RESUMEN
Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 ± 5% vs 61 ± 4%; Pâ¯=â¯.287), overall survival (72 ± 4% versus 68 ± 4%; Pâ¯=â¯.235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; Pâ¯=â¯.658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; Pâ¯=â¯.212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; Pâ¯=â¯.002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; Pâ¯=â¯.026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; Pâ¯=â¯.042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; Pâ¯=â¯.020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; Pâ¯=â¯.021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.
Asunto(s)
Antígenos HLA , Trasplante de Células Madre de Sangre Periférica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Hermanos , Donante no Emparentado , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudios Prospectivos , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Eighty-two children and adolescents who underwent allogeneic transplantation for acute lymphoblastic leukaemia in remission (period 2001-2011, median follow-up 4·9 years) had been assessed for minimal residual disease (MRD) by real-time quantitative polymerase chain reaction before and at 1, 3, 6, 9 and 12 months after transplantation. Five-year event-free survival (EFS) and cumulative incidence of relapse were 77·7% [standard error (SE) 5·7] and 11·4% (SE 4·4), respectively, for patients with pre-transplant MRD <1 × 10(-4) (68%), versus 30·8% (SE 9·1; P < 0·001) and 61·5% (SE 9·5; P < 0·001), respectively, for those with MRD ≥1 × 10(-4) (32%). Pre-transplant MRD ≥1 × 10(-4) was associated with a 9·2-fold risk of relapse [95% confidence interval (CI) 3·54-23·88; P < 0·001] compared with patients with MRD <1 × 10(-4). Patients who received additional chemotherapy pre-transplant to reduce MRD had a fivefold reduction of risk of failure (hazard ratio 0·19, CI 0·05-0·70, P = 0·01). Patients who experienced MRD positivity post-transplant did not necessarily relapse (5-year EFS 40·3%, SE 9·3), but had a 2·5-fold risk of failure (CI 1·05-5·75; P = 0·04) if any MRD was detected in the first 100 d, which increased to 7·8-fold (CI 2·2-27·78; P = 0·002) if detected after 6 months. Anticipated immunosuppression-tapering according to MRD may have improved outcome, nevertheless all patients with post-transplant MRD ≥1 × 10(-3) ultimately relapsed, regardless of immunosuppression discontinuation or donor-lymphocyte-infusion. In conclusion, MRD before transplantation had the strongest impact on relapse and MRD positivity after transplantation, mostly if detected early and at low levels, did not necessarily imply relapse. Additional intensified chemotherapy and modulation of immunosuppression may reduce relapse risk and improve ultimate outcome.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Adolescente , Niño , Preescolar , Terapia Combinada , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/patología , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Pronóstico , Resultado del TratamientoRESUMEN
Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.
Asunto(s)
Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Masculino , Periodo Perioperatorio , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Medición de Riesgo , Factores de Riesgo , Trasplante Homólogo , Resultado del TratamientoRESUMEN
BACKGROUND: Hemophagocytic lymphohistiocytosis is a life-threatening disease. Hematopoietic stem cell transplantation still represents the treatment of choice for most patients with this disease. DESIGN AND METHODS: We retrospectively analyzed 61 patients with hemophagocytic lymphohistiocytosis who underwent HSCT over a 17-year period at nine centers affiliated to the Italian Pediatric Hematology Oncology Association (AIEOP). The median time from diagnosis to hematopoietic stem cell transplantation was 0.6 years (range, 0.13-5). The donor for the first hematopoietic stem cell transplantation was either a relative (43%) or an unrelated volunteer (57%). Fifty-four patients (89%) had a complete genetic study, which led to the diagnoses of FHL2, due to perforin defect (21 patients), FHL3, due to Munc 13-4 defect (14 patients), Griscelli disease (2 patients), X-linked lymphoproliferative disease (1 patient), and CATCH22 syndrome (1 patient). No mutations were found in the remaining 15 patients. Twenty-one patients had neurological involvement at diagnosis. RESULTS: Three patients failed to engraft. Grade II-IV acute and chronic graft-versus-host disease occurred in 31% and 17% of patients, respectively. Overall, 39 patients are alive (64%), 15 died of toxicity, 6 of progressive disease and 1 of sudden death. The 8-year overall survival probability was 58.6% (95% confidence interval, 42-72), while the cumulative incidence of transplantation-related mortality was 25.7% (95% confidence interval, 16-40). The outcome of patients with a known genetic defect was comparable to that of patients without mutation. Neurological sequelae were reported in seven patients, six of whom had central nervous system disease at diagnosis. CONCLUSIONS: These data confirm that hematopoietic stem cell transplantation represents a curative treatment for a large proportion of patients with hemophagocytic lymphohistiocytosis, irrespective of the underlying genetic defect.
Asunto(s)
Neoplasias Hematológicas/cirugía , Trasplante de Células Madre Hematopoyéticas/métodos , Linfohistiocitosis Hemofagocítica/cirugía , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Terapia Combinada , Enfermedad Injerto contra Huésped/epidemiología , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Recién Nacido , Italia , Estudios Retrospectivos , Análisis de Supervivencia , SobrevivientesRESUMEN
BACKGROUND: Immune mechanisms of extracorporeal photochemotherapy (ECP) in refractory/resistant graft-versus-host disease (GvHD) are complex. We have previously analyzed the role of CD4CD25Foxp3 regulatory T cells (T-regs). METHODS: In the current study, we have enlarged the size of the population (n=27; chronic GvHD=18, acute GvHD=9) for a median follow-up of 24 months. T-regs were monitored for CD4, CD25, glucocorticoid-induced tumor necrosis factor receptor (GITR), CD62L, CCR7, Foxp3, and STAT-5. Immune analysis by interleukin (IL)-17 Elispot was carried out on circulating T-helper CD4 cells secreting IL-17, a subset of T cells considered relevant in the pathogenesis of GvHD. RESULTS: We confirm that ECP is accompanied by a significant increase of CD4CD25Foxp3GITRCD62LCCR7 T-regs. Sorted T-regs show augmented phosphorylation of STAT-5. Only ECP-responding patients demonstrate a raise of circulating T-regs, being mostly affected by chronic GvHD. Moreover, this phenomenon corresponds to a diminished secretion of IL-17. DISCUSSION: In conclusion, our study shows that T-regs represent important immune mediators of the clinical benefits of ECP in patients affected by GvHD.