RESUMO
Many patients with lower-risk myelodysplastic syndromes (LR MDS) require long-term red blood cell (RBC) transfusions to manage anemia. The consequences of RBC transfusions in LR MDS with ring sideroblasts (LR MDS-RS) are not well known. We estimated the association between cumulative RBC dose density and clinical and patient-reported outcomes using data from the MDS-CAN registry for patients enrolled between January 2008 and December 2018. Outcomes included overall survival, hospitalization, and health-related quality of life (HRQoL). A total of 145 enrolled patients with LR MDS and RS ≥5% had a median follow-up time of 27.1 months; 45 had no transfusions during follow-up, 51 had <1 transfusion per month, and 49 had ≥1 transfusion per month. The cumulative density of RBC transfusions was associated with significantly greater mortality, hospitalization, and inferior HRQoL, suggesting that exposure to RBC transfusion may constitute a significant treatment burden in patients with LR MDS-RS.
Assuntos
Transfusão de Eritrócitos , Síndromes Mielodisplásicas , Humanos , Transfusão de Eritrócitos/efeitos adversos , Síndromes Mielodisplásicas/tratamento farmacológico , Qualidade de Vida , Estudos Prospectivos , Sistema de RegistrosRESUMO
Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 µg/L, 501-800 µg/L, >800 µg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 µg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.
Assuntos
Ferro , Síndromes Mielodisplásicas , Humanos , Idoso , Canadá , Ferritinas , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Transferrinas , TransferrinaRESUMO
Patients with lower-risk (LR) myelodysplastic syndromes (MDS) with ring sideroblasts (RS) have better prognosis than those without RS, but how they fare over time is not fully understood. This study's objective was to assess the natural history of LR MDS with RS ≥5% using MDS-CAN registry individual data. Kaplan-Meier estimates and generalized linear mixed models were used to describe time-to-event outcomes and continuous outcomes, respectively. One hundred and thirty-eight patients were enrolled; median times from diagnosis to enrollment and follow-up were 6.6 and 39.6 months, respectively. Within 5 years of enrollment, 65% of patients had ≥1 red blood cell transfusion dependence episode. Within 5 years of diagnosis, 59% developed iron overload, 38% received iron chelation therapy, 14% progressed to acute myeloid leukemia, and 42% died. Patients exhibited inferior health-related quality of life trends. These first real-world data in LR MDS-RS in Canada indicate a high level of morbidity and mortality over a 5-year period. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02537990.
Assuntos
Síndromes Mielodisplásicas , Humanos , Terapia por Quelação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Qualidade de Vida , Sistema de RegistrosRESUMO
The incorporation of patient-reported outcomes with traditional disease risk classification was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). In the present Canadian MDS registry analysis, we validate a recently reported prognostic model, the Fatigue-International Prognostic Scoring System among higher-risk patients [FA-IPSS(h)], which incorporates patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), with a threshold of ≥45 points, in higher IPSS score, stratifying them into distinct subgroups with different survival outcomes. We further validated this concept, using the Revised IPSS >3·5 as cut-off for the definition of higher-risk MDS, and patients' reported fatigue according to Edmonton Symptom Self-Assessment Scale (ESAS) Global Fatigue Scale (GFS), a single-item fatigue rating scale, which is easier to deploy. This emphasises the power of self-reported fatigue at refining overall survival predictions in higher-risk MDS and further bolsters the importance of considering patient-related outcomes in global assessments.
Assuntos
Fadiga/complicações , Síndromes Mielodisplásicas/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Fadiga/diagnóstico , Fadiga/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Medidas de Resultados Relatados pelo Paciente , Prognóstico , Qualidade de Vida , Sistema de RegistrosRESUMO
With standard therapies for patients with acute myeloid leukemia (AML), many patients either do not achieve complete response (CR) or relapse after CR. There are a scarcity of real-world data on outcomes of unselected patients with relapsed/refractory acute myeloid leukemia (RR-AML). We retrospectively evaluated treatment patterns and survival outcomes of unselected patients aged ≥18 years diagnosed with RR-AML identified from the Alberta Cancer Registry, Alberta, Canada, between January 2013 and December 2016. We included 199 patients who met predefined criteria for RR-AML. Following RR-AML diagnosis, 23% of patients received intensive therapy (IT), 33% non-intensive therapy (NIT), and 44% best supportive care (BSC). The unadjusted median overall survival (OS) of the study cohort was 5.3 months from the time of RR-AML diagnosis, with a 5-year OS rate of 12.6% (95% confidence interval 7.5-21.1). According to treatment intensity after RR-AML, the median OS outcomes were 13.6, 9.4, and 2.0 months for IT, NIT, and BSC groups, respectively (P<0.001). Patients who received treatment (IT or NIT) had better survival than those who received only BSC. This study emphasizes the need for newer therapy options for patients with RR-AML.
RESUMO
Atopy is excessive production of IgE in response to allergens. We evaluated in patients undergoing allogeneic hematopoietic cell transplantation (HCT) the following hypotheses: (1) Atopy is "curable" in atopic patients receiving HCT from a nonatopic donor (D-R+), and (2) Atopy is transferable from atopic donors to nonatopic recipients (D+R-). Atopic patients with atopic donors (D+R+) and non-atopic patients with non-atopic donors (D-R-) served as controls. We measured levels of multiallergen-specific IgE (A-IgE, atopy defined as ≥0.35 kUA/L) in sera from 54 patients and their donors pre HCT and from the patients at ≥2 years post HCT. Only 7/12 (58%) D- R+ patients became nonatopic after HCT. Only 1/11 (9%) D+R- patients became atopic. Eleven of 13 (85%) D-R- patients remained nonatopic. Unexpectedly, 11/18 (61%) D+R+ patients became nonatopic. In conclusion, contrary to our hypothesis and previous reports, the "cure" of atopy may occur in only some D-R+ patients and the transfer of atopy may occur rarely. The "cure" may not be necessarily due to the exchange of atopic for nonatopic immune system, as the "cure" may also occur in D+R+ patients.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Hipersensibilidade Imediata , Alérgenos , Humanos , Imunoglobulina ERESUMO
In 2008 the first evidence-based Canadian consensus guideline addressing the diagnosis, monitoring and management of transfusional iron overload in patients with myelodysplastic syndromes (MDS) was published. The Canadian Consortium on MDS, comprised of hematologists from across Canada with a clinical and academic interest in MDS, reconvened to update these guidelines. A literature search was updated in 2017; topics reviewed include mechanisms of iron overload induced cellular damage, evidence for clinical endpoints impacted by iron overload including organ dysfunction, infections, marrow failure, overall survival, acute myeloid leukemia progression, and endpoints around hematopoietic stem-cell transplant. Evidence for an impact of iron reduction on the same endpoints is discussed, guidelines are updated, and areas identified where evidence is suboptimal. The guidelines address common questions around the diagnosis, workup and management of iron overload in clinical practice, and take the approach of who, when, why and how to treat iron overload in MDS. Practical recommendations for treatment and monitoring are made. Evidence levels and grading of recommendations are provided for all clinical endpoints examined.
Assuntos
Sobrecarga de Ferro , Síndromes Mielodisplásicas , Canadá , Feminino , Humanos , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Sobrecarga de Ferro/terapia , Masculino , Estudos Multicêntricos como Assunto , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Guias de Prática Clínica como AssuntoRESUMO
Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int - 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level < 100 mIU/mL (OR 8.7, p < 0.0001). We propose a new ESA response score, consisting of (a) IPSS low score (1 point) and (b) serum EPO levels < 100 mIU/ml (2 points), yielding scores ranging from 0 to 3, with response rates varying from 17 to 81%. The Nordic score has validity but we observed lower than the expected response rates in the best risk group. Our proposed scoring system appears more discriminating but needs validation.
Assuntos
Eritropoetina/sangue , Hematínicos/administração & dosagem , Modelos Biológicos , Síndromes Mielodisplásicas , Sistema de Registros , Canadá , Feminino , Ferritinas/sangue , Humanos , Lactente , Recém-Nascido , L-Lactato Desidrogenase/sangue , Masculino , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Estudos ProspectivosRESUMO
OBJECTIVES: A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT. METHODS: Patients (N = 237) received 300 mg of posaconazole iv twice daily on day 1, followed by 300 mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400 mg twice daily or 200 mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (Cavg) and posaconazole trough levels (Cmin). RESULTS: Mean posaconazole Cmin was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state Cmin was 1090 ng/mL (day 10). Mean steady-state posaconazole Cavg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable). CONCLUSIONS: Intravenous posaconazole at 300 mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk. TRIAL REGISTRY AND NUMBER: ClinicalTrials.gov, NCT01075984.
Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Quimioprevenção/efeitos adversos , Quimioprevenção/métodos , Infecções Fúngicas Invasivas/prevenção & controle , Triazóis/efeitos adversos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Triazóis/administração & dosagem , Adulto JovemRESUMO
Analyses suggest iron overload in red blood cell (RBC) transfusion-dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient-related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient-related factors. TD International Prognostic Scoring System (IPSS) low and intermediate-1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease-modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non-ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P < 0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P = 0·03). In matched pair analysis, OS remained superior for ICT patients (P = 0·02). In this prospective, non-randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease-modifying agents. This provides additional evidence that ICT may confer clinical benefit.
Assuntos
Transfusão de Eritrócitos/efeitos adversos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Causas de Morte , Terapia por Quelação , Comorbidade , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/epidemiologia , Sobrecarga de Ferro/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Sistema de Registros , Risco , Análise de Sobrevida , Transplante HomólogoRESUMO
BACKGROUND: In 'real-life', the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower-risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. OBJECTIVES: To validate existing ESA predictive scores and develop a new score that identifies non-responders. METHODS: ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, and MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS-CAN, and IPSS-R-based ESA scores were calculated and documented ESA responses compared. RESULTS: 996 ESA-treated patients were identified. Overall response rate (ORR) was 59%. The database was randomly divided into balanced derivation (n = 463) and validation (n = 462) cohorts. By multivariate analysis, transfusion independence, erythropoietin (EPO) level <100 IU/L, and IPSS low-risk were independently predictive of response. Assigning a score of 1 to each resulted in a scoring system of 0-3 with response rates of 23%, 43%, 67%, and 85%. ORR was concordant in the validation cohort. The 'ITACA' score had the highest discriminating power of response. CONCLUSION: ITACA is an internally-validated predictive SS of ESA response in real-life 'good risk' MDS patients derived from a large international dataset that surpasses others. The incorporation of biologic markers to better identify non-responders is still needed.
Assuntos
Hematínicos/uso terapêutico , Síndromes Mielodisplásicas , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Bases de Dados Factuais , Feminino , Humanos , Cooperação Internacional , Itália/epidemiologia , Modelos Logísticos , Masculino , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Sistema de Registros , Taxa de SobrevidaRESUMO
BACKGROUND: Hemorrhagic cystitis (HC) is a complication of allogeneic stem cell transplantation (SCT), associated with factors such as BK polyomavirus reactivation, age, conditioning regimen, and presence of graft-versus-host disease (GVHD). The incidence and impact of HC in patients receiving fludarabine (Flu), busulfan (Bu), and anti-thymocyte globulin (ATG) conditioning is unknown. METHODS: We conducted a case-control study of patients undergoing SCT at our center between January 1, 2003 and Dec 31, 2012, to determine the incidence of HC and its effect on patient outcomes including overall survival (OS), relapse, non-relapse mortality (NRM), GVHD, and healthcare resource use. RESULTS: In total, 94 cases of HC were identified and matched to controls based on age, donor type, disease type, and disease status at transplantation. The total incidence of HC was 17.7% (117 of 661 patients). Cases had a higher rate (43.6% vs 27.1%, P=.0394) of acute GVHD (Grade II-IV), and chronic GVHD requiring systemic steroids (34.9% vs 18.6%, P=.004). Male gender was found to be a risk factor (hazard ratio [HR]=1.725, P=.017). OS and progression-free survival did not differ between cases and controls (OS HR=1.128, 95% confidence interval [CI] 0.7807-1.639; progression-free survival HR=0.8809, 95% CI 0.6320-1.234), however the rate of NRM was higher in cases (HR=1.632, 95% CI 1.007-2.830). Median length of hospitalization was longer for patients with HC than matched controls (65.5 days vs 40.5 days, P<.0001). CONCLUSION: HC is common in patients undergoing allogeneic SCT with FluBuATG conditioning, and affects the duration of hospitalization. Rate of GVHD is higher among patients with HC. While OS is not affected, an association was seen with higher NRM in our study. Improvement in treatment for HC may lead to reductions in morbidity and healthcare resource utilization.
Assuntos
Cistite/epidemiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Agonistas Mieloablativos/uso terapêutico , Infecções por Polyomavirus/epidemiologia , Condicionamento Pré-Transplante/efeitos adversos , Soro Antilinfocitário/uso terapêutico , Vírus BK/isolamento & purificação , Bussulfano/uso terapêutico , Estudos de Casos e Controles , Cistite/virologia , Intervalo Livre de Doença , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Incidência , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/virologia , Recidiva , Fatores de Risco , Fatores Sexuais , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
UNLABELLED: Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi-centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS-related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System (IPSS-R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age-adjusted IPSS-R, frailty (Hazard ratio 2·7 (95% confidence interval [CI] 1·7-4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1-2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS-R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02537990.
Assuntos
Síndromes Mielodisplásicas/mortalidade , Atividades Cotidianas , Idoso , Comorbidade , Feminino , Idoso Fragilizado , Humanos , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Estudos Prospectivos , Qualidade de Vida , Sistema de Registros , Fatores de Risco , Taxa de SobrevidaRESUMO
A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation. Although there is some evidence that Bu exposures exceeding 6000 µM.min [corrected] may lead to excessive toxicity, there is little information on the effect of exposures below this level on outcomes. We studied Bu exposure, as measured by area under the concentration-time curve (AUC), in 158 patients with various hematologic malignancies in an attempt to identify an optimal range for targeted therapy. The preparative chemotherapy regimen comprised Flu 50 mg/m(2) on days -6 to -2 and i.v. Bu 3.2 mg/kg on days -5 to -2 inclusive. Graft-versus-host disease (GVHD) prophylaxis included methotrexate, cyclosporin A, and antithymocyte globulin. Patients with Bu exposures below the median AUC of 4439 µM.min [corrected] were at increased risk for acute GVHD grade II-IV (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.19 to 4.49; P = .014). Those in the highest and lowest Bu exposure quartiles (daily AUC <3814 µM.min and >4993 µM.min) [corrected] had an increased risk of nonrelapse mortality (subdistribution HR, 3.32; 95% CI, 1.46 to 7.54; P = .004), as well as worse disease-free survival (HR, 1.81; 95% CI, 1.09 to 2.99; P = .021) and overall survival (HR, 1.94; 95% CI, 1.12 to 3.37; P = .018). Bu exposures between 4440 and 4993 µM/min were accompanied by the lowest risk of both nonrelapse mortality and acute GVHD.
Assuntos
Soro Antilinfocitário/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bussulfano/administração & dosagem , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Vidarabina/análogos & derivados , Administração Intravenosa , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Bussulfano/farmacocinética , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/farmacocinéticaRESUMO
Patients over age 60 comprise the majority of those diagnosed with acute myeloid leukemia (AML), but treatment approaches in this population are variable, with many uncertainties and controversies. Our group conducted a literature review to summarize the latest information and to develop a consensus document with practical treatment recommendations. We addressed five key questions: selection criteria for patients to receive intensive induction chemotherapy; optimal induction and post-remission regimens; allogeneic hematopoietic stem cell transplantation (HSCT); treatment of patients not suitable for induction chemotherapy; and treatment of patients with prior hematological disorders or therapy-related AML. Relevant literature was identified through a PubMed search of publications from 1991 to 2012. Key findings included the recognition that cytogenetics and molecular markers are major biologic determinants of treatment outcomes in the older population, both during induction therapy and following HSCT. Although disease-specific and patient-specific risk factors for poor outcomes are more common in the older population, age is not in itself sufficient grounds for withholding established treatments, including induction and consolidation chemotherapy. The role of HSCT and use of hypomethylating agents are discussed. Finally, suggested treatment algorithms are outlined, based on these recommendations.
RESUMO
Hematopoietic stem cell transplantation (SCT) is routinely offered to suitable candidates with high-risk or advanced acute lymphoblastic leukemia (ALL). In this report, we update our experience with SCT in patients with ALL with a novel conditioning regimen. A total of 44 patients with high-risk or advanced (greater than first complete remission) ALL in remission underwent SCT after myeloablative conditioning with fludarabine + busulfan + total body irradiation. The median follow-up of surviving patients was 4.3 years (range, 1.0-9.0 years). The cohort consists of 32 patients with high-risk disease (median age, 40 years; range, 19-64 years) and 12 patients with advanced disease (median age, 25 years; range, 19-65 years) who underwent SCT: 25 with a related donor (21 fully matched) and 19 with an unrelated donor (16 fully matched). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 53.2%, and that of grade III-IV acute GVHD was 20.6%. The incidence of chronic GVHD was 55%. The 100-day nonrelapse mortality was 13.6%. Five-year progression-free survival was 56.7%, and 5-year overall survival was 66.0%. Nine patients (20%) died in remission, 6 (14%) died after relapse, and 2 survived after a second SCT for relapsed disease. Outcomes were inferior in older patients with comorbidities compared with other patients.
Assuntos
Soro Antilinfocitário/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total/métodos , Adulto , Fatores Etários , Idoso , Bussulfano/administração & dosagem , Estudos de Coortes , Comorbidade , Intervalo Livre de Doença , Humanos , Incidência , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto JovemRESUMO
Intravenous (i.v.) busulfan (Bu) administered once daily in myeloablative transplant regimens is convenient, effective, and relatively well tolerated. Therapeutic drug monitoring is recommended as nonrelapse mortality increases when daily exposure, as determined by the area under the plasma concentration versus time curve (AUC), exceeds 6000 µM·min. We describe sequential studies to achieve accurate prediction of treatment doses of Bu based on the kinetics of a smaller test dose. A total of 335 patients with hematologic malignancies were given daily i.v. Bu 3.2 mg/kg × 4 and fludarabine 50 mg/m(2) × 5. Pharmacokinetic monitoring was conducted for both the test dose and first treatment dose of Bu (day -5). Three different test dose schedules were evaluated: 12 mg Bu administered over 20 minutes, 0.8 mg/kg over 3 hours, and 0.8 mg/kg infused at 80 mg/h. The 3.2 mg/kg treatment doses were infused over a fixed time of 3 hours for the first 2 test dose trials and at a fixed rate of 80 mg/h for the final protocol. All test dose infusions were on day -7. In the first 2 schedules, Bu administered over a fixed time had significantly higher clearance for the test dose compared with the treatment dose. However, when both the test and the treatment doses were administered at the same infusion rate, clearance of the drug between the 2 dosing days was equivalent. Predicted day -5 AUC (AUC(-5)) showed a high linear correlation (r(2) = 0.74) to the actual AUC(-5). The error of these predictions was <20% in 98% of patients and <10% in 80%. In 24 individuals, the test dose predicted an AUC >5500 µM·min; therefore, the first Bu treatment dose was reduced to a desired target AUC. All adjusted doses fell within 20% of the targeted exposure. We conclude that a test dose strategy for therapeutic drug monitoring of daily i.v. Bu is accurate if the test and treatment doses are infused at the same rate. This approach allows targeting of therapeutic doses of Bu to desired levels and the potential for improved safety and efficacy.
Assuntos
Bussulfano/administração & dosagem , Bussulfano/farmacocinética , Monitorização Fisiológica , Agonistas Mieloablativos/administração & dosagem , Agonistas Mieloablativos/farmacocinética , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Bussulfano/efeitos adversos , Feminino , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/efeitos adversos , Fatores de Tempo , Transplante HomólogoRESUMO
A combination of fludarabine (Flu) and daily i.v. busulfan (Bu) is well tolerated and effective in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML). The addition of rabbit antithymocyte globulin (ATG) may reduce morbidity and mortality from graft-versus-host disease (GVHD), but lead to increased relapse. To compensate for this effect, we added 400 cGy of total body irradiation (TBI) to the Flu/Bu regimen in 89 patients, and compared outcomes with those achieved in 90 patients who received the drug combination alone. Although nonrelapse mortality (NRM) at 3 years did not differ between the groups, the inclusion of TBI significantly reduced relapse (hazard ratio [HR] = 0.29; 95% confidence interval [CI] = 0.15-0.54; P = .0001). Consequently, both overall survival (OS; HR = 0.50; 95% CI = 0.3-0.84; P = .009) and disease-free survival (DFS; HR = 0.43; 95% CI = 0.26-0.72; P = .001) were improved with the inclusion of TBI. This study confirms the importance of regimen intensity in allogeneic HSCT for AML. The combination of daily i.v. Bu, Flu, 400 cGy TBI, and ATG provides a well-tolerated regimen with antileukemic activity in AML comparable to that of other, conventional myeloablative (MA) regimens.