ALBERT

Description: Introduction: patients with hematologic malignancies (HM) admitted in intensive care units (ICU) have been traditionally seen as patients with very poor prognostic. Recently reports have informed that mortality has dropped and nowadays is in the order of 40-60 %, this is still high but closer to mortality in non-malignant patients admitted in an ICU. In an attempt to change this view we perform a study in order to evaluate the results and prognostic factors that contribute to mortality in HM patients who need critical care assistance. Methods: a retrospective study in 62 patients with HM who were admitted in ICU in the University Hospital, Hospital de Clinicas from Uruguay from 2003 to 2012. These 62 patients had 82 admissions, which are the population of our trial. Statistical analysis: Values are expressed as mean +/- standard deviation (SD), median and percentages. Comparison variable most used: discharge of ICU: dead or alive. Both groups were compared using Student's t test and Chi square. Multivariate logistic regression analysis was performed. Overall survival with Kaplan Meier. Significance p

Description: Abstract 4520 Between June 1995 and June 2011, we performed 133 Autologous Stem Cell Transplantation (ASCT) in patients with NHL. Long term results of treatment and outcome were analyzed. The data presented were obtained from the Statistical Center of the Center for International Blood and Marrow Transplant Research. Median age was 48 years (range 18–65), 9% ≥ 60 years, 77 males and 55 females. The histology was: 98 (74%) B NHL, Follicular Lymphoma (FL) 26 (20%), Diffuse large B Cell Lymphoma (DLBCL) 47 (35%), Primary Mediastinal Large B Cell Lymphoma 12 (9%), Mantle cell Lymphoma (MCL) 6(4.5%), Marginal Zone Lymphoma 4 (3%), Small Lymphoplasmocytic 2 (1.5%), precursor B Lymphoplasmoblastic 1 (1%), and 35 (26%) T NHL, Peripheral T Cell Lymphomas NOS 12 (9 %), Anaplastic LC, T/N Cell systemic 9 (6.5%), Anaplastic LC, T/N Cell cutaneous 1(1%) and T/NK Cell Lymphoma 7 (5%), Angioinmunoblastic T Cell Lymphoma 2 (1.5%), Mycosis Fungoides 2 (1.5%), other T Lymphoma 2 (1.5%). We emphasize that 59 % of the patients had advanced disease at the moment of the transplant: 41% CR1, 11% CR2, 5% REL1, 8% primary induction failure, other 33% (CR3+, PR, and REL2+), and 2% missing/unknown. Condition regimens were BEAC 88%, BEAM 10% and CBV 2%. Stem cells source: 74% peripheral blood stem cells (PBSC) and 26% received bone marrow (BM) and PBSC. Overall survival was 86% (95 CI, 80–92) at 1 year, 78% (95 CI, 70–85) at 3 years and 71% (95 CI, 62–79) at 5 years. Median follow up of survivors was 96 months (3–181). Primary cause of death was relapsed or progression. We concluded that high dose therapy and Autologous Stem Cell Transplantation is an effective and feasible therapy for patients with high risk NHL. However relapse continues to be the most common cause of treatment failure. Newer strategies such monoclonal antibodody, require further investigation but early reports appear promising in reducing relapses in ASCT. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Febrile neutropenia (FN) is among the leading causes of mortality and morbidity in hemato-oncologic patients undergoing cytotoxic chemotherapy. The management of FN is typically algorithm-driven. The effectiveness in reducing FN related mortality of the antibacterial protocol proposed by the international guidelines is already reported. In this regard, most of the popular guidelines are based on clinical trials conducted in developed countries. Little is known about results in developing countries where patients delay consultation and have socio-cultural vulnerabilities. The aim of our study was to assess the results of the implementation of a local FN protocol in patients undergoing intensive chemotherapy regimens at Hospital de Clinicas in Uruguay. Methods: We assessed a retrospective study with patients that have undergone intensive chemotherapy in our hemato-oncology service between 2011 and 2014. We included 127 neutropenia episodes (37 patients), with a median age of 37 years (18-79 years). Acute myeloid leukemia 26 (24.4%), acute lymphoblastic leukemia 12 (9.4%), non-Hodgkin lymphoma 74 (58.4%) and Hodgkin Lymphoma 15 (11.8%). Low risk patients were excluded. Additionally, episodes linked with high risk regimens as acute myeloid leukemia induction chemotherapy and alemtuzumab therapy were excluded from the analysis. The initial antibiotic protocol consisted in piperacillin-tazobactam (4.5 gr every 6 hours). For patients with warning signs, more than one week of hospital stay, or having received in the last 30 days ciprofloxacin or 3er generation cephalosporin as prophylaxis meropenem (1gr every 8 hours) was indicated. Prophylactic antiviral (acyclovir) and antifungal (fluconazole) were given in every case. Modification of initial empirical treatment with piperacillin-tazobactam, changing to meropenem, was done if there was: a) deterioration in the clinical state, b) warning signs, hemodynamic instability or other organ dysfunction, c) persistent fever after 4 days of treatment, d) culture with antibiotic-resistant. In patients with hemodynamic instability, skin or soft tissue infection, suspected catheter-related infection or methicillin-resistant Staphylococcus aureus culture positive, vancomycin was added. Empirical antifungal coverage was considered in patients who had persistent fever after 6-7 days of antibiotic treatment without identified fever source. Results: FN incidence was 33.1% (42 episodes). The presence of FN was associated with both the duration and severity of neutropenia. Median days of neutropenia (below 500/μL) in patients with FN was 10.0 ± 7.9 (standard deviation) vs 6.0 ± 3.7 (standard deviation) in patients without FN (p=0,001). Microbiological isolation from any source was achieved in 28.6% of the episodes and bacteremia was the most prevalent (77%). Multiple-antibiotic-resistant (MR) Gram-negative bacillus (GNB) were isolated in 58,3% of all microbiological documented infections, followed by GNB 25%. In 25 episodes the initial treatment was piperacilin/tazobactam (59%), while in 17 episodes Meropenem was. 15 episodes (35.7%) required vacomycin treatment. 32% of the episodes in which the initial treatment was piperacilin/tazobactam, needed to escalate to Meropenem. The mortality rate of febrile neutropenia episodes was 3.9% (40% related to sepsis). Conclusions: In this work we observed high rate of microbiological documentation in FN episodes being bacteriemia the most frequent form and there was a predominance of MR-GNB. The high rate of GNB resistant to piperacilin/tazobactam, front line antibiotics in our protocol, and the early need to escalate to carbapenems raises the question whether it is necessary to change our antibiotic treatment protocol. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy and the fifth leading cause of cancer death in the world; over 90% are B cell lymphomas and express CD-20 surface antigen [1]. CD-20 antigen is a transmembrane protein of 33-37 kDa protein located on the surface of pre-B and mature lymphocytes B [2, 3]. It is expressed in 90% of B-cell NHL [4]. Anti-CD20 antibody (Rituximab®), a specific chimeric monoclonal antibody directed against CD20 on B lymphocytes and the first monoclonal antibody approved for the treatment of CD20+ NHL. The development of new agents directed against specific targets may improve the sensitivity and specificity of imaging for its staging. Objective To radiolabel Rituximab with 99mTc and evaluate its properties as a potential imaging agent for NHL. Methodology Rituximab was derivatized with succinimidyl-hydrazinonicotinamide (Suc-HYNIC) and MALDI TOF/TOF was used to confirm the level of HYNIC conjugation to Rituximab. This antibody was radiolabeled with 99mTc using a mixture of Tricine/SnCl2.2H2O. Radiochemical purity was determined by ITLC-SG, size exclusion chromatography and HPLC. In-vitro stability was studied in solution; serum and L-Cysteine up to 24 h. In-vitro binding and competition assays were performed with Ramos and Raji NHL cell lines up to 120 min and were analyzed by laser confocal microscopy. Ramos and Raji cells were incubated with buffer to evaluate any degree of autofluorescence. Biodistribution studies were performed in normal Balb/C mice at 1, 4, 24 and 48 h (n = 5). Results HYNIC- Rituximab was efficiently labeled with 99mTc. The in-vitro radiochemical stability studies of the radiolabeled antibody showed that the complexes formed were stable and no significant transchelation was detected. In-vitro binding and displacement assays confirm that after derivatization and labeling, Rituximab retained its specificity of binding to CD-20 antigen. Immunoreactivity of HYNIC-Rituximab to Ramos and Raji cell lines was determined by direct immunofluorescence. We observed a remarkable cell membrane staining of the NHL cells. Nuclei were counterstained with 4',6-diamidino-2-phenylindole (DAPI). After its incubation with buffer, auto fluorescence was discarded. These results show that Rituximab´s affinity for NHL cells remained unaffected after its derivatization. Biodistribution studies were performed to quantify localization and clearance of the radiolabeled antibody complex in normal tissues. Significant accumulation of radioactivity was found in liver, indicating that the primary route of clearance was hepatic. Other major uptake was not found after evaluating the rest of the organs at the observed time points. Conclusions 99mTc-HYNIC-Tocilizumab was easily and rapidly labeled, with radiochemical purities greater than 90%, retaining its specificity of binding. Our results indicate that 99mTc-HYNIC-Rituximab represents a promising molecular imaging agent for NHL. Acknowledgments ANII, Roche Laboratories, Pro.In.Bio. PEDECIBA Química References [1] Swerdlow AJ. Epidemiology of Hodgkin’s disease and nonHodgkin’s lymphoma. Eur J Nucl Med Mol Imaging 2003; 30 Suppl 1:S2–12. [2] Einfield DA, Beown JP, Valentine MA, et al. Molecular cloning of the human cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 1988; 7, 711-717. [3] Valentine MA, Meier KE, Rossie S, et al. Phosphotylation of the CD20 phosphoprotein in resting B lymphocytes. Regulation by protein kinase. C J Biol Chem 1989; 264, 11282-11287. [4] Tedder TF, Boyd AW, Freedman As, et al. The B cell surface molecule B1 is functionally linked withBcell activation and differentiation. J Immunol 1985; 135, 973-979. Disclosures: No relevant conflicts of interest to declare.

Description: Between 1995 and 2005, we performed 329 hematopoietic stem cell transplantation (HSCT), 286 autoulogous and 43 allogeneic. Long term results of treatment and outcome of ASCT in 100 Non Hodgkin Lymphoma (NHL) were analyzed. Median age was 47 years (range18 – 64) and the histology was: Follicular Lymphoma 15%, diffuse large B cell lymphoma (DLBCL) 47%, T lymphoma 27% and 11% others. At diagnosis 66% had advanced stage (III/IV), 40% had B symptoms, and 34% had extranodal involvement. Disease status at HSCT was: 5 % primary induction failure, 41% CR1, 20% CR2 +, 7% CRU, 12% relapsed. Number of prior chemotherapy regimens was 47% 2 lines, 20% 3 lines and 3% 4 lines; 27% had received prior induction or consolidation radiotherapy. Condition regimens consisted of BEAC (81%), BEAM (15%), others (4%). Stem cell source: 39% received BM + PBSC and 61% PBSC. Sixty nine are alive with a median survival of 3448 days (9.5 years). Median overall survival was similar in DLBCL (59%) and peripheral T lymphoma (60%). The best overall survival was observed in CR1 (77%) versus 52% in CR2 and 66% in PR1. Primary cause of death was relapsed or progression (24/31). We concluded that high dose therapy and autologous HSCT is an effective therapy for patients with poor risk NHL however relapse continues to be the most common cause of treatment failure. Newer strategies such as monoclonal antibody, require further investigation but early reports appear promising in reducing relapses in autologous HSCT.

Description: Abstract 4976 Between January 2002 and December 2010, we treated 207 NHL at the Hospital de Clínicas, Uruguayan University Hospital. These are 10 % of the NHL diagnosed in our country. There were 72 Diffuse Large B Cell Lymphoma (DLBCL), 34 Follicular Lymphoma (FL), 33 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, 11 Mantle Cell, 10 T Cell, 7 MALT, 7 Anaplasic T, 6 Burkitt, 6 Lymphoblastic Lymphoma, 5 Lymphoplasmocytic, 4 Mycosis Fungoides, 3 Burkitt like, 2 Hairy cell Leukemia, 2 Esplenic Marginal zone, 2 LLGG, 2 angioinmunoblastic, 1 Prolymphocytic Leukemia. The mean of this retrospective study is to analyze the improvement in Overall Survival (OS) with the use of R in DLBCL and FL in HIV negative Uruguayan patients. The DLBCL were 72 patients, we analyze 61 because 5 were HIV positive and 6 were Primary CNS. There were 34 males and 27 females. The median age was 60 years (25-82). At diagnostics, the Ann Arbor Stratification was: 26 I-II, 10 with B symptoms, 35 III – IV, 20 with B symptoms. Nineteen (31 %) had Bulky disease and 18 (30 %) were primary extranodal disease. The International Prognostic Index was: 30%: 0–1; 28,5 %: 2; 28,5 %: 3; 13 %: 4. The delay between the first consult and treatment was 31 days (1-456). The Chemotherapy regimens used were in 35 CHOP-like (CHOP, CAPVE, CEOP, CMVP, CVP, m-BACOD) with a median of cycles of 6 (1-8), and in 22 R-CHOP with a median of cycles of 6 (1-8). Results DLBCL: In DLBCL treated with CHOP-like regimens the Overall Response (OR) (Complete Remission (CR) and Partial Remission (PR)) was 60 % with 37 % of CR and 23 % of PR. With R-CHOP the OR was 100 %, CR: 91 % and PR: 9 %. With a median of follow up of 23 month (0,8-106), the OS in patients treated with CHOP-like is 34,3 months and in R-CHOP it has not been reached yet, but it is not statistically significant: log rank (p=0,121). The OS at 24 months is 52 % in CHOP-like vs 80 % in R-CHOP. These results are very promising for the R- CHOP group. The Disease Free Survival (DFS) was 39,6 month (IC: 0–114,4) in CHOP-like and it has not been reached yet in patients with R-CHOP, but this is not statistically significant, log rank (p= 0,645). At 24 month the DFS was 60 % in CHOP-like and 67 % in R-CHOP. There were 34 patients with FL, we analyze 33 because we exclude HIV +. There were 19 females and 14 males. The median age was 62,5 years (33-79). At diagnostics, the Ann Arbor stratification was: 8 patients I -II, 3 with B symptoms, 25 III – IV, 12 with B symptoms. Twelve percent were bulky and 15 % begun with extranodal disease. Forty four percent had FLIPI 0–1, 36 % FLIPI 2 and 20 % 3 or more. The histological grade was in 3 % G1, 79 % G2 and 18 % G3 (15 % G3a and 3 % G3b). The median delay between the first consult and diagnostic was 24 days (5-765). The Chemotherapy regimens used were: in 18 patients CHOP like (CHOP, CAVPE, m-BACOD), median number of cycles 5 (1-6), in 9 patients R-CHOP with median of cycles of 6 (3-8) and in 3 patients R-CHOP-like (R-CAPVE, FCR, R-CVP), median of cycles 5 (3-6). Results FL: In FL treated with R-CHOP or R-CHOP-like regimens the OR was 92 % with 59 % CR and 33 % PR. With CHOP-like regimens the OR was 55 % with 17 % CR and 38 % PR. With a median follow up of 36 month (3-111), the median OS hasn't been reached. The OS at 24 and 36 month in patients treated with R-CHOP or R-CHOP-like was 82 % and 58 %, and in patients treated with CHOP-like 82 % and 67 % respectively. These are not statistically significant, log rank p=0,923. The median Progression Free Survival (PFS) in patients treated with CHOP-like regimens was 17 month (0-44) and it hasn't been reached in treated with R-Chemotherapy (R-CT). The PFS at 24 and 36 month was 36 % and 18 % in CHOP-like patients and 68 % and 55 % in R-CT patients. These difference also is not statistically significant, log rank p=0,66, but there is a great trend in benefit of R-CT. Discussion and conclusion: the use of the monoclonal antibodies in NHL's treatment has been an important issue and it is now use in first line treatment because it's benefits in OR, CR and OS. R was introduced in Uruguay in 2005 and it is government funded through Fondo Nacional de Recursos. In our series, there is an improvement in CR and a trend towards better results in OS and DFS when R-CHOP is used. In spite of the fact that it was not possible to demonstrate a statistically significant difference in view of the low number of patients, we think that this sample is highly representative of the reality of our country. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Survival of hemato oncologic patients has significantly improved in the last 50 years due to more intensive treatments and directed therapies. This has led to a paradigm shift focused not only in achieving cure but also addressing survivors' complications such as treatment toxicities and second malignancies. Cardiac toxicity is one of the most frequent long-term complications after cancer treatment leading to a significant burden in morbidity and mortality. Anthracyclines are type 1 cardiotoxic drugs. Risk of cardiotoxicity depends on patient characteristics and drug combinations as well as anthracyclines cumulative doses. Treatment of many hematologic malignancies often includes anthracyclines. Cardiac toxicity may limit oncologic treatment along with a negative impact on functional prognosis of survivors. Cardio oncology is an emerging field aimed at prophylaxis, early detection and proper treatment in order to improve quality of life in cancer survivors. This is the first Uruguayan experience in the implementation of a cardio oncology protocol. Methods This is a prospective interventional study conducted by a multidisciplinary team formed by hematologists and cardiologists. Inclusion criteria were patients older than 18 years old with hematologic malignancies who received anthracycline treatment between march 2017 and march 2019, treated at our institution. All patients gave their informed consent. This protocol was approved by our institution Ethical Committee. Patients who entered the protocol were followed at the Cardio Oncology Unit. Trans thoracic echocardiogram (TTE) were performed using the same equipment and by experimented operators. Left ventricular ejection fraction (LVEF) by Simpson and Global Longitudinal Strain (GLS) were measured. Figure 1 shows the algorithm used. We defined cardiotoxicity as the decrease of LVEF greater than 10% (relative to baseline LVEF) to a threshold inferior to 53%; or a relative reduction of GLS greater than 15%. Results We created a Cardio Oncology Unit (COU) at our institution with hematologists and cardiologists. Forty-four patients were included (table 1). Protocol compliance was 70%. Seven percent (3/44) of patients presented structural cardiopathy and 20% (9/44) were defined as high risk (figure 1). Cardiotoxicity was diagnosed in 16% (7/44) of patients. The diagnosis was made using LVEF decrease in every case, no patient was diagnosed based on GLS. Mean time of onset was 3 months (1-6). Mean doxorubicin dose was 115 mg/m2 (50-200). Four of the patients were asymptomatic and 3 presented with heart failure. Two patients required suspension of anthracyclines due to cardiotoxicity. Six of the 7 patients diagnosed with cardiotoxicity were treated with Beta blockers and ACE inhibitors and treatment was well tolerated. Of these patients, two died due to their oncologic disease, three improved their LVEF, one maintained the LVEF stable in spite of continuing on anthracyclines. Structural cardiopathy was associated with greater risk of cardiotoxicity (p=0.013). Conclusions We present the results of the implementation of a Cardio Oncology prospective protocol at our institution. The incidence of cardiotoxicity evidenced was greater than expected according to anthracycline used doses, with early onset during treatment. We identified structural cardiopathy as a risk factor for cardiotoxicity. Our results highlight the relevance of cardiologic follow up in patients receiving anthracyclines and makes us question whether prophylaxis would be beneficial for high risk patients. We strongly believe that cardiotoxicity is a major problem for hemato oncologic patients, and that a multidisciplinary approach with health care protocols is the best way to address it. Disclosures No relevant conflicts of interest to declare.