cells transfusion/reticulocyte <1.0% after initial trilineage reconstitution) failure. GVHD was the most common clinical condition associated with cytopenia (n=24). In all, 20 patients (47%) recovered at least partially with a median of 52 days (range 8-323) later, with 12 of those 20 patients recovering completely. The eventual reconstitution failure rate was 14% (23/163 patients). The number of cell lineages involved in the cytopenia was the only independent variable that predicted partial recovery (1 lineage vs 2-3 lineages with odds ratio of 8.69 (95% CI 1.96-38.60), P=0.004). Five/20 patients with vs 20/23 patients without partial recovery died. Trilineage reconstitution failures after allogeneic HCT need systematic analysis in the future studies.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adolescente , Adulto , Células Sanguíneas/fisiología , Linaje de la Célula , Distribución de Chi-Cuadrado , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/patología , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Hematopoyesis , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Neutrófilos/fisiología , Pancitopenia , Estudios Retrospectivos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
To evaluate the significance of clinical abnormalities occurring during the peri-engraftment period following allogeneic hematopoietic cell transplantation (HCT), we retrospectively analyzed the data of 216 allogeneic HCT recipients. The most frequently observed peri-engraftment clinical abnormality (PECA) was noninfectious fever in 58 patients, followed by hepatic dysfunction in 39, weight gain in 22, and renal insufficiency in 11. Frequently identified predictive factors for a higher incidence of each PECA were HCT from an unrelated or mismatched donor, GVHD prophylaxis with cyclosporine alone, and rapid engraftment. Considering that donor type and GVHD prophylaxis are closely related to GVHD, these observations suggest that the development of PECAs might be associated with a graft-versus-host reaction. This hypothesis was supported by the fact that the patient group with each PECA showed a higher incidence of grades 3-4 acute or chronic extensive GVHD, with varying degrees of statistical significance. Although our data should be interpreted cautiously in view of their retrospective nature, some of the PECAs occurring after allogeneic HCT may be atypical manifestations of GVHD and may be associated with severe forms of acute or chronic GVHD.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hepatopatías/diagnóstico , Hepatopatías/epidemiología , Adolescente , Adulto , Permeabilidad Capilar , Femenino , Fiebre/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/epidemiología , Estudios Retrospectivos , Trasplante Homólogo , Aumento de PesoRESUMEN
A total of 118 consecutive adult patients with acute leukemia (78 AML, 36 ALL, and four acute mixed lineage leukemia) underwent allogeneic hematopoietic cell transplantation (HCT) after conditioning with BuCy (n=113) or a nonmyeloablative regimen of busulfan-fludarabine (n=5). After a median follow-up of 35.8 months (range, 6.4-91.0), 34 patients experienced at least one episode of leukemia relapse. Of 34 initial episodes, 14 (41%) occurred in extramedullary sites, with (n=8) or without (n=6) concomitant bone marrow involvement. The median time to relapse in the extramedullary sites was longer than that of relapse in bone marrow only (13.5 vs 6.1 months, P=0.046). Acute leukemia subtype and disease status at HCT showed an independent predictive value for overall relapse, as well as for extramedullary relapse with or without bone marrow involvement (Philadelphia chromosome positive acute leukemia vs low-risk AML, relative risk 22.68 (95% CI, 2.18-235.64); other than first CR vs first CR, relative risk 5.61 (95% CI, 1.80-17.51)), but not for bone marrow relapse. Our study suggests that there may be different pathogenetic mechanisms for bone marrow vs extramedullary relapse of acute leukemia after allogeneic HCT. The mode of relapse needs to be investigated in future reports of acute leukemia treated with allogeneic HCT.
Asunto(s)
Enfermedades de la Médula Ósea/mortalidad , Trasplante de Médula Ósea , Trasplante de Células Madre Hematopoyéticas , Leucemia/mortalidad , Leucemia/terapia , Enfermedad Aguda , Adolescente , Adulto , Enfermedades de la Médula Ósea/patología , Femenino , Estudios de Seguimiento , Humanos , Leucemia/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Recurrencia , Factores de Riesgo , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
SUMMARY: Hematopoietic chimerism (HpC) was assayed monthly using a sensitive, polymerase chain reaction (PCR) -based method in consecutive patients. Between January 1998 and April 2002, 181 patients underwent non-T cell depleted allogeneic hematopoietic cell transplantation (HCT). A total of 163 patients were evaluable for HpC at 1 month (11 early deaths; no informative band for HpC analysis/no genomic DNA in seven). In all, 53 of 163 patients (33%, median recipient DNA of 15% (range 5-95)), 39 of 151 patients (26%), and 27 of 142 patients (19%) showed mixed chimerism (MC) at 1, 2, and 3 months after HCT, respectively. Conditioning regimen (busulfan-fludarabine-ATG vs BuCy, relative risk 3.99 (95% CI 1.16-10.92)), neutrophil engraftment (>/=day 17 vs =day 16, relative risk 2.49 (95% CI 1.14-5.41)), and acute graft-versus-host disease within 30 days (none vs yes, relative risk 4.78 (95% CI 1.50-15.17)) were independent variables that showed significant correlation with having >/=5% recipient DNA at 1 month. Five patients experienced secondary graft failure. All five patients showed MC at 1 month with median recipient DNA of 40%. None of the 109 patients with complete chimerism experienced graft failure (P=0.002). Our study showed that MC shown on monthly analysis of HpC after allogeneic HCT is a significant predictor of secondary graft failure. Bone Marrow Transplantation (2003) 32, 423-431. doi:10.1038/sj.bmt.1704147
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Adolescente , Adulto , ADN/química , ADN/metabolismo , Femenino , Rechazo de Injerto , Enfermedad Injerto contra Huésped , Enfermedad Veno-Oclusiva Hepática/patología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Reacción en Cadena de la Polimerasa , Estudios Prospectivos , Recurrencia , Riesgo , Factores de Tiempo , Donantes de Tejidos , Quimera por Trasplante , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The efficacy and side effects of intermediate-dose cytarabine, idarubicin plus etoposide and subsequent donor leukocyte infusion (DLI) were investigated in patients with acute leukemia who relapsed after allogeneic bone marrow transplantation (BMT). Patients were given cytarabine continuous i.v. (1 g/m2 per day x 5), idarubicin i.v. (12 mg/m2 per day x 3), and etoposide i.v. infusion (150 mg/m2 per day x 3). Two days later, G-CSF mobilized donor leukocytes were infused for 2 days. No graft-versus-host disease (GVHD) prophylaxis was given. Between August 1997 and February 2000, 13 patients enrolled (eight acute myeloid leukemia (AML) and five acute lymphoblastic leukemia (ALL)). All patients finished chemotherapy and DLI. Eleven patients (85%) achieved complete remission (CR) at median 27 days after DLI. After median follow up of 10.9 months (2.5-33.3), five of 11 patients who achieved CR relapsed. Overall, six of 13 patients were surviving (6/8 AML and 0/5 ALL, P=0.059). Marrow recovery after chemotherapy and DLI was rapid (12 days for absolute neutrophil count (ANC) >500/microl). Side effects included fever with neutropenia (100%), pneumonia (46%), grade II-IV mucositis (69%), grade III-IV acute GVHD (45%), and extensive chronic GVHD (64%). One patient died from chronic GVHD. Chemotherapy containing intermediate-dose cytarabine and DLI produced a high CR rate in acute leukemia in relapse after allogeneic BMT. A fraction of patients are surviving long term. Side effects were substantial but manageable.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia/terapia , Análisis Actuarial , Enfermedad Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/mortalidad , Trasplante de Médula Ósea/normas , Citarabina/administración & dosificación , Citarabina/toxicidad , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Etopósido/toxicidad , Femenino , Enfermedad Injerto contra Huésped/etiología , Movilización de Célula Madre Hematopoyética , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/toxicidad , Leucemia/complicaciones , Transfusión de Leucocitos , Masculino , Recurrencia , Tasa de Supervivencia , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/normasRESUMEN
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a TNF family member and potent apoptosis inducer. In contrast to TNF-alpha or Fas ligand, relatively little is known about the signaling events activated by TRAIL. In particular, the initial caspase(s) required for TRAIL-induced apoptosis remains to be determined Caspase-3-like protease but not caspase-1-like protease (YVADase) activity rapidly increased in HeLa cells in response to TRAIL treatment. The increase in protease activity correlated with the profile of apoptotic cell death that was inhibited by the pan-caspase inhibitor Z-VAD-fmk. In response to TRAIL, caspase-8, an initiator caspase in death receptor-mediated apoptosis, was activated within 1 h in association with Bid cleavage, cytochrome c release, caspase-3 activation, and DNA fragmentation factor 45 cleavage. Z-IETD-fmk, a caspase-8 inhibitor, completely blocked caspase-8 activation and resulted in inhibition of caspase-3 (a caspase-3-like protease) activation and apoptotic cell death. Overexpression of a caspase-8 dominant negative mutant inhibited apoptosis induced by TRAIL. Caspase-8-deficient Jurkat cells were resistant to both TRAIL and Fas-induced apoptosis, whereas wild-type Jurkat cells were susceptible to both TRAIL- and Fas-induced apoptosis. The caspase-8-reintro duced caspase-8-deficient Jurkat cells acquired normal susceptibility to both TRAIL and agonistic Fas antibody. Reverse transcription-PCR and sequence analyses have revealed that these caspase-8-deficient Jurkat cell express wild-type caspase-10. Therefore, our data indicate that caspase-8 is required for TRAIL-induced apoptosis and suggest that caspase-10 may play a minor role, if any, in TRAIL-induced apoptosis.