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Despite the practice-changing advances achieved in the prognostic stratification and treatment of chronic lymphocytic leukemia (CLL), a large fraction of the world population resides in countries where access to many of these advances remains unavailable or subject to severe constraints. Although some of these countries display incidence rates of CLL that are lower than those of developed Western countries, a large number of patients are expected to be diagnosed with CLL in these regions every year. In this article, we review issues regarding management of CLL in some less-resourced countries, with a focus on the evidence basis for epidemiological and clinical information on this disease, the availability of diagnostic and therapeutic resources, and participation in clinical trials. Going forward, challenges that still need to be addressed include the development of unified countrywide registries, guidelines for management applicable to each country, wider availability of prognostic tools, access to new drugs, and policies that ensure these drugs are affordable to all patients worldwide.

Aplastic anemia (AA) is a rare but serious disease that affects hematopoietic stem cells and is characterized by pancytopenia and a hypocellular bone marrow. It can be a hereditary or acquired condition. Acquired AA has an incidence of 2 per million per year in Europe, but the incidence is two to three times higher in Asia. In Latin America, there is little epidemiologic data on this disease. The most important treatments for AA are bone marrow transplantation and immunosuppressive treatment with antithymocyte globulin and cyclosporine. But access to these treatments is restricted in some areas of Latin America. At the American Society of Hematology (ASH) Annual Meeting in 2016, representatives of the Hematology Societies of Latin America, with the support of the ASH International Program, met to discuss possible collaborative efforts. Everyone agreed that lack of reliable information is one of the main barriers to designing significant clinical trials for the region; therefore, starting a registry of hematologic diseases for the region has become a main goal of the group. In April 2017, at the ASH Highlights meeting in Latin America, AA was selected as the first disease that would be used to begin the collaborative action. National hematology societies of Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Paraguay, Peru, Uruguay, and Venezuela have made a commitment to help develop the Latin American Registry for Aplastic Anemia (LARAA).

Summary Background Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL. Methods We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov , NCT01142674 . Findings 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20–61), overall survival at 5 years was 54% (95% CI 44–63) in patients with nasal disease (n=98) and 34% (27–46) in patients with extranasal disease (n=68). Interpretation To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL. Funding The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health.

Summary Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL‐NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL‐NOS were retained for study. At a median follow‐up of 46 months, the median overall survival (OS) and progression‐free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1–2), and high risk (HiR, 74 patients, 24%, score 3–4), having a 3‐year OS of 76% [95% confidence interval 61–88], 43% [35–51], and 11% [4–21], respectively (P

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a rare and unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features. Clinical presentation is varied with an aggressive course and dismal outcomes. Curative treatment modalities in AITLs are still an unmet need. Aims: In this study, we aimed to advance our understanding of clinical characteristics, prognostic factors, treatment strategies in patients with AITL in the international prospective T-Cell Project (TCP). Patients and methods: We did a sub-analysis of 282 patients with AITL out of 1,553 cases enrolled between 2006 and 2018 in the TCP, a global prospective registry of patients with PTCL involving 74 institutions in 13 countries in Europe, North/South America, and Asia. Eligible patients were >18 years old with baseline clinical data necessary for disease staging, treatment type, and follow-up for at least 5 years. The primary and secondary endpoints were 5-year OS and PFS. Additionally, we analyzed prognostic factors and POD24. The TCP is registered on ClinicalTrials.gov , NCT01142674 . Results: The median age at diagnosis was 64 years (range 22–88) and 63% of patients were >60 years old. The advanced stage had 90% of patients and 60% were males. According to the IPI, PIT, and PIAI, the majority of cases were in the high-risk groups. Anthracyclinecontaining chemotherapy was received by 81% of patients, and 27 (12.5%) underwent HDT/ASCT as consolidation. Five-year OS and PFS were 44% and 32%, respectively. CR was achieved in 106 patients. ASCT was associated with superior OS (89% vs 52%, p = 0.05) and PFS (79% vs 31, p = 0.02). In multivariate analysis, older age (p=0.003), ECOG PS >2 (p=0.0001), CRP>ULN (p=0.003) and Beta2 microglobulin >ULN (p=0.002) showed an independent prognostic value on PFS. Finally, POD24 was a powerful predictor of outcome: the 5-year PFS for patients with or without POD24 was 2% and 48%, respectively (p=0.0001). Conclusions: Our data confirmed the poor outcome of AITL, mostly in patients exhibiting POD24, and the promising efficacy of ASCT in CR1. Moreover, the collected data gave a better understanding of the need for more effective therapies and the importance to continue prospective studies in a real-world population.

Background Prognosis of patients with Diffuse Large B Cell Lymphoma (DLBCL) is highly variable, and despite the use of modern immunochemotherapy regimens, almost 50% of patients will eventually relapse. Standard risk models, like the International Prognostic Index or the Revised International Prognostic Index (R_IPI) incorporate patient and tumor characteristics but do not consider variables related to host adaptive immunity which have been shown to be of significant prognostic value in non-Hodgkin lymphomas. Aim To analyze the prognostic significance of the absolute monocyte count at diagnosis in diffuse large-B-cell lymphoma in a retrospective setting. Material and Methods We reviewed data of 171 patients with DLBCL treated with Rituximab-based immunochemotherapy at two reference public Hospitals in Montevideo-Uruguay. The outcome measures were overall and relapse free survival. Results The absolute monocyte count, analyzed as a dichotomized variable predicted progression-free and overall survival in low risk patients according to the R-IPI score. Worse outcomes were observed in those with high monocyte count al diagnosis. Conclusions Absolute monocyte count could help in the identification of high-risk patients otherwise expected to have a good prognosis according to traditional scores.

Bolivia is a developing country with ∼11 million inhabitants and is constantly growing. In recent years, Bolivia has experienced significant political, social, and economic changes. Positive changes in health were also achieved, mainly focused on prevalent diseases. However, in hematology, there

Lipoprotein lipase (LPL) mRNA expression in chronic lymphocytic leukaemia (CLL) is associated with an unmutated immunoglobulin profile and poor clinical outcome. We evaluated the subcellular localization of LPL protein in CLL cells that did or did not express LPL mRNA. Our results show that LPL protein is differently located in CLL cells depending on whether it is incorporated from the extracellular medium in mutated CLL or generated de novo by leukaemic cells of unmutated patients. The specific quantification of endogenous LPL protein correlates with mRNA expression levels and mutational IGHV status, suggesting LPL protein as a possible reliable prognostic marker in CLL. Fil: Prieto, Daniel. Instituto Pasteur de Montevideo; Uruguay. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay Fil: Seija, Noé. Universidad de la República; Uruguay. Instituto Pasteur de Montevideo; Uruguay Fil: Uriepero, Angimar. Instituto Pasteur de Montevideo; Uruguay Fil: Souto-Padron, Thais. Universidade Federal do Rio de Janeiro; Brasil Fil: Oliver, Carolina. Universidad de la República; Uruguay Fil: Irigoin, Victoria. Universidad de la República; Uruguay Fil: Guillermo, Cecilia. Universidad de la República; Uruguay Fil: Navarrete, Marcelo A.. Universidad de Magallanes; Chile Fil: Inés Landoni, Ana. Ministerio de Salud. Administración Servicios de Salud del Estado. Hospital Maciel; Uruguay Fil: Dighiero, Guillermo. Ministerio de Salud. Administración Servicios de Salud del Estado. Hospital Maciel; Uruguay Fil: Gabus, Raúl. Ministerio de Salud. Administración Servicios de Salud del Estado. Hospital Maciel; Uruguay Fil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay

Background Individual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. Methods 41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. Results Genotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28 bp copy number variation, SLCO1B1 T521C, DHFR C− 1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19 bp indel. Multivariate analysis showed that DHFR-1610G/T (OR = 0.107, p = 0.018) and MTHFR677T alleles (OR = 0.12, p = 0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR = 9, p = 0.045). No more associations were found. Conclusions The associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.

Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by accumulation of clonal B lymphocytes, resulting from a complex balance between cell proliferation and apoptotic death. Continuous crosstalk between cancer cells and local/distant host environment is required for effective tumor growth. Among the main actors of this dynamic interplay between tumoral cells and their microenvironment are the nano-sized vesicles called exosomes. Emerging evidence indicates that secretion, composition, and functional capacity of exosomes are altered as tumors progress to an aggressive phenotype. In CLL, no data exist exploring the specific changes in the proteomic profile of plasma-derived exosomes from patients during disease evolution. We hereby report for the first time different proteomic profiles of plasma exosomes, both between indolent and progressive CLLs as well as within the individual patients at the onset of disease and during its progression. Next, we focus on the changes of the exosome protein cargoes, which are found exclusively in patients with progressive CLL after disease progression. The alterations in the proteomic cargoes underline different networks specific for leukemia progression related to inflammation, oxidative stress, and NF-κB and phosphatidylinositol 3-kinase/AKT pathway activation. Finally, our results suggest a preponderant role for the protein S100-A9 as an activator of the NFκB pathway during CLL progression and suggest that the leukemic clone can generate an autoactivation loop through S100-A9 expression, NF-κB activation, and exosome secretion. Collectively, our data propose a new pathway for NF-κB activation in CLL and highlight the importance of exosomes as extracellular mediators promoting tumor progression in CLL.

Non-communicable diseases, including cancer, are overtaking infectious disease as the leading health-care threat in middle-income and low-income countries. Latin American and Caribbean countries are struggling to respond to increasing morbidity and death from advanced disease. Health ministries and health-care systems in these countries face many challenges caring for patients with advanced cancer: inadequate funding; inequitable distribution of resources and services; inadequate numbers, training, and distribution of health-care personnel and equipment; lack of adequate care for many populations based on socioeconomic, geographic, ethnic, and other factors; and current systems geared toward the needs of wealthy, urban minorities at a cost to the entire population. This burgeoning cancer problem threatens to cause widespread suffering and economic peril to the countries of Latin America. Prompt and deliberate actions must be taken to avoid this scenario. Increasing efforts towards prevention of cancer and avoidance of advanced, stage IV disease will reduce suffering and mortality and will make overall cancer care more affordable. We hope the findings of our Commission and our recommendations will inspire Latin American stakeholders to redouble their efforts to address this increasing cancer burden and to prevent it from worsening and threatening their societies.

BACKGROUND: In 2006 the Hematology Service of Hospital Maciel published its experience with peripheral blood progenitor cell harvesting for autologous stem cell transplantation using Filgen JP (Clausen Filgrastim). After mobilization with a mean filgrastim dose of 78 mcg/Kg, 4.7 x 10(6) CD34+ cells/Kg were obtained by apheresis. Age above 50, multiple myeloma as underlying disease and a malignancy that was not in remission were identified as frequent characteristics among patients showing complex mobilization. OBJECTIVE: The aim of this study was to compare stem cell mobilization using different brands of filgrastim. METHODS: One hundred and fifty-seven mobilizations performed between 1997 and 2006 were analyzed. This retrospective analysis comparative two groups of patients: those mobilized with different brands of filgrastim (Group A) and those who received Filgen JP (Clausen Filgrastim) as mobilizing agent (Group B). A cluster analysis technique was used to identify four clusters of individuals with different behaviors differentiated by age, total dose of filgrastim required, number of apheresis and harvested CD34+ cells. RESULTS: The mean total dose of filgrastim administered was 105 mcg/Kg, the median number of apheresis was 2 procedures and the mean number of harvested stem cells was 4.98 x 10(6) CD34+ cells/Kg. No significant differences were observed between Groups A and B regarding the number of apheresis, harvested CD34+ cells and number of mobilization failures, however the total dose of filgrastim was significantly lower in Group B. CONCLUSIONS: Among other factors, the origin of the cytokine used as mobilizing agent is an element to be considered when evaluating CD34+ cell mobilization results.

In recent years there has been great increase in the relationship between the Latin American Societies of Hematology and the American Society of Hematology. This led to the meeting Highlights of the American Society of Hematology (ASH) in Latin America (HOA-LA), first held in Sao Paulo and Rio de Janeiro, Brazil with its third meeting taking place in 2011 in Punta del Este in Uruguay. With this exchange, it soon proved necessary to know the reality of hematology in Latin America and the context of development in different countries, so that the links between the different scientific societies of the area would become stronger. With this in mind, information was collected using a standardized questionnaire provided to the participants of the 2011 HOA-LA accompanied by guidelines on how to complete the questionnaire. The information provided was discussed during a specific section of the 2011 HOA-LA on April 30 coordinated by Drs. Raul Gabus, Carmino Antonio de Souza and Scott Howard. The session was attended by representatives of Argentina, Brazil, Bolivia, Chile, Colombia, Mexico, Paraguay, Peru, Uruguay and Venezuela as well as those from the United States of America, Canada, Spain and Italy. The aim of the meeting was to prepare a document to evaluate the current status of hematology in Latin America in order to improve interactions between Latin American Societies of Hematology. An additional objective was to encourage the organization of cooperative projects on support and training for the diagnosis and treatment of patients with blood diseases in Latin America. Member societies of the OAH-LA were asked to designate a spokesperson for this activity before 15 December 2010. Questionnaires were distributed to these spokespeople to obtain a representative sample of partners and hematology services of each country. The questionnaires were then sent to the coordinators in January 2011. In February 2011, each representative wrote a brief summary of data on the general situation in their country that reflected the opinion of the respective Society of Hematology. Data were collected and analyzed by the coordinators of the LA-HOA in Uruguay in March 2011 with the reports being divulged to the participating scientific societies. In April 2011 the results were presented and the final text of the document was discussed. The estimated population of the countries involved (Argentina, Bolivia, Brazil, Chile, Colombia, Mexico, Paraguay, Peru, Uruguay and Venezuela) is approximately 475 million people in an area of 19,046,336 km2. There are currently 4,306 hematologists for this population which is a rate of 0.9/100,000 hematologists/inhabitants with a heterogeneous distribution between the countries and between regions within each country. A total of 76.7% hematologists are connected to hematology institutions in their countries (range: 45-100%). In the case of Colombia, the Hematology Society is linked to oncology and in five countries (Bolivia, Brazil, Chile, Paraguay and Venezuela) to transfusion medicine. In seven countries (Argentina, Bolivia, Brazil, Colombia, Paraguay, Uruguay and Venezuela), there are formal medical fellowships programs in hematology. Three countries (Brazil, Colombia and Uruguay) reported that it is the National Health System that regulates funds and supportive care. In the other countries the health care system is divided between the public health insurance, prepayments, loans and others. The participation of the public sector in different countries varies between 25 and 73%. Exclusive private healthcare covers 10 and 20% of care. There are few national records and those that exist are limited to specific diseases. The registries are mainly of isolated Hematology Centers with partial data and with little intervention of Hematology Societies (Figure 1). Figure 1 Registry With regards to healthcare in hematology, although most people can easily have access to referral centers, however there are geographic areas far from these centers, such as the Brazilian Amazon and Bolivian Altiplano (Figure 2). Figure 2 Healthcare in hematology accessibility The availability of cytogenetics, flow cytometry, molecular biology, immunohistochemistry, computed tomography, magnetic resonance imaging (MRI) and positron emission tomography (PET-CT) was found to be heterogeneous across countries and even within the same country. Some complex techniques such as computed tomography or immunophenotyping by flow cytometry (IHC) are generally accessible to the public. Some countries do not have cytogenetics, molecular biology, MRI or PET-CT availability. Moreover, even in countries that rely on these resources, access to them is not universal for all inhabitants (Figure 3). The reports also mention a need to develop IHC to assist diagnosis of hematologic diseases. Figure 3 Healthcare in hematology diagnosis About the availability of blood components and other resources in transfusion medicine, packed red blood cell and platelet concentrates are availability to the entire population and usually at no cost to the patient. The availability of platelets by apheresis and irradiated blood products is generally limited; normally they are only available to patients in Hematopoietic Stem Cell Transplantation (HSCT) units (Figure 4). It was found that in most countries, patients have access to basic hematology-oncology treatment, but only a part of the population has access to high-cost treatment. Monoclonal antibodies, new drugs and access to HSCT are considered high-cost (Figure 5). There are countries where HSCT is not performed or the program is poorly developed. Figure 4 Healthcare in hematology support Figure 5 Access to treatment and medications The financing of regular treatment is guaranteed by the state, by health insurance or medical organization to which the patient is affiliated. However, there are situations that hematological patients lack coverage (Figure 5). There is no guarantee of coverage of high-cost treatments and medications to all populations. In some countries it is the responsibility of the state, parastatal organizations, other health insurance institutions or medical organizations to which the patient is affiliated. Occasionally, this coverage is funded by a foundation or through a support program of the pharmaceutical industry (Figure 5). Regarding the study protocol and / or treatment, some hematology centers with guidelines or consensus on certain conditions, however almost none of them are national protocols. Most treatment programs follow international protocols with little or no adaptation to the country or region (Figure 6). Figure 6 Hemato-oncological protocol treatment This survey showed that the number of hematologists is inadequate and they are unevenly distributed (Figure 7). Figure 7 Human resources Most societies stated that the number of doctors who are currently in hematology specialist courses is insufficient to meet the needs of the population (Figure 7).

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of lymphoma in the world and corresponds to a heterogeneous entity, both from the clinical and molecular point of view, being its prognosis of survival very variable The IPI and the NCCN-IPI are powerful risk-stratification tools in patients with DLBCL. Although the IPI risk score is widely used, it doesn't discriminate very high risk patients. In 2014 the NCCN-IPI was published. It has shown a better discrimination of these patients in Asia, Europe and USA. GELL is a recently formed group of study in lymphomas from Latin America that includes eleven countries. The aim of this study was to validate whether the NCCN-IPI is of prognostic value in Latin-American patients with DLBCL. Methods: We included patients with a diagnosis of DLBCL treated at different institution between 2012-2013. IRB approval was obtained before the collection of the data. Pathological samples were reviewed at each participating institution to confirm the diagnosis. Pertinent clinical data were collected through chart review and are presented using descriptive statistics. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratio (HR) for overall survival (OS). Results: A total of 329 patients with the diagnosis of DLBCL were included in this analysis. The median age at diagnosis was 64 years (range 18-83 years) with a slight female predominance (54%). Clinically, 59% of patients were 60 or older, 34% presented with ECOG >1, 29% with elevated serum LDH, and 70% with extranodal disease; 49% had stage I/II and 51% had stage III/IV. The IPI score distribution was low-risk in 36% of patients, low-intermediate in 25%, high-intermediate in 22% and high-risk 17%. The NCCN-IPI score distribution was low risk in 17%, low-intermediate in 42%, high intermediate in 30% and high risk in 11%. 89% of patients received standard R-CHOP, 2% received R-miniCHOP, and 9% received other regimens. The overall response rate was 83%; 69% had complete response and 14% had partial response. The 5-year overall survival (OS) rate was 65%. DLBCL patients with low, low-intermediate, high-intermediate and high risk NCCN-IPI had 5-year OS rates of 89%, 71%, 55% and 38%, respectively (p Conclusion: We have validated the prognostic value of the NCCN-IPI in previously untreated Latin American patients with DLBCL. Figure. Figure. Disclosures Chiattone: Janssen: Honoraria, Research Funding. Castillo:Beigene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Consultancy, Research Funding.

Introduction: Diffuse large B-Cell Lymphoma (DLBCL) is the most frequent subtype of lymphoma in the world. The IPI score is a powerful risk-stratification tool in patients with DLBCL. The neutrophil-to-lymphocyte ratio (NLR) has shown to be prognostic in patients with DLBCL in Asia, Europe and USA. The GELL is a recently formed group for the study of lymphomas in Latin America composed by large institutions from eleven countries. The aim of this study was to evaluate whether the NLR is a prognostic factor in Latin American patients with DLBCL. Methods: We included patients with a pathological diagnosis of DLBCL who were diagnosed and treated at our institution between 2012-2013. IRB approval was obtained prior to research, and pathological samples were reviewed by hematopathologists at each of the participating institutions to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. The NLR was calculated by dividing the absolute neutrophil by the absolute lymphocyte count and dichotomized in NLR≥4 and NLR Results: A total of 329 patients with a diagnosis of DLBCL were included in this analysis. The median age at diagnosis was 64 years (range 18-83 years) with a slight female predominance (54%). Clinically, 59% of patients were 60 or older, 34% had ECOG >1, 29% had elevated LDH, and 70% had extranodal disease; 49% had early stage and 51% had stage III and IV. The IPI score was low risk in 36%, low-intermediate in 25%, high intermediate in 22% and high risk in 17%. 41% of patients had NLR ≥4. 89% of patients received standard R-CHOP, 2% received R-miniCHOP and 9% received other regimens. The overall response rate as 83%; 69% had complete response and 14% had partial response. The median follow-up for the entire group was 5 years (95% CI 4.9-5.4 years). The 5-year overall survival (OS) rate for the entire group was 65%. The 5-year OS rates for patients with NLR ≥4 and Conclusion: The NLR appears as a novel and easy to use prognostic factor for OS, independent of the IPI score, in previously untreated Latin American patients with DLBCL. Our findings support the need for validation of the NLR in larger retrospective or prospective studies in patients with DLBCL. Figure. Figure. Disclosures Chiattone: Janssen: Honoraria, Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Millennium: Research Funding; Genentech: Consultancy.

Publications of bone marrow transplants in Latin America. A report of the Latin American Group of Bone Marrow Transplantation

Functional inducible NOS (iNOS) may be involved in the prolonged lifespan of chronic lymphocytic leukemia cells (B-CLL), although the exact mechanisms implicated remain elusive as yet. In this work, we have examined iNOS expression in normal B lymphocytes and B-CLL cells in pro- and antiapoptotic conditions. Our results demonstrate: (1) The existence of a new splice variant characterized by a complete deletion of exon 14 (iNOS 13-16(14del)), which was preferentially detected in normal B lymphocytes and may represent an isoform that could play a role in the regulation of enzyme activity. (2) The existence of another alternatively spliced iNOS mRNA transcript involving a partial deletion of the flavodoxin region (iNOS 13-16(neg)) was correlated to a decreased B-CLL cell viability. The 9-beta-D-arabinofuranosyl-2-fluoradenine or fludarabine (F-ara) treatment induced iNOS 13-16(neg) transcript variants, whereas IL-4 enhanced both the transcription of variants, including these exons (iNOS 13-16(pos)), and the expression of a 122 kDa iNOS protein. These results suggest that in B-CLL, a regulation process involving nitric oxide (.- NO) levels could occur by a post-transcriptional mechanism mediated by soluble factors. Our results also provide an insight into a new complementary proapoptotic action of F-ara in B-CLL by the induction of particular iNOS splice variants, leading to the activation of a caspase-3-dependent apoptotic pathway.

Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27-Kip1 and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors. Fil: Palacios, F.. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay Fil: Abreu, C.. Instituto Pasteur de Montevideo; Uruguay Fil: Prieto, D.. Instituto Pasteur de Montevideo; Uruguay Fil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Pasteur de Montevideo; Uruguay Fil: Ruiz, S.. Instituto de Investigaciones Biológicas "Clemente Estable"; Uruguay Fil: Fernández Calero, T.. Instituto Pasteur de Montevideo; Uruguay Fil: Naya, H.. Instituto Pasteur de Montevideo; Uruguay Fil: Libisch, G.. Instituto Pasteur de Montevideo; Uruguay Fil: Robello, C.. Instituto Pasteur de Montevideo; Uruguay Fil: Landoni, A. I.. Hospital Maciel Montevideo; Uruguay Fil: Gabus, R.. Hospital Maciel; Uruguay Fil: Dighiero, G.. Hospital Maciel; Uruguay Fil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; Uruguay

We report the outcome of 50 consecutive patients with CR1 acute leukemia (AML = 22; ALL = 28) treated with autologous BMT, after cyclophosphamide and TBI, followed with a sequential high dose rIL2 regimen. rIL-2 (RU 49637 from Roussel-Uclaf, Romainville, France) was started after hematological reconstitution an average of 72 +/- 22 days post transplant. The schedule consisted of a continuous infusion over 5 cycles (Cycle 1: 5 days starting on day 1; cycle 2-5: 2 days starting on day 15, 29, 43 and 57). Patients were treated at 4 different dosages (12 (N = 40), 16 (N = 3), 20 (N = 2), 24 (N = 5) x 10(6) IU/m2/day). Toxicities were mainly related to capillary leak syndrome and thrombocytopenia. Patients received an average of 122 +/- 49 10(6) IU/m2. Two patients with AML died from toxicity. rIL-2 infusion was associated with very a high level of immune stimu-lation of both T-cells (P0.05) and natural killer (NK) cells (P0.05) and associated cytolytic functions (P0.05). With a minimal and median follow-up of 21 and 46 months, 3 year leukemia free survival is 41 +/- 6% overall, 39 +/- 10% and 43 +/- 8% for AML and ALL respectively. Relapse probabilities at 3 years are 59 +/- 11% for AML and 57 +/- 8% for ALL. We conclude that this short infusion of rIL-2 over 2 months, resulting in an increased immune stimulation, is not associated with a better leukemic control for patients with acute leukemia transplanted early after reaching first complete remission.

Among different prognostic factors in chronic lymphocytic leukemia (CLL), we previously demonstrated that lipoprotein lipase (LPL) is associated with an unmutated immunoglobulin profile and clinical poor outcome. Despite the usefulness of LPL for CLL prognosis, its functional role and the molecular mechanism regulating its expression are still open questions. Interaction of CLL B-cells with the tissue microenvironment favors disease progression by promoting malignant B-cell growth. Since tissue methylation can be altered by environmental factors, we investigated the methylation status of the LPL gene and the possibility that overexpression could be associated with microenvironment signals. Our results show that a demethylated state of the LPL gene is responsible for its anomalous expression in unmutated CLL cases and that this expression is dependent on microenvironment signals. Overall, this work proposes that an epigenetic mechanism, triggered by the microenvironment, regulates LPL expression in CLL disease. Fil: Abreu, Cecilia. Instituto Pasteur de Montevideo; Uruguay Fil: Moreno, Pilar. Instituto Pasteur de Montevideo; Uruguay Fil: Palacios, Florencia. Instituto Pasteur de Montevideo; Uruguay Fil: Borge, Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Landoni, Ana Inés. Hospital Maciel; Uruguay Fil: Gabus, Raul. Hospital Maciel; Uruguay Fil: Dighiero, Guillermo. Hospital Maciel; Uruguay Fil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Gamberale, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Oppezzo, Pablo. Universidad de la República; Uruguay

International audience; B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived circulating clonal leukemic B-cells, although the etiopathogenesis remains unclear. The incidence of CLL is variable in different regions around the world. While it is the most frequent chronic leukemia in Western countries, it has a low incidence in Asia. In this work we have investigated the immunoglobulin heavy chain gene rearrangements and mutational status in 80 Uruguayan patients with CLL, and compared these results with those obtained in other geographic regions. Our results demonstrate that Uruguayan patients with CLL display an IGHV gene usage which resembles that observed in Mediterranean countries and exhibits certain differences compared with Brazilian and Asian series, as expected, considering the ethnic basis of the Uruguayan population. This suggests that genetic influences could be important in the development and etiopathogenesis of CLL, but larger studies are necessary to substantiate this possibility.

Interaction of chronic lymphocytic leukemia (CLL) B cells with tissue microenvironment has been suggested to favor disease progression by promoting malignant B-cell growth. Previous work has shown expression in peripheral blood (PB) of CLL B cells of activation-induced cytidine deaminase (AID) among CLL patients with an unmutated (UM) profile of immunoglobulin genes and with ongoing class switch recombination (CSR) process. Because AID expression results from interaction with activated tissue microenvironment, we speculated whether the small subset with ongoing CSR is responsible for high levels of AID expression and could be derived from this particular microenvironment. In this work, we quantified AID expression and ongoing CSR in PB of 50 CLL patients and characterized the expression of different molecules related to microenvironment interaction. Our results show that among UM patients (1) high AID expression is restricted to the subpopulation of tumoral cells ongoing CSR; (2) this small subset expresses high levels of proliferation, antiapoptotic and progression markers (Ki-67, c-myc, Bcl-2, CD49d, and CCL3/4 chemokines). Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment. © 2010 by The American Society of Hematology. Fil: Palacios, Florencia. Instituto Pasteur de Montevideo; Uruguay Fil: Moreno, Pilar. Instituto Pasteur de Montevideo; Uruguay Fil: Morande, Pablo Elías. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex". Departamento de Inmunología y Medicina Experimental; Argentina Fil: Abreu, Cecilia. Instituto Pasteur de Montevideo; Uruguay Fil: Correa, Agustín. Instituto Pasteur de Montevideo; Uruguay Fil: Porro, Valentina. Instituto Pasteur de Montevideo; Uruguay Fil: Landoni, Ana Ines. Hospital Maciel; Uruguay Fil: Gabus, Raul. Hospital Maciel; Uruguay Fil: Giordano, Mirta Nilda. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex". Departamento de Inmunología y Medicina Experimental; Argentina Fil: Dighiero, Guillermo. Instituto Pasteur de Montevideo; Uruguay Fil: Pritsch, Otto. Instituto Pasteur de Montevideo; Uruguay Fil: Oppezzo, Pablo. Instituto Pasteur de Montevideo; Uruguay

Introduction. Stem cell (SC) mobilization and collection from peripheral blood (PB) is a broadly used strategy in the setting of autologous stem cell transplantation (ASCT). An adequate correlation between CD34+ cell count in PB and CD34+ cell count in apheresis product is essential for the planning of the mobilization-apheresis process. Prediction of SC yield in the basis of peripheral blood stem cell (PBSC) number and blood volume processed (BVP) was proposed by Pierelli et al (Vox Sanguinis (2006)91:126-34). Objective. Evaluation of correlation between pre-apheresis PBSC count and CD34+ cell dose collected in the first apheresis procedure. Evaluation of correlation between predicted CD34+ yield by Pierelli's method and actual CD34+ yield collected in the first apheresis procedure. Patients and Methods. Eighty-four apheresis procedures performed to 79 patients in a single institution between 2008 and 2015 were retrospectively evaluated. Data analyzed included age, gender, body weight, diagnosis, date of first apheresis, pre-apheresis PB CD34+ counts, CD34+ cell dose collected in the first apheresis product and total BVP. Only patients in whom pre-apheresis PBSC count was available were included in this analysis. Median age was 52 years (16-66), 30 (38%) were females. Median body weight was 71 kg (47 - 120). Diagnosis was non-Hodgkin lymphoma (48%), multiple myeloma (24%), Hodgkin lymphoma (22%), acute myeloblastic leukemia (4%), amyloidosis (1%) and solid tumor (1%). Using the method described by Pierelli et al, predicted CD34+ yields were calculated (predicted CD34+ cells/kg= PB CD34+ cells/mL x 0.4 x BVP per kg (mL/kg). Correlation between variables was analyzed by Pearson's coefficient (r). An r value close to 1 indicates significant correlation between variables. An r value close to 0 indicates no statistical correlation. Predicted yields were classified in low (lower than 2 x 106 CD34+ cells / kg) (n=34), intermediate (2 to 5) (n=28) or high (higher than 5) (n=22), according with the conventional limits for SC dose in the setting of ASCT. Positive predictive value (PPV) of predicted yields was calculated as the proportion of actual yields falling into each category of predicted yields. Results. Median pre-apheresis PBSC count was 25 CD34+ cells / uL (5-310). Median BVP was 240 mL/kg (143-360). Median predicted CD34+ yield was 2.1x106 CD34+ cells/kg (0.5-29.41) and median actual CD34+ yield was 2.84 x106 CD34+ cells/kg (0.26-38.21). Pearson's correlation coefficient (r) between pre-apheresis PBSC and collected CD34+ cells was 0.842 (p=0.000). Pearson's correlation coefficient (r) between predicted and actual CD34+ was 0.836 (p=0.000). Median ratio actual CD34+ cells / predicted CD34+ cells was 1.10 (0.31-4.55). PPV of predicted yields higher than 5 x 106 CD34+ cells /kg was high (95%). Only 18% of cases with a predicted yield between 2 and 5 x 106 CD34+/kg had an actual CD34+ yield lower than 2 x 106 CD34+/kg. Conclusion. The results show a significant correlation between PBSC count and collected SC during the first apheresis procedure. A significant correlation between predicted and actual CD34+ yields reproduce what has been shown by others regarding the predictive power of this formula. The PPV of this method is higher for predicted CD34+ yields higher than 5 x 106 CD34+ cells/kg. Disclosures No relevant conflicts of interest to declare.

Introduction. An early absolute lymphocyte count (ALC) recovery after high dose therapy (HDT) and autologous hematopoietic stem cell transplantation (HSCT) in non Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), multiple myeloma and acute leukemia patients has been related with an improved outcome due to a better immune restoration. In this retrospective study we analyze a population of NHL patients to evaluate ALC recovery after autologous HSCT and its relation with post-transplant survival. Patients and methods. Fifty-three consecutive adult NHL patients received HDT followed by autologous HSCT in a single center between 2000 and 2012. Only individuals with at least 6 months post-transplant follow up were included. All patients received the same conditioning regimen (BEAM: carmustine, etoposide, cytarabine and melphalan) followed by peripheral blood stem cells previously collected by leukapheresis. Median CD34+ cell dose was 4.13 x 106/kg (1.62 – 12.58). Patients were divided into two groups: ALC at day +15 inferior than 500/mm3 (group 1) and ALC at day +15 superior or equal than 500/mm3 (group 2). Differences between groups were analyzed using t-Student and Chi-Square tests, with statistical significance determined at p Results. No differences were observed between groups regarding gender, histology, disease status at transplant and cell dose. Patients into group 1 were older and more heavily pre-treated. Neutrophil and platelet engraftment were significantly faster in group 2 (Table 1). After a median follow-up of 56 months, progression-free survival (PFS) and overall survival (OS) were superior in group 2 patients. Median PFS was 47 months and not reached (p=0.013) and OS was 51 months and not reached (p=0.016) in groups 1 and 2 respectively (figures 1 and 2). Discussion. An early ALC recovery after autologous HSCT is associated with a better PFS and OS in NHL patients. Patients with ALC major or equal than 500/mm3 had a shorter time to neutrophil and platelet recovery and a shorter stay at transplant unit. In this study, CD34+ cell dose does not appears as a determinant factor for lymphocyte recovery. The extent of pre-transplant chemotherapy may influence ALC recovery after transplant. These results confirm the association between lymphocyte recovery and outcome in NHL patients after autologous HSCT. Table 1.Patient characteristics and comparison between groups 1 and 2.Group 1Group 2pALC< 500 /mm3> 500/mm3N2528Age, median (range)57 (29 - 66)41 (15 - 65)0.008Female gender (n)1214NSHistology (n)DLBCL1316 NSFollicular lymphoma62Mantle cell lymphoma32Peripheral T cell lymphoma13Indolent lymphoma12Others13Individuals who received two or more lines of pre-transplant treatment (n)1180.01Disease status at transplant (n)Complete remission711 NSPartial remission1613Progressive disease21CD34+ cells dose, median (range) (10E6/kg)3.45 (1.62 - 9.12)4.40 (2.28 - 12.58)NSMononuclear cells dose, median (range) (10E8/kg)8,84 (3,55 - 18,74)6,7 (1,94 - 27)NSDays to achieve ANC > 500/mm3, median (range)11 (7 - 30)8 (3 - 16)0.034Days to achieve platelets > 20.000/mm3, median (range)9 (2 - 49)5 (1 - 10)0.003Length of stay in transplant unit, days, median (range)30 (20 - 59)24 (20 - 35)0.001 Figure 1. PFS and ALC on day +15. Group 1: patients with ALC < 500/mm3 (dotted line); group 2: patients with ALC > 500/mm3 (solid line). Figure 1. PFS and ALC on day +15. Group 1: patients with ALC < 500/mm3 (dotted line); group 2: patients with ALC > 500/mm3 (solid line). Figure 2. Figure 2. OS and ALC on day +15. Group 1: patients with ALC < 500/mm3 (dotted line); group 2: patients with ALC > 500/mm3 (solid line). Disclosures No relevant conflicts of interest to declare.

Our main goal was to evaluate the CD34+ dose in patients undergoing haemotopoietic stem celltransplantation and its results in terms of recovery of neutrophile and platelet counts, transfusion requirements, days of fever, antibiotic requirements and length of hospital stay. We studied 38 consecutive patients with haematological malignancies transplanted at our Department, from Feb. 96 through Sept. 98. The CD34+ cell quantification technique was standardized, using a modification of the ISAGHE 96 protocol. Patients were sorted into three groups according to the CD34+ count administered: a) between 3 and 5 x 10(6) cells/kg; b) between 5 and 10 x 10(6) cells/kg; c)10 x 10(6) CD34+ cells/kg. As a secondary end point, results were assessed according to the number of aphereses required to arrive at the target count of CD34+, separating those patients that required only 1 or 2 aphereses versus those requiring 3 or more. Finally, an analysis was made of the results of transplantation comparing the different sources of stem cells (PBSC versus PBSC + B.M.). The best results were obtained in the group with cells between 3 and 5 x 10(6) CD34+. No statistically significant advantages were found in the group with cells over 5. The supra-optimal dose of more 10 x 10(6) would yield no additional beneficial results, while they can imply a greater infusion of residual tumor cells. The number of aphereses had no impact on engraftment. Results obtained with PBSC transplants were better than those with BM+PBSC in terms of neutrophile and platelet recovery. The number of CD34+ cells remains the main element in stem cell transplantation to evaluate the haematopoietic recovery after engraftment. Minimum and optimum yields remain unclear. Centers should establish their own optimal dose based on local methodologies and outcomes, maximizing costs and benefits.

We designed a phase II study to assess the activity of recombinant interleukin-2 (rIL-2) in patients with chronic myelogenous leukemia (CML). Study population included 11 patients in the chronic phase of CML (6 in hematologic remission and 5 with active disease), 6 patients in the accelerated phase, and 4 in blastic phase of CML. Patients received three 5-day cycles administrated every other week, rIL-2 was given as intravenous bolus infusions of 8 x 10 6 IU/m 2 three times a day during cycle I and twice a day during cycles 2 and 3. Response to rIL-2 was assessed on day 45. No hematologic response was achieved in the patients with evaluable disease. One patient in hematologic remission with rIL-2 achieved a major response (from 72% to 9% Ph + metaphases), and two patients had some degree of reduction of Ph + metaphases. Responses were short-lived (

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10(6) IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.

Introduction: The IgVH mutational profile ia a strong prognostic indicator in CLL patients (pts.), particularly in early stages, where clinical staging fails to accurately predict outcomes. Our center designed a prospective trial in newly diagnosed CLL pts; our aim was to evaluate peripheral blood inmunophenotype including CD38 and the IgVH and correlate these parameters with clinical evolution and treatment requirements. Methods: Inclusion criteria were: below 75 years old and CLL diagnosed by inmunophenotype (Matutes-Moreau score) with 3 colors flow cytometry (fluorescence by triples markers and a predetermined ACMo panel). We did a recruited plan of 20 pts. with stage Binet A, 10 pts. Binet B and 10 pts. Binet C. Anti-CD38 FITC monoclonal was from Becton Dickinson (code 340927) and Ig nucleotide sequence was carried out at the Medicine Public University in Montevideo. A watch and wait attitude Binet A indolent Binet B was adopted whatever IgVH mutation status and fludarabine based regimen as standard first line therapy for progressive disease under NCI criteria Binet A, aggressive Binet B and C. Results: From June 2003 to June 2006, we recruited 40 untreated CLL pts. Twenty-two males and 18 females entered the study, with a median age of 61 years (range: 38–73). The median lymphocytes counts at diagnosis was 53.100 per mm3 (range: 3.300–302.000); for Binet A 25.460 mm3, for Binet B 47.880 mm3 and for Binet C 113.820 mm3. Eight-five percent had typical immunophenotype pattern (score 4–5) and 15% had atypical one. Eighty percent were CD38 negative (cut off level: 30%). Among the 33 patients tested for IgVH: 48% (16/33) were mutated and 52% (17/33) were unmutated (cut off label ≤ 2% changes of näive pattern). IgVH mutation status by Binet are summarize in table n.1. All of the12 Binet A IgVH mutated pts. are in watch and wait strategy without signs of progression, but 5 over 6 Binet A IgVH unmutated pts. had criteria of progression and started into a Fludarabine regimen strategy. All aggresive Binet B and C patients received up-front therapy as scheduled. In contrast to other reports we failed to find a significant correlation between IgVH mutation status and CD38 expression, particularly in advanced stages of the disease. Median Progression Free Survival (PFS) in the untreated group (18 pts.) was 37 months and for the treated one (22 pts.) was 22 months. Median PFS for IgVH mutated and unmutated pts. were 39 and 22 months respectively; and median overall survival (OS) for IgVH mutated and unmutated pts were 45 and 28 months respectively. In Binet-A median OS for those mutated and untreated pts. was 47 months and for unmutated and treated pts. the median PFS and OS were 34 and 39 respectively. Median OS for Binet B and C were 23 and 21 months respectively. Conclusion: Unmutated patients display a worse prognosis when compared to mutated ones. This is particularly true is early stages where the presence of an unmutated status results in short PFS and treatment requirement in most cases. Table 1. IgVH mutation status by Binet stage BINET IgVH test performed Mutated, n (%) Unmutated, n(%) A n=18 12 (66) 6 (33) B n=7 2 (29) 5 (71) C n=8 2 (25) 6 (75)

Introduction. Multiple Myeloma (MM) is a heterogeneous, incurable disease. Several prognostic scores have been developed to estimate response to treatment, progression free survival (PFS) and overall survival (OS). The International Staging System defines 3 stages with distinct prognostic significance, using serum beta 2 microglobulin (b2M) and serum albumin. However, due to a higher power of risk discrimination, current guidelines recommend to stratify patients according to cytogenetics (CG) and treat high-risk patients with Bortezomib (BZ)-based therapies. In Uruguay, BZ is financed and regulated by a National Funding Board and is approved for high-risk MM or renal impairment at diagnosis or at relapse. As a consequence, the patients included in this study are a selected high risk MM subgroup. Even though proteasome inhibitors have improved outcomes for many high-risk MM patients, some still present short response duration and poor survival. Identifying simple factors that can predict response to BZ would be useful in order to better select the most appropriate therapeutic choice. Patients and Methods. We conducted a retrospective study to evaluate MM response to BZ-based therapy according to b2M, serum creatinin (Cr) and CG. Forty-seven MM patients [median age 59 years (38-77), females 25 (53%)] from two public centers treated with BZ-based combinations were included. According to local regulatory policies, only patients with renal failure and/or high risk CG features received BZ as first line therapy (n=31). Other 16 individuals received BZ combinations for relapsed/refractory disease. Patients received a median of 5 cycles of BZ (3-6). Nineteen individuals (40%) received high dose melphalan and autologous stem cell transplantation after BZ-based induction. At diagnosis, 28 (59%) had an ISS 3, 24 (51%) patients had serum Cr higher than 2 mg/dL and 14 (30%) exhibited high risk CG. Responses to BZ therapy were evaluated according with International Myeloma Working Group criteria as complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and progressive disease (PD). Responses were analyzed depending on b2M level, serum Cr and CG. Comparison between groups was made by chi-square test. PFS and OS were calculated by the Kaplan-Meier method. Survival was compared between groups by log-rank test. Results. No differences in responses to BZ-based therapies were found when comparing patients with low (lower than 5,5 mg/L) versus high b2M levels (CR/VGPR 44,4 vs 44% respectively, p=0.97), low versus high serum Cr (CR/VGPR 34 vs 55% respectively, p=0.18) and standard versus high risk CG (CR/VGPR 46,7 vs 38,5% respectively, p=0.62). Patients with renal failure (serum Cr 2 mg/dL or higher at diagnosis, n=23) had a median of 53% (0 - 88%) reduction in Cr levels after receiving at least three cycles of BZ therapy. Eleven of them (47,8%) had normal renal function after completing BZ treatment. From 9 patients requiring dyalisis at diagnosis, 4 were out of dyalisis after BZ treatment. No significant differences in PFS and OS were observed when patients with low versus high b2M levels and standard versus high risk CG were compared. Patients with low Cr levels at diagnosis show a significantly better OS compared with those with Cr higher than 2 mg/dL (median OS not reached versus 42 months respectively, p=0.004), with no differences in PFS. Conclusion. In a selected high risk MM patients group treated with BZ-based therapies, similar response rates were obtained in individuals with high or low b2M levels, Cr levels, and standard or high risk CG. Although individuals with renal failure at diagnosis exhibit similar quality of responses than standard patients, long term OS of this group is still impaired and further improvements in therapy are needed. Note: GB and ER have contributed in equal parts to this work. Disclosures No relevant conflicts of interest to declare.