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Introduction: Lymphomas are an important complication of HIV infection where they occur with high frequency and are a significant cause of morbidity and mortality.The most prevalent lymphoma subtype in HIV positive population is the diffuse large B cell lymphoma (DLCBL). Antiretroviral therapy (ART) and intensive chemotherapy have been introduced to these patients aiming to increase their response to treatment. Recently, dose adjusted-EPOCH (DA-EPOCH) was associated with better outcome when compared with CHOP. Since these publications, many centers in the world started treating HIV DLBCL patients with EPOCH. In Brazil, Rituximab is not allowed for the treatment of HIV lymphomas (any subtype) in the public health system, so HIV DLBCL patients usually are treated with CHOP or DA-EPOCH. Objective:To compare the progression free survival and overall survival in HIV DLBCL patients treated with CHOP and DA-EPOCH at Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, a university public hospital from the southern part of Brazil. Material and Methods:A retrospective cohort of all HIV positive patients and DLBCL, treated from 2007 to 2017 at HCPA. The medical records were reviewed to collect clinical data, reports on pathology, immunohistochemistry, computed tomography (TC) and/or FDG-PET scan from diagnosis and after treatment. Overall survival and progression free survival was determined by the Kaplan-Meier method, and statistical significance was determined by a log-rank test. The study was approved by the institutional review board and complied with the Declaration of Helsinki. All patients gave written informed consent. Results:Forty-three HIV positive patients with untreated DLBCL were enrolled. The median age was 44 years, and 93% had a intermediate or high age-adjusted international prognostic index (aa-IPI). Specific adverse prognostic features included elevated LDH in 84%, B symptoms in 82%, Ann Arbor stage III or IV in 70% and extra-nodal disease in 81%. Central nervous system involvement was found in 9% of patients before treatment. Patients had a median CD4 cell count of 113 cells/mm3 with 21% having a CD4 cell count less than 50 cells/mm3 and 16% of patients were ART naive. Until 2014, CHOP was the chosen treatment for 34 patients. After 2014, DA-EPOCH was the prefered chemotherapy for HIV DLBCL patients and 9 patients were treated with this protocol. The progression free survival at 24 months was 69% in the CHOP group and 83% in DA-EPOCH (p=0.68). Overall survival at same period was 34.5% for CHOP vs 37% for EPOCH (p=0.74). CHOP and DA-EPOCH treatment groups presented similar features regarding the lymphoma and HIV infection, except for higher LDH level and aa-IPI score in the CHOP arm (p=0.02 and p=0.03, respectively). Discussion:The acquired immunodeficiency syndrome-related to DLBCL in this subgroup of patients was associated with a very high-risk prognostic score group. Moreover, 21% of them presented a low count of CD4 cells (less than 50 cells/mm3) at diagnosis. The overall survival was lower than expected for both groups and DA-EPOCH was not associated with better outcome when compared to CHOP. This unexpected finding could be explained in part by the small sample of patients treated with DA-EPOCH, the population prognostic features and the unavailability of rituximab in the treatment of these patients. The follow up study will provide more informations about the impact of DA-EPOCH in our HIV patients. The access to rituximab in HIV DLBCL treatment should be an important point of discussion with public health care providers in Brazil. Disclosures No relevant conflicts of interest to declare.

Introduction: The advent of tyrosine kinase inhibitors has changed the natural history of chronic myelogenous leukemia (CML), promoting molecular remission in a high number of patients. In 40-60% of the patients that reach deep molecular responses (RM4.5 or more) and are using imatinib mesylate for 24 months or longer, a molecular response can be maintained after the cessation of the drug. Besides improving life quality in those patients, to withdraw the medication could have a great economic impact in the health system, what is extremely important in third world countries. Objective: To estimate the economic impact of stopping imatinib mesylate in CML chronic phase patients, receiving treatment for at least 36 months and presenting deep molecular response, determinate by BCR-ABL transcripts with quantitative reverse transcriptase polymerase chain reaction (QRT-PCR), in the last 24 months. Patients and methods: A single center observational retrospective study, including all patients diagnosed with chronic phase CML, confirmed by cytogenetic or molecular exams receiving treatment at a tertiary hospital in Brazil. All patients received imatinib mesylate either in first or second line therapy. Patients presenting deep molecular response for at least 24 months, under imatinib mesylate for 36 months or more were considered eligible for discontinuation the drug. The annual coast with the treatment was estimated considering the coasts of the medication and the QRT-PCR molecular exams in the Brazilian public health system. Results: In this study, 169 patients date were analyzed, the median follow up time is 5 years (range 1-13 years), 26 (15%) of those patients are eligible for stopping imatinib mesylate according to the criteria previously mentioned. Considering the requirement of QRT-PCR exams every month in the first year of discotinuating the drug, these patients would coast proximally 1.550,00 dollars/ patients year for the public health system. This coast could be reduced to 800,00 and 520 dollars/patients year, after the second and third year of the medication withdraw, when monitoring molecular response can be done every 2 and 3 months respectively. The patients receiving imatinib mesylate, and having QTR-PCR exams every six months, in the other hand, would coast the Brazilian public health system over 31.000, 00dollars /patients year. Stopping imatinib mesylate could reduce CML chronic phase treatment coasts in up to 95%. Discussion: Discontinuating imatinib mesylate is something that must be done only in clinical trial. The economic impact projection shown in this study observed the eligibility criteria described in the literature. If stopping imatinib mesylate proves to be a safe option, studies promoting it should be done in Brazil and other third world countries, as a manner of saving resources in the health system. Furthermore, the impact in life quality free of adverse effects and the possibility of gestation in young woman is not to be ignored. Disclosures No relevant conflicts of interest to declare.

Introduction: Imatinibe, a target tyrosine kinase inhibitor, have revolutionized CP-CML treatment. Considering that it is being discussed imatinibe treatment interruption in patients with MR ≥ 4.5 lasting two years or more, we believe to be important to establish predictors of major molecular response (MMR) loss. Fluctuations in BCR-ABL transcripts are being advocated to be able to predict MMR loss, although the real impact of small fluctuations among patients with in MR ≥ 4.5 is uncertain. Objective: Correlate BCR-ABL fluctuations and MMR loss in patients considered to be in MR ≥ 4.5, as well as to recognize possible factors associated with these small fluctuations. Methods: We conducted a retrospective analysis in CP-CML patients receiving imatinibe (as first or second treatment line) that achieved MR ≥ 4.5 (defined as a 4.5 log reduction on an international scale) and surveyed for BCR-ABL fluctuations. We considered a fluctuation to be a rise of at least 0.5 log of BCR-ABL transcripts. Treatment interruptions were considered only when imatinibe was not taken for 15 or more consecutive days. The presence of comorbities was evaluated by applying the Charlson Index. Results: Fifty-eight patients were evaluated between with a median follow-up 7 years. Fifty-five percent were men and 28 were women, with a median age of 46 (18 - 93) years-old, most of the patients were older than 60 yo (75,9%). Among 32 patients evaluated by the Sokal risk score 97,5% were estimated to be low or intermediate. Twenty six patients presented at least one fluctuation. Regarding the number of fluctuations per patient, 18 presented only 1 fluctuation, 5 presented 2 fluctuations and 3 patients presented 3 fluctuations. Among those patients with at least one fluctuation 3 (11%) presented MMR loss, while there was none among patients without documented fluctuations (p=0,15). Among these three patients considered to have MMR loss, two presented fluctuations that reached MR 3.0, while the other patient presented a history of long treatment suspension. More patients that interrupted treatment presented BCR-ABL fluctuations, although this difference was not statically significant (78% vs 50% p=0,11). Conclusion: Small fluctuations among patients with MR ≥ 4.5 didn't seem to correlate with MMR loss, however we do believe that our population is underpowered to rule out this difference. We considered that it very interesting that patients which reached MR 3.0 presented MMR loss (considering that the other patient had to abandon treatment during pregnancy). Disclosures No relevant conflicts of interest to declare.

Background Monitoring response to TKI therapy is one of the key management strategies of chronic myeloid leukemia (CML). Early molecular response to first-line TKI therapy is emerging as an effective prognostic factor indicator of long-term durable response and survival. Objectives We conducted a study to evaluate the importance of the early molecular response (EMR) at 3, 6 and 12 months (mo), and 3-year event free survival (EFS). Methods This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results We analyzed data from 517 pts with CML-CP diagnosed since 1990. After a median observation time of 46 months, 5-year overall survival (OS) was 86% and 5-year event-free-survival was 53%. At 3 mo, EFS was 72,5% for 46 pts with BCR-ABLIS ≤10% compared to 58% for 14 pts with BCR-ABLIS >10% (p1% (p0,1% (p Conclusions A significant proportion of pts achieve ERM after 3,6 and 12 mo of imatinib therapy with better 3-year EFS. ERM may could identify those pts more likely to have a favorable outcome. Disclosures No relevant conflicts of interest to declare.

Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment. OBJECTIVES The main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial. PATIENTS AND METHODS This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated in 14 hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (EFS) was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive. RESULTS Data from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information. CONCLUSION In our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.

Background Polycythemia vera (PV) is a subgroup of myeloproliferative neoplasm (MPN) BCL-ABL1 negative. The current therapy of PV should be aimed at preventing vascular complications and avoid increasing the risk of leukemic transformation. The therapy response monitoring is based in the European LeukemiaNet (ELN) unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera consensus process, published by Barbui T et al in Br J Haematol 2010;148(6):961-963. Objectives We conducted a study to assess in our clinical practice the aplicability of the standard criteria for resistance and intolerance proposed by ELN in patients (pts) with PV that have been treated with hydroxycarbamida (HU). Methods This is a retrospective study in a cohort of pts with PV enrolled in a single Hematology University center in South Brazil. All pts were treated according to PV guidelines, and the response monitoring was based on clinical practice. All database was compared to standard criteria proposed by ELN. Intolerance /resistance was defined by: a) need for phlebotomy to keep hematocrit < 45% after 3 months of at least 2 g/d of HU or b) uncontrolled myeloproliferation (ie, platelet count > 400 x109/L and white blood count (WBC) > 10 x109/L) after 3 months of at least 2g/d of HU or c) failure to reduce massive splenomegaly by 50% as measured by palpation or failure to completely relieve symptoms related to splenomegaly after 3 months of at least 2 g/d of HU or d) absolute neutrophil count < 1.0 x109/L or platelet count < 100 x109/L or hemoglobin < 10 g/dL at the lowest dose of HU required to achieve a complete or partial clinicohematologic response or e) presence of leg ulcers or other unacceptable HU related nonhematologic toxicities, such as mucocutaneous manifestations, GI symptoms, pneumonitis or fever at any dose of HU. Results We analyzed data from 33 patients with PV assisted in the last five years in our outpatient clinical data. The ELN criteria for resistance and intolerance were accessed in these patients. At diagnosis, 42,4% of pts were younger than 61yo, and 54,5 were male. Arterial hypertension, diabetes mellitus and dyslipidemia were identified on 21, 2 and 7 pts, respectively. Only one patient was tobacco smoker at diagnosis. Total of 5 pts showed WBC > 15 x109/L, and 7 pts showed platelets > 450 x109/L. Massive splenomegaly is a rare PV manifestation in our series, occurring in 2 pts. Five patients complained of symptoms related to PV as pruritus and vasomotor phenomena at diagnosis. Less than 5% of patients had been treated with 2 g of HU for more than 3 months. In daily practice, when the patient presented hematologic toxicity, the HU was decreased and, if the hematocrit was over 45%, an occasional phlebotomy was performed. In relation to platelets (less than 400 x 109/L) and leucocyte (less than 10 x109/L) counts, these targets were not used exclusively in the clinical practice to change treatment. The intolerance was easily discriminated in patients with leg ulcers and other non-hematological events. Conclusion These criteria were done based on an expertise consensus for international criteria standardization for clinical studies. Its application in a retrospective study, using clinical daily practice data is not adequate. The reason is that in the last years the main target to treat patients was the hematocrit above 45%, the exact number of platelets and leucocytes is still not a consensus to define resistance, so different counts had been used to guide treatment, we rarely used HU doses above 1500 mg/daily to treat our patients and massive splenomegaly was observed in very few patients. These criteria should be used most for prospective studies. Disclosures No relevant conflicts of interest to declare.

Although bone marrow (BM) and peripheral blood mobilized hematopoietic stem cells (PBSC) are widely used as graft sources in patients undergoing hematopoietic stem cell transplantation (HSCT), the graft of choice for each subset of patients remains to be determined. Several studies have, prospectively and retrospectively, addressed this question with inconsistent results. While the increased incidence of chronic graft versus host disease (cGVHD) in PBSC recipients has been unanimously found, data regarding disease free survival (DFS), overall survival (OS) and acute graft versus host disease (aGVHD) incidence have been controversial, mainly for patients with high risk disease. We retrospectively compared the clinical outcomes of 334 patients with acute leukemia and chronic myeloid malignancies receiving related BMT or PBSCT after myeloablative conditioning regimen, treated at seven transplantation centers in Brazil from 2008 to 2009. Median OS was 2.85 and 2.39 years (HR 1.19; 95% CI, 0.84 to 1.68, p=0.34), and DFS was 2.48 and 2.18 years for BM and PBSC recipients respectively (HR 1.07; 95% CI, 0.77 to 1.48, p=0.70). For patients with high risk disease, median OS was 2.1 and 1.72 years (HR 1.18; 95% CI, 0.73 to 1.91, p=0.50) and DFS was 0.46 and 0.58 years (HR 1.04; 95% CI, 0.66 to 1.64, p=0.86) for BMT and PBSCT respectively. Additionally, in agreement with previous reports, the cumulative incidence of chronic GVHD at three years was 53.7% and 79.8% (HR 1.93; 95% CI 1.38 to 2.69, p< 0.001) for BM and PBSC respectively (Figure 1). On the other hand, aGVHD incidence / severity, cumulative incidence of relapse and non relapse mortality (NRM) were not different between BM or PBSC recipients. The same being true when only patients with high risk disease were evaluated. Figure 1 Major outcomes after transplant according to bone marrow (dark line) and peripheral blood (gray line) as the graft sources. Overall survival for the whole cohort (panel A), high risk (panel B), cumulative incidences of: and standard risk (panel C) patients; disease free survival for the whole cohort (panel D), high risk (panel E) and standard risk (panel F) patients, and relapse (panel G), grades III-IV aGVHD (panel H) and cGVHD (panel I) for the whole cohort. The only outcome that was statistically different was the cumulative incidence of cGVHD – (item I) Figure 1. Major outcomes after transplant according to bone marrow (dark line) and peripheral blood (gray line) as the graft sources. Overall survival for the whole cohort (panel A), high risk (panel B), cumulative incidences of: and standard risk (panel C) patients; disease free survival for the whole cohort (panel D), high risk (panel E) and standard risk (panel F) patients, and relapse (panel G), grades III-IV aGVHD (panel H) and cGVHD (panel I) for the whole cohort. The only outcome that was statistically different was the cumulative incidence of cGVHD – (item I) In conclusion, in our cohort, there was no OS or DFS benefit for patients receiving PBSC when compared to BM recipients, even when only high risk patients were analyzed. Disclosures: No relevant conflicts of interest to declare.

Abstract 4394 Introduction and objectives: Studies with mesenchymal stem cells (MSCs) have shown its benefits in hematology, mainly for Graft-versus-host disease (Lancet 371:1579–86, 2008), with three unsettled matters: (1)MSCs expansion in medium supplemented with Fetal Calf Serum (FCS) and its risk of xenoreaction (Blood 89:776–9, 1997); (2)The optimal number of cells needed for therapy is not yet defined, but there is an empirical indication for 2×106células/Kg with the need to optimize expansion, number and time wise; and (3)the utilization of third party donors. This study was designed to determine the superiority or no-inferiority of the Platelet Lysates (PL) over FCS on the expansion of MSC, the optimal cell plating density and days between each pass, and to investigate if in our conditions total nucleated cells (TNC) obtained from the washouts of HSCT explants can expand to be used at clinical grade. Methods and Results: TNC were removed from the filters and bags used in the HSCT (Cytotherapy 11:403–13, 2009) and after the first passage were plated in different concentrations (2000/cm2, 3000/cm2, 4000/cm2, 5000/cm2, 6000/cm2 and 7000/cm2) with 10% FBS or 10% PL, and the number of days reach 80% of confluence was observe (Transfusion, 49:2680–5, 2009). Next, cultures with the same plating density were fed either with 10% PL or 10% FCS and were trypsinized after seven days and counted to analyze how much they have grown in that time period. And finally, cultures were allowed to growth up to Passage 3 (P3) to test the ability to obtain clinical grade number of cells. The proliferation of mesenchymal stem cells in the presence of PL and SFB was averaged 11.88 and 2.5 times, respectively, in a period of 7 days (p = 0.005). The highest concentration of plating cells using PL, took less time (6 days) to reach confluence as compared with the three lower (7.55 to 8.55 days) (p = 0.005), and at P3 with PL we obtained from 10×109 up to 10 × 1011 cells. Conclusion: This study suggests that the PL is the best choice as a supplement to expand MSC, and allow the proliferation of a sufficient number of MSC at P3 for clinical use obtained from the washouts of HSCT explants. Disclosures: No relevant conflicts of interest to declare.

Abstract 4423 Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patient, but in some patients (pts) controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of therapy. Objectives We conducted a study to evaluate the importance of the early complete cytogenetic response (CCyR) and the factors associated with its achievement. Methods This is a retrospective study in a cohort of pts with chronic-phase chronic myeloid leukemia (CP-CML) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results We analyzed data from 450 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 60% pts. The median of follow-up was 47 mo. With 6 months of imatinib therapy, 198 pts (44%) achieved CCyR. In this group, the four year cumulative incidence of events was 33 (17%) and the EFS was 75,5%. 252 (56%) were not in CCyR at 6 months of therapy. In this group, a greater proportion of cumulative of events was observed: 86 (34%), and the EFS was 62,3%. This difference was significant (P=0,03; Figure 1). In this group of pts, 63% achieved CCyR after 6 months any time during follow up and the median time for CCyR in these pts was 17 months. The chance of achieving major molecular response (MMR) during follow up was 79% for the pts with CCyR at 6 months compared to 53% for the group with no CCyR at 6 months (P Conclusions A great proportion of pts achieve CCyR after 6 months of imatinib therapy, nevertheless, the pts who achieve CCyR by 6 months of therapy have greater proportion of major molecular response and event-free survival. Imatinib therapy should be started as soon as possible and additional efforts must be taken to avoid nonadherence. Finally, special attention should be given to pts with comorbidities as their results tend to be worse. Disclosures: No relevant conflicts of interest to declare.

Abstract 4425 Adherence to imatinib therapy has proven to be a major determinant of treatment results, but the degree of impact and the determinants of nonadherence are still contradictory. There is no information regarding adherence to imatinib therapy in the Brazilian public health system. The aims of this study were to identify the characteristics related to treatment interruptions and nonadherence and to examine how these interruptions affect treatment responses and survival. Materials and Methods We conducted a retrospective study in a cohort of patients (pts) with CP-CML enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. Two levels of analysis were performed: all kinds of interruptions (nonadherence and toxicity) and only nonadherence ones. Information for nonadherence was taken from medical and pharmacy registers (pt self-report, missing scheduled appointments and pill counts). Results We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 70% pts. The median of follow-up was 47 mo. Treatment interruption was observed in 63/185 patients (34%) and was related to toxicities in 35/63 pts (55%) and to nonadherence in 28/63 pts (45%). The adherence rate was 85%. In a multivariate analysis, only late-onset imatinib treatment (Odds Ratio [OR]=36,05; p Conclusions In this cohort, a substantial proportion of pts failed to take imatinib properly, decreasing the chances of disease control. The late onset of imatinib therapy correlates with lower adherence, so front-line imatinib therapy should be started as soon as possible. Special attention should be given to pts with severe comorbidities, as they are more prone to suffer side effects or to lack adherence. Finally, pts who interrupted treatment had lower CCyR, MMR and EFS. Clinical and patient characteristics related to nonadherence Disclosures: No relevant conflicts of interest to declare.

Abstract 4291 Natural Killer (NK) cells have important and potent innate immunoregulatory and immune surveillance functions against tumor. The paradoxical coexistence of tumors and anti-tumor immune cells (“Hellstrom Paradox”) may in part be explained by the pathophysiology of the “hostile” tumor microenvironment which suppress immune-cell function, such as hypoxia, low pH, low tissue glucose, and the presence of immunosuppressive cytokines and metabolites. However, the effect of the malignant environment on the ability of NK cells to infiltrate tumor and exhibit effector function is largely unknown. Therefore, we investigated the ability of NK cells to operate under conditions of hypoxia. Importantly, NK cells showed a 1,000-fold reduction in proliferative capacity when grown under chronic hypoxia (4 weeks of 1% O2). In addition, there was a corresponding decrease in cytotoxicity as revealed by chromium release assay. This was in contrast to autologous T cells which could numerically expand under corresponding growth conditions. Expression profiling uncovers profound upregulation of hypoxia-inducible genes such as EGLN1(9.9x), EGLN3(52x), LDHA(11.5x), SLC2A1(30.5x), PDK1(16.8x), VEGFA(286x) and BNIP3(138x) in hypoxic NK cells. Protein expression confirmed these changes, as NK cells under normoxic culture produced 520 nmoles/million cells of ATP, while those under hypoxic culture managed only 100 nmoles/million cells. This is consistent with a bioenergetic switch from oxidative phosphorylation to glycosis resulting from PDK1 upregulation. NK cells in hypoxia produced 61 pg/mL of VEGF compared to 1480 pg/mL for NK cells in normoxia (20% O2), as determined by ELISA. The inability of NK cells to propagate under conditions of hypoxia may be due to a drop in mitochondrial content we observed when cells were exposed to chronic hypoxia, a potential mitophagic effects of BNIP3 upregulation. In addition to the poor proliferative capacity of NK cells under hypoxia, we also noted the loss of CD56 expression on hypoxic NK cells which is associated with loss of cytotoxicity. Sequence analysis reveals that miR-210 can bind to the 3′UTR of CD56 mRNA, targeting it for degradation. Therefore, we investigated whether miR-210 levels are upregulated in hypoxic NK cells and found that increased presence correlated with loss of CD56 expression. This leads to the conclusion that NK-cell immunotherapy may be improved by downregulating miR-210 levels. Indeed, our findings help shape strategies for obtaining robust and sustained NK-cell effector function for adoptive immunotherapy in the hypoxic tumor microenvironment. Disclosures: No relevant conflicts of interest to declare.

Abstract 4487 Background: Imatinib treatment for Chronic Myeloid Leukemia (CML) was first introduced in Brazil in 2001, initially used as second line therapy for patients resistant or intolerant to interferon (IFN). In 2008 imatinib was adopted as front-line therapy for chronic-phase (CP-CML) and clinical experience is improving since then, but little is known about the result of its introduction in our clinical practice. Aims: To evaluate the impact of imatinib treatment in the outcomes of a cohort of CP-CML and the prognostic significance of Sokal and Hasford scores and late-onset treatment. Methods: We conducted a retrospective study in a cohort of patients with CP-CML from a south Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the European LeukemiaNet. The outcomes were response to treatment, event-free survival (EFS) and overall survival (OS). Results: We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (4 – 85). The median time from diagnosis to imatinib was 7 months (0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with IFN was used in 70% pts. All pts had a minimum follow-up of 12 months. At baseline, 57 pts (31%) were in complete hematological response (CHR) due to the use of previous treatment. Of the 127 pts not in CHR at baseline, 98% achieved CHR early during imatinib treatment. 177 pts had cytogenetic evaluation during treatment and 9 pts were in complete cytogenetic response (CCyR) due to the use of previous IFN. Of the 168 pts not in CCyR at baseline, 86,4% achieved a major cytogenetic response (MCyR) during imatinib treatment (84% had a CCyR and 2,4% had a partial cytogenetic response). The rate of pts achieving MCyR any point during treatment differed significantly in the low, intermediate and high risk Sokal score groups (97%, 81% and 78% respectively, P=0,04), but not in the Hasford score groups (90%, 85% and 72%, P=0,22). Minor cytogenetic response was seen in 3,6% of pts, minimal cytogenetic response in 6% and 9,5% had no cytogenetic response. The median time to a MCyR was 9 months, with 62% of pts achieving MCyR at 12 months. The rate of pts achieving MCyR in 12 months differed significantly between pts who start imatinib before 12 months from diagnosis (68%) and those late treated (47%, P=0,02). Evaluation of minimal residual disease at the molecular level was available for 155 pts: 25,5% of pts had a complete molecular response (CMR), 43% had a major molecular response (MMR) and 2 pts were in MMR at baseline due to previous IFN. The projected EFS and OS rates at 4 years were, respectively, 68% and 92% after a median follow-up time of 4 years. The rate of EFS differed significantly in the low, intermediate and high risk Sokal score groups (80%, 66% and 52% respectively, P=0,04), but not in the Hasford score groups (78%, 62% and 44%, P=0,09). During treatment with imatinib, 120 pts (65%) had a register of any grade hematologic adverse event (21% being grades 3 or 4) and 165 pts (90%) had a register of any grade nonhematologic adverse event (9,3% being grades 3 or 4). Of the 185 pts who received treatment, 134 (72%) continue to receive imatinib and 51 (28%) discontinued treatment. The reasons for discontinuation were: 11 (6%) pts had drug-related adverse events (3 [1,6%] hematologic and 8 [4,3%] nonhematologic), 17 (9,2%) had disease progression (5 [2,7%] loss of CHR, 10 [5,4%] loss of CCyR, 2 [1%] had progression to accelerate or blastic phase), 22 (11,9%) had treatment failure (3 [1,6%] had no CHR, 13 [7%] had no CCyR and 6 [3,2%] had no MMR), 1 pt (0,5%) discontinued due to comorbidity. For the 51 (100%) pts that discontinued imatinib, 31 (61%) switched to dasatinib, 17 (33%) to nilotinib, 1 (2%) to hydroxyurea, 1 (2%) to other treatment and 1 (2%) remained without treatment. Sixteen pts (8,6%) died during imatinib treatment or during long-term follow-up after discontinuation of imatinib. Conclusions: In our population of CP-CML pts treated with imatinib, a majority of patients achieved complete cytogenetic and major molecular responses, with a prolonged of OS and EFS and good safety profile. Sokal score showed better prognosis prediction than Hasford. Early onset of imatinib therapy led to better outcomes and justifies imatinib as front-line treatment of our patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 2300 Introduction: Imatinib mesylate (Gleevec) treatment for Chronic Myelogenous Leukemia (CML) was first introduced in Brazil in 2003, initially used as second line therapy for patients resistant or intolerant to interferon. In 2004 imatinib was adopted as front-line therapy for chronic phase (CP) and clinical experience improving since then. Close monitoring of responses achievement at scheduled time has proven to provide good predictive value for progression and event-free survival. Failure and sub-optimal responses correspond to indications for dose change or therapy switching and the identification of patients at greater risk for such events has a vital role. The aim of this study is to evaluate the impact of temporary imatinib therapy discontinuation on achievement of Major Cytogenetic Response (MCyR) and event-free survival (EFS). Materials and Methods: During the period of 1990 to 2010 a total of 185 patients from 7 CML treatment centers from Rio Grande do Sul, south Brazil, with a confirmed diagnosis of CML (Philadelphia chromosome positive [Ph+]) at CP under imatinib treatment were retrospectively analyzed. A major cytogenetic response was considered complete plus partial cytogenetic responses (Ph+ less than 35%). At least 20 metaphases were analyzed for a cytogenetic response to be evaluable. Temporary treatment discontinuation (TTD) corresponds to 20 days or more off-medication for any reason during the follow-up. Were included patients in imatinib second-line and first-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months from diagnosis and late-imatinib treatment when more then 12 months lapse. EFS was measured from the start of imatinib to the date of any the following events while on therapy: death of any cause, therapy failure, any response loss, disease progression, definitive treatment discontinuation or therapy change. Descriptive statistics and Kaplan-Meier analysis (to estimate event-free survival [EFS]) were performed using SPSS software. Results: The median age at diagnosis was 48 years (range, 4–85 years) median of follow-up was 47 months (range, 7–113 months) and 55% of male sex. Preferential previous treatment was interferon in 70% of the patients and 71% were early-imatinib treatment. TTD was observed in 63/185 patients (34%) and was related to toxicities in 35/63 patients (55%), including hematological and non-hematological. Nonadherence was attributed to the remaining TTD, 28/63 patients (44%). Late-imatinib patients had significant more TTD (62%) than early-imatinib patients (26,2% [p Conclusion: In our cohort, patients with TTD were associated with lower rate of MCyR and it may be a risk factor for failure or sub-optimal responses to imatinib therapy. TTD also has a negative effect in terms of EFS in patients under imatinib treatment, possibly related to worsen cytogenetic disease control. The late onset of imatinib therapy correlates with more toxicity leading to treatment interruptions and front-line imatinib therapy should be started as soon as possible. Special attention should be given to patients who presents with side effects of any nature that could preclude the correct use of the medication. Close monitoring and early management of such adverse reactions, frequent assessment of compliance should be warrant as effort to guarantee the best chance for therapy success. Disclosures: No relevant conflicts of interest to declare.

Abstract 4557 INTRODUCTION: Advanced low grade non-Hodgkin Lymphomas have many and varied treatment options. For patients with relapsed or refractory disease, outcome following only chemotherapy protocols remains poor. The standard Conditioning Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) might be an alternative for relapsed low grade non-Hodgkin lymphomas, but its high Transplant Related Mortality (TRM), varying from 24% to 54%, accounts for a lower overall survival in this group. Reduced Intensity Conditioning (RIC) HSCT has been shown to be a good alternative to myeloablative regimens, with lower TRM, Graft versus Lymphoma Effect, and appears to be associated with improved outcome, presenting a 3 years disease free survival and overall survival from 32% to 66% and from 32% to 73%, respectively, depending on factors such as disease stage before transplantation. PATIENTS, METHODS AND RESULTS: Sixteen heavily pretreated patients with low grade non-Hodgkin Lymphoma (NHL) were submitted to RIC HSCT with matched related donors at the Bone Marrow Transplantation Unit at HCPA between the period of September 2002 to October 2009. The mean age was 43 years and were 7 patients male and 9 female. Fifty percent (8) of the patients had refractory disease pre-HSCT, 43.8% (7) were at third complete remission (CR) and 6.2% (1) at second CR. Median of CD34/kg infused was 10.7 × 106 and the median of days for engraftment was 14.53. Conditioning regimens were Fludarabine + Cyclophosphamide in 3 patients, Fludarabine + Melphalan in 7, Fludarabine + Cyclophosphamide + Rituximab in 2, Fludarabine + Cyclophosphamide + Melphalan in 1, Cyclophosphamide + Total Body Irradiation (TBI) in 1 and Fludarabine + Cyclophosphamide + TBI in 2. Acute Graft versus Host Disease (aGVHD) occurred in 50%, with 37.5% of those were steroids resistant; and 62.5% of the patients evolved to chronic GVHD, with 80% of them classified as extensive. Chimerism from 9 patients was analyzed, and 89% of them were complete. Mean overall survival was 2.95 years; 62.5% of patients were alive within 1 year and 40% within 3 years. TRM was 6.66%. Eight patients died, five of them were transplanted with refractory disease. Only 2 patients died of relapse, 5 of infections and 1 of aGVHD. CONCLUSION: Low grade NHL patients treated at HCPA with RIC HSCT had an overall survival and TRM comparable to the observed at other centers, appearing as a good alternative for this heavily treated group of patients with less toxicity than myeloablative regimens. Disclosures: No relevant conflicts of interest to declare.

PURPOSE: To compare pediatric and adult therapeutic practices in the treatment of acute lymphoblastic leukemia (ALL) in adolescents. PATIENTS AND METHODS: From January 1997 to December 2007, 34 and 11 adolescents (10 to 20 years of age) were treated according to German pediatric BFM 90 and 95 and adult BFM 84 protocols, respectively. Age, B/T lineage, WBC count, complete remission, cytogenetics, and response to steroids were analyzed. Age, B/T lineage and WBC count were similar. Poor risk-cytogenetics (t (9;22),t(4;11) and hypodiploidy less than 45 chromosomes were present only in BFM 90 and 95 group. Among the different prognostic factors, we retrospectively analyzed the effect of the trial on achieving overall survival (OS) and event-free survival (EFS). RESULTS: OS in 10 years and EFS was, respectively, 68.6% and 68.7% for the pediatric protocol and 31.4% and 21.6% for the adult protocol. CONCLUSION: This study’s findings were similar to others in USA, UK, France, Italy and Holland that clearly demonstrate that current pediatric regimens are more effective for adolescents and may contribute to indicate that adolescents should be included in intensive pediatric protocols. Keywords: leukemia, survival, adolescent.

CML is a well characterized disease with a known chromosomal abnormality. The inhibition of BCR-ABL protein tyrose kinase activity represented an advance in the treatment of this disease. Imatinib is effective in chronic, accelerated and blastic phase disease, and is the CML first line treatment around the world. In Brazil, this drug is provided by the State since 2003. The drug is available for second line treatment in chronic phase and for accelerated and blastic phase as the first line therapy. In chronic phase, the patients are treated first with interferon. If this treatment is too toxic or not effective, the choice therapy is imatinib 400 mg and the dose can be escalated up 600 mg. In accelerated and blastic phases the treatment is imatinib 600 mg. Mutational studies are not routinely performed and the failing patients are encourage to participate in bone marrow transplantation programs or clinical research centers. The present data are obtained from public health hospital database and included 400 CML Ph+ patients from Rio Grande do Sul, south of Brazil. 232 patients are male and 158 female and around 70% were Caucasian. The median age at diagnosis was 46, 79 y (median 49, 28). The mean laboratory values at diagnosis were: hematocrit 33 (median 34, 8), hemoglobin 11, 08 (median 11, 40), white blood cells 158.594 (median 110.000) and platelets 466.000 (median 380.000). From the 400 patients, 300 pts were diagnosed in chronic phase, 52 pts in accelerated phase and 20 pts in blastic phase. In 28 patients the disease phase was unknown. In the majority of patients Imatinib was started because interferon treatment was not tolerated (121 patients) or ineffective (123 patients). Of these patients 285 were in chronic, 59 pts in accelerated and 17 pts in blastic phases. The cytogenetic response evaluated at 12 months of treatment was available in 231 patients: 164 complete responses, 20 major responses, 15 minor responses and 32 patients demonstrated none or minimal response to therapy. In 169 patients the response is unknown. The progression free survival for the chronic phase patients in 80 months of observation is 90% and the event free survival for the entire group is 60% in the same period. The progression from chronic to accelerated or blastic phase was more common in the first year of imatinib treatment and decreased progressively until the fifth year of therapy. This data demonstrate the epidemiologic profile and the treatment results of CML patients in south of Brazil. Imatinib is available in public health system as a second line treatment and the survival rate is quite good. Since last July this drug has been available as first line treatment, even in chronic phase. A longer follow up and a uniform database registry are needed to study the impact of imatinib treatment in this population.

We ran a study on the prevalence of anemia in the state of Rio Grande do Sul (RS), southern Brazil. RS is in a sub-tropical Latin American area, near Uruguay and Argentina. There is no Malaria, a low prevalence of hemoglobinopaties, and HIV/AIDS. METHODS: Capillary blood of children less then 7 and women from 14 to 30 years of age were tested. Socioeconomic status was determined utilizing the classification designed by the Brazilian Association of Market Research Agencies for this purpose. A second sample of 1 year old children was submitted to total blood cell count and serum ferritin determination, and in a third group of individuals, total blood count was done along with stool parasitic analysis. RESULTS: A total of 2198 children and 1999 women with capillary blood measured were analyzed. The median prevalence of anemia in the whole state and the median hemoglobin concentration was 45, 4% and 9.90g/dl for children, and 36.1% and 11 g/dl for women, respectively. Of the aforementioned group, before two years of age, 76% were anemic, and anemia prevalence decreased with age, suggesting a nutrition deficiency. There were very few cases of severe anemia. A significant percentage of children and women belong to the middle class, with access to food and medical care. Of the 356 children tested at one year of age, 67% were anemic and of these, 90% had ferritin < 15μg/L. In the third group of individuals, 31% of 424 children less then 6 years of age were anemic and of these, only 13% tested positive for parasitic infection. CONCLUSION: The prevalence of iron deficiency anemia is very high and constitutes a severe public health problem for 1 year old children in RS, and probably for those younger then 7, and for fertile women as well, irrespectively of their socioeconomic level. Micronutrients supplementation has being neglected in RS health system. The definition of anemia plays a central role in this and has to be addressed if we want to overcome the biologic factors involved in childhood psychosocial development in Brazil.

Imatinib has profoundly change indication of allogeneic bone marrow transplantation (alloBMT) worldwide for CML and is now the first line of treatment in most countries. However, in Brazil, Imatinib for CML in first chronic phase is provided by Federal Health Agency only for patients refractory/intolerant to interferon (IFN). In order to study results of treatment with imatinib and alloBMT in this particular scenario we retrospectively analyzed 266 patients treated for CML in first chronic phase (less than 60 years-old) in three different institutions in Brazil. End points were event free survival (EFS = absence of hematological response, lost of hematological/cytogenetic response, relapse in accelerated phase/blast crisis or death) and overall survival (OS). From jan/2001 to dec/2006, 176 patients received imatinib 400 mg after failure or intolerance to IFN. Median time from diagnosis to imatinib treatment was 19 months (range: 2 to 205). At the same period of time, 90 patients received an allo-BMT from an HLA-matched sibling (n=83) or an unrelated donor (n=7). Patients receiving peripheral blood stem cell or umbilical cord blood were excluded. Eighty-two patients received busulfan+cyclophsphamide as conditioning regimen and all patients received cyclosporin+methotrexate±steroids as GVHD prophylaxis. Median time from diagnosis to allo-BMT was 16 (range: 5 to 104) months. Gender distribution was similar between groups. Imatinib group had a higher median age (40.7 vs. 32.8 years, P

Background: Imatinib mesylate (Glivec,Novartis), an inhibitor of Bcr-abl tyrosine kinase, is currently being used in the treatment of CML with hematological, cytogenetic and molecular response. In Brazil, this drug is approved by Health Department for chronic phase (CP) as a second line drug and as first line for accelerated (AP) and blastic phase (BP). Rio Grande do Sul (RS) Cooperative Group for Treatment of CML coordinates the treatment of this disease in Rio Grande do Sul, the southern most state of Brazil that differs from the north part of the country regarding climate, population profile (mostly European descendents) and a high number of farm workers. Methods: 211 CML Ph+ patients are presently being treated in RS. Sex distribution: 96 male and 115 females, aged 11–80 years (median 48 y);166/211 in CP, 42/211 in AP and 11/211 in BP. Imatinib daily dose is 400 mg (CP) and 600 mg (AP and BP). 166/211 patients are in treatment with imatinib and 32/211, interferon or hydroxyureia. In imatinib group, 144/166 patients are in complete hematologic response and 57/166 in complete cytogenetic remission. Conclusions: in Brazil, imatinib treatment is limited by economic problems and the drug is used latter in course of disease. This may compromise the results, as seen in the low cytogenetic complete response described above. We are now investigating this results in order tofind other related factors.

Hydroxyurea (HU) is an antineoplastic drug, which also plays an important role in treatment of sickle cell disease patients (SCD). Short-term HU toxicities primarily include transient myelosuppression, but long-term HU risks have not been defined. The mutagenic and carcinogenic potential of HU is not established, although HU has been associated with an increased risk of leukemia in some patients with myeloproliferative disorders. In the present study we analyzed the presence of DNA damage in patients with SCD treated with HU, in peripheral blood lymphocytes, using micronucleus assay. We analyzed 36 patients with SCD (16 males and 20 females), aged 2–59 years (mean 25,75 ± 14,5), received oral HU median dose of 26,5 mg/Kg/day, for a period of 0.6– 11,8 years (mean 5,01). The control group was composed of 34 healthy individuals (16 males and 18 females), aged 4–52 years (mean 26,61 ± 7,20). The results revealed that frequency of micronucleus was significantly higher in SCD patients using HU than in controls(p=0,0182). This study indicates a possible genotoxicity of the HU, although further works are necessary to evaluate its mutagenicity.

CFSA, an 18-year-old woman with a history of weight loss and abdominal discomfort was diagnosed with chronic myelogenous leukemia (CML) in December 2002. The WBC were 440 x 109 /L with 25% neutrophils, 20% bands, 9% metamyelocytes, 9% myelocytes, 8% promyelocytes, 10% basophils, 9% eosinophils, 1% lymphocytes and 8% blasts. The hemoglobin was 9,8 g/dL and platelet count 416 x 109/ L. A bone marrow examination demonstrated granulocytic hyperplasia and the presence of Philadelphia chromosome in 100% of the metaphasis. A diagnosis of CML was made and she was started on hydroxyurea and imatinib 600mg daily. No matched HLA donor was found. There was a partial hematological response. In February 2005 on imatinib (600 mg) she was pregnant and an ultrasound scan showed a viable fetus of 17 weeks. The WBC were 22 x 109 /L with 50% neutrophils, 23% bands, 8% metamyelocytes, 12% myelocytes, 1% promyelocytes, 5% lymphocytes, hemoglobin 11,4 g/dl and platelet count 290 x 109. Imatinib was stopped and she remained off treatment during pregnancy. Cesarean section was performed at 38th week because of preeclampsia (hypertension, headache and scotomas). A healthy girl weighing 2980 g, 46,5 cm in length with Apgar score of 9 was delivered. The infant’s physical examination, WBC, hemoglobin, platelet count and cranial ultrasonography were normal. The baby is presently healthy with no developmental abnormalities. There are few reports on the use of 600 mg a day of imatinib and pregnancy. It is of notice, although probably unrelated, the event of preeclampsia. The effects of imatinib on fetus are unkown and should be considered teratogenic until more studies or cases are reported.

Background: Patients with a primary central nervous system (CNS) lymphoma are very difficult to be treated. Regarding elderly patients, the side effects of the established strategies are considerable, particularly those caused by radiotherapy. Although with poor long term results, surgery, high dose chemotherapy and focal radiotherapy have been advised for these patients. Thus, new therapeutics strategies are needed. We report two cases of primary CNS B-cell lymphomas treated with rituximab intrathecally (ith). Case 1: In September 2003, a 59-year-old female with headache, paresthesia and weakness of the right limbs presented at our clinic. In August 2003 a brain biopsy of a parenchymal lesion was performed, vasculitis and cerebritis were found. The patient’s condition progressively worsened during the next 3 months and she developed a right-side hemiparesis. A PCR test to ascertain the presence of Mycobacterim tuberculosis in brain tissue was positive and rifampicin was prescribed. The patient presented at our clinic in September 2003, and in December 2003 she underwent another brain biopsy and CD20+ diffuse large B-cell lymphoma was diagnosed. Chemotherapy with high-dose methotrexate (MTX) 3.5 g/m2 iv, MTX 12 mg ith and vincristine 1.4 mg/m2 was scheduled every 15 days for a total of 5 cycles. The patient experienced a partial remission. In February 2004, rituximab 25 mg ith was administered on days 1–2 and days 8–9. There was no toxicity during, or after the rituximab infusions. In March, after a total dose of 200 mg, there was a complete radiological remission of the lymphoma and a consistent clinical improvement. In June 2004, the lymphoma relapsed, affecting the same area of the brain and in July 2004 a re-treatment protocol consisting of MTX 8g/m2 and high dose cytarabine was started, without response. The patient died of sepsis, secondary to mucositis and pancytopenia in August 2004. Case 2: a 67-year-old male with a primary malignant B lymphoma CD20+ of the posterior fossa which relapsed after two surgeries, high dose chemotherapy and focal radiotherapy with lymphomatous meningitis. Complete remission was obtained after one course of high dose MTX (4g/m2) and intrathecal MTX, intercalated with three courses of systemic (350 mg/m2) and intrathecal rituximab (25mg/d - 8 days). The patient presented hepatotoxicity after the first dose of MTX iv. The relapse free survival is seven months until now and the patient is physically and intellectually fully recovered. No major side effects were observed with the administration of rituximab intrathecally. Conclusion: Intrathecal administration of rituximab had no toxicity and was well-tolerated. Further studies are necessary to establish the best dose and schedule to achieve an improvement in the therapeutic response.

In the last two decades, we have seen a radical change in the therapy and prognosis of Multiple Myeloma (MM). Recent research on the role of the bone marrow microenvironment as integrant part of the biology of MM and the possible therapeutic interference at this level are leading to control and regression of the malignant plasma cell clone with a recognized clinical impact. Thalidomide, an old drug thought to interfere on the bone marrow microenvironment, is active not only for the treatment of refractory patients but also, as was recently shown, for induction and/or remission maintenance therapy. Most of the side effects (somnolence, constipation, fatigue, tremor, bradycardia, edema, and neuropathy) can be managed by reducing the dose and most patients need a dose reduction. The appropriate dose of thalidomide in myeloma is unknown. We treated thirty-five patients with MM with low-dose thalidomide (200mg or less). Twenty four patients were on maintenance therapy (13 after bone marrow transplantation, and 11 after chemotherapy with VCAP/VMCP); 5 patients were treated after relapse, 4 with refractory disease and 2 for remission induction as a first line therapy. Patients were treated at the Hematology and Bone Marrow Transplantation Service of the Hospital de Clínicas de Porto Alegre, RS, Brazil, from march/2001 to December/2003. The response as measured by hemoglobin level, immunoglobulin (M component) or urinary light chain concentration and bone marrow examination was evaluated before, 3, 6, and 12 months after the beginning of thalidomide. Results: All patients are alive and well. Fifty one percent are on 100mg schedule; of the patients on maintenance therapy 90% are on complete remission or on a sustained plateau. A Wilcoxon ranks test for the immunoglobulin level before and after 6 months for the entire group showed p=0.001 (25–75%). Conclusion: Low dose thalidomide is tolerable and effective.

We report the case of a 12 year old girl admitted to the hospital in August 2004 presenting acute hepatic failure with grade IV encephalopathy without stigmatic of chronic liver disease. Investigation for A, B and C hepatitis was negative as well as the tests for HIV, Toxoplasmosis, EBV, B19 parvovirus and CMV. Diagnosed as fulminant hepatitis she received an ortotopic hepatic transplant 25 days after admission. She had an excellent clinical recovery on tracolimus for immunossupression, except for an asymptomatic pancytopenia unresponsive to drug dose reduction, which progressed to severe bone marrow aplasia in a four months period. A second round of virus screening tests was still negative. She was then submitted to bone marrow transplantation from her twin identical sister utilizing 50mg/kg/day of cyclophosphamide for two days as conditioning regimen. She received 6.6 x 106 CD34+ cells/kg and engrafted at D+22. She was discharged at D+ 33 on tracolimus without any sign of liver or bone marrow rejection. She is presently in complete clinical recovery after 7 months of BMT. This is, from our knowledge, the first report of a successful hepatic transplant followed by an equally successful syngeneic bone marrow transplant.

Purpose: Imatinib Mesilate is currently considered the most advanced therapy for CML due to its innovative molecular targeting mechanism of action, resulting in a high level of efficacy with a favorable toxicity profile which results in health-related quality of life (HRQL) benefits. We therefore decided to evaluate 230 patients with chronic myeloid leukemia (CML) treated with Imatinib Mesilate (Gleevec) as second line therapy, along 12 months, after failing Interferon (IFN) based therapy, due to lack of efficacy or toxicity, in an a Quality of Life (QoL) Study in Brazil, here presented as an interim analysis. Patients and Methods: From July 2002 until December 2003, 230 Patients from 21 Brazilian Medical Institutions, were enrolled in a Quality of Life (QoL) Study, where patients completed FACT-BRM questionnaire at baseline and during treatment. FACT-BRM includes 4 subscales appropriate for any chronic illness or treatment [physical (PWB), social/family (SFWB), emotional (EWB), functional (FWB)] and 2 treatment-specific subscales [BRM-physical (BRMP). The primary endpoint was the composite Trial Outcomes Index (TOI=PWB + FWB +BRMP + BRMCE). The questionnaire was applied at baseline (visit 0),monthly thereafter during the first 6 months on imatinib therapy (visits 1 through 7) and finally after 12 months on treatment (visit 8). Study population was distributed as following: gender 55,9% male and 44,1% female, mean age 46 years (range 18 to 76), Karnofsky status 100% in 56.7% and 80–90% in 29.9%. Initial Imatinib Mesilate dose was 400mg for 81,3% and 600mg for 18,7%. All patients were evaluated at baseline and at visits 7 (six months) and 8 (12 months) 147 (63.9%) and 45 (19.5%) patients were evaluated, respectively. Results: An increase of 5 or more from baseline was defined as a clinically relevant improvement 6. Patients had clinically relevant mean estimated improvement in TOI along treatment. After 1 treatment month TOI had an estimated mean increase of 5.4 (p Conclusion: Imatinib offers remarkable QoL improvement even as a second line treatment in CML as reported previously on IRIS Study, where patients were allowed to cross over to the Imatinib treatment arm, after receiving Interferon based therapy.

This is a retrospective analysis of 1084 patients who received an allogeneic HSCT in 10 Brazilian Centers, from February 1983 to March 2003, aiming to validate the EBMT risk score. Data from transplanted patients and donors regarding patients age, disease stage at transplantation, HLA full-match sibling donor or full-match unrelated donors, donor-recipient gender match and the interval from diagnosis to transplantation, were used as variables to calculate the EBMT risk score. This score was analyzed using Cox Proportional Hazards Model. The OS, DFS, TRM and relapse were analyzed using Kaplan-Meier and cumulative incidence, whenever appropriate. In all there were 647 (60%) males and 437 (40%) females, the median age was 32 years old (range 1 – 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1025 (95%) received HLA full-match sibling transplant and only 59 (5%) received an unrelated transplant. Female donor to male recipient occurred in 283 (26%) transplants. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The OS, DFS, TRM and, relapse were 49%, 50%, 45%, 25%, respectively. The risk score 0–1 occurred in 179 (17%), score 2 in 397 (37%), score 3 in 345 (32%), score 4 in 135 (12%), and score 5–6 in 28 (2%). The risk scores 0–1 and 2 did not show any difference in terms of OS (58% and 55%, respectively) but they were significantly better than scores 3 or more (score 3 – 44%, 4 – 36 % and, 5-6 - 27%, respectively) (P

Uncertainty still exists with the effects of allogeneic PBSCT on the clinical outcomes of patients with hematological malignancies. Our aim was analyzed retrospectively the clinical outcomes of 483 patients who underwent an allo PBSCT in 9 Brazilians centers from May 1994 to February 2004. The analyzes included patients with hematological malignancies who underwent PBSCT from HLA identical siblings donors treated with G-CSF at a dose of 10mgr/kg/day, 5 days. Median age was 34ys old (2–57), advanced disease was present in 58%, conditioning without irradiation was 85%; GVHD prophylaxis with MTX/CsA was 91%; CD34+ median was 4.7X106/kg (0.51–71.6); the median follow-up for surviving patients was 797 days (8–3420); median day for neutrophils and platelets engraftment was 15 and 14, respectively; cumulative incidence (CI) for ³ 2 aGVHD was 38%; extensive cGVHD 63%; CI for transplant relate mortality (TRM) 59%; CI for relapse 37%; the estimates of OS and DFS at 9 ys are 33% and 42, respectively. The following factors were significantly associated with better outcomes for engraftment, aGVHD, cGVHD, OS, DFS, relapse, and TRM in univariate analyzes, respectively: neutrophils and platelets engraftment: CD34+ cell dose > 2.8X106/kg, GVHD prophylaxis other than MTX/CsA, and sex match other than female donor for male recipient; aGVHD: age 4.7X106/kg; cGVHD: age < 25ys, sex match other than female donor for male recipient, advanced disease and CD3+ dose < 170X106/kg; OS: early disease; DFS: early disease, CD34+ dose > 4.7X106/kg; relapse: age> 25ys, CD34+ cell dose > 2.8X106/kg, and early disease; TRM: early disease. All the results remained significant in multivariate analyzes, but CD34+ dose and platelet engraftment; age and CD34+ dose in aGVHD; age and CD3+ in cGVHD, and age in relapse. In our experience, sex match, CD34+ dose, GVHD prophylaxis may influence the engrafment, and sex match and disease phase the cGVHD. Furthermore, advanced disease had a negative impact on OS and TRM;. CD34+ higher dose and early disease were associated with better DFS and lower relapse.