RESUMEN
BACKGROUND: In adult patients with acute myeloid leukemia (AML), a matched sibling donor (MSD) is considered the first choice for an allogeneic transplantation. However, a female donor for a male recipient is a poor prognostic factor. The authors compared haploidentical (HAPLO) donors with female MSDs. METHODS: In total, 834 men underwent allogenic transplantation from a female MSD, and 232 men underwent allogenic transplantation from a HAPLO donor. Of these, 86% of HAPLO recipients and 3% of MSD recipients received graft-versus-host disease (GVHD) prophylaxis posttransplantation with high-dose cyclophosphamide. A significant qualitative interaction was observed between donor type and cytogenetics, Therefore, the analyses were stratified on cytogenetics. RESULTS: Of the men with intermediate-risk AML, 638 received transplantation from a female MSD, and 160 received transplantation from a HAPLO donor. In multivariate analysis, poor risk factors were a HAPLO donor versus an MSD for nonrelapse mortality (hazard ratio [HR], 1.7; P = .02) and patient age for nonrelapse mortality and overall survival (HR, 1.22 [P = .02] and 1.15 [P = .02], respectively). HAPLO transplantation resulted in less chronic GVHD (HR, 0.43; P < 10-4 ) but lower leukemia-free survival (HR, 1.7; P = .04). The GVHD/relapse-free survival (GRFS) was not different. Of the men with high-risk AML, 196 received transplantation from a female MSD, and 72 received transplantation from a HAPLO donor. By multivariate analysis, HAPLO recipients had a lower incidence of relapse (HR, 0.40; P = .004), better leukemia-free survival (HR, 0.46; P = .003), better overall survival (HR, 0.43; P = .003), and better GRFS (HR, 0.54; P = .006). CONCLUSIONS: In men who have intermediate-risk AML, allogenic transplantation from a sister MSD or a HAPLO donor produces similar GRFS. However, in men who have high-risk AML, a HAPLO donor combined with prophylactic high-dose cyclophosphamide posttransplantation may be a better choice.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Medición de Riesgo/estadística & datos numéricos , Hermanos , Donantes de Tejidos/provisión & distribución , Trasplante Haploidéntico/métodos , Adolescente , Adulto , Anciano , Médula Ósea/química , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a poor-risk entity, commonly associated with FLT3-ITD (internal tandem duplication). Allogeneic stem-cell tranplantation (allo-SCT) is recommended, although studies analysing the outcome of allo-SCT in this setting are lacking. We selected 195 patients with t(6;9) AML, who received a first allo-SCT between 2000 and 2016 from the EBMT (European Society for Blood and Marrow Transplantation) registry. Disease status at time of allo-SCT was the strongest independent prognostic factor, with a two-year leukaemia-free survival and relapse incidence of 57% and 19% in patients in CR1 (first complete remission), 34% and 33% in CR2 (second complete remission), and 24% and 49% in patients not in remission, respectively (P < 0·001). This study, which represents the largest one available in t(6;9) AML, supports the recommendation to submit these patients to allo-SCT in CR1.
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Proteínas Cromosómicas no Histona/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 9/genética , Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia Mieloide Aguda/terapia , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Oncogénicas/genética , Trasplante de Células Madre de Sangre Periférica , Proteínas de Unión a Poli-ADP-Ribosa/genética , Translocación Genética , Adulto , Aloinjertos , Cromosomas Humanos Par 6/ultraestructura , Cromosomas Humanos Par 9/ultraestructura , Supervivencia sin Enfermedad , Femenino , Duplicación de Gen , Enfermedad Injerto contra Huésped/etiología , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Inducción de Remisión , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Deletion 5q or monosomy 5 (-5/5q-) in acute myeloid leukemia (AML) is a common high-risk feature that is referred to allogeneic stem cell transplantation. However, -5/5q- is frequently associated with other high-risk cytogenetic aberrations such as complex karyotype, monosomal karyotype, monosomy 7 (-7), or 17p abnormalities (abn (17p)), the significance of which is unknown. In order to address this question, we studied adult patients with AML harboring -5/5q- having their first allogeneic transplantation between 2000 and 2015. Five hundred and one patients with -5/5q- have been analyzed. Three hundred and thirty-eight patients (67%) were in first remission and 142 (28%) had an active disease at time of allogeneic transplantation. The 2-year probabilities of overall survival and leukemia-free survival were 27% and 20%, respectively. The 2-year probability of treatment-related mortality was 20%. We identified four different cytogenetic groups according to additional abnormalities with prognostic impact: -5/5q- without complex karyotype, monosomal karyotype or abn(17p), -5/5q- within a complex karyotype, -5/5q- within a monosomal karyotype and the combination of -5/5q- with abn(17p). In multivariate analysis, factors associated with worse overall survival and leukemia-free survival across the four groups were active disease, age, monosomal karyotype, and abn(17p). The presence of -5/5q- without monosomal karyotype or abn(17p) was associated with a significantly better survival rate while -5/5q- in conjunction with monosomal karyotype or abn(17p) translated into a worse outcome. The patients harboring the combination of -5/5q- with abn(17p) showed very limited benefit from allogeneic transplantation.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Adulto , Humanos , Cariotipificación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Monosomía , Pronóstico , Trasplante HomólogoRESUMEN
Monosomy 7 or deletion 7q (-7/7q-) is the most frequent adverse cytogenetic features reported in acute myeloid leukemia (AML), and is a common indication for allogeneic stem cell transplantation (SCT). Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion of chromosome 3 (inv(3)), the presence of which may influence the outcomes after SCT. A total of 1109 patients were allocated to this study. Two-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. Two-year probability of non-relapse mortality (NRM) was 20%. We defined five different cytogenetic subgroups: the "-7/7q- ± CK group- designated group1," the "MK group-designated group 2," the "-5/5q- group- designated group 3," the "abn(17p) group- designated group 4" and the "inv(3) group- designated group 5." The 2-year probability of LFS in first remission was 48% for group 1, 36.4% for group 2, 28.4% for group 3, 19.1% for group 4 and 17.3% for group 5, respectively (P < .001). Multivariate analysis confirmed those significant differences across groups. Note, SCT in -7/7q- AML provides durable responses in one third of the patients. The presence of -7/7q- with or without CK in the absence of MK, abn(17p) or inv(3) is associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of patients with poor prognosis even after SCT.
Asunto(s)
Leucemia Mieloide Aguda , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Aloinjertos , Deleción Cromosómica , Cromosomas Humanos Par 7/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Prueba de Histocompatibilidad , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Acute myeloid leukemia (AML) in first remission (CR1) with isolated NPM1 mutation (iNPM1m) is considered a good prognosis genotype, although up to one-third relapse. To evaluate the best transplant strategy, we retrospectively compared autologous stem cell transplantation (auto-SCT), related (MSD), and fully matched unrelated (MUD) allogeneic stem cell transplantation (allo-SCT). We identified 256 adult patients including 125 auto-SCT, 72 MSD, and 59 MUD. The 2-year leukemia-free survival (LFS) was 62% in auto-SCT, 69% in MUD, and 81% in MSD (P = .02 for MSD vs others). The 2-year overall survival (OS) was not different among auto-SCT, MUD, and MSD, reaching 83% (P = .88). The 2-year non-relapse mortality (NRM) was 2.5% in auto-SCT and 7.5% in allo-SCT (P = .04). The 2-year cumulative incidence of relapse (RI) was higher after auto-SCT (30%) than after MUD (22%) and MSD (12%, P = .01). In multivariate analysis, MSD versus auto-SCT but not MUD versus auto-SCT was associated with lower RI (P < .01 and P = .13, respectively) and better LFS (P = .01 and P = .31, respectively). Age correlated with higher NRM (P < .01). Allo-SCT using MSD appears as a reasonable transplant option for young patients with iNPM1m AML in CR1. Auto-SCT was followed by worse RI and LFS, but similar OS to both allo-SCT modalities.
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Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Adulto , Femenino , Trasplante de Células Madre Hematopoyéticas/normas , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación , Proteínas Nucleares/genética , Nucleofosmina , Recurrencia , Inducción de Remisión , Trasplante Autólogo , Trasplante Homólogo , Donante no EmparentadoRESUMEN
BACKGROUND: Intestinal inflammation in Crohn's disease (CD) is caused by mucosal immune system reactivity to luminal antigen and results in debilitating symptoms, reduced quality of life, impaired work productivity and significant health care costs. Not all patients respond to conventional and biologic therapies, with chronic inflammation ensuing. Although surgical resection may be required, disease frequently returns and surgery may not be an option, or may be declined. Case reports suggest potential benefit after haematopoietic stem cell transplant (HSCT) for patients with refractory CD. The ASTIC trial asked whether HSCT could cure CD. Few patients achieved the primary endpoint of clinical remission for 3 months, off all medication with no evidence of active disease, and there were a high number of adverse events (AEs) and serious adverse events (SAEs), including one patient death. However, beneficial effects were observed in some aspects of disease activity. The ASTIClite trial will investigate these potential benefits and safety using a lower intensity regimen than ASTIC. METHODS: Ninety-nine participants will be recruited from secondary care IBD centres in the UK into a multicentre, randomised controlled trial (RCT, ASTIClite) and an observational follow-up, and randomised to autologous HSCT versus standard care (ratio 2:1). The primary endpoint is treatment success at week 48, defined as mucosal healing without surgery or death. Secondary endpoints relating to efficacy, safety and mechanistic analyses will be evaluated at week 8, 14, 24, 32, 40 and 48. Long-term safety of the low intensity HSCT regimen forms the primary endpoint for the EBMT follow-up study and will be assessed annually for 4-7 years. DISCUSSION: ASTIClite will compare HSCTlite with standard care with respect to safety, efficacy and quality of life, and capture outcomes allowing findings to be generalised to current clinical practice in the UK. It will also provide significant mechanistic insights into the immunological consequences of HSCTlite and its impact on treatment outcomes. The observational follow-up will provide information, which is currently unavailable for this population. TRIAL REGISTRATION: The ASTIClite RCT was registered on 31st October 2017 ( ISRCTN17160440 ) and the EBMT follow-up study on 19th January 2018 ( ISRCTN31981313 ).
Asunto(s)
Enfermedad de Crohn/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Adulto , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Trasplante Autólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Busulfan/fludarabine (BuFlu) is a widely used conditioning regimen for patients with myeloid malignancies. The sequential FLAMSA (fludarabineâ¯+â¯Ara-Câ¯+â¯amsacrine chemotherapy) protocol followed by either cyclophosphamide and total body irradiation (FLAMSA-TBI) or cyclophosphamide and busulfan (FLAMSA-Bu) has shown remarkable activity in high-risk acute myelogenous leukemia (AML) patients. Here we compare the outcomes of AML patients transplanted in first complete remission (CR1) or second complete remission (CR2) after conditioning with BuFlu or FLAMSA. Eligible patients had their first allogeneic stem cell transplantation for AML in CR1 or CR2 between January 2005 and June 2016. Donors were matched related or unrelated with up to 1 mismatch. Conditioning consisted of either BuFlu or FLAMSA. Propensity score matching was applied and comparisons were performed using weighted Cox regression. BuFlu conditioning was used in 1197 patients, whereas FLAMSA-TBI and FLAMSA-Bu were used in 258 and 141 patients, respectively. Median follow-up of survivors was 24.72 months. In univariate analysis, relapse incidence (RI) was 30.3%, 21.9%, and 23.1% in the BuFlu, FLAMSA-TBI, and FLAMSA-Bu groups, respectively (P < .01), and nonrelapse mortality at 2 years was 16.1%, 16.4%, and 26.7%, respectively (P < .01). Leukemia-free survival (LFS) at 2 years was 53.6%, 61.6%, and 50.1%, respectively (P = .03). Weighted Cox regression revealed that FLAMSA-TBI compared with BuFlu was associated with lower RI (hazard ratio [HR], .64; 95% confidence interval [CI], .42 to .98; P = .04) and a trend for better LFS (HR, .72; 95% CI, .49 to 1.06; P = .09). These results suggest that compared with BuFlu, conditioning with FLAMSA-TBI leads to reduced RI at 2 years in AML patients transplanted in CR1 or CR2.
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Busulfano/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inducción de Remisión/métodos , Vidarabina/análogos & derivados , Busulfano/farmacología , Europa (Continente) , Femenino , Humanos , Incidencia , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Vidarabina/farmacología , Vidarabina/uso terapéuticoRESUMEN
BACKGROUND: Despite recent advances in allogeneic hematopoietic stem cell transplantation (AHSCT), the outcome of patients who have acute myeloid leukemia (AML) with a complex karyotype (CK) remains poor. The objective of this study was to identify prognostic factors associated with post-transplantation survival in a large cohort of patients with CK AML. METHODS: In total, data on 1342 consecutively patients who underwent transplantation for CK (≥3 chromosomal abnormalities) AML were provided by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation and from the University of Texas MD Anderson Cancer Center database were included in the analysis. The median patient age was 52 years. The donors were human leukocyte antigen-matched related donors (N = 749), matched unrelated donors (N = 513), and mismatched unrelated donors (N = 80). RESULTS: Relapse was the main cause of treatment failure. Overall, 51% of patients relapsed, 17.6% died of treatment-related mortality, and 31.3% survived leukemia-free. In multivariate analysis, the factors associated with an increased risk of relapse were age (>40 years; hazard ratio [HR], 1.1 per 10 years; P = .02), secondary AML (HR, 1.35; P = .01), active disease at transplantation (HR, 1.98; P < .001), and deletion/monosomy 5 (HR, 1.5; P < .001); whereas age (HR, 1.15 per 10 years; P < .001), secondary AML (HR, 1.36; P = .001), active disease at transplantation (HR, 1.99; P < .001), deletion/monosomy 5 (HR, 1.24; P = .008), and deletion/monosomy 7 (HR, 1.44; P < .001) predicted for leukemia-free survival. CONCLUSIONS: Disease relapse remains the most common cause of treatment failure for patients with CK AML after transplantation. Novel approaches to decrease the relapse rate and improve survival are needed in these patients. Cancer 2018;124:2134-41. © 2018 American Cancer Society.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Primarias Secundarias/terapia , Adulto , Anciano , Aberraciones Cromosómicas , Bases de Datos Factuales/estadística & datos numéricos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Prueba de Histocompatibilidad , Humanos , Cariotipo , Cariotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/mortalidad , Estudios Retrospectivos , Texas/epidemiología , Donantes de Tejidos/estadística & datos numéricos , Acondicionamiento Pretrasplante/métodos , Acondicionamiento Pretrasplante/estadística & datos numéricos , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodos , Trasplante Homólogo/estadística & datos numéricos , Adulto JovenRESUMEN
Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3-ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P<0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft-versus-host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients ≥ 60 with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients.
Asunto(s)
Duplicación de Gen , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Tirosina Quinasa 3 Similar a fms/genética , Anciano , Aloinjertos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Análisis de SupervivenciaRESUMEN
Patients with acute myeloid leukemia (AML) who relapse after autologous stem cell transplantation (ASCT) can be rescued by allogeneic SCT. We identified 537 adult patients with AML allografted in second complete remission (CR2) or first relapse after ASCT in the European Society for Blood and Marrow Transplantation (EBMT) registry. At 3 years post allograft, leukemia free survival (LFS) was 31.4% [95%CI 27.3-35.6], overall survival (OS) 39.5% [95%CI 35.1-43.9], relapse incidence (RI) 34.6% [95%CI 30.4-38.8], and nonrelapse mortality (NRM) 33.7% [95%CI 29.6-37.9]. RI was higher in patients transplanted in relapse in comparison to those transplanted in CR2 (HR 1.76, P = .004) and in patients who relapsed later after ASCT (HR 0.97 per month, P < 10-3 ), both translating into better LFS/ OS. Relapse was also lower in patients undergoing allogeneic stem cell transplantation (allo-HSCT) from an unrelated donor (UD) in comparison to those transplanted from a matched sibling donor (MSD) (HR 0.49, P < 10-3 ). NRM was increased in patients who received total body irradiation (TBI) pre-ASCT (HR 2.43; P < 10-4), translating into worse LFS/OS. LFS/OS did not differ between patients allotransplanted with reduced intensity (RIC) or myeloablative (MAC) conditioning. In conclusion, one third of adult patients with AML relapsing post ASCT can be rescued with allo-HSCT, with better LFS/OS in patients who relapsed later post ASCT, those transplanted in CR2 and those who had not received TBI pre-ASCT.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Adulto , Humanos , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante Autólogo/efectos adversos , Trasplante Homólogo , Irradiación Corporal TotalRESUMEN
Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre-allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or ≥50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000-2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), chronic graft-vs-host (cGVHD), and GVHD-free and relapse-free survival (GRFS). The 2292 eligible patients were categorized into four paired groups: <50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58); <50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); ≥50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and ≥50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo-HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for ≥50y AML CR1 MRD POS.
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Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Neoplasia Residual/diagnóstico , Acondicionamiento Pretrasplante/métodos , Adulto , Factores de Edad , Anciano , Europa (Continente)/epidemiología , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/normas , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Pronóstico , Recurrencia , Sistema de Registros , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Secondary acute myeloid leukemia (sAML) traditionally has inferior outcomes compared to de novo AML. Allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy. This study analyzes the outcomes for unmanipulated haploidentical HCT (haploHCT) for sAML using the Acute Leukemia Working Party (ALWP) registry of the European Society for Blood and Marrow Transplantation (EBMT). We identified 154 patients with sAML who underwent haploHCT from 2006 to 2016. Median age at HCT was 60 years with time from diagnosis to HCT 5 months. At transplantation, 69 patients were in first CR and 85 had active disease. Fifty-seven (38.0%) patients underwent myeloablative conditioning and 97 (62.0%) reduced intensity conditioning (RIC) conditioning. Multivariate analysis showed that there was no difference in RI, nonrelapse mortality (NRM), leukemia free survival (LFS), overall survival (OS), or GVHD-free/relapse free survival (GRFS) for conditioning intensity, age, performance status, or graft source. Active disease was associated with higher RI and inferior LFS, OS, and GRFS compared with patients in CR at time of transplant. T-cell depletion with anti-thymoglobulin resulted in higher NRM and inferior LFS, OS, and GRFS compared to post-transplant cyclophosphamide (PTCy) (HR 2.25, 2.01, 2.16, and 1.73, respectively with P values <.05). Our data shows that haploHCT is a feasible alternative for sAML when matched transplantation is unavailable.
Asunto(s)
Leucemia Mieloide Aguda/terapia , Trasplante Haploidéntico/métodos , Adulto , Anciano , Ciclofosfamida/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Depleción Linfocítica/métodos , Depleción Linfocítica/mortalidad , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias , Acondicionamiento Pretrasplante/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for patients with acute myeloid leukemia (AML). However, post-HCT relapse and regimen-related toxicity remain significant barriers to long-term survival. In recent years, new conditioning regimens have been explored to improve transplantation outcomes in patients with AML. Treosulfan combines a potent immunosuppressive and antileukemic effect with a low toxicity profile. METHODS: To investigate the role of treosulfan-based conditioning, the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party performed a registry analysis of 520 adult patients with AML who received treosulfan-based conditioning and underwent HCT between 2000 and 2012, including 225 patients in first complete remission, 107 in second or later complete remission, and 188 with active/advanced disease 188 (88 with primary refractory disease). The median patient age was 57 years (range, 20-73 years). Donors were human leukocyte antigen-identical siblings (n = 187), unrelated donors (n = 235), or mismatched related donors (n = 98). Conditioning regimens included treosulfan (42 g/m2 [n = 396], 36 g/m2 [n = 109], or 30 g/ m2 [n = 15]) with fludarabine or alkylating agents followed by infusion of hematopoietic stem cells (bone marrow, n = 52; peripheral blood, n = 468). RESULTS: At a median follow-up of 61 months, the 5-year overall survival, leukemia-free survival, relapse incidence, and nonrelapse mortality rates were 38%, 33%, 42%, and 25%, respectively. The incidence of grade II-IV acute and chronic graft-versus-host disease was 24% (grade III-V, 11%) and 38%, respectively. Only 11 patients (2%) developed veno-occlusive disease, with two deaths (0.4%) from veno-occlusive disease. CONCLUSIONS: Treosulfan-based conditioning regimens provide an acceptable long-term survival with favorable nonrelapse mortality and a very low risk of veno-occlusive disease. Further studies are needed to optimize the treosulfan-based conditioning regimen for patients with AML. Cancer 2017;123:2671-79. © 2017 American Cancer Society.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Busulfano/análogos & derivados , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapéutico , Sistema de Registros , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Alquilantes/uso terapéutico , Busulfano/uso terapéutico , Causas de Muerte , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND: Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation. METHODS: From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%. RESULTS: Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03). CONCLUSIONS: In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Trasplante de Células Madre , Trasplante Autólogo , Adolescente , Adulto , Anciano , Busulfano/uso terapéutico , Terapia Combinada , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/patología , Masculino , Melfalán/uso terapéutico , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia (AML) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced-intensity conditioning (RIC) and allogeneic haematopoietic stem cell transplantation (HSCT). The transplants in 77 patients were from matched sibling donors (MSDs) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti-T-cell antibodies. The incidence of acute graft-versus-host disease (GVHD) of grades II-IV was 32·1% and that of chronic GVHD was 30·2%. The 3-year probability of non-relapse mortality (NRM) was 25·9%, that of relapse was 48·5%, that of GVHD-free and relapse-free survival (GRFS) was 17·8% and that of leukaemia-free survival (LFS) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II-IV [hazard ratio (HR) = 1·98, P = 0·017] and suffered less relapses (HR = 0·62, P = 0·01) than MSD recipients. Treatment with anti-T-cell antibodies reduced NRM (HR = 0·35, P = 0·01) and improved survival (HR = 0·49, P = 0·01), GRFS (HR = 0·37, P = 0·0004) and LFS (HR = 0·46, P = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti-T-cell antibodies seems promising in patients with refractory AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Terapia Recuperativa/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Aloinjertos , Anticuerpos/administración & dosificación , Anticuerpos/uso terapéutico , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Encuestas y Cuestionarios , Tasa de Supervivencia , Linfocitos T/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
To analyze the influence of distinct combinations of molecular aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for cytogenetically normal acute myeloid leukemia (CN-AML), a retrospective registry analysis was performed on 702 adults undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1(mut)) and FLT3 internal tandem duplications (FLT3-ITD). Double-negative patients were evaluated for mutations of the CCAAT/enhancer binding protein α gene (CEBPα). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. Two-year OS from HSCT was 81 ± 5% in NPM1(mut)/FLT3(wt), 75 ± 3% in NPM1(wt)/FLT3(wt), 66 ± 3% in NPM1(mut)/FLT3-ITD, and 54 ± 7% in NPM1(wt)/FLT3-ITD (P = .003). Analysis of CEBPα among patients with NPM1(wt)/FLT3(wt) revealed excellent results both in patients with CEBPα(mut) and with a triple negative genotype (2-year OS: 100%/77 ± 3%). In a Cox-model of predefined variables, age, FLT3-ITD and >1 course of chemotherapy to reach CR were risk factors associated with inferior outcome, regardless of NPM1 mutational status, variations of transplant protocols, or development of graft-versus-host disease. In a prognostic risk classification, 2-year OS/LFS rates were 88 ± 3%/79 ± 4% without any, 77 ± 2%/73 ± 3% with one, and 53 ± 4%/50 ± 4 with ≥2 risk factors (P = .003/.002).
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/genética , Secuencias Repetidas en Tándem/genética , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Análisis Citogenético , Femenino , Estudios de Seguimiento , Genotipo , Enfermedad Injerto contra Huésped , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Nucleofosmina , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
The feasibility and efficacy of high-dose melphalan followed by autologous hematopoietic stem cell transplantation in newly diagnosed elderly patients with multiple myeloma was analyzed prospectively. Fifty-six multiple myeloma patients, aged 65 years or over, from 6 French centers were studied. The induction therapy was bortezomib-based in combination with dexamethasone and either thalidomide, cyclophosphamide or lenalidomide, for 4-6 cycles. Peripheral blood stem cells were collected after high-dose cyclophosphamide plus G-CSF or G-CSF alone, with plerixafor if needed. The conditioning regimen consisted of melphalan at 140 mg/m2 in 18 patients (36%) and 200 mg/m2 in 32 (64%). Three months post autologous hematopoietic stem cell transplantation, a 2-month consolidation phase with either lenalidomide plus dexamethasone or bortezomib-based combination therapy was allowed, but maintenance treatment was not given. All but 6 patients underwent autologous hematopoietic stem cell transplantation and 3 had tandem transplantations. The treatment-related mortality was 0% at 100 days post transplantation. Sixty-eight percent received consolidation therapy following transplantation. The best response achieved was 40% complete response, 36% very good partial response, and 18% partial response. After a median follow up of 21 months (range 6-31), the estimated progression-free and overall survival rates at two years were 76% [95%CI: (61.6-94.1)] and 88% [95%CI: (76.7-100)], respectively. The higher dose of melphalan (200 mg/m2) afforded superior progression-free and overall survival rates. This prospective study provides evidence for the safety and efficacy of autologous hematopoietic stem cell transplantation as a first-line treatment approach in elderly multiple myeloma patients. (clinicaltrials.gov identifier: 01671826).
Asunto(s)
Mieloma Múltiple/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Anciano , Anciano de 80 o más Años , Autoinjertos , Quimioterapia de Consolidación , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Melfalán/administración & dosificación , Mieloma Múltiple/mortalidad , Estudios Prospectivos , Inducción de Remisión , Análisis de Supervivencia , Acondicionamiento PretrasplanteRESUMEN
Increasing numbers of patients are receiving reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation. We hypothesized that the use of bone marrow graft might decrease the risk of graft-versus-host disease compared to peripheral blood after reduced intensity conditioning regimens without compromising graft-versus-leukemia effects. Patients who underwent reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation from 2000 to 2012 for acute leukemia, and who were reported to the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation were included in the study. Eight hundred and thirty-seven patients receiving bone marrow grafts were compared with 9011 peripheral blood transplant recipients after reduced intensity conditioning regimen. Median follow up of surviving patients was 27 months. Cumulative incidence of engraftment (neutrophil ≥0.5×10(9)/L at day 60) was lower in bone marrow recipients: 88% versus 95% (P<0.0001). Grade II to IV acute graft-versus-host disease was lower in bone marrow recipients: 19% versus 24% for peripheral blood (P=0.005). In multivariate analysis, after adjusting for differences between both groups, overall survival [Hazard Ratio (HR) 0.90; P=0.05] and leukemia-free survival (HR 0.88; P=0.01) were higher in patients transplanted with peripheral blood compared to bone marrow grafts. Furthermore, peripheral blood graft was also associated with decreased risk of relapse (HR 0.78; P=0.0001). There was no significant difference in non-relapse mortality between recipients of bone marrow and peripheral blood grafts, and chronic graft-versus-host disease was significantly higher after peripheral blood grafts (HR 1.38; P<0.0001). Despite the limitation of a retrospective registry-based study, we found that peripheral blood grafts after reduced intensity conditioning regimens had better overall and leukemia-free survival than bone marrow grafts. However, there is an increase in chronic graft-versus-host disease after peripheral blood grafts. Long-term follow up is needed to clarify whether chronic graft-versus-host disease might increase the risk of late morbidity and mortality.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Trasplante de Células Madre de Sangre Periférica , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Sistema de Registros , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Femenino , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
We analyzed the prognostic impact of donor and recipient cytomegalovirus (CMV) serostatus in 16,628 de novo acute leukemia patients after allogeneic stem cell transplantation (allo-SCT). Compared with CMV-seronegative recipients who underwent allograft from a CMV-seronegative donor, cases of CMV seropositivity of the donor and/or the recipient showed a significantly decreased 2-year leukemia-free survival (44% vs 49%, P < .001) and overall survival (50% vs 56%, P < .001), and increased nonrelapse mortality (23% vs 20%, P < .001). Both groups showed a comparable relapse incidence and 2-year probability of graft-versus-host disease. The negative prognostic effects of CMV seropositivity of the donor and/or the recipient (vs CMV seronegativity of both) were significantly stronger for acute lymphoblastic leukemia (ALL) than for acute myeloid leukemia (AML), resulting in a markedly reduced 2-year overall survival (46% vs 55% for ALL compared with 52% vs 56% for AML). The important prognostic impact of donor/recipient CMV serostatus remained in a multivariate Cox regression analysis including the other prognostic variables. We conclude that donor and/or recipient CMV seropositivity is still associated with an adverse prognosis in de novo acute leukemia patients after allo-SCT despite the implementation of sophisticated strategies for prophylaxis, monitoring, and (preemptive) treatment of CMV.
Asunto(s)
Anticuerpos Antivirales/sangre , Infecciones por Citomegalovirus/virología , Citomegalovirus/aislamiento & purificación , Enfermedad Injerto contra Huésped/virología , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/virología , Leucemia-Linfoma Linfoblástico de Células Precursoras/virología , Adolescente , Adulto , Anciano , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/mortalidad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Análisis Multivariante , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Pronóstico , Recurrencia , Análisis de Supervivencia , Donantes de Tejidos , Trasplante HomólogoRESUMEN
Patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have a poor prognosis with conventional chemotherapy. In the present study, we retrospectively analyzed the outcome of patients with BPDCN who underwent allogeneic stem cell transplantation (allo-SCT) or autologous stem cell transplantation (auto-SCT). A total of 39 patients (allo-SCT, n = 34; auto-SCT, n = 5) were identified in the European Group for Blood and Marrow Transplantation registry. The 34 allo-SCT patients had a median age of 41 years (range, 10-70) and received transplantations from sibling (n = 11) or unrelated donors (n = 23) between 2003 and 2009. MAC was used in 74% of patients. Nineteen allo-SCT patients (56%) received transplantations in first complete remission. The 3-year cumulative incidence of relapse, disease-free survival, and overall survival was 32%, 33%, and 41%, respectively. By univariate comparison, being in first remission at allo-SCT favorably influenced survival, whereas age, donor source, and chronic GVHD had no significant impact. We conclude that high-dose therapy followed by allo-SCT from related or unrelated donors can provide durable remission even in elderly patients with BPDCN. However, it remains to be shown if graft-versus-malignancy effects can contribute significantly to BPDCN control after allo-SCT.