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In recent years, the genetic landscape of B-cell derived lymphoid malignancies, including chronic lymphocytic leukemia (CLL), has been rapidly unraveled, identifying recurrent genetic mutations with potential clinical impact. Interestingly, ~30% of all CLL patients can be assigned to more homogeneous subsets based on the expression of a similar or “stereotyped” B-cell receptor (BcR). Considering that biased distribution of genetic mutations was recently indicated in specific stereotyped subsets, in paper I, we screened 565 subset cases, preferentially assigned to clinically aggressive subsets, and confirm the SF3B1 mutational bias in subset #2 (45%), but also report on similarly marked enrichment in subset #3 (46%). In contrast, NOTCH1 mutations were predominantly detected in subsets #1, #8, #59 and #99 (22-34%). This data further highlights a subset-biased acquisition of genetic mutations in the pathogenesis of at least certain subsets. Aberrant NF-κB signaling due to a deletion within the NFKBIE gene previously reported in CLL warranted extended investigation in other lymphoid malignancies. Therefore, in paper II, we screened 1460 patients with various lymphoid malignancies for NFKBIE deletions and reported enrichment in classical Hodgkin lymphoma (27%) and primary mediastinal B-cell lymphoma (PMBL) (23%). NFKBIE-deleted PMBL cases had higher rates of chemorefractoriness and inferior overall survival (OS). NFKBIE-deletion status remained an independent prognostic marker in multivariate analysis. EGR2 mutations were recently reported in advanced stage CLL patients; thus, in paper III we screened 2403 CLL patients for mutations in EGR2. An overall mutational frequency of 3.8% was reported and EGR2 mutations were associated with younger age, advanced stage and del(11q). EGR2 mutational status remained an independent marker of poor outcome in multivariate analysis, both in the screening and validation cohorts. Whole-genome sequencing (WGS) of 70 CLL cases, assigned to poor-prognostic subsets #1 and #2 and indolent subset #4, were investigated in Paper IV and revealed a similar skewing of SF3B1 mutations in subset #2 and NOTCH1 mutations in subset #1 to that reported in Paper I. Additionally, an increased frequency of the recently proposed CLL driver gene RPS15 was observed in subset #1. Finally, novel non-coding mutational biases were detected in both subset #1 and #2 that warrant further investigation.

A caquexia associada ao câncer deflagra, entre outros sintomas, uma acentuada redução de peso, além de um estado sistêmico inflamatório. O tecido adiposo branco é um importante órgão endócrino, capaz de sintetizar mediadores pró-inflamatórios, que contribuem para tal inflamação sistêmica. Há uma relação direta entre o aumento da ativação da via do receptor Toll-like 4 (TLR-4) dependente do fator 88 de diferenciação mielóide (MyD88) e a inflamação, e portanto, foi objetivo do presente estudo examinar o papel desta via no TAB subcutâneo de pacientes com câncer e caquexia. Os dados obtidos apontam que a via do TLR-4 dependente do MyD88 mostrou estar afetada no TAB destes pacientes. / Cancer cachexia triggers, among other symptoms, severe weight loss, as well as chronic systemic inflammation. The white adipose tissue (WAT) is an important endocrine organ, capable of synthesising pro-inflammatory mediators, which contribute to systemic inflammation. Pro-inflammatory cytokines are pointed out to be responsible for WAT catabolism activation, increasing lipolysis and also contributing to cachexia associated systemic inflammation. There is parallelism between increased activation of the myeloid differentiation primary response 88 (MyD88) dependent Toll-like receptor 4 (TLR-4) pathway and inflammation, and thus, the objective of this study was to examine the role of one such pathway in the inflammation of subcutaneous WAT in cachectic cancer patients. The data show that MyD88 dependent TLR-4 pathway is affected during cachexia.

On 26 April 1986 an accident occurred in the Chernobyl nuclear power plant resulting in the release of large amount of radionuclides. Almost five percent of the total released caesium-137 was deposited in Sweden. The incidence of malignancies in the most affected counties in Sweden was investigated in three epidemiological studies. In the first study the incidence of malignancies in children and adolescents was studied for the period 1978-1992. The parishes and their inhabitants were classified according to the ground deposition of caesium-137 on an analogue map provided be the Swedish Radiological Protection Authority. A continuous increase of brain tumour incidence observed during the time of the study had no clear relationship to the Chernobyl fallout. A somewhat decreased relative risk of ALL was observed in areas with increased deposition. Other malignancies showed no changes in incidence over time or with regard to the exposure of caesium-137. In study II and III we enlarged the study base by including adults. We improved the methodology by defining a cohort of subjects who lived in the same parish from 31 December 1985 to 31 December 1987. The inhabitants from seven counties were included. Parishes were classified the same way as in study I. Due to the large number of individuals six exposure categories could be created; <3, 3–29, 30–39, 40–59, 60–79, and 80–120 kBq caesium-137/m2. The inhabitants of the 117 non-affected parishes (<3 kBq/m2) served as reference. During the 1988-1996 followup, 22,409 malignancies were recorded. The MH-IRR in the fully adjusted model was 1.00 (reference), 1.05, 1.03, 1.08, 1.10 and 1.21, respectively. ERR was 0.11 per 100 kBq/m2 (95% CL 0.03;0.20). A more advanced method was used in Study III by ignoring the exposure classification for parishes, and instead matching the dwelling coordinate to a digital map of deposition of casesium-137. In spite of a more valid exposure classification the risk estimates were similar in study II and III. Also, the ERR during the longer follow-up of 1988-1999 was almost identical, 0.10 per 100 kBq/m2 (95% CL 0.00;0.23). The strongest dose-response relationship was seen in the first four years (1988-1991). No obvious excess for leukaemia or thyroid cancer was recognised in either study II or III. The estimated number of exposure related cases was calculated to 849 in study II and 1,278 in study III. Our interpretation is that we have shown an increased incidence of total malignancies with dose-response relationship for caesium-137, only a few years after the Chernobyl accident. In study IV we compared the two different ways of classifying the exposure in study II and III. Out of the 450 parishes 111 got a different classification. The similar risk estimates in study II and III could probably be explained by relatively homogenous exposure in the parishes making the intra-parish difference less influential, especially when included in categories. In study V we examined the urinary excretion of 8-OHdG in Belarussian children from areas with high and low fallout of caesium-137, respectively. We found significantly lower urinary 8-OHdG levels in children from rural contaminated areas compared to urban uncontaminated areas, suggesting an urban, rather than a radiation related, risk factor. Using the Hill criteria for causality there is support for a causal inference between the fallout of caesium-137 from the Chernobyl accident and the increased incidence in total malignancies in Northern Sweden.

Immunotherapy for cancer is a young research field progressing at high speed. The first chimera of an antibody and a signaling chain was designed by Zelig Eshhar and was later further developed to enhance existing T cell therapy by combining a single-chain fragment of an antibody with the CD3 zeta chain of the TCR complex. T cells expressing these chimeric antigen receptors (CARs) could recognize and specifically kill tumor cells. However the T cells, lacked in persistence and tumor rejection did not occur. Thus, the CAR constructs have been improved by providing the T cell with costimulatory signals promoting activation. The focus of this thesis has been to evaluate second and third generation αCD19-CAR T cells for the treatment of B cell leukemia and lymphoma. B cell tumors commonly upregulate anti-apoptotic proteins such as Bcl-2, which generates therapy resistance. In the first paper a second generation (2G) αCD19-CD28-CAR T cell was combined with the Bcl-2 family inhibitor ABT-737. ABT-737 sensitized tumor cells to CAR T cell therapy and may be an interesting clinical combination treatment. In paper II, the phenotype and function of a third generation (3G) αCD19-CD28-4-1BB-CAR T cell were evaluated. B cell-stimulated CAR T cells showed increased proliferation and an antigen-driven accumulation of CAR+ T cells. 3G CAR T cells had equal cytotoxic capacity, similar lineage, memory and exhaustion profile phenotype compared to 2G CARs. However, 3G CAR T cells proliferated better and had increased activation of intracellular signaling pathways compared to 2G CAR T cells. In paper III, αCD19-CD28-4-1BB-CAR T cells were used to stimulate immature dendritic cells leading to an upregulation of maturation markers on co-cultured dendritic cells. Hence, CAR T cells may not only directly kill the tumor cells, but may induce bystander immunity that indirectly aids tumor control. This thesis also include supplementary information about the development and implementation of protocols for GMP production of CAR T cell batches for a phase I/IIa clinical trial currently ongoing for patients with refractory B cell leukemia and lymphoma. So far, two patients have safely been treated on the lowest dose.

Research Doctorate - Doctor of Philosophy (PhD) / Endometrial cancer is one of the most common female cancers in industrialized countries. Traditional risk factors associated with endometrial cancer are well understood and include excessive exposure to estrogen or estrogen unopposed by progesterone. However, variations in the genes that influence these hormones and their association with endometrial cancer have not been well investigated. By studying genetic variation in endometrial cancer, novel markers of risk may be discovered that can be used to identify women at high risk and for the implementation of specialised treatments. Polymorphisms in the genes involved in the following pathways; hormone biosynthesis, hormone receptors, estrogen metabolism, DNA repair and cell cycle control, have been suggested to be involved in the initiation and development of endometrial cancer. The focus of this study was to examine genetic variants in these pathways to assess the existence of an association with the risk of endometrial cancer. In the first part of this study, the COMT V158M polymorphism was examined in a hereditary non-polyposis colorectal cancer (HNPCC) cohort to determine its association with disease expression. The heterozygous genotype was over-represented in women with endometrial/ovarian cancer that did not harbour mismatch repair (MMR) gene mutations. This result suggested that the COMT V158M polymorphism may alter the risk of developing HNPCC related endometrial/ovarian cancer in MMR mutation negative women. Since COMT is involved in the metabolism of estrogen and that estrogen is the main risk factor for endometrial cancer development, closer examination was warranted to determine the association of genetic variation involved in hormone-related pathways and endometrial cancer risk, outside of the context of an inherited predisposition to disease. In the second part of this study, a cohort of 191 women with endometrial cancer and 291 healthy control women were genotyped for polymorphisms in genes involved in hormone biosynthesis, hormone receptors, estrogen metabolism, DNA repair and cell cycle control. The results revealed that variations in estrogen receptor alpha (ESR1) and beta (ESR2), and the androgen receptor (AR), were associated with an increase and decrease in endometrial cancer risk, respectively. Additionally, polymorphisms in CYP1A1, CYP1B1, GSTM1 and GSTP1 were related to a decrease in endometrial cancer risk. A trend was observed for the cyclin D1 870 G>A polymorphism and an increase in endometrial cancer risk, however, this result did not reach significance. Taken together, these results revealed that perturbations in the hormone receptors and estrogen metabolism genes, may aid in the identification of women at high risk of developing endometrial cancer. Interestingly, stratification of the women with endometrial cancer revealed that combinations of polymorphisms in TP53 and MDM2 were associated with higher grades of cancer. This finding may possibly have significant implications as women with reduced apoptotic ability, due to combinations of polymorphisms in these genes, have an increased risk of presenting with higher grades of endometrial cancer, that are associated with lower survival rates. In summary, the results of this thesis showed that variation in the estrogen and androgen receptors, and estrogen metabolism genes, may alter the risk of developing endometrial cancer. Moreover, polymorphisms in the cell cycle control genes, TP53 and MDM2, appear to be associated with higher grades of endometrial cancer. This study of polymorphisms may help explain genetic differences in individual susceptibility to endometrial cancer and are markers of risk that aid in the development of effective and personalised strategies to prevent disease development. This study has improved the understanding of genetic variation associated with endometrial cancer risk. It has the potential to enhance our ability to treat women with endometrial cancer through improved identification and treatment strategies, by virtue of the genetic variation identified, that appears to predispose to disease.

Thesis (MNutr (Interdisciplinary Health Sciences. Human Nutrition))--Stellenbosch University, 2008. / Background This study aimed to define the prevalence of side-effects and the change in weight and BMI during radical radiotherapy for head and neck malignancies (HNM) at Tygerberg Academic Hospital (TBH), Western Cape, South Africa. Acute side-effects may delay or prevent the delivery of a complete curative radiotherapy dose. Weight loss has been shown to significantly worsen prognosis and increase prevalence of treatment complications. However, weight maintenance may lead to beneficial outcomes. Assessing the impact of radical radiotherapy on patients with HNM is therefore critical and can promote development and implementation of medical and nutritional interventions. Methods Patients were weighed before and weekly during radiotherapy. Blood was drawn before, during and at the end of radiotherapy so that the Prognostic Inflammatory and Nutritional Index (PINI) could be calculated. Selected clinical data, clinical grades of mucositis and the diagnosis of a fungal infection of the oral cavity were extracted from clinical records. The McMaster Head and Neck Radiotherapy Questionnaire and a Lifestyle and Dietary Questionnaire were administered weekly. Descriptive statistics and the following were used: ANOVA, Repeated Measures ANOVA and McNemar Chi-square tests. Results Thirty-eight patients were recruited and 21 completed the study. Follow-up occurred over a maximum of nine weeks. A decrease in the weight (p = 0.01) and BMI (p = 0.01) and increase in the PINI (p = 0.04) occurred during radiotherapy. The mean absolute weight loss was 3.2kg (4.8), the mean percentage weight loss was 4.5% (6.7) and the mean decrease in BMI was 1.2kg/m2 (1.8). There was an increase in the prevalence of malnutrition (p = 0.02), as defined in this study. Oral mucositis occurred in all participants from Week 4; the majority developing Grade II or III Mucositis. Fungal infection of the oral cavity was prevalent throughout radiotherapy, with the highest prevalence (30%) in Week 4. Increases in severity of symptoms related to the mouth (p = 0.0000), throat (p = 0.05) and skin domains (p = 0.0000) occurred. Fifty-nine percent of inpatients and 45% of outpatients were prescribed supplementation drinks and most participants reported that a dietitian had not consulted them, in each week of radiotherapy. Discussion Severe side-effects in the mouth, throat and skin were experienced and a decline in nutritional status was observed. The poor nutritional status prior to commencing and weight loss during radiotherapy could have increased the severity of side-effects. The induction of the acute phase response indicated that this could have contributed to the decline in nutritional status observed. In addition, the infrequent nutritional support is likely to have further contributed to the lack of weight maintenance. Conclusion This first study conducted in South Africa has demonstrated the prevalence of significant side-effects and change in weight and BMI in this patient population. It is recommended that more effective analgesic medication is prescribed and that measures are taken to improve oral hygiene of participants to prevent fungal infection of the oral cavity. Improved nutritional support in terms of regular dietetic follow-up of all patients and more frequent prescription of supplementation drinks during radiotherapy is also recommended.

Les cellules Natural Killer (NK) sont des lymphocytes cytotoxiques innés qui jouent un rôle important dans le contrôle immunitaire de la formation de cellules tumorales et de l'infection virale. Chez les personnes en bonne santé, les cellules NK représentent des populations hétérogènes définies par différents marqueurs phénotypiques et exécutant des fonctions spécifiques. Les cellules NK provenant de patients présentant des tumeurs malignes néoplasiques et une infection virale sont cependant typiquement distinctes des personnes en bonne santé par l'apparition de sous-ensembles de cellules NK, qui sont différenciées par leur profil d'isoformes CD45. CD45 est une tyrosine phosphatase leucocytaire commune abondamment exprimée sur toutes les cellules immunitaires hématopoïétiques nucléées. Un variant d'épissage alternatif a entraîné la génération de l'isoforme CD45RA longue et de l'isoforme courte CD45RO, qui s'expriment différemment sur les cellules T naïves et effectrices / mémoires. L'expression des isoformes CD45 sur les cellules NK est largement inconnue. Nous avons précédemment montré que l'expression différentielle des isoformes CD45RA et CD45RO a identifié des sous-ensembles de cellules NK spécifiques dans les maladies hématologiques. Une question reste floue: comment ces cellules CD45RARO + NK changent-elles lorsque leurs cellules cibles disparaissent? Nous avons utilisé des cellules NK de patients traités avec Lenalidomide et l'anticorps anti-CD20 Obinutuzumab pour étudier cela et montré une réduction des cellules CD45RARO / CD45RO + NK après la clairance des cellules tumorales (Chater 4). Nous avons observé la même chose chez les patients atteints de LMA après une chimiothérapie. Dans ce cas, le sous-ensemble de cellules CD45RARO + NK est fortement corrélé avec la trogocytose du marqueur monocyte / macrophage CD14 (Chapitre 5). L'immunophénotypage de cellules NK provenant de patients infectés par le VIH a révélé la présence de cellules CD45RAdim et CD45RO + avec une expression réduite de CD16 et une diminution de la modulation NKG2D totale. En résumé, les cellules NK des cancers hématologiques et l'infection par le VIH présentaient des caractéristiques dysfonctionnelles et l'analyse du profil isoforme CD45 dans ces conditions pathologiques dévoile ces caractéristiques.Enfin, afin de retrouver la réponse immunitaire anti-tumorale chez les patients cancéreux, nous présentons une méthode efficace pour l'expansion in vitro de cellules NK hautement activées à partir du sang du cordon ombilical (UCB). Ces cellules NK prouvent une cytotoxicité cellulaire dépendante des anticorps (ADCC) importante lorsqu'elles sont utilisées en combinaison avec des anticorps monoclonaux approuvés sur le plan clinique ciblant divers antigènes tumoraux. Ceci ouvre leur utilisation dans les immunothérapies à base de cellules NK allogéniques. / Natural Killer (NK) cells are innate cytotoxic lymphocytes that play an important role in immune control of tumor cell formation and virus infection. In healthy people, NK cell represents heterogeneous populations defined by different phenotypical markers and performing specific functions. NK cells from patients with neoplastic malignancies and viral infection are however typically distinctive from healthy people by the appearance of NK cell subsets, which are differentiated by their CD45 isoform profile. CD45 is a common-leukocyte tyrosine phosphatase abundantly expressed on all nucleated hematopoietic immune cells. Alternative splicing variant resulted in generation of the long-isoform CD45RA and the short-isoform CD45RO, which express differently on naïve and effector/memory T cells. Expression of CD45 isoforms on NK cells is largely unknown. We have previously shown that differential expression of CD45RA and CD45RO isoforms identified specific NK cell subsets in hematological diseases. One question remained unclear: how do these CD45RARO+ NK cell changes when their target cells disappeared? We used NK cells from patients treated with Lenalidomide and the anti-CD20 antibody Obinutuzumab to investigate this and showed a reduction in CD45RARO/CD45RO+ NK cells upon clearance of tumor cells (Chater 4). We observed the same in AML patients after chemotherapy. In this case the CD45RARO+ NK cell subset strongly correlates with trogocytosis of the monocyte/macrophage marker CD14 (Chapter 5). Immunophenotyping of NK cells from HIV-infected patients revealed the presence of CD45RAdim and CD45RO+ cells with reduced CD16 expression and total NKG2D down-modulation. In summary, NK cell from hematological cancers and HIV infection displayed dysfunctional hallmarks and analyzing CD45 isoform profile in these pathological conditions unveils these hallmarks.Finally, in order to regain the anti-tumor immune response in cancer patients, we present an efficient method for expansion of highly activated NK cells from umbilical cord blood (UCB) in vitro. These NK cells prove substantial antibody-dependent cell cytotoxicity (ADCC) when used in combination with clinical-approved monoclonal antibodies targeting various tumor antigens. This paves their use in allogeneic NK cell-based immunotherapies.

A neutropenia induzida pela quimioterapia é o mais comum efeito adverso da quimioterapia sistêmica para o câncer e é frequentemente complicada por neutropenia febril (NF). O uso profilático de fatores de crescimento hematopoiéticos pode reduzir o risco, a severidade e a duração da NF. Na prática clínica atual, a decisão de administrar ao paciente profilaxia com fatores de crescimento é baseada principalmente no potencial mielotóxico dos esquemas de QT, mas riscos específicos dos regimes não são definidos. Em muitos estudos, a toxicidade da quimioterapia é analizada em termos de alta dosagem versus baixa dosagem, sem uma regra geral que considere os diferentes esquemas de QT em uma única escala. O objetivo desse estudo é validar uma classificação de toxicidade de um esquema de QT e avaliar sua utilidade em um modelo de predição de risco de neutropenia febril em pacientes com câncer hematológico no começo de um ciclo de quimioterapia. Foram avaliados prospectivamente duzentos e sessenta e oito pacientes e acompanhados durante 1053 ciclos de quimioterapia na Bélgica, entre 2001 e 2005. Informações relevantes foram coletadas no começo do primeiro ciclo e o número de dias de neutropenia febril foi contabilizado no acompanhamento dos pacientes [dicotomizada (sem neutropenia versus >= dia de NF)]. A relação entre o desfecho e as co-variáveis foi analisada usando a Equação de Estimativa Generalizada (GEE). Um regime de quimioterapia agressiva é o maior preditor de NF [razão de chances (OR) 5.2 (3.2-8.4)]. Os outros preditores independentes são: doença subjacente, o comprometimento de medula óssea, superfície corporal <= 2m², uma contagem pré-tratamento de monócitos <150µl e a interação entre o primeiro ciclo na mesma linha de tratamento e uma dosagem de hemoglobina pré-tratamento. Usando as estimativas dos coeficientes de regressão, uma regra de predição clínica de NF foi desenvolvida com essas características: sensibilidade 78.6%, especificidade 62.3%, valor preditivo positivo de 42.7%% e um valor preditivo negativo de 89.1%. Estudos posteriores são necessários para validar esse escore bem como investigar novos potenciais fatores com o intuito de melhor prever a NF. / Chemotherapy-induced neutropenia is the most common adverse effect of chemotherapy and is often complicated by febrile neutropenia (FN). As prophylactic use of colonystimulating factors (CSF) can reduce the risk, severity, and duration of FN, it is of great importance to identify as soon as possible after or even before the start of chemotherapy, the patients who will develop FN. In the current clinical practice, the decision to give to the patient a colony-stimulating factor (CSF) prophylaxis is mainly based on the myelosuppressive potential of the chemotherapy regimen. The objective of this study is to validate a classification of aggressiveness of a chemotherapy regimen and to evaluate its usefulness in a risk prediction model of FN in patients with hematological cancer at the beginning of a chemotherapy cycle. Two hundred and sixty-six patients were prospectively enrolled and followed during 1053 cycles. Relevant patient informations were collected at the beginning of the first cycle and the number of days of FN were counted in the follow-up [dichotomized (no FN versus>= 1 day of FN)]. Aggressive chemotherapy regimen is the major predictor of FN [odds ratio 5.2 (3.2 - 8.4)]. The other independent predictors are the underlying disease, an involvement of bone marrow, body surface<= 2m², a baseline monocyte count <150/µl and the interaction between the first cycle in the same treatment line and a baseline hemoglobin dosage. A rule of prediction of FN was computed with these characteristics: sensitivity 78.6%, specificity 62.3%, positive predictive value 42.7% and negative predictive value 89.1%. Further studies are needed to validate this score.

A neutropenia induzida pela quimioterapia é o mais comum efeito adverso da quimioterapia sistêmica para o câncer e é frequentemente complicada por neutropenia febril (NF). O uso profilático de fatores de crescimento hematopoiéticos pode reduzir o risco, a severidade e a duração da NF. Na prática clínica atual, a decisão de administrar ao paciente profilaxia com fatores de crescimento é baseada principalmente no potencial mielotóxico dos esquemas de QT, mas riscos específicos dos regimes não são definidos. Em muitos estudos, a toxicidade da quimioterapia é analizada em termos de alta dosagem versus baixa dosagem, sem uma regra geral que considere os diferentes esquemas de QT em uma única escala. O objetivo desse estudo é validar uma classificação de toxicidade de um esquema de QT e avaliar sua utilidade em um modelo de predição de risco de neutropenia febril em pacientes com câncer hematológico no começo de um ciclo de quimioterapia. Foram avaliados prospectivamente duzentos e sessenta e oito pacientes e acompanhados durante 1053 ciclos de quimioterapia na Bélgica, entre 2001 e 2005. Informações relevantes foram coletadas no começo do primeiro ciclo e o número de dias de neutropenia febril foi contabilizado no acompanhamento dos pacientes [dicotomizada (sem neutropenia versus >= dia de NF)]. A relação entre o desfecho e as co-variáveis foi analisada usando a Equação de Estimativa Generalizada (GEE). Um regime de quimioterapia agressiva é o maior preditor de NF [razão de chances (OR) 5.2 (3.2-8.4)]. Os outros preditores independentes são: doença subjacente, o comprometimento de medula óssea, superfície corporal <= 2m², uma contagem pré-tratamento de monócitos <150µl e a interação entre o primeiro ciclo na mesma linha de tratamento e uma dosagem de hemoglobina pré-tratamento. Usando as estimativas dos coeficientes de regressão, uma regra de predição clínica de NF foi desenvolvida com essas características: sensibilidade 78.6%, especificidade 62.3%, valor preditivo positivo de 42.7%% e um valor preditivo negativo de 89.1%. Estudos posteriores são necessários para validar esse escore bem como investigar novos potenciais fatores com o intuito de melhor prever a NF. / Chemotherapy-induced neutropenia is the most common adverse effect of chemotherapy and is often complicated by febrile neutropenia (FN). As prophylactic use of colonystimulating factors (CSF) can reduce the risk, severity, and duration of FN, it is of great importance to identify as soon as possible after or even before the start of chemotherapy, the patients who will develop FN. In the current clinical practice, the decision to give to the patient a colony-stimulating factor (CSF) prophylaxis is mainly based on the myelosuppressive potential of the chemotherapy regimen. The objective of this study is to validate a classification of aggressiveness of a chemotherapy regimen and to evaluate its usefulness in a risk prediction model of FN in patients with hematological cancer at the beginning of a chemotherapy cycle. Two hundred and sixty-six patients were prospectively enrolled and followed during 1053 cycles. Relevant patient informations were collected at the beginning of the first cycle and the number of days of FN were counted in the follow-up [dichotomized (no FN versus>= 1 day of FN)]. Aggressive chemotherapy regimen is the major predictor of FN [odds ratio 5.2 (3.2 - 8.4)]. The other independent predictors are the underlying disease, an involvement of bone marrow, body surface<= 2m², a baseline monocyte count <150/µl and the interaction between the first cycle in the same treatment line and a baseline hemoglobin dosage. A rule of prediction of FN was computed with these characteristics: sensitivity 78.6%, specificity 62.3%, positive predictive value 42.7% and negative predictive value 89.1%. Further studies are needed to validate this score.