ALBERT

Description: Abstract 4986 Background. Splenic marginal zone lymphoma (SMZL) is an uncommon indolent B-cell non-Hodgkin's lymphoma usually presenting with marked splenomegaly and bone marrow (BM) and/or peripheral blood (PB) involvement. Although splenectomy has traditionally been the treatment of choice in symptomatic patients, systemic treatment is required in cases of widespread disease, high risk from surgery, or relapse after splenectomy. There is no standard first line treatment in SMZL, but the anti-CD20 monoclonal antibody Rituximab has shown encouraging results in SMZL, with sustained responses. Aims. To assess, retrospectively, response to treatment, toxicity profile, progression-free survival (PFS) and overall survival (OS) after treatment with rituximab in SMZL. Methods. Twenty-nine patients from two different centers, diagnosed with SMZL between 1982 and 2011, received one or more treatments with rituximab. Eighteen patients (62%) received rituximab alone and 20 (69%) combined with chemotherapy; thus 9 patients received each of these treatments sequentially, to improve response, with or without interim relapse. The median age at diagnosis was 62 years (range 37–89 years); the male:female ratio was 2:3; B symptoms were present in 12 patients; ECOG performance status was 0–2 in 28/29 patients. All presented with splenomegaly, with involvement of the BM in 27 patients, PB in 24, lymph nodes in 11 and extranodal involvement in 7 patients. Diagnosis was made according to the WHO 2008 classification by spleen histology (n=12), BM histology (n=19), PB morphology (n=12) and immunophenotype (n=13). Rituximab monotherapy was administered at 375 mg/m2/weekly x4 weeks. In combination with fludarabine-based regimens (n=14), or other regimens including CHOP (n= 6), rituximab was administered on day 1 of each cycle. Responses were assessed according to the Response Criteria Guidelines for SMZL (Matutes, Leukemia 2008). Toxicity was graded according to the CTCAE v3.0. The Fisher exact test was used to compare best responses between groups. Survival was estimated using the Kaplan-Meier method. Results. All patients responded to rituximab monotherapy and/or to a combination treatment. At least one complete response (CR) was achieved in 20/29 patients (69%). This compares with a CR in only 4/17 (24%) of these same patients after any prior therapy (p=0.005): 11 patients had received splenectomy, with or without chemotherapy and 6 had received chemotherapy only. There was no difference in the CR rate between rituximab monotherapy (71%) versus rituximab combinations (68%). The most common adverse event was grade 3–4 neutropenia (n=7, 24%). Two patients had grade 3–4 infections. Anemia (n=3) and thrombocytopenia (n=2) were grade 1–2 only. Four cases presented with histological transformation prior to rituximab, all achieving CR with rituximab combination therapy. After a median follow-up of 24 months from rituximab treatment (range 4–102 months), progression-free survival (PFS) has been evaluated in 28/29 patients (1 patient not assessed yet at the time of presenting these data). PFS was longer after rituximab (n=32 evaluable treatments), either alone or in combination, than it had been in these same patients after prior therapy (n=17 prior treatments in total) (p=0.002) (Fig 1). When we compared PFS between rituximab monotherapy (n=17) and rituximab combined with chemotherapy (n=15 combined treatments), single agent rituximab was superior to rituximab in combination (p=0.02) (Fig 2). The median overall survival was not yet reached. Survival at 2 years after rituximab was 100%. Only one death, due to lung cancer, occurred at 48 months follow-up. Conclusions. In patients with SMZL, the CR rate after rituximab, either alone or in combination with chemotherapy, was significantly better than the CR rate after other prior treatments in the same patients, with manageable toxicity. Although we observed no difference in the CR rate between rituximab monotherapy or combination therapy, PFS was longer in patients receiving rituximab as single agent. Therefore, the addition of chemotherapy did not appear to add any advantage over rituximab alone in our cohort. Rituximab, with or without splenectomy, should be considered in the therapeutic scenario of SMZL. Disclosures: No relevant conflicts of interest to declare.

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: Background: MCL is a heterogeneous disease and the existence of indolent clinical forms is increasingly recognized although their biological ground is not fully elucidated. The aim of this study was to propose a frontline tailored treatment for indolent clinical forms with a chemo-free regimen, ibrutinib in combination with rituximab. In addition, an extensive genomic study was associated to gain biological insight into these clinical forms. Methods: This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 14 Spanish GELTAMO sites (NCT02682641). Centralized histology, PET-CT review as well as minimal residual disease (MRD) studies (qPCR and NGS in peripheral blood [PB] and bone marrow [BM]) and biological studies are conducted. A total of 50 previously untreated MCL patients with indolent clinical forms are planned to be recruited, defined by the following criteria: no symptoms attributable to MCL, ECOG 0-1, stable disease without therapy need at least for 3 months, non-blastoid variants, Ki-67

Description: Background and objective. Idelalisib is an oral inhibitor of the p110δ isoform of PI3K (phosphoinositide 3-kinase) approved in Europe and USA as monotherapy in relapsed/refractory follicular lymphoma (FL) after 2 previous lines of therapy based on a phase 2 study (Gopal et al, N Eng J Med 2014). However, there are scarce data on the use of idelalisib in clinical practice (Eyre et al, Br J Haematol 2017). The objective of this study was to analyze the efficacy and toxicity of idelalisib in relapsed/refractory FL patients in clinical practice in Spanish hospitals of GELTAMO group (GELT-IDE-2018-02 Study). Patients and Methods. Retrospective study of relapsed/refractory FL patients treated with idelalisib as salvage therapy in clinical practice. Demographic and clinical and biological variables were analyzed at FL diagnosis and at the time of idelalisib therapy, as well as its efficacy and toxicity. Results. A total of 43 patients from 20 hospitals were included. At time of idelalisib therapy, median age was 63 years (range 44-83), number of previous lines of therapy was 3 (2-7), 42% (n=18) were refractory to last previous treatment and 42% (n=18) had received an autologous stem cell transplantation (SCT); 56% (n=24) had progressed in the first 24 months after FL diagnosis (POD24). Median duration of treatment with idelalisib at time of analysis was 8.1 months (1.1-37.4) and 28/43 patients (65%) discontinued therapy, 13 due to progression, 12 due to adverse events (AE) and 3 due to physician's decision. Overall response rate (ORR) was 73% (32% CR) and median PFS 14.6 months (95% CI 0-32.2), with a trend to be higher in non-POD24 group (median PFS of 9.4 months [95% CI 1.7-16.9] in POD24 vs. 27 months [95% CI NA] in non-PO24 patients, p=0.082); median duration of response to idelalisib was 25.1 months (95% CI 13.1-37.6). Median overall survival (OS) was not reached at the time of analysis, with a 2-year OS of 74% (95% CI 58%-90%) (Figure). In 4 patients, an allogeneic SCT was performed after idelalisib. A total of 86% (n=37) of patients showed any AE, being in 56% (n=24) of grade ≥3 AE. Toxicities of grade ≥3 more frequent were: neutropenia (23% of patients), diarrhea (23%), infections (23%: pneumonia in 4 patients, CMV infection in 2, febrile neutropenia in 1 and other infections in 3 [1 of them died due to Aspergillus infection]), and increased transaminases (9%). Conclusions. In this series of patients with relapsed/refractory FL, several previous lines of therapies and factors associated with poor prognosis, the treatment with idelalisib was associated with efficacy and toxicity similar to published studies. These results support the use of idelalisib as an option for FL patients with multiple or poor risk relapses. Financial support: Gilead Figure. Progression-free survival (PFS) and overall survival (OS) for patients with follicular lymphoma treated with idelalisib. Figure Disclosures Sancho: SERVIER: Honoraria; SANOFI: Honoraria; Novartis: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CELLTRION: Consultancy; Kern-Pharma: Honoraria; Sandoz: Consultancy. Lopez Jimenez:GILEAD SCIENCES: Honoraria, Other: Education funding. Ramirez Payer:GILEAD SCIENCES: Research Funding. Cordoba:Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Speakers Bureau; Kyowa-Kirin: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; FUNDACION JIMENEZ DIAZ UNIVERSITY HOSPITAL: Employment; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy. Martín:Kiowa Kirin: Consultancy; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; iQone: Consultancy; Teva: Research Funding; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses. Armando:Roche: Consultancy, Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Description: Rituximab (R) maintenance has demonstrated a significant increase in both median PFS and OS in follicular lymphoma. However, such an effective strategy carries a concern about the long-term effects of rituximab on the immune system and the risk of infectious complications. In fact, neutropenia, and less frequently, hypogammaglobulinemia, occur with rituximab treatment, but this is still a scarcely explored issue. We analyzed our experience with R-maintenance in patients with indolent non-Hodgkin lymphoma (NHL) to evaluate the incidence of neutropenia and hypogammaglobulinemia, the type and incidence of infections and the factors associated with infection. Patients and Methods: Patients (pts) with indolent NHL in CR or PR after induction or salvage treatment (either with or without R), receiving R maintenance (R= 375 mg/m2; 2 schedules: 4 weekly doses every 6 months (4/6) in high-risk patients and 1 dose every 3 months (1/3) in low-risk. Total duration= 2 years) from June 2003 to June 2007. We examined the following variables for correlation with the incidence of infection: number and type of previous treatments (with/without R, with/without fludarabine), previous splenectomy and/or radiotherapy, response to previous treatments before R-maintenance, and R-maintenance schedule used. Results: Forty-seven pts (age (Mean[R]): 57[34–76]; gender F26:M21) with indolent NHL [FL 27 (57.4%), MCL 2 (4.3%), MZL 7 (14.9%), LPL/Waldestrom 5 (10.6%), MALT 6 (12.8%)] were retrospectively evaluated. At diagnosis: ECOG 0–1: 29 (61.7%), 2–3: 6 (12.8%); stage III–IV 43 (91.5%); B-symptoms 23 (48.9%); FLIPI 0–2: 56.4%, 3–5: 43.6%. Marrow involvement 34 (72.3%), splenomegaly 14 (29.8%) and hepatomegaly 5 (10.5%). LDH (Mean[R]): 346 [115–854], b2–microglobulin: 3.17 [1.3–7.9], Neutrophil count (x 109/L): 8.89 [0.14–31.6], IgG: 1044.8 [214–2080], IgA: 186.8 [35–570], IgM: 532.3 [17–6670]. Number of treatments before R-maintenance (M[R]): 1 [1–3]. Thirty-eight (80.9%) pts had received R-containing therapy and 43 (91.5%) fludarabine-containing regimens. Forty (85.1%) had achieved CR and 7 (15.2%) PR. Follow-up from diagnosis (Mean[R]): 35.4 months [8–116]; follow-up from start of R-maintenance: 16.8 months [1–53]. After R-maintenance, 9 pts (19.1%) presented neutropenia grade 3–4. The presence of splenomegaly (p=0.03) and hepatomegaly (p=0.03) at diagnosis significantly correlated with neutropenia 3–4. No relationship was found with the maintenance schedule used (4/6 vs 1/3), previous R or fludarabine, or with the number of previous treatments. Incidence of hypogammaglobulinemia was (*data available from 33 pts): IgG

Description: Abstract 3660 Poster Board III-596 Introduction Despite the major advances in the treatment of classical Hodgkin Lymphoma (cHL) patients, around 30% to 40% of cases in advanced stages may relapse or die as result of the disease. Current predictive systems, based on clinical and analytical parameters, fail to identify accurately this significant fraction of patients with short failure-free survival (FFS). Transcriptional analysis has identified genes and pathways associated with clinical failure, but the biological relevance and clinical applicability of these data await further development. Robust molecular techniques for the identification of biological processes associated with treatment response are necessary for developing new predictive tools. Patients and Methods We used a multistep approach to design a quantitative RT-PCR-based assay to be applied to routine formalin-fixed, paraffin-embedded samples (FFPEs), integrating genes known to be expressed either by the tumor cells and their reactive microenvironment, and related with clinical response to adriamycin-based chemotherapy. First, analysis of 29 patient samples allowed the identification of gene expression signatures related to treatment response and outcome and the design of an initial RT-PCR assay tested in 52 patient samples. This initial model included 60 genes from pathways related to cHL outcome that had been previously identified using Gene Set Enrichment Analysis (GSEA). Second, we selected the best candidate genes from the initial assay based on amplification efficiency, biological significance and treatment response correlation to set up a novel assay of 30 genes that was applied to a large series of 282 samples that were randomly split and assigned to either estimation (194) or validation series (88). The results of this assay were used to design an algorithm, based on the expression levels of the best predictive genes grouped in pathways, and a molecular risk score was calculated for each tumor sample. Results Adequate RT-PCR profiles were obtained in 264 of 282 (93,6%) cases. Normalized expression levels (DCt) of individual genes vary considerably among samples. The strongest predictor genes were selected and included in a multivariate 10-gene model integrating four gene expression pathway signatures, termed CellCycle, Apoptosis, NF-KB and Monocyte, which are able to predict treatment response with an overall accuracy of 68.5% and 73.4% in the estimation and validation sets, respectively. Patients were stratified by their molecular risk score and predicted probabilities identified two distinct risk groups associated with clinical outcome in the estimation (5-year FFS probabilities 75.6% vs. 45.9%, log rank statistic p≈0.000) and validation sets (5-year FFS probabilities 71.4% vs. 43.5%, log rank statistic p

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 chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. 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 is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) cohort 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 (CXCL12+ 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). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in patients who received standard of care treatment. Results As of 25 July 2018, 34 PTCL pts (13 AITL, 1 ALK- ALCL, 20 PTCL-NOS) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 15 pts in the ongoing AITL histology and CXCL12 cohorts. Median number of prior treatment regimens was 3. The most common treatment-related adverse events (AE) (grade ≥ 3) are hematological, including neutropenia (50%), thrombocytopenia (43%), leukopenia (33%), febrile neutropenia (27%), and anemia (20%). Skin and subcutaneous tissue disorders were reported in 9 pts, 6 of them with AITL histology. One pt with AITL experienced an episode of possible Stevens Johnson Syndrome that resolved with dose discontinuation and did not recur upon re-challenge at one dose level reduction. Of 18 evaluable patients enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. Pre-treatment tumor tissue CXCL12 expression correlated with favorable pt outcomes. In the AITL cohort (10 evaluable pts), 1 PR and 1 SD have been observed so far, with 5 pts pending cycle 2 response evaluation. In the CXCL12+ cohort (n=3 evaluable pts), 1 SD has been observed, with 2 pts pending cycle 2 response evaluation. Plasma levels of CXCL12 decreased over time with tipifarnib treatment. Expression of CXCL12 mRNA and other biomarkers in pre-treatment biopsies of pts in the AITL and CXCL12+ cohorts are being evaluated using RT-PCR assays. In addition, the prognostic value of CXCL12 is being investigated in approximately 100 diagnostic specimens of PTCL pts who received standard therapy. Preliminary data suggest that CXCL12 overexpression is observed in approximately 25% of PTCL and negatively affects pt survival. Conclusion Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment continues. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Kim:Takeda: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding. Foss:Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Seattle genetics: Consultancy; Mallinkrodt: Consultancy. Advani:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Infinity: Research Funding. Marin Niebla:Amgen: Other: Medical education of Staff, Speakers Bureau; Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau. Piris:Kura: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Curry:Kura Oncology: Employment, Equity Ownership. Gualberto:Kura Oncology: Employment, Equity Ownership.

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: BACKGROUND: Fludarabine (F), already demonstrated to be a highly active drug in the management of relapsing or refractory CLL, presents improved clinical and molecular responses when it is associated to alkylating agents such as Cyclophosphamide (C). This combination (FC) appears as a promising option as front-line treatment in CLL patients with good performance status and no previous treatments, in whom a much better outcome, and perhaps curation, is expectable. Objectives: 1) Evaluation of the clinical and molecular response to FC as front-line treatment of CLL. 2) Assessment of toxicity and complications associated to this combination. Patients and method : Since June 2001 to August 2004, 26 B-CLL untreated patients (pts) (19M/7F; M age: 60 years (43–74); ECOG:0 (0–1); Binet AII 4 pts, BI 4 pt, BII 14 pt, CIII 4 pt) were included in the trial to receive treatment with FC combination (F:25 mg iv/m2/d x3 d; C: 300 mg/m2/d x3d). Initially, 6 courses at 28-day intervals were programmed, but the scheme was reduced to 4 courses in accordance with the Local Ethics Committee due to the toxicity observed in the first patients. Anti-infectious prophylaxis: Trimetoprim-sulfametoxazol and fluconazol. Hemogram at inclusion: (Median (R) values) WBC: 70.7x109/L (7.93–242), lymphocytes: 64,7x109/L (6,2–179), Hb: 138 g/L (71–162), platelets: 151x109/L (62–324). Renal and hepatic parameters within normal range limits. Cytogenetics by FISH: No alterations (9), +12 (8), p53 (4), 13q (17), ATM (6). Response to treatment was first assessed at course 3 and then at course 6 in pts receiving 6 courses, and after the 4th course in those receiving 4 courses. The assessment was made according to the revised NCI criteria as well as by PCR amplification of the VDJ segment of IgH with FR3 and JH regions primers. Results: 6/26 pts did not complete 4 courses yet, so they are not evaluable. Among the 20 evaluable: 6 pts completed 6 full courses, 5 courses: 1pt, 4 courses: 9 pts, 3 courses: 1 pt (due to renal toxicity), 2 courses: 2 pts (exitus before 3rd course). Responses: CR: 15 pts (75%); PR: 3 pts (15%); No response: 2 pts (10%). Only 1 pt, with initial PR, progressed after 21 months follow-up. Median follow-up: 11,5 months (2–30). Up to 147 toxicity events were recorded (84 FC total), assessed according to WHO criteria, but only 50 were grade III-IV : 72% hematological (neutropenia most frequently), 18% liver toxicity, 10% renal. Toxicity occurred mainly after the first 3 courses, with increasing severity and extension, but regressing when the treatment was withdrawn, being hematological toxicity the most severe and prolongued. After reducing the number of courses from 6 to 4, hematological toxicity decreased, while other types of toxicity did not significantly improve. Complications: 40 episodes of infection (associated neutropenia 12/40, requiring hospitalization 21/40), 2 cases of bleeding and 3 cases of thrombosis. Six patients died: 3 died of infectious complications due to prolongued hematologic toxicity: TRM: 3/20 (15%) and 3 pts due to disease progression. Conclusions : 1) FC combination as front-line treatment is effective in B-CLL (90% overall response rate and 75% CR -clinical and molecular-). 2) Hematological toxicity is the most severe observed, causing treatment delays and leading to infections. 3) Reducing the number of FC courses from 6 to 4 caused a decrease in haematological toxicity, so 4 FC appears as an effective scheme in terms of efficacy and safety.

Description: Abstract 2690 Poster Board II-666 Background Despite of all the strategies carried out in the management of Follicular Lymphoma (FL), this disease has remained incurable, and still none of the schedules tested in newly diagnosed patients has yielded a “standard” front-line regimen for FL. The synergistic association of Fludarabine-Cyclophosphamyde (FC) is known as one of the most active regimens for FL, and the addition of Rituximab (R) has improved the efficacy of FCR combination. However, the associated severe myelosuppression when this regimen is administered at standard doses has clearly limited a more extended use. Therefore, different low-intensity schedules have been tested in order to decrease toxicity. The availability of oral F has allowed a more adequate outpatient management of FCR regimen, with expected similar efficacy as the standard intravenous administration. Oral FCR would carry a better compliance and quality of life during treatment, and of course lower hospital expenses. Aims 1) To evaluate efficacy and safety of a lower intensity FCR in first-line for FL. 2) To assess the potential advantages in efficacy and toxicity profile of the oral versus intravenous administration. Methods Follicular lymphoma (WHO histological grades 1-2) patients (pts) aged = 18, previously untreated, WHO-PS= 2, = 2-fold renal and hepatic function values were eligible. Outpatient treatment: Intravenous FC/ FCR (iv): Fludarabine (F) 25 mg/m2/d plus Cyclophosphamyde (C) 250 mg/m2/d (d 1-3), Rituximab (R) 375 mg/m2 (d1) × 4 28-day cycles; Oral FCR (po): F 30 mg/m2/d plus C 175 mg/m2/d (d 1-3), R 375 mg/m2/ (d1) × 4-6 28-day cycles. Stages III-IV and FLIPI= 3 patients at diagnosis achieving CR1 received R maintenance: R 375 mg/m2 q/3 months x 8 doses. Toxicity was recorded at every cycle and thereafter during follow-up, and classified according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Results From march 1999 to august 2009, 92 pts were prospectively included: M age: 57 (32–81), M:F 44:48, Stages III-IV: 81 (88%), B-symptoms: 29.3%, FLIPI= 3: 36 (39.1%). BM and PB involvement: 52 (56.5%) and 31 (33.7%) respectively. Bcl-2 rearrangement by PCR and/or FISH: 46 (50%). Thirty-seven (40.3%) pts received FC or FCR iv; 55 (59.7%) FCR po. M number of cycles: 4 (3-4) FC/FCRiv; 6 (3-6) FCRpo. Eighty-six pts were evaluable for response: ORR rates FCRiv versus FCRpo: 89.2% vs 100% (p=0.03); CR rate FCRiv versus FCRpo: 54% vs 70.9% (p=0.01). Regarding grades 3-4 (g3-4) toxicity, neutropenia was the most frequent and limiting AE: 53/86 pts presented neutropenia g3-4: 21 (56.7%) and 32 (65.3%) in FCRiv and FCRpo respectively (p=0.02). However, infection rate was 35.1% in FCRiv and 30% in FCRpo (NSD), with a tendency to a higher severity and even causing 1 death FCRiv (NSD). Grade 3-4 thrombocytopenia occurred in 7 FCRiv and 1 FCRpo pts (p=0.03), with severe hemorrhage in 2 FCRiv pts (1 subaracnoid and 1 intestinal in a patient with colon angiodysplasia), and anemia g3-4 in 5 FCRiv and 1 FCRpo (p=0.02). Liver toxicity occurred only with g1-2, and no renal toxicity at all was observed. Fifty-three pts received R-Maintenance: FCRiv: 25/37 (67.5%), FCRpo: 28/49 (57.1%). Withdrawal of R-maintenance occurred in 21 pts (12 FCRiv; 9 FCRpo) due to neutropenia and mild but recurring infections in 18 (85.7%) and in 3 pts due to progression. Four pts relapsed with a M TTP: 13 m (9–48); and 3 pts died (1 infection, 2 progression). Transformation to aggressive NHL occurred in 2 pts, and 1 patient was diagnosed with AML/MDS 4 years after ASCT. With a MFU: 25.7 m (0.3–119.4), overall survival (OS) was 95.4% (IC 95% = 9.3–100%), mean OS= 114.6 m (IC95% 109.3–119.9) and event-free survival (EFS) -considering progression, relapse or death- was 85.3% (IC95% 73.7–96.8%), mean EFS= 106.2 m (IC95% 96.6–115.8 m. No significant differences were found between oral and iv FCR. Conclusions 1) Low-dose FCR is a potent first-line and safe regimen for FL (including pts〉 60 yo), with very high ORR and CR rates. Oral low-dose FCR shows better results (ORR and CR) than FCRiv in our series. 2) Although neutropenia remains the major concern with this regimen, oral FCR is associated to a lower incidence of mild and severe infections. Oral low-dose FCR appears as an effective outpatient treatment for untreated FL, with manageable toxicity. Disclosures: No relevant conflicts of interest to declare.