Introdução: O transplante de células tronco hematopoiéticas é capaz de curar as doenças hematológicas. O papel da repopulação linfocitária precoce no período pós transplan te visa combater a células neoplásicas que resistiram ao regime de condicionamento e prevenir as infecções oportunistas graves. Sendo assim, uma contagem elevada de linfócitos no período pós transplante é capaz de reduzir a mortalidade relacionada ao transplante (TRM), melhorar a sobrevida livre de doença e reduzir a taxa de recidiva. Objetivos: Avaliar a recuperação linfocitária precoce no D+21 e D+30 pós transplante correlacionado com a taxa de recidiva da doença de base, mortalidade, sobrevida global e livre de doença. Analisar a freqüência das complicações infecciosas neste período. Métodos: Analisado o número absoluto de linfócitos no D+21 e D+30 pós transplante de células tronco hematopoiéticas. Conforme dados da literatura definiu-se no D+21 e no D+30 aqueles com número absoluto de linfócitos abaixo e acima de 300 e se correlacionou os dados obtidos com a taxa de óbito, taxa de recidiva, sobrevida global em 5 anos, sobrevida livre de doença, em 5 anos, TRM em 100 dias. e mortalidade não relacionada a recaída (NRM). Resultados: Neste estudo foram incluídos 100 pacientes portadores das seguintes neoplasias hematológicas: leucemia mielóide aguda, leucemia linfocítica aguda, leucemias secundárias e síndrome mielodisplásica. Destes, 55 pacientes eram do sexo masculino e 45 do sexo feminino. A média de idade foi de 27,9 anos (mínima 9 meses e máxima 55 anos). A mediana do tempo de seguimento foi de 601 dias (IC 95% 106-1845). A mediana de CD 34 infundidos foi de 4,0 (IC 95% 2,4-5,7) e quanto a origem destas células CD 34 infundidas 85% foram de medula óssea (MO), 12% periférica (PBSC) e 3% sangue de cordão umbilical (SCU). Quanto ao tipo de condicionamento realizado 22% foram não mieloablativos e 78% mieloablativos.A mediana de linfócitos no D+21 foi de 460 (IC 95% 0 - 6250) e no D+30 foi de 760 (IC 95% 40-6370). Com relação a taxa de infecções observou-se que 19% das infecções foram de etiologia viral, 65 % bacteriana e 17% fúngicas. A sobrevida global (OS) em 5 anos foi de 44 % , sobrevida livre de doença (DFS) foi de 37,7% , a mortalidade relacionada ao transplante (TRM) em 100 dias foi de 32,5%. E a mortalidade não relacionada a recidiva (NRM) em 5 anos foi de 40,2%. No desfecho óbito observamos que 69% dos pacientes que foram a óbito no D+21 tinham linfócitos abaixo de 300, e 43,9% tinham linfócitos acima de 300 (p<0,05). Pacientes com valores menores que 300 no dia 30 tem 2,20 vezes o risco de irem a óbito quando comparados com aqueles com valores acima de 300 (IC 95% 1,03-4,69) ajustado para DECH e CD34. Pacientes com valores menores que 300 no dia 30 tem 3,76 vezes o risco de irem a óbito em menos de 100 dias quando comparados com aqueles com valores acima de 300 (IC 95% 1,23-11,46) Conclusões: A reconstituição linfocitária precoce (> 300) no D+21 e no D+30 melhora a sobrevida global e livre de doença, bem como reduz a taxa de recidiva da doença de base e reduz a mortalidade. / Background: The role of repopulating lymphocyte after allogenic stem cell transplantation (SCT) includes the prevention of serious infections and attacking residual tumor cells in the early post transplant phase. Therefore, the current study analysed the role of the absolute lymphocyte count (ALC) on day 21 and 30 after SCT in predicting transplant outcomes of patients in terms of the risk of transplant related mortality (TRM) recurrence of original disease and risk of opportunistic infections. Objective: Evaluate early lymphocyte recovery on D +21 and D +30 posttransplant correlated with the rate of recurrence of the underlying disease, mortality, overall survival and disease free survival. Analyzed the frequency of infectious complications in this period. Methods: Analyzed the absolute lymphocyte count in the D +21 and D +30 after hematopoietic stem cell transplantation. According to literature data set the we correlate the absolute lymphocyte count in the D +21D +30 below and above 300 these data with the rate of death, relapse rate, overall survival in 5 years, disease-free survival in 5 years , TRM in 100 days and mortality unrelated to relapse (NRM). Results : Included in the study 100 patients with the following hematologic malignancies: acute myeloid leukemia, acute lymphocytic leukemia, secondary leukemia and myelodysplastic syndrome. Of these, 55 patients were male and 45 female. The average age was 27.9 years (minimum 9 months and maximum 55 years). The median follow-up was 601 days (95% CI 106-1845). The CD 34 median that was infused was 4.0 (95% CI 2.4 to 5.7).The source of stem cells infused was 85% of bone marrow (BM), peripheral 12% (PBSC) and 3 % of umbilical cord blood (UCB). Regarding the type of conditioning performed 22% were non myeloablative and 78% of lymphocytes were mieloablativos. The median of absolute lymphocyte count in the D +21 was 460 (95% CI 0 to 6250) and D +30 was 760 (95% CI 40- 6370 ). Regarding the rate of infections were observed 19% viral infections , bacterial in 65% and fungal in 17%. Overall survival (OS) at 5 years was 44%, disease-free survival (DFS) was 37.7%, transplant related mortality (TRM) in 100 days was 32.5%. Non relapsed mortality (NRM) at 5 years was 40.2%. The death rate found that 69% of patients who died at the D +21 had presented lymphocytes count below 300, and 43.9% were above 300 lymphocytes (p <0.05). Patients with counts less than 300 in D+30 presented 2.20 times risk of death when compared with those who presented values above 300 (95% CI 1.03 to 4.69) adjusted for GVHD and CD34. Patients presenting values less than 300 in 30 days have 3.76 times more risk of death in less than 100 days compared with those with values above 300 (95% CI 1.23 to 11.46). Conclusions: The early lymphocyte reconstitution (> 300) in D +21 D +30 improves overall survival and disease-free and reduces the relapse rate of the underlying disease and reduces mortality.

Introdução: O transplante de células tronco hematopoiéticas é capaz de curar as doenças hematológicas. O papel da repopulação linfocitária precoce no período pós transplan te visa combater a células neoplásicas que resistiram ao regime de condicionamento e prevenir as infecções oportunistas graves. Sendo assim, uma contagem elevada de linfócitos no período pós transplante é capaz de reduzir a mortalidade relacionada ao transplante (TRM), melhorar a sobrevida livre de doença e reduzir a taxa de recidiva. Objetivos: Avaliar a recuperação linfocitária precoce no D+21 e D+30 pós transplante correlacionado com a taxa de recidiva da doença de base, mortalidade, sobrevida global e livre de doença. Analisar a freqüência das complicações infecciosas neste período. Métodos: Analisado o número absoluto de linfócitos no D+21 e D+30 pós transplante de células tronco hematopoiéticas. Conforme dados da literatura definiu-se no D+21 e no D+30 aqueles com número absoluto de linfócitos abaixo e acima de 300 e se correlacionou os dados obtidos com a taxa de óbito, taxa de recidiva, sobrevida global em 5 anos, sobrevida livre de doença, em 5 anos, TRM em 100 dias. e mortalidade não relacionada a recaída (NRM). Resultados: Neste estudo foram incluídos 100 pacientes portadores das seguintes neoplasias hematológicas: leucemia mielóide aguda, leucemia linfocítica aguda, leucemias secundárias e síndrome mielodisplásica. Destes, 55 pacientes eram do sexo masculino e 45 do sexo feminino. A média de idade foi de 27,9 anos (mínima 9 meses e máxima 55 anos). A mediana do tempo de seguimento foi de 601 dias (IC 95% 106-1845). A mediana de CD 34 infundidos foi de 4,0 (IC 95% 2,4-5,7) e quanto a origem destas células CD 34 infundidas 85% foram de medula óssea (MO), 12% periférica (PBSC) e 3% sangue de cordão umbilical (SCU). Quanto ao tipo de condicionamento realizado 22% foram não mieloablativos e 78% mieloablativos.A mediana de linfócitos no D+21 foi de 460 (IC 95% 0 - 6250) e no D+30 foi de 760 (IC 95% 40-6370). Com relação a taxa de infecções observou-se que 19% das infecções foram de etiologia viral, 65 % bacteriana e 17% fúngicas. A sobrevida global (OS) em 5 anos foi de 44 % , sobrevida livre de doença (DFS) foi de 37,7% , a mortalidade relacionada ao transplante (TRM) em 100 dias foi de 32,5%. E a mortalidade não relacionada a recidiva (NRM) em 5 anos foi de 40,2%. No desfecho óbito observamos que 69% dos pacientes que foram a óbito no D+21 tinham linfócitos abaixo de 300, e 43,9% tinham linfócitos acima de 300 (p<0,05). Pacientes com valores menores que 300 no dia 30 tem 2,20 vezes o risco de irem a óbito quando comparados com aqueles com valores acima de 300 (IC 95% 1,03-4,69) ajustado para DECH e CD34. Pacientes com valores menores que 300 no dia 30 tem 3,76 vezes o risco de irem a óbito em menos de 100 dias quando comparados com aqueles com valores acima de 300 (IC 95% 1,23-11,46) Conclusões: A reconstituição linfocitária precoce (> 300) no D+21 e no D+30 melhora a sobrevida global e livre de doença, bem como reduz a taxa de recidiva da doença de base e reduz a mortalidade. / Background: The role of repopulating lymphocyte after allogenic stem cell transplantation (SCT) includes the prevention of serious infections and attacking residual tumor cells in the early post transplant phase. Therefore, the current study analysed the role of the absolute lymphocyte count (ALC) on day 21 and 30 after SCT in predicting transplant outcomes of patients in terms of the risk of transplant related mortality (TRM) recurrence of original disease and risk of opportunistic infections. Objective: Evaluate early lymphocyte recovery on D +21 and D +30 posttransplant correlated with the rate of recurrence of the underlying disease, mortality, overall survival and disease free survival. Analyzed the frequency of infectious complications in this period. Methods: Analyzed the absolute lymphocyte count in the D +21 and D +30 after hematopoietic stem cell transplantation. According to literature data set the we correlate the absolute lymphocyte count in the D +21D +30 below and above 300 these data with the rate of death, relapse rate, overall survival in 5 years, disease-free survival in 5 years , TRM in 100 days and mortality unrelated to relapse (NRM). Results : Included in the study 100 patients with the following hematologic malignancies: acute myeloid leukemia, acute lymphocytic leukemia, secondary leukemia and myelodysplastic syndrome. Of these, 55 patients were male and 45 female. The average age was 27.9 years (minimum 9 months and maximum 55 years). The median follow-up was 601 days (95% CI 106-1845). The CD 34 median that was infused was 4.0 (95% CI 2.4 to 5.7).The source of stem cells infused was 85% of bone marrow (BM), peripheral 12% (PBSC) and 3 % of umbilical cord blood (UCB). Regarding the type of conditioning performed 22% were non myeloablative and 78% of lymphocytes were mieloablativos. The median of absolute lymphocyte count in the D +21 was 460 (95% CI 0 to 6250) and D +30 was 760 (95% CI 40- 6370 ). Regarding the rate of infections were observed 19% viral infections , bacterial in 65% and fungal in 17%. Overall survival (OS) at 5 years was 44%, disease-free survival (DFS) was 37.7%, transplant related mortality (TRM) in 100 days was 32.5%. Non relapsed mortality (NRM) at 5 years was 40.2%. The death rate found that 69% of patients who died at the D +21 had presented lymphocytes count below 300, and 43.9% were above 300 lymphocytes (p <0.05). Patients with counts less than 300 in D+30 presented 2.20 times risk of death when compared with those who presented values above 300 (95% CI 1.03 to 4.69) adjusted for GVHD and CD34. Patients presenting values less than 300 in 30 days have 3.76 times more risk of death in less than 100 days compared with those with values above 300 (95% CI 1.23 to 11.46). Conclusions: The early lymphocyte reconstitution (> 300) in D +21 D +30 improves overall survival and disease-free and reduces the relapse rate of the underlying disease and reduces mortality.

Introdução: O transplante de células tronco hematopoiéticas é capaz de curar as doenças hematológicas. O papel da repopulação linfocitária precoce no período pós transplan te visa combater a células neoplásicas que resistiram ao regime de condicionamento e prevenir as infecções oportunistas graves. Sendo assim, uma contagem elevada de linfócitos no período pós transplante é capaz de reduzir a mortalidade relacionada ao transplante (TRM), melhorar a sobrevida livre de doença e reduzir a taxa de recidiva. Objetivos: Avaliar a recuperação linfocitária precoce no D+21 e D+30 pós transplante correlacionado com a taxa de recidiva da doença de base, mortalidade, sobrevida global e livre de doença. Analisar a freqüência das complicações infecciosas neste período. Métodos: Analisado o número absoluto de linfócitos no D+21 e D+30 pós transplante de células tronco hematopoiéticas. Conforme dados da literatura definiu-se no D+21 e no D+30 aqueles com número absoluto de linfócitos abaixo e acima de 300 e se correlacionou os dados obtidos com a taxa de óbito, taxa de recidiva, sobrevida global em 5 anos, sobrevida livre de doença, em 5 anos, TRM em 100 dias. e mortalidade não relacionada a recaída (NRM). Resultados: Neste estudo foram incluídos 100 pacientes portadores das seguintes neoplasias hematológicas: leucemia mielóide aguda, leucemia linfocítica aguda, leucemias secundárias e síndrome mielodisplásica. Destes, 55 pacientes eram do sexo masculino e 45 do sexo feminino. A média de idade foi de 27,9 anos (mínima 9 meses e máxima 55 anos). A mediana do tempo de seguimento foi de 601 dias (IC 95% 106-1845). A mediana de CD 34 infundidos foi de 4,0 (IC 95% 2,4-5,7) e quanto a origem destas células CD 34 infundidas 85% foram de medula óssea (MO), 12% periférica (PBSC) e 3% sangue de cordão umbilical (SCU). Quanto ao tipo de condicionamento realizado 22% foram não mieloablativos e 78% mieloablativos.A mediana de linfócitos no D+21 foi de 460 (IC 95% 0 - 6250) e no D+30 foi de 760 (IC 95% 40-6370). Com relação a taxa de infecções observou-se que 19% das infecções foram de etiologia viral, 65 % bacteriana e 17% fúngicas. A sobrevida global (OS) em 5 anos foi de 44 % , sobrevida livre de doença (DFS) foi de 37,7% , a mortalidade relacionada ao transplante (TRM) em 100 dias foi de 32,5%. E a mortalidade não relacionada a recidiva (NRM) em 5 anos foi de 40,2%. No desfecho óbito observamos que 69% dos pacientes que foram a óbito no D+21 tinham linfócitos abaixo de 300, e 43,9% tinham linfócitos acima de 300 (p<0,05). Pacientes com valores menores que 300 no dia 30 tem 2,20 vezes o risco de irem a óbito quando comparados com aqueles com valores acima de 300 (IC 95% 1,03-4,69) ajustado para DECH e CD34. Pacientes com valores menores que 300 no dia 30 tem 3,76 vezes o risco de irem a óbito em menos de 100 dias quando comparados com aqueles com valores acima de 300 (IC 95% 1,23-11,46) Conclusões: A reconstituição linfocitária precoce (> 300) no D+21 e no D+30 melhora a sobrevida global e livre de doença, bem como reduz a taxa de recidiva da doença de base e reduz a mortalidade. / Background: The role of repopulating lymphocyte after allogenic stem cell transplantation (SCT) includes the prevention of serious infections and attacking residual tumor cells in the early post transplant phase. Therefore, the current study analysed the role of the absolute lymphocyte count (ALC) on day 21 and 30 after SCT in predicting transplant outcomes of patients in terms of the risk of transplant related mortality (TRM) recurrence of original disease and risk of opportunistic infections. Objective: Evaluate early lymphocyte recovery on D +21 and D +30 posttransplant correlated with the rate of recurrence of the underlying disease, mortality, overall survival and disease free survival. Analyzed the frequency of infectious complications in this period. Methods: Analyzed the absolute lymphocyte count in the D +21 and D +30 after hematopoietic stem cell transplantation. According to literature data set the we correlate the absolute lymphocyte count in the D +21D +30 below and above 300 these data with the rate of death, relapse rate, overall survival in 5 years, disease-free survival in 5 years , TRM in 100 days and mortality unrelated to relapse (NRM). Results : Included in the study 100 patients with the following hematologic malignancies: acute myeloid leukemia, acute lymphocytic leukemia, secondary leukemia and myelodysplastic syndrome. Of these, 55 patients were male and 45 female. The average age was 27.9 years (minimum 9 months and maximum 55 years). The median follow-up was 601 days (95% CI 106-1845). The CD 34 median that was infused was 4.0 (95% CI 2.4 to 5.7).The source of stem cells infused was 85% of bone marrow (BM), peripheral 12% (PBSC) and 3 % of umbilical cord blood (UCB). Regarding the type of conditioning performed 22% were non myeloablative and 78% of lymphocytes were mieloablativos. The median of absolute lymphocyte count in the D +21 was 460 (95% CI 0 to 6250) and D +30 was 760 (95% CI 40- 6370 ). Regarding the rate of infections were observed 19% viral infections , bacterial in 65% and fungal in 17%. Overall survival (OS) at 5 years was 44%, disease-free survival (DFS) was 37.7%, transplant related mortality (TRM) in 100 days was 32.5%. Non relapsed mortality (NRM) at 5 years was 40.2%. The death rate found that 69% of patients who died at the D +21 had presented lymphocytes count below 300, and 43.9% were above 300 lymphocytes (p <0.05). Patients with counts less than 300 in D+30 presented 2.20 times risk of death when compared with those who presented values above 300 (95% CI 1.03 to 4.69) adjusted for GVHD and CD34. Patients presenting values less than 300 in 30 days have 3.76 times more risk of death in less than 100 days compared with those with values above 300 (95% CI 1.23 to 11.46). Conclusions: The early lymphocyte reconstitution (> 300) in D +21 D +30 improves overall survival and disease-free and reduces the relapse rate of the underlying disease and reduces mortality.

Treatment of patients with multiple sclerosis (MS) and development of new therapies have been challenging due to the disease complexity and slow progression, and the limited sensitivity of available clinical outcomes. Modeling and simulation has become an increasingly important component in drug development and in post-marketing optimization of use of medication. This thesis focuses on development of pharmacometric models for characterization and quantification of the relationships between drug exposure, biomarkers and clinical endpoints in relapse-remitting MS (RRMS) following cladribine treatment. A population pharmacokinetic model of cladribine and its main metabolite, 2-chloroadenine, was developed using plasma and urine data. The renal clearance of cladribine was close to half of total elimination, and was found to be a linear function of creatinine clearance (CRCL). Exposure-response models could quantify a clear effect of cladribine tablets on absolute lymphocyte count (ALC), burden of disease (BoD), expanded disability status scale (EDSS) and relapse rate (RR) endpoints. Moreover, they gave insight into disease progression of RRMS. This thesis further demonstrates how integrated modeling framework allows an understanding of the interplay between ALC and clinical efficacy endpoints. ALC was found to be a promising predictor of RR. Moreover, ALC and BoD were identified as predictors of EDSS time-course. This enables the understanding of the behavior of the key outcomes necessary for the successful development of long-awaited MS therapies, as well as how these outcomes correlate with each other. The item response theory (IRT) methodology, an alternative approach for analysing composite scores, enabled to quantify the information content of the individual EDSS components, which could help improve this scale. In addition, IRT also proved capable of increasing the detection power of potential drug effects in clinical trials, which may enhance drug development efficiency. The developed nonlinear mixed-effects models offer a platform for the quantitative understanding of the biomarker(s)/clinical endpoint relationship, disease progression and therapeutic response in RRMS by integrating a significant amount of knowledge and data.