ALBERT

Description: The development of the NCCN International Prognostic Index (NCCN-IPI) for patients with DLBCL treated in the rituximab era improves discrimination when compared to the original IPI model. The aim of the present study is to validate the results of the NCCN-IPI in a large independent series of patients in a different geographical area. Materials & Methods. This nation-wide retrospective study includes 2156 patients with de novo DLBCL diagnosed in 20 (mostly) large academic Spanish centers within the Grupo Español de Linfomas y Transplante de Médula Osea (GELTAMO) network between 1998 to July 2014. Patients had to be ≥ 18 years-old, treated with rituximab plus chemotherapy (R-CHOP or variants and also more intense treatments) and a minimum of 1 year of follow-up; all histological subtypes of DLBCL and primary extranodal cases were acceptable, with the only exclusion of primary testicular or CNS sites. In the whole series the scoring of the IPI and NCCN-IPI indexes were used and 5-year Overall Survival (5y-OS) estimated with the Kaplan-Meier method and compared with the log-rank test. Results. Debugging the database resulted in a final working series that included 1885 patients. The demographics of the series were comparable to the NCCN series: NCCN/GELTAMO male gender(%) 54 vs 50.4, Age(y) 57 vs 60, LDH〉1(%) 50 vs 54.7, Ann Arbor stage III-IV (%) 59 vs 62.5, ECOG PS≥2(%) 11 vs 30, extranodal disease(%) 36 vs 40.7. The IPI scoring (1760 patients) significantly separated the four risk groups, low (LR, 33.6% of the patients), low/intermediate (LI, 22.7%), intermediate/high (HI, 25.1%) and high (HR, 18.6%) with significantly different (p

Description: Introduction: Cerebrovascular disease (CVD) is a multifactorial disease caused by the interaction of genetic and environmental factors. The atherosclerotic plaque, the pathological hallmark of CVD, is an inflammatory process, where pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα). TNFα secretion shows a high degree of interindividual variability, which is at least partly genetically determined. We have analysed the prevalence of −238 G/A and −308 G/A polymorphisms in the regulatory region of the TNFα gene promoter in CVD. Patients and methods: Genotypic analyses were performed on 308 consecutive unrelated patients diagnosed with ischemic CVD, 147 women and 161 men, mean age 70±0.8 years, who were diagnosed according to the Trial of Org 10172 in Acute Stroke Treatment. All included cases were age and sex matched to a control from the same geographic area who had no history of vascular disease. Patients and controls completed a questionnaires including blood pressure, diabetes status, total serum cholesterol level and smoking history. The TNFα variants were detected by PCR using primers containing a single base-pair mismatch to introduce a restriction site into the wild-type nucleotide sequences after amplification. PCR products were digested with NcoI and MspI to detect −308 and −238 variants, respectively. The strength of the association of the polymorphisms with the occurrence of CVD was estimated by calculation of the OR and its 95%CI by exact method. P values less than 0.05 were considered significant. Logistic regression analysis was applied to estimate the risk in a multivariable predictive model with dependent variable (case/control) and all independent variables significant in the bivariate analysis. SPSS 9.0 was used for the statistical analysis. Results: Genotype analysis showed a significant higher prevalence of the G/A and A/A genotypes of −238 G/A TNFα in patients (p〈 0.01;OR= 2.16;95%CI= 1.40–3.34). The prevalence of the A allele was also significantly increased in the group of CVD patients than in the controls (13.6% vs 7.0%; p

Description: Abstract 1596 Background: The IPI, which takes into consideration both host and tumor factors, is the standard method used to stratify aNHL into different risk categories. The IPI was derived in the pre-rituximab era and confirmed as valid in the Rituximab (R) era. The major mechanism of action of R appears to be through the host's immune system. Host factors related to the immune status have been recently recognized as significant in predicting outcome. The ALC, AMC, and ALC/AMC ratio were identified by Wilcox et al. as having an impact on both progression free survival (PFS) and overall survival (OS) (Leukemia 2011;25:1502-09). In order to confirm these findings in a different population of aNHLs we have studied 402 patients with aNHL treated in the R era at 5 centers: 1 in Puerto Rico, 4 in Spain (1 Barcelona, 2 Madrid, 1 Valencia). Methods: 402 patients diagnosed between December 2000 and April 2011 with aNHL were included. ALC and AMC were obtained from pretreatment CBC. All patients received anthracycline and R based chemotherapy. ALC was divided in quartiles (Q): 1st Q ALC ranged between 277 and 950, 2nd Q ALC 951–1352, 3rd Q ALC 1353–1870, and the 4th Q ALC 1871– 5400. The lower Q ALC of 950 and the median of 1353, as well as the lower Q AMC of 366 and the median AMC of 504 were assessed as cutoffs to divide patients into groups with low or high ALC and AMC. Results: Median age was 64 (17–92) and 55% were females. Median follow up was 50 months. FFS and OS at 4 years were 73% and 79% respectively. FFS was superior for patients with an ALC 〉950 vs

Description: Phase II trials have shown that lenalidomide alone is active in relapsed and refractory CLL. When the initially dose is reduced from 25mg to 5-10mg associated toxicities as the tumor lysis syndrome (TLS) or tumor flare reaction (TFR) nearly disappeared (J Clin Oncol 2006,24:5343). There is synergistic activity between rituximab and lenalidomide against CLL and non-Hodgkin lymphoma cells in vitro, and recently a Phase II study demonstrated that the combination of lenalidomide and Rituximab is active in patients with recurrent CLL (J Clin Oncol, 2012,31: 584). However neither the dose of lenalidomide nor the optimal schedule of administration has been defined. Furthermore since median age of CLL patients is high the emergence of a nonchemotherapy containing regimen with a lower toxicity seems an attractive approach for them. In 2008 we designed a trial that explore the optimal doses of lenalidomide in combination with rituximab for patients with relapsed or refractory CLL and analized also its safety and efficacy (ClinicalTrials.gov:NCT01185262). Our primary endpoint was to define the recommended dosage regimen for the combination of lenalidomide plus rituximab in patients with relapsed/refractory CLL. From June 2009 to November 2012 a dose escalation study was performed starting at a lenalidomide daily dose of 2,5mg and rituximab (375mg/m2 cycle 1 and 500mg/m2 cycles 2-6/28 days) with cohorts of 3 patients (if no DLT move to a higher dose; if one DLT ocurred in the cohort expand 3 more patients)(Tables 1 and 2). 29 patients has been registered in the trial. 4 of them were screening failures either because did not fullfilled criteria (2) or early withdrawal of patient consent before receiving treatment(2). Median age was 75 years (45-86). Median number of previous lines of treatment were 2 (1-4) and all but 2 patients were treated previously with fludarabine. In the first cohort of 2.5 mg we treated 6 patients and because of persistent neutropenia (more than 7 days grade 4) MTD ocurred. This was because the original protocol did not accept the prohylactic use of G-CSF. From that moment the use of G-CSF was free and based on the investigator criteria but mandatory for all those patients that started with less than 1000 neutrophils/mm3. A total of 33 SAEs were recorded among the 25 patients included in the two periods of the study (before and after the free use of G-CSF)(7/26 respectively) and during all the treatment. Main SAEs were as follows: Infections (23 SAEs with one case of Multifocal leukcoencephalophaty), constipation (2), autoimmune hemolytic anemia (1), allergic reaction to rituximab infusion (1), amyotrophic lateral sclerosis (1), gastrointestinal bleeding(1) and others (4). No case of TLS has been reported and only one case of mild TFR. By June 1st 2013 9/29 patients included has died and one is still receiving treatment. Causes of death were disease progression (5) and infection (4). In our experience the combination of lenalidomide and rituximab was a well tolerated regimen for this old (median age 75y) and heavely pre-treated population. In our experience lenalidomide at 15 mg was defined at the MTD. Neutropenia was the main adverse event associated with the regimen and nearly all patients needed G-CSF support. Clinical eficacy data is on evaluation.Table 1Dose LevelDose of lenalidomideTotal dose of rituximab (Cycle1/Cycle2 & subsequently)I2,5 mg/day375/500 mg/m2II5 mg/day375/500 mg/m2III10 mg/day375/500 mg/m2IV15 mg/day375/500 mg/m2V20 mg/day375/500 mg/m2VI25 mg/day375/500 mg/m2Table 2N patientsDLT2,5 mg3No5 mg4No10 mg4No15 mg82 Disclosures: Tomas: Celgene: Research Funding.

Description: Objectives. To evaluate clinical efficacy, molecular response and safety following the use of a regimen of fludarabine (25 mg/m2 x 3 days) Cy (1g/m2 x 1 day) and Rituximab (375 mg/m2/ x 1 day) (FCR)x 6 cycles, followed by maintenance with rituximab (375 mg/m2/week/x 4 weeks every 6 months x 2 years). (LNHF-03 Study). Patients and methods. Seventy-five (75) patients with a diagnosis of follicular NHL were included in the study between October 2004 and January 2006. The median age was 54 years (30–75). Twenty-one per cent (21%) of the patients had bulky disease. According to the FLIPI index: (0–1): 22.6%; 2: 40,3%; 3: 37,1%. Minimal residual disease (MRD): A clonal population on diagnosis was identified by means of the bcl–2/IgH major and minor rearrangement study by means of quantitative PCR rearrangements of the Igs by means of fluorescent PCR. Subsequently, samples were studied following the induction treatment and during the maintenance treatment. The analysis is performed in the 70 patients that completed the six induction regimens and were evaluated. Results. 64/70 patients were given the six cycles planned (91%). The presence of persistent cytopenia limited the cycles given in the other 6 patients to 4 or 5. Three hundred and thirty-eight (338) adverse effects were documented in the 414 cycles given to the 70 patients evaluated, almost all of them being mild, and 26 severe (degree 3–4), and almost all the cases were neutropenias. Infectious complications were frequent and many were severe: herpes zoster (5), pneumonia (5), cerebral toxoplasmosis (1), aspergillosis (1), infection by CMV (2). One patient developed erythroleukaemia within the first year following completion of the treatment. Three patients died ( CMV + aspergillosis, pneumonia, erythroleukaemia). 86% of the patients reached CR following induction, 6% unconfirmed CR and 8% partial response. On diagnosis, a clonal population was identified in 63% (45/71) of the cases. Of these 45 patients, samples are available following induction treatment in 35 cases. The molecular disease was negativised in all the cases, except one case with persistence of positive bcl2/IgH (0.3% as opposed to diagnosis) and is in uncertain CR. Of the 34 cases with negative ER, 32 are in CR or uncertain CR and 2 PR. Conclusions. The FCR regimen has proven to have a potent antitumoral activity in recently diagnosed follicular lymphoma patients with very high clinical (86% CR) and molecular (95%) responses. The immunosuppression caused is profound, with the appearance of opportunistic infections, and in some cases prolonged lymphopenias and neutropenias that call for future assessment and follow-up.

Description: Introduction and Objective: Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL-NT) is associated with Epstein-Barr virus (EBV) and is much more common in Asia and Latin America than in western countries. Data on disease presentation and outcome from European series are very limited. The objective of the study is to analyze the clinical characteristics at diagnosis, treatment received and outcome of a series of patients from Spain. Patients and Methods: Eigthy-seven patients with ENKTL-NT diagnosed from 2000 to 2017 were identified in 24 academic centers in Spain. Clinical data were collected retrospectively. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Variables included in the univariate analysis were: race, gender, age, previous sinusitis, nasal localization, Ann Arbor stage, ECOG performance status (PS), B symptoms, LDH, beta2-microglobulin, albumin and C-reactive protein. Multivariate analyses were performed by Cox proportional hazard regression model. Results: Clinical characteristics at diagnosis are shown in Table 1. Seventy-seven patients received active treatment, 31 (40%) with chemotherapy (CT) alone, 39 (51%) with CT and radiotherapy (RT), 7 (9%) with RT alone (median dose 50 Gy). First line therapies were: CHOP/CHOP-like in 30 (42%) patients, high-dose L-Asparaginase-containing regimens in 27 (38%), and other regimens in 14 (20%); 12 patients proceeded to stem-cell transplant in first line (10 auto / 2 allo). Response rate was evaluable in 70 patients (by PET/TC in 55%): CR 35 (50%), PR 9 (13%), SD/progression 26 (37%). Median number of CT lines was 2 (1-6). With a median follow-up of 38 months, 3 yr OS was 38% (95% CI 27-49), and 3 yr PFS 25% (95% CI 14-35). Causes of death were: progression 35 (67%), toxicity 12 (23%), second neoplasms 5 (10%). The variables at diagnosis significantly associated with poor OS were: age ≥ 60 yr, extranasal disease, Ann Arbor III-IV, ECOG PS 2-4, increased LDH, and decreased albumin. In the multivariate analysis including all the previous variables, ECOG 2-4 PS (HR 3.3, 95% CI 1.4-7.0) and low albumin (HR 3.6, 95% CI 1.4-9.3) maintained the negative influence in OS. Patients treated with regimens that included high dose L-Asparaginase had 3 yr OS of 61% (95%CI 40-82), compared with patients treated with CHOP/CHOP-like 3 yr OS of 19% (95%CI 5-32) (p=0.009). These differences were statistically significant both in patients with nasal involvement (3 yr OS 82% with L-Asparaginase vs 21% with CHOP, p=0.01) or with localized disease (3 yr OS 71% with L-Asparaginase vs 24% with CHOP, p=0.03). Differences were not statistically significant in patients with extranasal involvement (3 yr OS 48% with L-Asparaginase vs 14% with RCHOP, p=0.2), or advance disease (3 yr OS 48% with L-Asparaginase vs 14% with CHOP, p=0.2), probably because the low number of patients. Conclusion: This is the largest series reported of Caucasian patients with ENKTL-NT. Patients are young at diagnosis and one fourth had a previous history of chronic sinusitis. This population has a poor outcome, being progression the main cause of death. Poor clinical condition at diagnosis (high ECOG PS and low albumin level) is the main factor related with poor survival. Therapies with high dose L-Asparaginase improve the survival in this western population compared with the classical CHOP regimen. Disclosures González-Barca: Roche: Speakers Bureau; Celtrion: Consultancy; Gilead: Consultancy; janssen: Consultancy, Speakers Bureau. Martín:Celgene: Consultancy, Honoraria, Other: Travel expenses; Roche: Consultancy, Honoraria, Other: Travel expenses; Janssen: Honoraria, Other: Travel expenses; Servier: Honoraria, Other: Travel expenses. Panizo:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Sanchez Blanco:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria. Marin Niebla:Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Amgen: Other: Medical education of Staff, Speakers Bureau. Queizan:Janssen: Consultancy. Lopez:Roche: Research Funding.

Description: Abstract 3654 Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, showing affected patients a highly variable outcome. The improvement in survival gained with the addition of rituximab to CHOP chemotherapy (R-CHOP) led to re-define the international prognostic index (IPI). The new index, known as revised IPI (R-IPI), showed to be simpler as it groups the patients in only 3 risk groups. However, the effect of prior rituximab-therapy upon the usefulness and significance of previously recognized prognostic factors on patients relapsed or refractory and receiving subsequent treatment with rituximab plus chemotherapy in DLBCL remains unexplored. Biological parameters, including expression of Bcl-6, Bcl-2, p53 and MUM-1 have been described as IPI-independent prognostic factors. Objectives: The objective of this study was to evaluate the benefit of the R-IPI to predict the outcome of DLBCL patients at the relapse time following a front line treatment with chemotherapy and rituximab. We also aimed to establish in this population the relationship between immunohistochemical expression of biological parameters and outcome. Patients and methods: this was a multicentric, observational, post-authorization and cross-sectional study (ClinicalTrials.gov identifier: NCT01369784). Inclusion criteria were: patients with age ≥ 18 years with DLBCL refractory/relapsed after first line treatment with rituximab, with or without transplantation. Patients must have finished a rescue treatment including rituximab. Written informed consent was obtained from participants. When the data of the biopsies at diagnosis and relapse were available, immunohistochemical results of bcl-2, bcl-6, p53 and MUM-1 were obtained. Results: 152 patients were included (146 evaluables) with a median age of 58 years. At LDBCG diagnosis 48% had 〉 1 extranodal localization (29% had bone marrow disease), and 30% had ECOG 2 or greater. Eighty-one percent presented stages III or IV and 72% had elevated LDH. Three percent had very good prognosis R-IPI, 69% good prognosis R-IPI and 27% poor prognosis R-IPI. Most patients received R-CHOP as first line therapy. Overall response rate was 79% (40% complete remission). Relapse was confirmed with biopsy and histological study in 55 patients. At relapse 31% presented 〉 1 extranodal localization, 30% ECOG 2–4, 64% stages III-IV and 72% elevated LDH. R-IPI prognostic groups distribution at relapse were as follows: 8% very good, 75% good and 27% poor. R-ESHAP and R-GEMOX were the two more used rescue therapies resulting in 60% overall response rate (31% complete remission). R-IPI at relapse was significantly associated (p 〈 0,05) with overall response rate following R-chemotherapy rescue therapy. None of the immunohistochemical parameters analized correlated with rescue therapy results. Conclusions: This is the largest reported series analizing R-IPI in DLBCL at relapse/refractory in patients receiving R-chemotherapy. In this series of patients R-IPI calculated at the relapse time was the only prognostic factor capable of predicting the overall response to the second line of treatment. Thus R-IPI prognostic score is a simple and useful predictor for outcome in DLBCL at relapse/refractory Disclosures: No relevant conflicts of interest to declare.

Description: Background and Aim:It is increasingly recognized that patients with a de novomyelodysplastic syndrome (MDS) onset as young adults, lacking any other feature of a congenital disorder, may share a pathogenic overlap due to the presence of both germline and somatic variants. Identifying an inherited pathogenic variant has important therapeutic implications beyond family counselling: adapting the selection of sibling donor, the use of highly cytotoxic therapy and the monitoring for other cancer development. However, most studies have focused on patients with suspected inherited disorders based on the presence of physical abnormalities and/or family history. In addition, a mixture of pediatric and adult cases is usually reported. The aim of this study is to characterize the germline and tumor variants in a group of adult MDS patients without accompanying congenital physical anomalies and or family antecedent of bone marrow failure. Methods: We included 72 patients from 15 Spanish centers with a diagnosis of MDS between 18 and 60 years old (y.o). Patients with a previously diagnosed or suspected (one physical anomaly or family history) congenital syndrome were excluded. Diagnoses were made in accordance with the WHO 2016 classification. Whole-exome sequencing (WES) libraries were prepared using SureSelectXT Target Enrichment and sequenced on a HiSeq4000 platform (IlluminaInc.). Mean number of reads per sample was 138,726,017 with a Phred Quality Score 〉30 in 95.05% of bases. Read mapping sequence alignment and variant calling were performed using Biomedical Workbench (Qiagen). WES was performed on 72 tumor and 32 paired germinal DNA (buccal swab). To identify potential germline-causal mutations, a selection tool was implemented incorporating 239 genes associated with cause or predisposition to bone marrow failure or cancer. Variants with an ExAC, TOPMed and/or European 1000 Genomes minor allele frequency ≥0.01 were discarded. Results: The median age at diagnosis was 49 y.o. The cohort was categorised into two groups, less or equal 50 y.o. (62.5%) and between 50 and 60 y.o. (37.5%). In the first group, the frequency according to the WHO classification were 12% MDS with single lineage dyplasia (MDS-SLD), 8% MDS with ring sideroblasts (MDS-RS), 11% MDS with multilineage dyplasia (MDS-MLD), 24% MDS with excess blasts(MD-EB), 4% MDS with isolated del(5q)(MDS-del5q), 4% MDS unclassifiable and 4% chronic myelomonocytic leukemia (CMML). Meanwhile, in the group with age more than 50 y.o., the subtypes were 3.7% MDS-SLD, 7.4% MDS-RS, 29.6% MDS-MLD, 40.7% MD-EB, 3.7% MDS-del5q, and 14.8% CMML.Patients less or equal 50 y.o. were stratified based on IPSS-R as very low (4%), low (64%), intermediate (20%), high (12%) and very high (0%); and the group of more than 50 y.o. as very low (14.8%), low (33.3%), intermediate (29.6%), high (11.1%) and very high (11.1%).The mean number of somatic mutations was 0.68 in patients with less or equal 50 y.o. and 1.37 in those between 50 and 60 y.o., p=0.033 (U Mann-Whitney); and regarding germline variants, the first group mean number was 2.44 (p25-75, 1-3) and the second group showed a mean of 1.85 (QI 25-75, 1-3), p= 0,331.In the whole cohort, germline variants were found in 62 out of 72 patients, with the following frequencies: ATR(N=5, 6.9%), followed by BARD1(N=5, 6.9%), ERCC6L2(N=4, 5.6%), MSH6(N=4, 5.6%), TCIRG1(N=4, 5.6%), NBEAL2(N=4, 5.6%), ASXL1(N=3, 4.2%), ATM(N=3, 4.2%), MPL(N=3, 4.2%), NF1(N=3, 4.2%), RECQL4(N=3, 4.2%), SAMD9L(N=3, 4.2%), WRN(N=3, 4.2%).Among germline variants, those reported previously as pathogenic or likely pathogenic, or involving genes associated with familial MDS/AML included: ERCC6L2(N=4, 5.6%), SAMD9L(N=3, 4.2%), and one case mutated for DDX41, FANCC, JAK2, MSH6, SETBP1, MUTYH, BRCA1and RECQL4. In the whole cohort, somatic variants were found in 38 patients, with the following frequencies: TP53(N=7, 9.7%), ASXL1(N=7, 9.7%), SETBP1(N=5, 6.9%), NF1(N=5, 6.9%), SRSF2(N=4, 5.5%). Conclusion:In this subset of young adults with de novo MDS without congenital anomalies and/or familial history suggesting the presence of an undiagnosed congenital syndrome, 18% of the cohort harbored a likely causative germline variant. In addition, we noted a predominance of variants affecting genes with a cancer predisposition limited to the hematopoietic system, rather than classical telomere, DNA damage genes with an established mendelian link. Table. Table. Disclosures Díez-Campelo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a ligand for CXCR4 that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. We have previously shown that FT inhibition by tipifarnib downregulates CXCL12 secretion. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age 〉/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (wt CXCL12 3'UTR cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Tumor Whole Exon Sequencing (WES) was generated by NGS and gene expression data generated by RNA Seq. Ancillary studies also investigated the prognostic value of CXCL12 expression in pts who received standard of care treatment. Results As of 24 May 2019, 50 PTCL pts (23 AITL, 25 PTCL-NOS, 1 ALK- ALCL, 1 gamma-delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 31 pts in the ongoing AITL histology and wt CXCL12 3'UTR cohorts. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts (n=48 with available safety data) had at least one treatment-emergent adverse event (TEAE); 42 (88%) had at least 1 study drug-related TEAE and 13 (27%) at least 1 drug related SAE. The most frequently observed drug-related TEAEs of Grade 〉3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (40%), thrombocytopenia (33%), leukopenia (25%), anemia and febrile neutropenia (19% each). There have been 14 deaths on study; one related to study drug (lung infection). Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 5 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable of 16 pts enrolled), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the wt CXCL12 3'UTR cohort (n=12 evaluable pts), a 42% ORR was observed (3 CR, 2 PR), with 2 of the 3 CRs observed in patients of AITL histology (n=4). A total of 23 AITL subjects were enrolled in the overall study of whom 16 had WES data. A strong association with the activity of tipifarnib was observed in 8 of the 16 (50%) carrying KIR3DL2 gene variants C336R/Q386E: 50% CR rate, 75% ORR, 100% clinical benefit rate. These tumors expressed also very low levels of CXCL5, a ligand for CXCR2, that may mediate resistance to tipifarnib. High Allele Frequency of KIR3DL2 variants predicted CR to tipifarnib treatment (ROC AUC=0.94, p

Description: Invasive fungal infections (IFI) remain as an important cause of morbidity and mortality in adult patients with acute leukemia (AL). The incidence of proven or probable mold and yeast infections ranges from 5–24% among this selected high-risk patients. Prophylaxis is a commonly used treatment strategy, because the diagnosis of IFI is difficult and often delayed. A meta-analysis showed that itraconazole was more effective than fluconazole as prophylaxis of IFI, and a recent randomized trial demonstrated that in patients undergoing chemotehrapy for acute myelogenous leukemia (AML) posaconazole prevented IFI more effectively than did either fluconazole or itraconazole. Voriconazole (Vor) is a second-generation triazole with an extended spectrum of activity and is the drug of choice for invasive aspergillosis, the main mould that causes IFI among patients with acute leukemia. The drug is available for intravenous or oral administration and is well tolerated with transient visual disturbances, liver enzyme abnormalities and skin rashes being the most common adverse events reported, that rarely lead to treatment discontinuation. In this pilot study we evaluated Vor as prohylaxis treatment for IFI in 70 consecutive cases that underwent induction chemotherapy treatment for acute leukemia in two Clinical Units of Hematology in Spain. Methods:Oral prophylaxis with VOR at a fixed dose of 200mg/12h after two loading doses of 400mg was started on the first day of chemotherapy and continued until recovery from neutropenia or until ocurrence of an IFI. Patients who were unable to tolerate orally could receive VOR intravenously. Galactomanan was measured twice a week. HR-CT were performed in selected cases. The primary efficacy end point was the incidence of proven/probable IFI. Secondary end points included treatment success (vs failure) and the ocurrence of emergent mould infections. Treatment failure was defined as the ocurrence of proven/probable IFI; receipt of any other systemic antifungal agent for suspected IFI; discontinuation of the study drug for an adverse event; or withdrawal from the study with no additional follow-up. Results:From Jan 06 to Feb 07, 70 consecutive cases of AL that received induction chemotherapy for AML(58) or ALL(12) were included in the study. Median age was 57 (20–75). Median days with 0.1x109/L and 0.5x109/L were 16(10–35) and 19(12–38) respectively. Neutropenic fever ocurred in 62 cases (88,5%) and in 53% of them (33/62) a documented bacteria was isolated from the blood cultures. Galactomanan was possitive in only two cases (2,8%). HR-CT findings consisting with IFI were observed in 3 cases. Proven or probable IFI ocurred in 3 cases (A, flavus, A. fumigatus and Fusarium) (4,2%). Treatment failure as defined ocurred in 10 cases (16%). Conclusions: Prophylaxis with voriconazole was an effective and well tolerated regimen for IFI prevention in adult patients with acute leukemia.