RESUMO
Allogeneic immune responses underlie the graft-versus-leukaemia effect of stem cell transplantation, but disease relapse occurs in many patients. Minor histocompatibility antigen (mHAg) peptides mediate alloreactive T cell responses and induce graft-versus-leukaemia responses when expressed on patient haematopoietic tissue. We vaccinated nine HA-1-negative donors against HA-1 with a 'prime-boost' protocol of either two or three DNA 'priming' vaccinations prior to 'boost' with modified vaccinia Ankara (MVA). HA-1-specific CD8+ T cell responses were observed in seven donors with magnitude up to 1·5% of total CD8+ T cell repertoire. HA-1-specific responses peaked two weeks post-MVA challenge and were measurable in most donors after 12 months. HA-1-specific T cells demonstrated strong cytotoxic activity and lysed target cells with endogenous HA-1 protein expression. The pattern of T cell receptor (TCR) usage by HA-1-specific T cells revealed strong conservation of T cell receptor beta variable 7-9 (TRBV7-9) usage between donors. These findings describe one of the strongest primary peptide-specific CD8+ T cell responses yet recorded to a DNA-MVA prime-boost regimen and this may reflect the strong immunogenicity of mHAg peptides. Prime-boost vaccination in donors or patients may prove of substantial benefit in boosting graft-versus-leukaemia responses.
Assuntos
Antígenos de Neoplasias/imunologia , Efeito Enxerto vs Leucemia/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Oligopeptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinação , Vacinas de DNA/uso terapêutico , Vaccinia virus/imunologia , Vacinas Virais/uso terapêutico , Adulto , Idoso , Aloenxertos , Citotoxicidade Imunológica , Epitopos/imunologia , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Antígeno HLA-A2/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunogenicidade da Vacina , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Vacinas Atenuadas , Vacinas de DNA/imunologia , Vacinas Virais/imunologiaRESUMO
PURPOSE: Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS: Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS: There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION: The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.
Assuntos
Amsacrina/administração & dosagem , Bussulfano/administração & dosagem , Citarabina/administração & dosagem , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/administração & dosagem , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Idoso , Amsacrina/efeitos adversos , Bussulfano/efeitos adversos , Citarabina/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/efeitos adversos , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Intervalo Livre de Progressão , Recidiva , Transplante de Células-Tronco/efeitos adversos , Transplante de Células-Tronco/mortalidade , Fatores de Tempo , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/mortalidade , Transplante Homólogo , Reino Unido , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: The importance of chimerism status in the very early period after hematopoietic stem cell transplantation is unclear. We determined PBMC and T-cell donor chimerism 50 days after transplantation and related this to disease relapse and overall survival. METHODS: 144 sequential patients underwent transplantation of which 90 had AML/MDS and 54 had lymphoma. 'Full donor chimerism' was defined as ≥99% donor cells and three patient groups were defined: 40% with full donor chimerism (FC) in both PBMC and T-cells; 25% with mixed chimerism (MC) within both compartments and 35% with 'split' chimerism (SC) characterised by full donor chimerism within PBMC and mixed chimerism within T-cells. RESULTS: In patients with myeloid disease a pattern of mixed chimerism (MC) was associated with a one year relapse rate of 45% and a five year overall survival of 40% compared to values of 8% and 75%, and 17% and 60%, for those with SC or FC respectively. The pattern of chimerism had no impact on clinical outcome for lymphoma. CONCLUSION: The pattern of lineage-specific chimerism at 50 days after transplantation is highly predictive of clinical outcome for patients with myeloid malignancy and may help to guide subsequent clinical management.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Linfoma , Síndromes Mielodisplásicas , Linfócitos T/metabolismo , Quimeras de Transplante/sangue , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Linfoma/sangue , Linfoma/mortalidade , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Taxa de SobrevidaRESUMO
Transplantation is an effective treatment of many clinical disorders, but the mechanisms that regulate immunological tolerance are uncertain and remain central to improving patient outcome. Hemopoietic stem cell transplantation (SCT) often establishes "mixed chimerism" in which immune cells from both the donor and patient coexist in vivo in a setting of immunological tolerance. We studied immune function in 69 patients within 2 months following SCT; 37 were fully donor and 32 displayed mixed chimerism. The proportion of T regulatory (Treg) cells was increased during mixed chimerism and comprised equal numbers of donor and host-derived regulatory cells. This was associated with a tolerogenic PD-L1+ profile on dendritic cells. Importantly, effector T cells from patients with mixed chimerism exhibited reduced cytotoxicity against host target cells in vitro, but this was restored following depletion of CD4+ Treg cells. These data show that Treg cells play a major role in sustaining immunological tolerance during mixed chimerism. These insights should help to guide novel interventions to improve clinical transplantation.
Assuntos
Quimerismo , Transplante de Células-Tronco Hematopoéticas , Linfócitos T Reguladores/imunologia , Antígeno B7-H1/metabolismo , Células Dendríticas/metabolismo , Reação Enxerto-Hospedeiro/imunologia , Humanos , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/citologia , Doadores de Tecidos , Tolerância ao Transplante/imunologiaRESUMO
Allogeneic stem cell transplantation (allo-SCT) can cure some patients with hematopoietic malignancy, but this relies on the development of a donor T cell alloreactive immune response. T cell activity in the first 2 weeks after allo-SCT is crucial in determining outcome, despite the clinical effects of the early alloreactive immune response often not appearing until later. However, the effect of the allogeneic environment on T cells is difficult to study at this time point due to the effects of profound lymphopenia. We approached this problem by comparing T cells at week 2 after allograft to T cells from autograft patients. Allograft T cells were present in small numbers but displayed intense proliferation with spontaneous cytokine production. Oligoclonal expansions at week 2 came to represent a substantial fraction of the established T cell pool and were recruited into tissues affected by graft-versus-host disease. Transcriptional analysis uncovered a range of potential targets for immune manipulation, including OX40L, TWEAK, and CD70. These findings reveal that recognition of alloantigen drives naive T cells toward a unique phenotype. Moreover, they demonstrate that early clonal T cell responses are recruited to sites of subsequent tissue damage and provide a range of targets for potential therapeutic immunomodulation.
Assuntos
Transplante de Células-Tronco , Doença Enxerto-Hospedeiro/imunologia , Humanos , Transplante HomólogoRESUMO
Natural killer (NK) cells rapidly reconstitute following allogeneic stem cell transplantation (allo-SCT), at the time when alloreactive T cell immunity is being established. We investigated very early NK cell reconstitution in 82 patients following T cell-depleted allo-SCT. NK cell number rapidly increased, exceeding T cell reconstitution such that the NK:T cell ratio was over 40 by day 14. NK cells at day 14 (NK-14) were donor-derived, intensely proliferating and expressed chemokine receptors targeted to lymphoid and peripheral tissue. Spontaneous production of the immunoregulatory cytokine IL-10 was observed in over 70% of cells and transcription of cytokines and growth factors was augmented. NK-14 cell number was inversely correlated with the incidence of grade II-IV acute graft versus host disease (GVHD). These findings reveal that robust reconstitution of immunoregulatory NK cells by day 14 after allo-SCT is an important determinant of the clinical outcome, suggesting that NK cells may suppress the development of the T cell-mediated alloreactive immune response through production of IL-10.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Células Matadoras Naturais/imunologia , Transplante de Células-Tronco , Doença Aguda , Adolescente , Adulto , Idoso , Autorrenovação Celular , Células Cultivadas , Progressão da Doença , Feminino , Humanos , Terapia de Imunossupressão , Interleucina-10/metabolismo , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Linfócitos T/patologia , Transplante Homólogo , Adulto JovemRESUMO
Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML.Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients.Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment.Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430-40. ©2017 AACR.
Assuntos
Azacitidina/administração & dosagem , Inibidor de Quinase Dependente de Ciclina p18/genética , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversos , Terapia Combinada , Inibidor p16 de Quinase Dependente de Ciclina , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/efeitos adversos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Resultado do Tratamento , VorinostatRESUMO
Alemtuzumab conditioning is highly effective at reducing the incidence of acute and chronic graft-versus-host disease (GVHD) in reduced-intensity fludarabine and melphalan transplantation with cyclosporine monotherapy. Less frequent and lower dose scheduling may be used with sibling donors, but an optimal regimen for matched unrelated donors has not been defined. In this retrospective observational study of 313 patients, the incidence and severity of GVHD was compared in patients receiving 3 different dose schedules: the standard 100-mg regimen (20 mg on days -7 to -3), 60 mg (30 mg on days -4 and -2), or 50 mg (10 mg on days -7 to -3). Patients treated with 100 mg, 60 mg, or 50 mg developed acute GVHD grades I to IV with an incidence of 74%, 65%, and 64%, respectively, whereas 36%, 32%, and 41% developed chronic GHVD. An excess of severe acute grades III/IV GVHD was observed in the 50-mg cohort (15% versus 2% to 6%; P = .016). The relative risk of severe acute grade GVHD remained more than 3-fold higher in the 50-mg cohort compared with the 100-mg cohort after adjustment for differences in HLA match, age, gender mismatch, cytomegalovirus risk, and diagnosis (P = .030). The findings indicate that the 60-mg alemtuzumab schedule was comparable with the 100-mg schedule, but more attenuated schedules may increase the risk of severe grade GVHD.
Assuntos
Alemtuzumab/administração & dosagem , Doença Enxerto-Hospedeiro/tratamento farmacológico , Adulto , Idoso , Aloenxertos/química , Aloenxertos/imunologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Doadores não Relacionados , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto JovemRESUMO
Disease relapse is the major causes of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). As well as demonstrating significant clinical activity in AML, azacitidine (AZA) upregulates putative tumor antigens, inducing a CD8(+) T cell response with the potential to augment a graft-versus-leukemia effect. We, therefore, studied the feasibility and clinical sequelae of the administration of AZA during the first year after transplantation in 51 patients with AML undergoing allogeneic SCT. Fourteen patients did not commence AZA either because of transplantation complications or withdrawal of consent. Thirty-seven patients commenced AZA at a median of 54 days (range, 40 to 194 days) after transplantation, which was well tolerated in the majority of patients. Thirty-one patients completed 3 or more cycles of AZA. Sixteen patients relapsed at a median time of 8 months after transplantation. No patient developed extensive chronic graft-versus-host disease. The induction of a post-transplantation CD8(+) T cell response to 1 or more tumor-specific peptides was studied in 28 patients. Induction of a CD8(+) T cell response was associated with a reduced risk of disease relapse (hazard ratio [HR], .30; 95% confidence interval [CI], .10 to .85; P = .02) and improved relapse-free survival (HR, .29; 95% CI, .10 to .83; P = .02) taking into account death as a competing risk. In conclusion, AZA is well tolerated after transplantation and appears to have the capacity to reduce the relapse risk in patients who demonstrate a CD8(+) T cell response to tumor antigens. These observations require confirmation in a prospective clinical trial.
Assuntos
Antígenos de Neoplasias/metabolismo , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto , Idoso , Aloenxertos , Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
Allogeneic stem cell transplantation (allo-HSCT) provides a unique opportunity to track Epstein-Barr virus (EBV) infection in the context of the reconstituting B-cell system. Although many allo-HSCT recipients maintain low or undetectable levels of EBV DNA posttransplant, a significant proportion exhibit elevated and rapidly increasing EBV loads which, if left untreated, may lead to potentially fatal EBV-associated posttransplant lymphoproliferative disease. Intriguingly, this high-level EBV reactivation typically arises in the first 3 months posttransplant, at a time when the peripheral blood contains low numbers of CD27+ memory cells which are the site of EBV persistence in healthy immunocompetent donors. To investigate this apparent paradox, we prospectively monitored EBV levels and B-cell reconstitution in a cohort of allo-HSCT patients for up to 12 months posttransplant. In patients with low or undetectable levels of EBV, the circulating B-cell pool consisted predominantly of transitional and naive cells, with a marked deficiency of CD27+ memory cells which lasted >12 months. However, among patients with high EBV loads, there was a significant increase in both the proportion and number of CD27+ memory B cells. Analysis of sorted CD27+ memory B cells from these patients revealed that this population was preferentially infected with EBV, expressed EBV latent transcripts associated with B-cell growth transformation, had a plasmablastic phenotype, and frequently expressed the proliferation marker Ki-67. These findings suggest that high-level EBV reactivation following allo-HSCT may drive the expansion of latently infected CD27+ B lymphoblasts in the peripheral blood.
Assuntos
Linfócitos B/virologia , Transformação Celular Viral/fisiologia , Infecções por Vírus Epstein-Barr/complicações , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4/fisiologia , Ativação Viral/imunologia , Adulto , Idoso , Subpopulações de Linfócitos B/virologia , DNA Viral/sangue , Feminino , Humanos , Memória Imunológica/imunologia , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Carga Viral/imunologiaRESUMO
Chemokines regulate the migration of hemopoietic cells and play an important role in the pathogenesis of many immune-mediated diseases. Intradermal recruitment of CD8(+) T cells by CXCL10 is a central feature of the pathogenesis of cutaneous acute GVHD (aGVHD), but very little is known about the pathogenesis of chronic GVHD (cGVHD). Serum concentrations of the 3 CXCR3-binding chemokines, CXCL9, CXCL10, and CXCL11, were found to be markedly increased in patients with active cGVHD of the skin (n = 8). An 80% decrease in CD4(+) cells expressing CXCR3 was seen in the blood of these patients (n = 5), whereas CD4(+) cells were increased in tissue biopsies and were clustered around the central arterioles of the dermis. The well-documented increase in expression of CXCL10 in aGVHD therefore diversifies in cGVHD to include additional members of the CXCR3-binding family and leads to preferential recruitment of CD4(+) T cells. These observations reveal a central role for chemokine-mediated recruitment of CXCR3(+) T cells in cGVHD.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Quimiocina CXCL10/fisiologia , Quimiocina CXCL11/fisiologia , Quimiocina CXCL9/fisiologia , Doença Enxerto-Hospedeiro/imunologia , Receptores CXCR3/fisiologia , Doença Aguda , Arteríolas/imunologia , Quimiocina CXCL10/sangue , Quimiocina CXCL11/sangue , Quimiocina CXCL9/sangue , Quimiotaxia de Leucócito , Derme/irrigação sanguínea , Derme/imunologia , Derme/patologia , Progressão da Doença , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Condicionamento Pré-TransplanteRESUMO
Bone marrow transplantation is frequently used as a consolidation therapy in patients with haematological malignancies to improve the outcome of these patients. Obese individuals have larger absolute lean body and fat masses than non-obese individuals of the same age, gender and height, which might lead to altered pharmacokinetics of chemotherapeutic agents. Data on the impact of body mass on transplant outcome is conflicting. This study included 331 patients (M, 230; F, 101) with 336 allogeneic transplant episodes from two large teaching hospitals in the West Midlands region in United Kingdom. A total of 105 patients had acute myeloid leukaemia, 83 had non-Hodgkin's lymphoma, three had myeloma, 21 had Hodgkin's lymphoma, 34 had acute lymphoblastic leukaemia, 19 had chronic myeloid leukaemia, 22 had chronic lymphocytic leukaemia, 24 had myelodysplasia, seven had T cell non-Hodgkin's lymphoma, six had aplastic leukaemia and seven had myelofibrosis. At transplantation, 40% (N = 133) of the patients had normal and 60% (N = 198) had high body mass index (BMI) with 14% of the patients being obese (BMI >30). After a median follow-up of 24 months (range, 2-79), the mean overall survival (OS) in patients undergoing allograft with normal BMI was 31 months as compared to 39 with high BMI (p:0.06). The mean progression free survival (PFS) in patients undergoing allograft with normal BMI was 33 months as compared to 38 with high BMI (p = 0.13). Of the patients in the high and obese BMI group, 16% developed acute GvHD with 8% grade III-IV and 28% in the normal BMI group with 14% grade III-IV acute GvHD (p = 0.11). Of the patients in the high BMI group, 17% developed chronic GvHD and 30% of the patients in the normal BMI group (p = 0.09). However, higher infection rates and more days of inpatient stay in the first year post-transplant were observed in the high BMI and obese patients, but there was no difference in ITU admissions. This study shows that high BMI and obesity does not adversely impact on either OS or PFS in patients undergoing allogeneic transplantation for haematological malignancies, but it does have a significant impact on infection rates and hospitalisation of high BMI and obese patients. We recommend that patients with high BMI should not be excluded from allogeneic transplantation; however, good supportive care and careful patient selection on the basis of comorbidity index should be undertaken in order to avoid the risks from the increased rates of infection.
Assuntos
Índice de Massa Corporal , Transplante de Medula Óssea , Neoplasias Hematológicas/terapia , Transplante Homólogo , Adolescente , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Currently, routine monitoring of cyclosporine in patients undergoing allogeneic stem cell transplantation is based on analysis of trough, or C0, predose concentrations. However, recent studies in solid organ transplant recipients have demonstrated that monitoring cyclosporine exposure by analyzing 2-hour postdose concentrations (C2) or area under the concentration-time curve (AUC) may improve clinical outcome. This study investigated the ability of single samples to predict exposure to intravenous cyclosporine in eight patients undergoing allogeneic stem cell transplantation. Patients received cyclosporine at a starting dose of 2.5 mg/kg 12-hourly by intravenous infusion over 4 hours. Blood samples were taken at 0, 1, 2, 3, 4, 4.17, 4.33, 4.67, 5, 6, 8, and 12 hours after the start of the infusion. Linear regression was undertaken to investigate the relationship between AUC and concentrations measured at individual time points; bias and precision were also examined. Cyclosporine doses ranged from 250 mg to 430 mg/day, AUC from 3.85 to 8.39 mg.h/L, clearance from 19.1 to 48.1 L/h, and elimination half-life from 3.7 to 15.5 hours. Although Cmax and the concentration measured at 3 hours (C3) provided the best prediction of AUC (r = 0.90 and r = 0.87, respectively), the infusion protocol made the time of Cmax difficult to predict. Concentrations measured at the end of the infusion (Cend) and 12 hours postdose (C12) gave similar results (r = 0.87 and 0.77, respectively). These data suggest that C12 concentrations provide an acceptable marker of total exposure to intravenous cyclosporine in patients undergoing allogeneic stem cell transplantation.
Assuntos
Área Sob a Curva , Ciclosporina/sangue , Imunossupressores/sangue , Ácido Micofenólico/farmacocinética , Transplante de Células-Tronco/métodos , Testes Genéticos , Meia-Vida , Humanos , Imunossupressores/administração & dosagem , Infusões Intravenosas/métodos , Ácido Micofenólico/administração & dosagem , Transplante Homólogo/métodosRESUMO
BACKGROUND: Reduced intensity conditioning regimens permit the delivery of a potentially curative graft-versus-leukemia effect in older patients with acute myeloid leukemia. Although T-cell depletion is increasingly used to reduce the risk of graft-versus-host disease its impact on the graft-versus-leukemia effect and long-term outcome post-transplant is unknown. DESIGN AND METHODS: We have characterized pre- and post-transplant factors determining overall survival in 168 patients with acute myeloid leukemia transplanted using an alemtuzumab based reduced intensity conditioning regimen with a median duration of follow-up of 37 months. RESULTS: The 3-year overall survival for patients transplanted in CR1 or CR2/CR3 was 50% (95% CI, 38% to 62%) and 44% (95% CI, 31% to 56%), respectively compared to 15% (95% CI, 2% to 36%) for patients with relapsed/refractory disease. Multivariate analysis demonstrated that both survival and disease relapse were influenced by status at transplant (P=0.008) and presentation cytogenetics (P=0.01). Increased exposure to cyclosporine A (CsA) in the first 21 days post-transplant was associated with an increased relapse risk (P<0.0001) and decreased overall survival (P<0.0001). CONCLUSIONS: Disease stage, presentation karyotype and post-transplant CsA exposure are important predictors of outcome in patients undergoing a T-cell depleted reduced intensity conditioning allograft for acute myeloid leukemia. These data confirm the presence of a potent graft-versus-leukemia effect after a T-cell depleted reduced intensity conditioning allograft in acute myeloid leukemia and identify CsA exposure as a manipulable determinant of outcome in this setting.