ALBERT

Description: Introduction:Potent antiretroviral drugs block the progression of HIV infection and inhibit virus integration into the host DNA. Response to therapy is typically monitored by counting CD4+ T cells and measuring plasma viral load, which becomes undetectable in most patients. However, at present HIV cannot be eradicated and persists in the host. Robust data are needed to understand the importance and clinical meaning of the residual activity of the virus, and it is crucial to investigate the role of intracellular HIV reservoirs in patients with undetectable viremia. Since HIV establishes latent infection at different degrees within central memory (CM), effector memory (EM) or naïve (TN) CD4+ T cells, measuring the content of HIV-DNA in different lymphocyte populations is a novel approach to follow the infection. Similarly, the residual capacity of the host to reconstitute the immune system can be accurately monitored by measuring: i) the amount of cells expressing signal-joint (sj) T cell receptor (TCR) rearrangement excision circles (sjTREC), that are a marker of homeostatic proliferation, and ii) telomere length, for evaluating cell senescence. Thus, using flow cytometry and cell sorting along with a molecular biology approach based on droplet digital PCR (ddPCR), we have quantified proviral HIV DNA, the amount of sjTREC+ cells and telomere length in different subsets of CD4+ T cells, such as TN, CM and EM. Methods:According to the Declaration of Helsinki, after informed consent and approval by the local Ethical Committee, we enrolled 32 HIV+ patients (mean age 49.0±7.2 years, 11 females) successfully treated for 〉2 years, with a CD4+ T cell count 〉500 cells/uL and plasma viremia undetectable from at least one year. After staining with fluorochrome-labeled mAbs, TN, CM and EM CD4+ T cells were sorted with a S3e sorter (Bio-Rad, CA, USA) equipped with a specifically designed biosafety containment hood (Biobubble, UK). Cell purity was always 〉95%. Proviral HIV-DNA and sjTREC were quantified in each lymphocyte subset with QX200 droplet digital PCR (Bio-Rad); telomere length, expressed as relative T/S (the ratio between telomere length and single gene copy, related to CD178, i.e., Fas Ligand) was quantified with CFX9600 Real time PCR (Bio-Rad). Viro-immunological parameters such as CD4+ and CD8+ T cell counts and percentages, and viral load were collected for each withdrawal together with the clinical characteristics of patients. Results:Considering all patients, HIV proviral DNA, measured as LTR copies/1,000 cells, was significantly lower in TN cells (mean±SEM: 0.77±0.23) compared to CM (2.42±0.38) or to EM (2.34±0.33), with p

Description: Allogeneic hematopoietic stem cell (HSC) transplantation is currently the only curative treatment for the bone marrow failure in Fanconi anemia (FA) patients. However, recent advances in lentiviral-mediated gene therapy have shown that corrected FA HSCs develop an in vivo proliferation advantage, facilitating the engraftment of corrected HSCs in non-conditioned FA patients. Based on these observations, we proposed that gene editing might constitute a promising alternative to correct patients' hematopoietic stem and progenitor cells (HSPCs) in this disorder. Since non-homologous end joining (NHEJ) is the most frequent repair pathway in HSCs, particularly in FA-HSCs, we aimed at exploiting this DNA repair mechanism to remove/compensate specific mutations in different FANC genes by the use of CRISPR/Cas9 system, thus mimicking spontaneous genetic reversions observed in FA mosaic patients. Our results in lymphoblastic cell lines from five different complementation groups (FANCA, FANCB, FANCC, FANCD2 and FANCD1/BRCA2) demonstrated the efficiency of this approach to generate potentially corrective events in all the different complementation groups studied. Importantly, corrected cells showed a marked proliferative advantage after in vitro culture and the analysis by next generation sequencing confirmed the expansion of cells harboring therapeutic events. Functional studies showing the reversion of mitomycin C sensitivity, FANCD2 foci formation and chromosomal instability supported the phenotypic correction of different mutations by NHEJ-mediated gene editing. Moving towards the clinical application of NHEJ-mediated repair we focused on improving the gene editing efficiency in HSCs. To this aim, chemically modified small guide RNAs (MS-sgRNAs) enabled us to increase the editing efficacy 8-fold compared to efficacies obtained with in vitro transcribed sgRNAs, reaching up to 89% indels in healthy donor hematopoietic stem/progenitor cells. Moreover, the CRISPR/Cas9 system demonstrated high editing capacity in the primitive HSCs capable of engrafting immunodeficient NSG mice, confirming the efficacy of NHEJ-editing to correct the phenotype of long-term repopulating HSCs. Finally, studies conducted in mobilized peripheral blood and bone marrow CD34+ cells from FA patients demonstrated the feasibility to correct FA HSCs by NHEJ-mediated gene editing and confirmed the proliferative advantage of NHEJ-mediated corrected cells both in vitro and in vivo. Our results suggest that NHEJ-mediated gene editing should constitute a versatile and simple therapeutic approach to efficiently correct specific mutations in FA and other monogenic disorders of the hematopoietic system. Disclosures Sevilla: Rocket Pharmaceuticals, Inc.: Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rocket: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Honoraria. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding. Rio:Rocket Pharmaceuticals, Inc.: Equity Ownership, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents, Research Funding.

Description: Key Points Tcl1 cooperates with the NF-kB pathway in the pathogenesis of the aggressive form of CLL.

Description: Introduction Outpatient autologous stem cell transplantation (ASCT) has become standard of care in many centres due to limited inpatient resources and rising financial constraints. Outpatient ASCT involves family members/friends assuming some patient care responsibilities during the acute transplant period. Although this may be associated with reduced direct medical costs, little work has been done to ascertain the "out of pocket costs" and "lost opportunity costs" to patients and their caregivers. Outpatient transplantation is perceived to provide superior quality of life (QOL) for patients, but there is little evidence to support this. In addition to patients' QOL, there is limited data on the impact of these treatments on caregivers' QOL. Thus, our objectives were to compare the QOL of patients and their caregivers undergoing outpatient and inpatient ASCT, and to quantify indirect costs to them. Methods This is a single centre cohort study of consecutive patients with lymphoma and plasma cell disorders undergoing ASCT at Princess Margaret Cancer Centre from April 2016 - July 2019. Patients without a primary caregiver were still eligible to complete the QOL portion of the study. All patients completed four questionnaires: Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT); FACT-Fatigue (FACT-F); EQ-5D-3L; and a distress impact thermometer. Clinically meaningful differences between the groups and serially were defined as ≥ 4 points on the FACT-BMT and FACT-F, and ≥0.08 on the EQ-5D-3L. Caregivers completed three questionnaires: Caregiver Quality of Life Index-Care (C-QOLC), a distress impact thermometer, and a caregiver self-administered financial expenditure survey (C-SAFE). Indirect costs were defined as lost opportunity costs (i.e., wages) and out-of-pocket costs (e.g., parking, accommodations). Questionnaires were completed at 5 time points: D0 (prior to ASCT), D+7, D+14 (discharge from daily visits), D+28 (discharge from ASCT) and D+100 (follow-up). Results In total, 68 patients have been enrolled to date (41 outpatients and 27 inpatients), and 54 caregivers (38 outpatients and 16 inpatients). Median patient age was 57 yrs (range: 18-71), and 66% were male. Of the 68 patients, 69% had a diagnosis of multiple myeloma and 31% lymphoma. Majority of caregivers were spouses (74%). In the overall sample, FACT-F scores (fatigue) increased significantly at D+7, D+14, and D+28, with improvement at D+100 (all p

Description: Hematopoietic progenitor cells of myeloproliferative neoplasms with myelofibrosis (MPN-MF) exhibit constitutive activation of JAK-STAT5/3 and NFkB signaling. Transformation of MPN-MF to AML (post-MPN sAML) occurs in up to 15% of patients with MPN-MF. Standard induction anti-AML chemotherapy and the JAK1 & 2 inhibitor (JAKi) ruxolitinib are ineffective in post-MPN sAML. BET protein BRD4 is a non-oncogene addiction target in AML, and treatment with acetyl-lysine mimetic BET protein inhibitor (BETi) disrupts binding of BRD4 to acetylated chromatin and transcription factors (TFs). This attenuates transcription of super-enhancer regulated oncogenes, including MYC, Bcl-xL, PIM1 and CDK4/6, inhibiting growth and survival of post-MPN sAML blasts. BETi treatment also inhibits binding of BRD4 to acetylated RELA (NFkB-p65), inhibiting its transcriptional activity and attenuating levels of its target cytokines. However, BETi treatment induces BRD4, potentially reducing BETi activity in repressing oncogenes. Preclinical and clinical studies have demonstrated that innate or adaptive BETi-resistance is common in sAML cells. To model BETi-resistance, we repeatedly exposed (10 times) secondary (s) AML SET2 and HEL92.1.7 (HEL) cells to 1.0 µM of the BETi OTX015 for 48 hours followed by full recovery, thus generating BETi persister-resistant (BETi-P/R) SET2-P/R and HEL-P/R cells. These cells showed 〉 10-fold resistance to OTX015 and cross-resistance to other BETis. Compared to the parental controls, BETi-P/R cells lacked additional genetic alterations or altered levels of TRIM33, SPOP, DUB3 or phosphorylated BRD4 (previously described mechanisms of BETi-resistance). However, ATAC-Seq and ChIP-Seq (H3K27Ac mark) analyses demonstrated that, as compared to their parental controls, BETi-P/R cells showed gain of peaks and active enhancers with enrichment of STAT5, MYC, PU.1 and GATA2 binding sites. Newly gained peaks were in the enhancers of JAK1/2, RUNX1, PU.1, MYC and BCL2L1. RNA-Seq determined mRNA level alterations, included induction of gene-sets involving MYC/MAX, STAT5, NFkB and TCF7L2 targets. QPCR and Western analyses confirmed increase in the mRNA and protein levels of TCF7L2, JMJD6, c-Myc, Survivin and PIM1 in HEL-P/R over HEL92.1.7 cells. Expression of the arginine demethylase JMJD6, recruited by BRD4 to regulate enhancer-mediated transcriptional pause-release, was also increased. This was associated with increased expression of the nuclear β-catenin-TCF7L2 targets, including Cyclin D1, TERT, survivin, c-Myc and PU.1. Patient-derived human AML blasts that exhibited innate resistance ex vivo to BETi, also demonstrated increased expression of TCF7L2, JMJD6 and c-Myc. We next probed the mechanistic role of the β-catenin-JMJD6-TCF7L2-MYC axis in conferring BETi-resistance. CRISPR-Cas9-mediated knockout of TCF7L2 or JMJD6 significantly reversed BETi-resistance in BETi-P/R sAML cells (p 〈 0.001). Conversely, ectopic overexpression of TCF7L2 or JMJD6 significantly conferred BETi-persister-resistance in HEL and SET2 cells (p 〈 0.001). Notably, confocal microscopy demonstrated increased binding of β-catenin with TBL1 and TCF7L2 in the nucleus of BETi-P/R sAML cells. BC2059, which disrupts binding of nuclear β-catenin with TBL1 and TCF7L2, depleted β-catenin levels and exerted similar lethality in BETi-P/R sAML and control sAML cells. shRNA-mediated knockdown of BRD4 and treatment with BRD4-PROTAC (proteolysis-targeting chimera) ARV-771 (Arvinas, Inc.) that degrades BRD4/3/2, also induced similar levels of apoptosis in BETi-P/R and control sAML cells. Co-treatment with ARV-771 and BC2059 synergistically induced lethality in BETi-P/R sAML cells as well as in patient-derived, CD34+ sAML BPCs (combination indices 〈 1.0). This was associated with marked attenuation of c-Myc, TCF4, Survivin, CDK6, PIM1 and Bcl-xL levels. Also, compared to each agent alone, in vivo treatment with ARV-771 (30 mg/kg SQ daily x 5, per week) and BC2059 (30 mg/kg IP BIW per week) for 3 weeks, significantly reduced sAML burden and improved survival of NSG mice engrafted with HEL-P/R cells (p 〈 0.01). Collectively, these findings underscore that increased levels and activity of β-catenin-TCF7L2-JMJD6-MYC axis is mechanistically responsible for BETi-P/R, and co-targeting with BRD4 degrader and β-catenin-TCF7L2 inhibitor is a promising therapeutic strategy against BETi-P/R sAML BPCs. Disclosures Bhalla: Beta Cat Pharmaceuticals: Consultancy. Verstovsek:Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding.

Description: Background: Many older adults (≥60) with AML have a poor prognosis and spend a high portion of their life from diagnosis until death in the hospital. Using a large cohort, we examined the reasons for hospitalizations and identified those which are potentially avoidable. Methods: We conducted a retrospective analysis of 329 consecutive patients (≥60) diagnosed with AML between 5/1/2005 and 12/31/2011 at two major tertiary care hospitals to examine the reasons for hospitalizations during treatment. Practicing physicians used a consensus-driven medical record review process to identify primary reason for each hospitalization and categorize it as "potentially avoidable" or "not avoidable" based on a novel adaptation of the Graham's criteria for potentially avoidable hospital admissions. We compared the rate of potentially avoidable hospitalizations between older patients receiving intensive chemotherapy (n=197) versus non-intensive chemotherapy (n=132) using multivariate logistic regression analysis controlling for age, gender, marital status, disease risk, comorbidities, and the receipt of stem cell transplantation. Results: We evaluated 1040 hospitalizations after the diagnosis of AML in 329 unique patients. The median age was 69.9 years [range 60-90] and the median number of hospitalizations was 4.2 [range 0-18]. 33.1% (109/329) of patients underwent stem cell transplantation. The most common primary reasons for hospitalizations were: fever/infection (38.0%), planned hospitalizations for chemotherapy or transplantation (37.7%), and uncontrolled symptoms (9.8%). We identified 180/1040 hospitalizations (17.4%) as potentially avoidable; among these, 47.8% were due to premature hospital discharge, 18.9% could have been managed in the outpatient setting, and 16.1% were due to failure of timely outpatient follow-up. Potentially avoidable hospitalizations represented 12.9% (76/589) and 23.1% (10/451) of hospitalizations among patients who received intensive chemotherapy and non-intensive chemotherapy, respectively. In multivariate logistic regression analysis, the receipt of non-intensive chemotherapy was associated with higher risk of potentially avoidable hospitalization [OR 2.01, 95% CI 1.27-3.20, P = 0.003]. Conclusions: Although many hospitalizations in older patients with AML are unavoidable and driven by the illness course and its treatment, a substantial proportion are potentially avoidable. Patients with AML undergoing non-intensive chemotherapy are at higher risk of having potentially avoidable hospitalization. Future interventions to reduce health care utilization in this population are needed, especially among those who are treated with non-intensive chemotherapy. Disclosures Steensma: Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. LeBlanc:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Epi-Q: Consultancy; Flatiron: Consultancy; Helsinn Therapeutics: Honoraria, Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Merck: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding. DeAngelo:Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Agios: Consultancy; Bristol Myers Squibb: Consultancy. Stone:Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Agios: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Roche/Genetech: Consultancy; AROG: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Celator: Consultancy. Chen:Bayer: Consultancy, Research Funding.

Description: Generation of hematopoietic stem cells (HSCs) from pluripotent stem cells, in vitro, holds great promise for future somatic gene and cell therapy. So far, HSCs capable of long-term multilineage reconstitution in mice have only been obtained when the homeodomain transcription factor HOXB4 was ectopically expressed during pluripotent stem cell differentiation (Kyba et al. Cell 109(1): 29-37, 2002; Pilat et al. Proc Natl Acad Sci USA 102(34): 12101-12106, 2005; Lesinski et al. Stem Cells Transl Med 1(8): 581-591, 2012). However, the primary "target" cell of HOXB4 during hematopoietic development, in vitro, is not yet known. Its identification is a prerequisite for unambiguously identifying the molecular circuits driving HSC development, at least in vitro. To pin down this cell, we retrovirally expressed HOXB4 or a Tamoxifen-inducible HOXB4-ERT2 fusion protein in different reporter and knock-out mouse embryonic stem cell (ESC) lines. For these experiments, ESCs were differentiated for 6 days as embryoid bodies (EBs), dissociated and subsequently cocultured on OP9 stroma cells in medium supplemented with 100 ng/ml mSCF, 40 ng/ml mTPO, 100 ng/ml hFlt3L and 40 ng/ml hVEGF (STFV) for further 3 days. Use of a Runx1(-/-) ESC-line containing a doxycycline-inducible Runx1 coding sequence (“iRunx1”; kindly provided by G. Lacaud, Manchester) uncovered that HOXB4 acts during formation of the hemogenic endothelium (HE) from which HSCs arise. Without Runx1 induction, which arrests hematopoietic development at the HE-stage, ectopic HOXB4 expression mediated an approximately 30-fold increase in the number of circular endothelial, bona fide HE-sheets being Flk1+VE-Cadherin+Tie2+ (mean values: control: 11+/-4.8 n=7; HOXB4: 301+/-47 n=7; P

Description: INTRODUCTION: Chronic lymphocytic leukemia (CLL)-like monoclonal B cell lymphocytosis (MBL) is considered a precursor of CLL. It is found in 5-10% of elderly healthy individuals and shows a progression rate to CLL requiring therapy of 1.1% per year. A balance between microenvironmental factors and intrinsic properties of the emerging B cell clone may be decisive for the transition from MBL to CLL, although biomarkers of progression remain unknown. The objective is to describe biological markers (B cell gene expression profiles and serum cytokine levels) that predict progression from MBL to CLL. METHODS: Gene expression profiles of clonal B cells from 14 MBL subjects (median age: 76 years, clonal B cells: 0.5-4.3 x109/L) were evaluated. With a median follow-up from analysis of 59 months (range: 10-77), 3 cases (21.4%) had progressed to CLL Binet stage A at last follow-up (clonal lymphocytosis 〉5x109/L, range: 6.2-7.9). Clonal B cells (CD19+CD5+) were isolated from peripheral blood by immunomagnetic methods (Miltenyi Biotec). Extracted RNA (RIN〉7) was hybridized to GeneChip Human Gene 2.0 ST arrays (Affymetrix). Gene expression profiles were compared between MBL cases that progressed to CLL (P-MBL, n=3) and non-progressive MBL cases (NP-MBL, n=11). Differential gene expression was evaluated employing linear models for microarrays in R, and genes with P1.5 or 5x109/L, range: 6.4-17.3). Clonal B cells and cytokine levels were compared between P-MBL (n=5) and NP-MBL (N=36). For cytokine levels, the optimal cut-off values to stratify MBL cases according to their progression risk were assessed using the maxstat R package, whereas for clonal B cells a cut-off value of 3.9 x109/L was considered according to the results obtained by Kostopoulos et al (Blood Cancer J, 2017). The effect of different covariates on progression-free survival was evaluated using log-rank test. Cox proportional hazards regression models were performed to assess their independent prognostic value. P

Description: Introduction. Prefibrotic myelofibrosis (pre-PMF) is a unique entity in the 2016 WHO classification of myeloproliferative neoplasms with distinct clinical phenotype and outcome [Guglielmelli P, Blood 2017]. Compared to essential thrombocythemia (ET), pre-PMF is characterized by more pronounced disease manifestations, adverse mutation profile and worse outcome. Previous studies [Rumi E, Oncotarget 2017] showed that patients (pts) with pre-PMF present a risk of vascular events similar to ET. However, no studies performed a comprehensive assessment of risk factors for thrombosis in pre-PMF. The current study aimed to identify risk factors for thrombosis and bleeding in a large series of pre-PMF pts and explore the effectiveness of contemporary prognostic models developed specifically for ET. Patients and Methods. The study included 382 pre-PMF pts, diagnosed by 2016 WHO criteria, referred by 4 Italian Centers. Previously published methods were used to genotype JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2; a high molecular risk (HMR) category was defined according to Vannucchi A, [Leukemia 2013]. Thrombosis‐free survival (TFS) was determined from diagnosis to the first thrombotic event. Pts were grouped according to the conventional risk stratification system [Barbui T, JCO 2011], IPSET‐thrombosis [Barbui T, Blood 2012] and revised IPSET‐thrombosis [Barbui T, BCJ 2015]. Cox-regression model was used for univariate analysis. Harrell's concordance (C) statistic was calculated to measure the incremental accuracy of multivariable models sequentially adjusted for new predictors of thrombotic risk. A P 65y (HR 2.88; P=0.005), WBC〉10x109/L (HR 2.43; P=0.026), presence of 〉1 generic CV risk factor (HR 2.16; P=0.047), JAK2V617F (HR 3.35; P=0.027) and HMR status (HR 13.1; P=0.027). Conversely, only history of previous thrombosis (HR 3.06; P=0.005) and previous venous event (HR 5.53; P10x109/L or HMR variables were incorporated into IPSET model, the C-statistic increased significantly for the prediction of arterial events: from baseline value of 0.68 to 0.74 adding WBC and 0.91 HMR status. The proportion of pts who experienced major bleeding was 3% prior/at diagnosis,and 7% during follow-up, with total incidence rate of 0.94% pt-y. In univariate analysis, predictors for major bleeding during follow-up were age 〉75y (HR 3.34; P=0.011), WBC〉13x109/L (HR 2.33; P=0.035), presence of 〉1 generic CV risk factor (HR 2.41; P=0.035), particularly hypertension (HR 2.63; P=0.016) and grade-1 fibrosis (HR 2.28; P=0.05). High platelet count and treatment, including antiplatelet and anticoagulant drugs, did not reach statistical significance. Conclusions. Overall, this study identified independent risk factors for major thrombosis and bleeding in pre-PMF. Of interest, we report that HMR status predicted for arterial thrombosis during the follow-up. Pre-PMF pts showed remarkably high rate of venous thrombosis, mostly represented by SVT. The 3-tiered IPSET prognostic model for thrombosis reliably predicted occurrence of thrombotic events in pre-PMF and should be considered as standard reference. Figure 1 Disclosures Rumi: novartis: Honoraria, Research Funding. Thiele:Shire: Research Funding; Incyte: Consultancy, Honoraria, Other: Remuneration, Research Funding; Sanofi: Consultancy, Honoraria, Other: Remuneration; Novartis: Consultancy, Honoraria, Other: Remuneration, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Research Funding. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Background Mature nodal or extranodal T-cell and NK-cell NHL are a rare and heterogeneous group of NHL with aggressive behavior and poor clinical outcome. Their incidence varies according to geographical region and racial characteristics. Mexico is included in those countries known to have a high incidence of extranodal T/NK-cell lymphoma, type nasal (NKTCL). Objective To evaluate the outcome and prognosis of patients with mature nodal or extranodal T-cell or NK-cell NHL in a single institution in Mexico City. Methods Clinicopathological characteristic, treatment, outcome, and prognosis of patients admitted to our institution between August, 1991 and December 2009 were analyzed. Prognostic Index T-cell (PIT) was used in all subtypes of lymphomas except in NKTCL subtype. All tissue biopsies and immunophenotypic markers were reviewed by an expert hematopathologist and reclassified according to the WHO 2008 classification. Univariate analysis using log-rank test was used to determine the correlation between clinical features and overall survival (OS). Multivariate analysis using Cox proportional hazard models were performed. A p value 〈 0.05 was considered significant. Results A total of 67 patients were analyzed. Median age was 37 years. B symptoms were presented in 83.6%, 74.6% had at least one site with extranodal disease, 73.1% advanced clinic stage, 32.8% high risk by International Prognostic Index (IPI) and 47.5% high risk by PIT. According to WHO 2008 classification the most common subtype was peripheral T-cell lymphoma not otherwise (PTCL NOS) specified in 38 patients (56.7 %), angioimmunoblastic T-cell lymphoma (AITL) and NKTCL were the second most common subtypes with 8 cases in each group (11.9 %), anaplastic large cell lymphoma (ALCL) kinase-positive (ALK-positive) was identified in 3 patients (4.5 %), ALCL ALK-negative in 2 cases (3.0 %), lymphoblastic lymphoma and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with 3 patients in each group (4.5 %), hepatosplenic T-cell lymphoma (HSTL) and aggressive NK-cell leukemia with one case in each group (1.5 %). CHOP-like therapy was used in 71.6 % of patients. Nine percent of patients did not receive treatment. The response was evaluated in 53 patients in whom overall response was 71.7 % with 44.8 % achieving complete remission (CR). Median OS was 2760 days (CI 95 % 1153.145-4366.855). Histopathology subtype did not predict OS. Both prognostic scores, IPI and PIT, were able to identify 4 groups of patients with different outcomes. The analysis failed to demonstrate any advantage of adding etoposide to the chemotherapy schedule. Multivariate analysis showed that, IPI, PIT, and CR were predictive for OS (Table 1). Conclusion Previous publications in Mexican population, with larger number of patients included, were particularly focus on clinical characteristics and prognosis of NKTCL. Our series provides data of mature nodal or extranodal T-cell and NK-cell NHL in Mexico. The current study confirms the poor prognosis of aggressive forms of mature nodal or extranodal T-cell and NK-cell NHL regardless of the chemotherapy schedule employed. Disclosures: No relevant conflicts of interest to declare.