RESUMO
Acute graft-versus-host disease (aGvHD) contributes to about 50% of transplant-related mortality (non-relapse mortality) after allogeneic hematopoietic stem cell transplantation (HSCT). Here the predictive value of a urinary proteomic profile (aGvHD_MS17) was tested together with preemptive prednisolone therapy. Two-hundred and fifty-nine of 267 patients were eligible for analysis. Ninety-two patients were randomized upon aGvHD_MS17 classification factor above 0.1 to receive either prednisolone (2-2.5 mg/kg, N = 44) or placebo (N = 47; N = 1 randomization failure) for 5 days followed by tapering. The remaining 167 patients formed the observation group. The primary endpoint of the randomized trial was incidence of aGvHD grade II between randomization and day +100 post HSCT. Analysis of the short-term preemptive prednisolone therapy in the randomized patients showed no significant difference in incidence or severity of acute GvHD (HR: 1.69, 95% CI: 0.66-4.32, P = 0.27). Prednisolone as preemptive treatment did not lead to an increase in relapse (20.2% in the placebo and 14.0% in the prednisolone group (P = 0.46)). The frequency of adverse events was slightly higher in the placebo group (64.4% versus 50%, respectively). Taken together, the results of the Pre-GvHD trial demonstrated the feasibility and safety of preemptive prednisolone treatment in the randomized patients.
Assuntos
Anti-Inflamatórios/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Prednisolona/uso terapêutico , Proteoma/metabolismo , Doença Aguda , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Proteoma/análise , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
PURPOSE: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION: Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.
Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Sorafenibe/uso terapêutico , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Quimioterapia Adjuvante , Método Duplo-Cego , Feminino , Alemanha , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Inibidores de Proteínas Quinases/efeitos adversos , Recidiva , Sorafenibe/efeitos adversos , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Strategies for relapse prevention after allogeneic transplantation in acute leukaemia are warranted. A registry-based matched-pair analysis evaluated the efficacy of prophylactic donor lymphocyte infusion (proDLI). Adults receiving proDLI in complete remission (CR) and controls were pair-matched for age, diagnosis, cytogenetics, stage, donor, gender, conditioning and T-cell depletion. Eighty-nine pairs were identified (median follow-up: 6.9 years). Within the entire cohort, no difference was observed. However, among patients with high-risk acute myeloid leukaemia (AML) (unfavourable cytogenetics and/or transplanted beyond first CR), proDLI recipients had improved overall survival (69.8% vs. 40.2% in controls, P = 0.027). ProDLI has moderate efficacy, but can contribute to improved outcome in high-risk AML.
Assuntos
Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos , Transplante de Células-Tronco , Doadores de Tecidos , Adulto , Idoso , Aloenxertos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de RiscoRESUMO
No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation (P<0.001), advanced disease (P=0.001), older age (P=0.007), unrelated donor (P=0.008) and acute graft-versus-host disease before relapse (P<0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation (P<0.001) and younger age (P=0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation (P<0.001), complete remission at second transplant (P=0.008), no prior chronic graft-versus-host disease (P<0.001) and change to a new donor (P=0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Aloenxertos , Europa (Continente) , Feminino , Humanos , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Recidiva , Sistema de Registros , Reoperação , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% (P = .01) and 46% (P = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Idoso , Citomegalovirus/imunologia , Europa (Continente) , Feminino , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Avaliação de Estado de Karnofsky , Leucemia Mieloide Aguda/mortalidade , Masculino , Síndromes Mielodisplásicas/mortalidade , Recidiva , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/mortalidade , Transplante HomólogoRESUMO
To assess current clinical practice in diagnosis and treatment of acute graft-versus-host disease (aGVHD), we performed a survey among German, Austrian, and Swiss allogeneic hematopoietic stem cell transplantation (allo-HSCT) centers. Thirty-four of 72 contacted centers (47%) completed both the diagnostic and therapeutic sections of the survey, representing 65% of allo-HSCT activity within the participating countries in 2011. Three pediatric centers answered as requested only the diagnostic part of the survey. In the presence of diarrhea and decreased oral intake after engraftment, only 4 centers (12%) do not perform any endoscopy before the start of immunosuppressive treatment. In case of a skin rash with the differential diagnosis of drug reaction, only 12 centers (35%) perform a skin biopsy up front, whereas 19 do so after failure of systemic steroids. In the presence of rapidly increasing cholestasis occurring without any other signs of aGVHD, 11 centers (32%) perform a liver biopsy up front and 14 only after failure of steroid treatment, whereas 9 centers do not perform a liver biopsy at all. Twenty centers (59%) use a percutaneous approach, 12 a transvenous approach, and 1 mini-laparoscopy for liver biopsies. First-line treatment of cutaneous aGVHD stage 1 consists of topical treatment alone in 17 of 31 responding centers (61%), whereas isolated cutaneous aGVHD stage III is treated with systemic steroids (prednisolone below 0.5 mg/kg/day n = 2, 0.5 to 1.0 mg/kg/day n = 10, above 1.0 to 2.5 mg/kg/day n = 19) without or with topical agents (steroids n = 10; calcineurin inhibitors n = 3). In gastrointestinal manifestations of aGVHD, 9 centers (29%) add topical to systemic steroids, and 3 consider topical steroids as the only treatment for mild gastrointestinal and cutaneous aGVHD. The choice of agent for second-line treatment as well as the sequence of administration are extremely heterogeneous, most likely due to a lack of convincing data published. Most frequently used are mycophenolate mofetil (n = 14) and extracorporeal photopheresis (n = 10). Our survey also demonstrates that clinicians chose salvage therapies for steroid-refractory aGVHD based on their centers' own clinical experience.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/terapia , Padrões de Prática Médica/estatística & dados numéricos , Doença Aguda , Áustria , Coleta de Dados , Alemanha , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Suíça , Resultado do TratamentoRESUMO
Based on molecular aberrations, in particular the NPM1 mutation (NPM1(mut)) and the FLT3 internal tandem duplication (Flt3-ITD), prognostic subgroups have been defined among patients with acute myeloid leukemia with normal karyotype. Whereas these subgroups are known to play an important role in outcome in first complete remission, and also in the indication for allogeneic stem cell transplantation, data are limited on their role after transplantation in advanced disease. To evaluate the role of molecular subgroups of acute myeloid leukemia with normal karyotype after allogeneic stem cell transplantation beyond first complete remission, we analyzed the data from 141 consecutive adults (median age: 51.0 years, range 18.4-69.3 years) who had received an allogeneic transplant either in primary induction failure or beyond first complete remission. A sequential regimen of cytoreductive chemotherapy (fludarabine, high-dose AraC, amsacrine) followed by reduced intensity conditioning (FLAMSA-RIC), was uniformly used for conditioning. After a median follow up of three years, overall survival from transplantation was 64 ± 4%, 53 ± 4% and 44 ± 5% at one, two and four years, respectively. Forty patients transplanted in primary induction failure achieved an encouraging 2-year survival of 69%. Among 101 patients transplanted beyond first complete remission, 2-year survival was 81% among patients with the NPM1(mut)/FLT3(wt) genotype in contrast to 43% in other genotypes. Higher numbers of transfused CD34(+) cells (hazard ratio 2.155, 95% confidence interval 0.263-0.964, P=0.039) and favorable genotype (hazard ratio 0.142, 95% confidence interval: 0.19-0.898, P=0.048) were associated with superior overall survival in multivariate analysis. In conclusion, patients with acute myeloid leukemia with normal karyotype can frequently be rescued after primary induction failure by allogeneic transplantation following FLAMSA-RIC. The prognostic role of NPM1(mut)/FLT3-ITD based subgroups was carried through after allogeneic stem cell transplantation beyond first complete remission.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Quimioterapia de Indução/métodos , Leucemia Mieloide/genética , Leucemia Mieloide/terapia , Doença Aguda , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Cariótipo , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Recidiva , Terapia de Salvação/métodos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Acute and chronic graft-versus-host disease (GVHD) are potentially lethal complications after stem cell transplantation (SCT). Steroids are the appropriate first-line treatment for both. However, if patients do not adequately benefit from steroid therapy, mortality is high and standardized treatment algorithms are lacking. This is mainly because of limited data from prospective, randomized clinical trials. In addition, most of the available treatment options only induce clinical benefits in a limited proportion of patients. Thus, there is an urgent clinical need to develop more potent immunosuppressive treatment strategies for patients suffering from acute or chronic steroid-refractory GVHD while maintaining the graft versus tumor effect to avoid a potential rise in relapse-related mortality. The increasing knowledge about host- as well as donor-derived variables favoring GVHD development and the increasing armamentarium of immune-modulatory agents entering preclinical and clinical research will probably allow more effective treatment of GVHD in the future. This review describes novel developments in the treatment of steroid-refractory GVHD, with a special focus on the rationale behind promising pharmacologic compounds or up-coming cellular therapies.
Assuntos
Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/etiologia , HumanosRESUMO
This retrospective study analyzes 34 patients with severe sclerodermatous chronic graft-versus-host disease (cGVHD) treated with inhibitors of the mammalian target of rapamycin (mTOR-I). Twelve patients received mTOR-I as monotherapy and 22 a combination therapy. Four patients also received extracorporal photopheresis. mTOR-I were applied as first-line therapy (n = 15) or in refractory disease (n = 19). Drug doses were adjusted to low therapeutical levels (3-8 ng/mL). Six and 20 patients had a complete and a partial response, respectively, with an overall response rate of 76%. Two additional patients had stable disease. Six refractory patients required alternative therapy. Comedication, especially steroids, could be tapered and stopped in a significant number of patients. No difference in response was observed in everolimus- and sirolimus-treated patients. Major adverse events possibly related to mTOR-I were hyperlipidemia and impaired wound healing. Two patients developed thrombotic microangiopathy. Eight patients died, 5 of the nonresponders (cGVHD; n = 3, infection; n = 2) and 3 of the responders (relapse of the underlying malignancy; n = 1, secondary malignancy; n = 1, unknown cause; n = 1). Twenty-six of the 34 patients remain alive, 18 still on therapy with mTOR-I. Median follow-up for surviving patients is 723 days (range 88-1621). The overall survival at 3 years since mTOR-I is 72%. In conclusion, mTOR-I seem to be an effective and well-tolerated treatment option for patients with sclerodermatous cGVHD.
Assuntos
Doença Enxerto-Hospedeiro/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Escleroderma Sistêmico/terapia , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Adulto , Terapia Combinada/métodos , Everolimo , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fotoferese , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Recidiva , Estudos Retrospectivos , Escleroderma Sistêmico/mortalidade , Escleroderma Sistêmico/patologia , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Esteroides/administração & dosagem , Esteroides/uso terapêutico , Análise de Sobrevida , Serina-Treonina Quinases TOR/metabolismo , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
To determine the impact of imatinib therapy prior to allogeneic stem-cell transplantation in advanced stage chronic myelogenous leukaemia (CML), 30 CML patients who had received imatinib as part of pre-transplant treatment were analysed, with special emphasis on the cytogenetic response to imatinib therapy shortly before transplantation. Median patient age was 51 years (range, 24 - 64). At the time of transplantation all patients were in second or higher chronic phase (CP). The median follow-up after allogeneic transplantation was 360 days (range, 24 - 1524). Cox regression analysis revealed that the quality of cytogenetic response was a prognostic factor for transplant-related mortality (p = 0.050), relapse incidence (p = 0.015), leukaemia-free survival (p = 0.002) and overall survival (p = 0.006). A cytogenetic response with <35%BCR-ABL-positive interphase nuclei in FISH analysis from bone marrow was associated with a probability of overall survival of 81% at 3 years. In conclusion, our data suggest that advanced stage CML has an excellent outcome after allogeneic haematopoietic stem-cell transplantation when transplanted in the phase of cytogenetic response to imatinib.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Transplante de Células-Tronco , Adulto , Benzamidas , Terapia Combinada , Feminino , Efeito Enxerto vs Leucemia , Humanos , Mesilato de Imatinib , Incidência , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Proteínas Tirosina Quinases/antagonistas & inibidores , Indução de Remissão , Taxa de Sobrevida , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: Imatinib is an effective treatment for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, relapse is common in patients with advanced or high risk disease. Such patients may be eligible for allogeneic stem cell transplantation (SCT), raising the question whether imatinib therapy may compromise the outcome of subsequent SCT. DESIGN AND METHODS: We retrospectively analyzed 70 patients with CML and 21 with Ph+ ALL who had received imatinib prior to SCT. Data were retrieved by directly contacting centers. Multivariate analysis was used to define factors associated with major outcomes (engraftment, graft-versus-host disease, relapse, non-relapse mortality) in addition to descriptive statistics. For the CML patients major outcomes were compared with those of historical controls drawn from the EBMT registry. RESULTS: At SCT, 44% of CML patients were in accelerated phase or blast crisis and 40% of ALL patients had active disease compared to 84% and 95% prior to imatinib. At 24 months, estimated transplant-related mortality was 44% and estimated relapse mortality 24%. Factors associated with shorter overall and progression-free survival were advanced disease at SCT and a female donor/male recipient pairing. No unusual organ toxicities were observed. Compared to historical controls, prior imatinib treatment did not influence overall survival, progression-free survival or non-relapse mortality, while there was a trend towards higher relapse mortality and significantly less chronic graft-versus-host disease. INTERPRETATION AND CONCLUSIONS: Within the limits of a heterogeneous and relatively small cohort of patients, we found no evidence that imatinib negatively affects major outcomes after SCT, suggesting that imatinib prior to SCT is safe.
Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Piperazinas/farmacologia , Pirimidinas/farmacologia , Adolescente , Adulto , Benzamidas , Criança , Pré-Escolar , Feminino , Humanos , Mesilato de Imatinib , Leucemia/mortalidade , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Mortalidade , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A sequential regimen of chemotherapy, reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), and prophylactic donor lymphocyte transfusion (pDLT) was studied in 103 patients with refractory acute myeloid leukemia (AML). According to published criteria, refractoriness was defined by primary induction failure (PIF; n = 37), early (n = 53), refractory (n = 8), or second (n = 5) relapse. Chemotherapy consisted of fludarabine (4 x 30 mg/m(2)), cytarabine (4 x 2 g/m(2)), and amsacrine (4 x 100 mg/m(2)), followed 4 days later by RIC, comprising 4 Gy total body irradiation (TBI), cyclophosphamide, and antithymocyte globulin. Patients without graft-versus-host disease (GvHD) at day +120 received pDLT in escalating doses. Patients' median age was 51.8 years. Before conditioning, 99 patients had active disease, 3 were aplastic, 1 was in second complete remission (CR2). Forty-one patients had family donors, 62 had unrelated donors. With a 25-month median follow-up, overall survival (OS) at 1, 2, and 4 years was 54%, 40%, and 32%; the respective leukemia-free survival (LFS) was 47%, 37%, and 30%. Patients with PIF showed a 2-year OS of 62.5%. OS was 87% in 17 patients receiving pDLT. One-year cumulative incidence of leukemic death and non-relapse-mortality was 28.7% and 17.2%. In a multivariate analysis, more than 2 courses of prior chemotherapy were the strongest predictor for poor outcome (P = .007; HR = 3.01 [OS]; P = .002; HR = 3.25 [LFS]). These results indicate a high activity of the regimen in refractory AML.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide/terapia , Terapia de Salvação/métodos , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Idoso , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro , Humanos , Leucemia Mieloide/mortalidade , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Taxa de Sobrevida , Transplante HomólogoRESUMO
PURPOSE: To improve the effect of allogeneic stem-cell transplantation by sequential use of intensive chemotherapy, reduced-intensity conditioning (RIC), and prophylactic donor lymphocyte transfusions (pDLTs) in high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). PATIENTS AND METHODS: In a prospective study of 75 consecutive patients (median age, 52.3 years), high risk was defined by progressive or refractory disease (n = 59), second remission after early relapse (n = 8), or first remission with poor prognosis based on cytogenetics or delayed response to induction therapy (n = 8). Unfavorable karyotypes were found in 49% of informative patients, and 68 patients had medical contraindications against standard conditioning. Fludarabine (30 mg/m2), cytarabine (2 g/m2), and amsacrine (100 mg/m2) for 4 days were used for cytoreduction. After 3 days of rest, RIC consisted of 4 Gy total-body irradiation, antithymocyte globulin, and 80 to 120 mg/kg cyclophosphamide. Thirty-one patients had an HLA-identical sibling donor; 44 patients had an unrelated and/or HLA-mismatched donor. pDLT was given from day +120 in patients who were not receiving immunosuppression and were free of graft-versus-host disease (GvHD). RESULTS: Complete remission was induced in 66 patients (88%). With a median follow-up of 35.1 months (range, 13.6 to 47.6 months), 2-year overall and leukemia-free survival were 42% and 40%, respectively. Outcome of patients with refractory disease or with complex cytogenetic aberrations was identical to that of better prognostic subgroups. Survival was best in patients who received high CD34+ cell numbers, and in patients with limited GvHD. CONCLUSION: Sequential use of intensive chemotherapy, RIC transplantation, and pDLT represents a promising approach to the treatment of high-risk AML and MDS, particularly in patients with most unfavorable prognoses.
Assuntos
Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Amsacrina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Distribuição de Qui-Quadrado , Citarabina/administração & dosagem , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Indução de Remissão , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
We studied 228 consecutive stem cell transplant recipients, screened for reactivation of human herpesvirus-6 (HHV-6) in peripheral blood and other specimens as clinically indicated by means of qualitative polymerase chain reaction. Among them, 197 received an allograft and 31 autograft. Ninety-six of 228 patients (42.1%) showed HHV-6 reactivation in peripheral blood and 129 of 228 (56.6%) demonstrated HHV-6 in at least one of the specimens tested. 41.9% of patients were asymptomatic when HHV-6 was identified. Clinical features, noted when HHV-6 was detected, included interstitial or alveolar pneumonia, gastroduodenal and colorectal disease, bone marrow suppression and liver disease. However, based on clinical and histopathological criteria, HHV-6 was considered a causal agent in only a minority of patients, in particular, those suffering from bone marrow suppression (n = 11), gastroduodenitis (five), colitis (three), interstitial/alveolar pneumonia (five), skin rash (one), pericarditis (two) and encephalitis (one). HHV-6 reactivation was significantly associated with the occurrence of graft-versus-host disease [odds ratio (OR) 5.31], Epstein-Barr virus coinfection (OR 8.89) and unrelated donor transplantation (OR 5.67) indicating an increased stage of immunosuppression.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 6/fisiologia , Infecções por Roseolovirus/diagnóstico , Adolescente , Adulto , DNA Viral/análise , Infecções por Vírus Epstein-Barr/complicações , Feminino , Doença Enxerto-Hospedeiro , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Período Pós-Operatório , Estudos Prospectivos , Fatores de Risco , Condicionamento Pré-Transplante , Transplante Homólogo , Ativação ViralRESUMO
In a retrospective analysis, we identified 38 evaluable patients who received intravenous ribavirin after adenovirus or RSV detection in the respiratory and/or gastrointestinal tract throughout the years 1998 and 2001. A total of 43 treatment cycles are analyzed. Intravenous ribavirin was combined with cidofovir in about half of the patients. In six out of eight patients treated because of RSV isolates from the respiratory tract, the virus was no longer detectable after treatment. In case of adenovirus isolates, the treatment was efficacious in eradicating the virus from the respiratory tract in more than 60% and from the gastrointestinal tract in 75% of treatment cycles. The addition of cidofovir was not beneficial in eradicating RSV isolates, but somewhat improved the virus clearance of adenovirus. Virus clearance was associated with a trend to a better median survival after virus detection. There were some episodes of suspected hemolysis and a trend towards lower leukocyte counts, reaching grade 3 toxicity in about 15% of treatment cycles. However, in general, intravenous ribavirin was well tolerated. In conclusion, the possible efficacy of intravenous Ribavirin in controlling RSV or adenovirus infections after allogeneic stem cell transplantations should be evaluated in prospective clinical trials.
Assuntos
Infecções por Adenovirus Humanos/tratamento farmacológico , Antivirais/administração & dosagem , Citosina/análogos & derivados , Citosina/administração & dosagem , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Organofosfonatos , Compostos Organofosforados/administração & dosagem , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Ribavirina/administração & dosagem , Adenoviridae/efeitos dos fármacos , Infecções por Adenovirus Humanos/etiologia , Infecções por Adenovirus Humanos/virologia , Adolescente , Adulto , Idoso , Antivirais/toxicidade , Cidofovir , Citosina/toxicidade , Feminino , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Humanos , Terapia de Imunossupressão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos Organofosforados/toxicidade , Infecções por Vírus Respiratório Sincicial/etiologia , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sinciciais Respiratórios/efeitos dos fármacos , Sistema Respiratório/patologia , Sistema Respiratório/virologia , Ribavirina/toxicidade , Resultado do TratamentoRESUMO
Allogeneic stem cell transplantation has a well-defined indication in the treatment of hematological malignancies. The beneficial immune effect of allogeneic marrow transplantation has long been known, but only recently have methods been developed to separate the graft-versus-leukemia (GVL) effect from graft-versus-host disease (GVHD). Animal experiments have shown that lymphocytes from the marrow donor can be transfused without causing severe GVHD if stable chimerism and tolerance is established. First clinical studies have been preformed in patients with recurrent chronic myelogenous leukemia. In these patients complete molecular remissions were induced that persist without further maintenance treatment. These results have been confirmed in larger multicenter studies in Europe and the USA. The best results were obtained in chronic myelogenous leukemia (CML); repeated successes have been reported in relapsing acute myeloid leukemia (AML), myelodysplastic syndromes and multiple myeloma (MMY), and rare responses were reported for acute lymphoid leukemia. Contrary to animal experiments GVHD has been observed in human patients although to a lesser extent than expected in transplants not given immunosuppression. Secondly myelosuppression has been observed in patients treated with relapsing CML. In CML the incidence of GVHD could be reduced by depleting CD8+ T cells from the donor lymphocyte concentrate. Alternatively only small numbers of T lymphocytes can be transfused and in the case of failing responses, the numbers of donor lymphocytes may be increased. Results in recurrent AML have been improved by the use of low-dose cytosine arabinoside, granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor mobilized blood cells as compared to lymphocytes only. In MMY the response rate is higher than in AML, but the remissions are of limited duration in most patients. Several protocols have been designed to include preemptive donor lymphocyte transfusion in patients with a high relapse risk after transplantation. Problems remain to avoid chronic GVHD and to circumvent the immune escape mechanisms of leukemia.
Assuntos
Transferência Adotiva/métodos , Leucemia/terapia , Animais , Quimera , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Tolerância Imunológica , Leucemia/imunologia , Linfócitos/imunologiaRESUMO
Stem-cell transplantation from human leukocyte antigen (HLA)-haploidentical family members carries a high risk of rejection and graft-versus-host disease (GVHD) if donor and recipient differ by more than one HLA antigen. The authors have developed treatment protocols from studies in dog leukocyte antigen-haploidentical dogs that prevent rejection and modify GVHD to the extent that patients with aggressive hematologic neoplasia can be treated with success. Principal improvements have been achieved in the use of cyclophosphamide and total-body irradiation for conditioning and T-cell depletion for prevention of GVHD. More recently, the combination of marrow and CD6-depleted mobilized donor blood cells (MDBC) has been introduced for HLA-haploidentical transplantation on the basis that CD6-depleted MDBC contain immunoregulatory cells besides stem cells and natural killer cells. Clinical results are reported on 36 patients with high-risk hematologic neoplasia. The results encourage the use of HLA-haploidentical stem-cell transplantation at an earlier stage of the disease. This method could also be of use for tolerance induction in organ transplantation.
Assuntos
Quimeras de Transplante , Tolerância ao Transplante , Animais , Incompatibilidade de Grupos Sanguíneos , Ciclofosfamida/farmacologia , Cães , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia/cirurgia , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Irradiação Corporal TotalRESUMO
OBJECTIVE: Sickle cell disease generates considerable morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (SCT) has the potential of curing the disease and halting end-organ damage. However, in older patients this treatment is associated with a significant risk of toxicity and death. SCT after reduced-intensity conditioning (RIC) might be a safer approach for the treatment of sickle cell disease. MATERIALS AND METHODS: A 22-year-old male had experienced multiple, life-threatening hemolytic crises. We treated him with G-CSF-mobilized stem cells from his heterozygote, human leukocyte antigen-matched brother after RIC with fludarabine and cyclophosphamide. GVHD prophylaxis consisted of cyclosporine (CyA) and mycophenolate mofetil (MMF). Chimerism of peripheral blood mononuclear cells was evaluated using short tandem repeat analysis and hemoglobin analysis was performed by high-performance liquid chromatography. RESULTS: There were no major treatment-related toxicities. At day +30 after transplantation the patient had mixed hematopoietic chimerism, which later converted to full chimerism. Hemoglobin analysis revealed 3.4% HbA(2), 1.0% HbF, and 41.2% HbS, which essentially is the same hemoglobin partition as in his brother's blood. MMF was discontinued on day +35 and CyA on day +120. After discontinuation of CyA the patient developed mild chronic GVHD, which resolved with continued CyA, low-dose steroids, and the retinoid isotretinoin. He is doing well on day +315 without evidence of GVHD. CONCLUSIONS: Allogeneic SCT after RIC is feasible in adult patients with sickle cell disease. Mixed chimerism is sufficient to relieve disease-related symptoms and is possibly correlated with less acute GVHD.