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In the workup of follicular lymphoma (FL), bone marrow biopsy (BMB) assessment is a key component of FLIPI and FLIPI2, the most widely used outcome scores. During the previous decade, several studies explored the role of FDG-PET/CT for detecting nodal and extranodal disease, with only one large study comparing both techniques.The aim of our study was to evaluate the diagnostic accuracy and the prognostic impact of both procedures in a retrospective cohort of 299 FL patients with both tests performed at diagnosis. In order to avoid a collinearity bias, FLIPI2 was deconstructed in its founding parameters, and the bone marrow involvement (BMI) parameter separately included as: a positive BMB, a positive PET/CT, the combined "PET/CT and BMB positive" or "PET/CT or BMB positive". These variables were also confronted independently with the POD24 in 233 patients treated with intensive regimens.In the total cohort, bone marrow was involved in 124 and 60 patients by BMB and PET/CT, respectively. In terms of overall survival, age 60 y.o. and the combined "PET/CT or BMB positive" achieved statistical independence as a prognostic factor. In patients treated with an intensive regimen, only the combined "PET/CT or BMB positive" added prognostic value for a shorter overall survival, when confronted with the POD24.Our results show that in FL both BMB and PET/CT should be considered at diagnosis, as their combined assessment provides independent prognostic value in the context of the most widely use clinical scores.

Purpose: Arsenic trioxide (ATO) induces B-cell chronic lymphocytic leukemia (B-CLL) cell apoptosis in vitro. We sought to study the mechanism involved in this effect and whether ATO is suitable for combination therapies with protein kinase inhibitors.Experimental Design: B-CLL cells were isolated from the peripheral blood of 28 patients. Cell viability studies with ATO alone or in combination with kinase inhibitors were done by flow cytometry, Western blotting, and immunofluorescence analyses.Results: After 48 hours, 3 μmol/L ATO induced apoptosis (average 75%) in all B-CLL samples studied and with minimal effect on normal peripheral blood lymphocytes. Apoptosis entailed Akt and NF-κB inactivation, XIAP downregulation, and PTEN upregulation, thus implying inhibition of the phosphoinositide 3-kinase (PI3K) survival pathway. Indeed, the combination of ATO and PI3K inhibitors increased the apoptotic effect of either agent alone. ATO also induced c-jun-NH2 terminal kinase (JNK) activation, and this was crucial and required for subsequent apoptotic events, as inhibiting JNK activity by either gene silencing or specific inhibitors prevented Akt and NF-κB inactivation, caspase activation, and mitochondrial damage. Moreover, JNK activation was the earliest response to ATO, preceding and determining reactive oxygen species production.Conclusions: We identified the mechanism involved in ATO action on B-CLL cells and show that the combination of low doses of ATO and PI3K inhibitors efficiently induces B-CLL cell death. ATO may therefore constitute an efficient treatment for B-CLL, particularly in combined therapies. Clin Cancer Res; 16(17); 4382–91. ©2010 AACR.

Supplementary Data from Induction of B-Chronic Lymphocytic Leukemia Cell Apoptosis by Arsenic Trioxide Involves Suppression of the Phosphoinositide 3-Kinase/Akt Survival Pathway via c-jun-NH2 Terminal Kinase Activation and PTEN Upregulation

CCR Translation for This Article from Induction of B-Chronic Lymphocytic Leukemia Cell Apoptosis by Arsenic Trioxide Involves Suppression of the Phosphoinositide 3-Kinase/Akt Survival Pathway via c-jun-NH2 Terminal Kinase Activation and PTEN Upregulation

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to 90Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m2 every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving 90Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.

Background: Axicabtagen Ciloleucel (axi-cel) is approved in Europe for the treatment of adults with R/R large B-cell lymphoma (LBCL), primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (tFL). In Spain, nationwide CAR-T administration requests are reviewed centrally within the Ministry of Health. We analyzed the real-world outcomes of patients treated with axicel under the commercial label in Spanish centers. Methods: Six designated centers for commercial CAR-T administration collected data on behalf of GETH-GELTAMO. Data were collected retrospectively from consecutive patients in whom apheresis was performed for axi-cel treatment from Febrruary-2019 to November-2020. CRS and ICANS were graded with the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Results: 106 patients with R/R lymphoma underwent apheresis for axi-cel. At data cutoff, 92 (87%) received infusion. The reasons for not undergoing infusion were progression-related death in 12 (86%), tumor lysis syndrome in 1 (7%) and complete response after bridging therapy in 1 (7%). Of note, 14 patients were conditioned and infused during the peak of COVID-19 epidemic in Spain (March-April 2020). Median time from Ministry approval to infusion was 54 days. Histology consisted of 74% DLBCL with 11% tFL, and 15% PMBCL. Disease status at lymphodepletion was PD in 69%, SD in 22% and PR in 9%. All patients received lymphodepletion. Median time from leukapheresis to start of lymphodepletion was 34 days. Median time from leukapheresis to infusion was 39 days. Median hospitalization period was 21 days. Any grade of CRS occurred in 86% of pts (18% grade 2, 6.5% grades 3-4). Tocilizumab was used in 58% of patients who developed CRS, corticosteroids in 19%. ICANS was diagnosed in 42.5% of pts (10% grade 2, 15% grade 3-4). Treatment for ICANS included corticosteroids in 78%, tocilizumab in 31%, siltuximab in 15%, and anakinra in 21%. ICU admission was needed in 20 patients (22%). 4 patients died in the context of ICANS, 1 due to CRS, and 1 due to infection. Of 80 patients evaluable and restaged at day 30, ORR was 78% with 40% CR, 38% PR, 11% PD and 11% SD or indeterminate. Of 58 patients evaluable at day 100, 66% had ongoing response (CR 48%, PR 18%). Of 23 patients evaluable at day 180, 65% presented CR. Of 39 patients who showed PR/SD at day 30, 9 (23%) converted to CR. After a median follow-up of 6.3 months, EFS and OS were 55.5% and 78%, respectively in the infused population, with an estimated median EFS and OS of 13.1 and 7.3 months. In the intention-to-treat analysis for all patients who underwent apheresis, median estimated OS and EFS were 12.3 (95%CI 8.9-15.7) and 6.6 months (95%CI 4.6-8.5), respectively (Figure 1). Conclusions: This Spanish multicenter retrospective analysis shows encouraging results of axi-cell treatment in patients with R/R aggressive B-cell lymphoma in the real-world setting. Significant toxicity events were less frequent than those reported in the pivotal trial, however events of mortality associated to toxicity occurred. With a limited follow-up time, response outcomes are favorable.

Lymphomas are a large, heterogeneous group of neoplasms with well-defined characteristics, and this heterogeneity highlights the importance of epidemiological data. Knowledge of local epidemiology is essential to optimise resources, design clinical trials, and identify minority entities. Given there are few published epidemiological data on lymphoma in Spain, the Spanish Lymphoma and Autologous Bone Marrow Transplant Group created the RELINF project. The aim of this project is to determine the frequencies and distribution of lymphoid neoplasms in Spain and to analyse survival. We developed an online platform for the prospective collection of data on newly diagnosed cases of lymphoma in Spain between January 2014 and July 2018; 11,400 patients were registered. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) were the most frequent lymphomas in our series. Marginal B cell lymphoma frequency was higher than that reported in other studies, representing more than 11% of mature B cell lymphomas. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) was the most common subtype of T cell lymphoma, and NK/T cell lymphomas were more frequent than expected (5.4% of total). Hodgkin's lymphoma accounted for 12% of lymphoproliferative syndromes. Overall survival was greater than 90% at 2 years for indolent B cell lymphomas, and approximately 60% for DLBCL, somewhat lower than that previously reported. Survival was poor for PTCL-NOS and angioimmunoblastic T cell lymphoma, as expected; however, it was somewhat better than that in other studies for anaplastic large cell anaplastic lymphoma kinase lymphomas. This is the first prospective registry to report the frequencies, distribution, and survival of lymphomas in Spain. The frequencies and survival data we report here are globally consistent with that reported in other Western countries. These updated frequencies and survival statistics are necessary for developing appropriate management strategies for neoplasias in the Spanish population.

CAR-T cell therapy; Real world evidence; B cell lymphoma Terapia con células CAR-T; Evidencia del mundo real; Linfoma de células B Teràpia amb cèl·lules CAR-T; Evidència del món real; Limfoma de cèl·lules B Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4–6 months, p ≤ 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44–0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31–0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria.

The frequency of aggressive subtypes of B-cell non-Hodgkin lymphoma (B-NHL), such as high-grade B-cell lymphomas (HGBL) with MYC and BCL2 and/or BCL6 rearrangement (HGBL-DH/TH) or Burkitt-like lymphoma (BL) with 11q aberration, is not well known in the HIV setting. We aimed to characterise HIV-associated aggressive B-NHL according to the 2017 WHO criteria, and to identify genotypic and phenotypic features with prognostic impact. Seventy-five HIV-associated aggressive B-NHL were studied by immunohistochemistry (CD10, BCL2, BCL6, MUM1, MYC, and CD30), EBV-encoded RNAs (EBERs), and fluorescence in situ hybridisation (FISH) to evaluate the status of the MYC, BCL2, and BCL6 genes and chromosome 11q. The 2017 WHO classification criteria and the Hans algorithm, for the cell-of-origin classification of diffuse large B-cell lymphomas (DLBCL), were applied. In DLBCL cases, the frequencies of MYC and BCL6 rearrangements (14.9 and 27.7%, respectively) were similar to those described in HIV-negative patients, but BCL2 rearrangements were infrequent (4.3%). MYC expression was identified in 23.4% of DLBCL cases, and coexpression of MYC and BCL2 in 13.0%, which was associated with a worse prognosis. As for BL cases, the expression of MUM1 (30.4%) conferred a worse prognosis. Finally, the prevalence of HGBL-DH/TH and BL-like with 11q aberration are reported in the HIV setting. The phenotypic and genotypic characteristics of HIV-associated aggressive B-NHL are similar to those of the general population, except for the low frequency of BCL2 rearrangements in DLBCL. MYC and BCL2 coexpression in DLBCL, and MUM-1 expression in BL, have a negative prognostic impact on HIV-infected individuals.

Background: Glofit is a novel, CD20xCD3 T-cell-engaging bispecific antibody that provides monovalent binding to CD3 on T cells and bivalent binding to CD20 on B cells. As monotherapy, Glofit has shown promising response rates with manageable safety in R/R B-cell non-Hodgkin lymphoma (B-NHL) patients (pts; [Carlo-Stella et al. EHA 2021]). Because of their distinct and complementary mechanism of action, there is a rationale for combining Glofit with the anti-CD79b-targeted antibody-drug conjugate, Pola. NP39488 (NCT03533283) is a Phase Ib/II, open-label, multicenter, dose-escalation (DE) and expansion study evaluating Glofit + Pola or atezolizumab in R/R B-NHL pts (Hutchings et al. ASH 2019). Here, we report preliminary safety and efficacy data for Glofit + Pola in pts with R/R DLBCL during DE and expansion at the recommended Phase II dose (RP2D). Methods: To mitigate the risk of cytokine release syndrome (CRS), a single 1000mg dose of obinutuzumab pre-treatment was administered on Cycle (C) 1 Day (D) 1 alongside step-up dosing (SUD) of Glofit on C1D8 and C1D15. Glofit was subsequently administered at the target dose from C2D1, every 3 weeks up to C12. Pola was administered at 1.8mg/kg on C1D2 and then on D1 of each subsequent cycle up to C6. The primary objective was to establish the RP2D of Glofit in combination with Pola. Results: As of June 10, 2021 (clinical cut-off date [CCOD]), 44 pts were treated with ≥1 cycle; median follow-up was 3.2 months (95% confidence interval: 1.4-3.5). In the first DE cohort, 7 pts had received Glofit at 2.5mg (C1D8)/10mg (C1D15)/10mg (C2D1 onwards) plus Pola. In the second DE cohort, 4 pts received the Glofit target dose of 30mg on C1D15 and this was established as the RP2D. During the expansion phase at RP2D, an additional 34 pts were treated with ≥1 cycle. Of 44 pts, 29 (66%) had histology of R/R DLBCL, 8 (18%) had R/R high-grade B-cell lymphoma (HGBCL; 2 HGBCL not otherwise specified; 5 double-hit DLBCL; 1 triple-hit DLBCL) and 7 (16%) had R/R transformed follicular lymphoma. Pts (61% male) had a median age of 65.5 years (range: 29-82) and received a median of two prior lines (range: 1−5). Twenty-eight (64%) pts were refractory to their last therapy; 2 pts had not been treated with Glofit at the CCOD. The most frequent adverse event (AE) was CRS (55%; 23/42 pts): Grade (Gr) 1 (n=18); Gr 2 (n=7); no Gr ≥3 CRS events were observed (Lee et al. 2019 ASTCT criteria). Of the 7 pts with Gr 2 CRS, 5 were treated with tocilizumab and fluids for hypotension, and 4 pts were treated with low-flow oxygen due to hypoxia. None of the pts required vasopressors or intensive care unit admission. Gr >3 AEs occurred in 52% (n=23) of pts; most commonly, neutropenia (27%) and anemia (23%). For neurological AEs (NAEs), 13 events were reported in 13 patients (29.5%, 13/44 pts), all were limited to Gr 1−2. The most common NAEs were headache and (11%, 5/44 pts) and insomnia (4.5%, 2/44 pts). No immune effector cell-associated neurotoxicity syndrome-like AEs were reported. Peripheral neuropathy due to Pola was reported in 5/44 pts (11%); all events were Gr 1. Serious AEs occurred in 22 pts (52%); none were CNS or neurological events. One pt experienced fatal COVID-19 pneumonia (not related). Study treatment was discontinued in 2 pts due to AEs (Gr 4 thrombocytopenia, and Gr 3 worsening of pre-existing renal impairment; both events were related to Glofit and Pola). At CCOD 33/44 pts were evaluable for interim (after 2 cycles, 1 target dose of Glofit) or primary (after 8 cycles) response; 6/33 pts had experienced progressive disease and discontinued study treatment. Overall response (OR) rate for both dosing cohorts was 73% (24/33) and complete response (CR) rate, per investigator was 51.5% (17/33). Of 7 pts treated with 2.5/10/10mg SUD Glofit, OR and CR rates were both 86% (6/7); durable responses at ≥6 months post-end of treatment were observed. Of 26 pts treated with 2.5/10/30 mg SUD Glofit, OR rate was 73% (19/26) and CR rate was 46% (12/26); 11.5% (3/26) pts had stable disease after 2 cycles of therapy. Duration of response and time on study by dosing cohort is shown in Figure. Biomarker and pharmacokinetic data will be provided. Conclusions: Glofit in combination with Pola showed tolerable safety and encouraging preliminary efficacy in R/R DLBCL pts. CRS and NAEs were limited to Gr 1 or 2, no new safety signals were detected for this combination, and the safety profile was consistent with that of the individual drugs. Updated data will be presented. Figure 1 Figure 1. Disclosures Hutchings: Genmab: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding. Sureda: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; MSD: Consultancy, Honoraria, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Terol: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; BMS: Consultancy; Hospital Clinico Valencia: Current Employment; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Bosch Albareda: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Kite: Honoraria; Sanofi: Honoraria; Lilly: Honoraria. Corradini: KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations. Larsen: Novartis: Consultancy; Gilead: Consultancy; Odense University Hospital, Denmark: Current Employment; Celgene: Consultancy; BMS: Consultancy. Rueda Dominguez: Hospital Regional Universitario de Malaga: Current Employment; Roche: Consultancy; Takeda: Consultancy; Gilead: Consultancy; Merck Serono: Consultancy; BMS: Consultancy; MSD: Consultancy. Panchal: F. Hoffmann-La Roche Ltd: Current Employment. Bottos: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Carlile: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Wang: F. Hoffmann-La Roche Ltd: Current Employment; Peking University Third Hospital, Beijing, China: Ended employment in the past 24 months. Filézac De L'Étang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Tandon: Roche Products Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sellam: Roche: Current Employment, Current equity holder in publicly-traded company. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. OffLabel Disclosure: Glofitamab is a full-length, humanized immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent. Polatuzumab vedotin (Polivy) is a CD79b-directed antibody-drug conjugate indicated in combination with bendamustine and a rituximab product for the treatment of adult pts with relapsed or refractory DLBCL, not otherwise specified, after at least two prior therapies.

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to

Ibrutinib demonstrated robust efficacy, regardless of high-risk features, in previously untreated or relapsed/refractory chronic lymphocytic leukemia (CLL). The IBRORS-CLL study supports the effectiveness and the manageable safety profile of single-agent ibrutinib, which was not adversely affected by high-risk characteristics in real-world CLL patients in Spain. We also found a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status. Background: Ibrutinib demonstrated remarkable efficacy and favorable tolerability in patients with untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including those with high-risk genetic alterations. The IBRORS-CLL study assessed the characteristics, clinical management and outcome of CLL patients receiving ibrutinib in routine clinical practice in Spain.Patients: Observational, retrospective, multicenter study in CLL patients who started single-agent ibrutinib as first-line treatment or at first or second relapse between January 2016 and January 2019. Results: A total of 269 patients were included (median age: 70.9 years; cardiovascular comorbidity: 55.4%, including hypertension [47.6%] and atrial fibrillation [AF] [7.1%]). Overall, 96.7% and 69% of patients underwent molecular testing for del(17p)/TP53 mutation and IGHV mutation status. High-risk genetic features included unmutated IGHV (79%) and del(17p)/TP53 mutation (first-line: 66.3%; second-line: 23.1%). Overall, 84 (31.2%) patients received ibrutinib as first-line treatment, and it was used as second- and third-line therapy in 121 (45.0%) and 64 (23.8%) patients. The median progression-free survival and overall survival were not reached irrespective of del(17p)/TP53, or unmutated IGHV. Common grade >= 3 adverse events were infections (122%) and bleeding (3%). Grade >= 3 AF occurred in 1.5% of patients. Conclusion: This real-world study shows that single-agent ibrutinib is an effective therapy for CLL, regardless of age and high-risk molecular features, consistent with clinical trials. Additionally, single-agent ibrutinib was well tolerated, with a low rate of cardiovascular events. This study also emphasized a high molecular testing rate of del(17p)/TP53 mutation and IGHV mutation status in clinical practice according to guideline recommendations. (C) 2021 The Author(s). Published by Elsevier Inc.

Progressió clínica; Evasió immune Progresión clínica; Evasión inmune Clinical progression; Immune evasion Background Mechanisms driving the progression of chronic lymphocytic leukemia (CLL) from its early stages are not fully understood. The acquisition of molecular changes at the time of progression has been observed in a small fraction of patients, suggesting that CLL progression is not mainly driven by dynamic clonal evolution. In order to shed light on mechanisms that lead to CLL progression, we investigated longitudinal changes in both the genetic and immunological scenarios. Methods We performed genetic and immunological longitudinal analysis using paired primary samples from untreated CLL patients that underwent clinical progression (sampling at diagnosis and progression) and from patients with stable disease (sampling at diagnosis and at long-term asymptomatic follow-up). Results Molecular analysis showed limited and non-recurrent molecular changes at progression, indicating that clonal evolution is not the main driver of clinical progression. Our analysis of the immune kinetics found an increasingly dysfunctional CD8+ T cell compartment in progressing patients that was not observed in those patients that remained asymptomatic. Specifically, terminally exhausted effector CD8+ T cells (T-betdim/−EomeshiPD1hi) accumulated, while the the co-expression of inhibitory receptors (PD1, CD244 and CD160) increased, along with an altered gene expression profile in T cells only in those patients that progressed. In addition, malignant cells from patients at clinical progression showed enhanced capacity to induce exhaustion-related markers in CD8+ T cells ex vivo mainly through a mechanism dependent on soluble factors including IL-10. Conclusions Altogether, we demonstrate that the interaction with the immune microenvironment plays a key role in clinical progression in CLL, thereby providing a rationale for the use of early immunotherapeutic intervention. This work was supported by the Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias (PI17/00950, M.C., PI18/01392, P.A. and PI17/00943, F.B.) and co-financed by the European Regional Development Fund (ERDF) and Fundación Asociación Española Contra el Cáncer (M.C. and P.A.), Gilead Fellowships (GLD16/00144, GLD18/00047, F.B.) and Fundació la Marató de TV3 (201905–30-31 F.B). S.B. is the recipient of a postdoctoral fellowship from Fundación Alfonso Martin Escudero. R.V-M. is supported by a Torres Quevedo fellowship from the Spanish Ministry of Science and Innovation (PTQ-16-08623). A.E-C. is funded by ISCIII/MINECO (PT17/0009/0019) which is co-funded by FEDER. M.C. holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-2018).

Angiogenesis process contributes to the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) being the levels of VEGFA and bFGF higher in patients than in healthy controls. Our aim was to evaluate the implication of angiogenesis factors genetic variants in the predisposition to B-CLL and their association with clinical factors and survival. We performed a population-based case-control study in 224 Spanish B-CLL patients and 476 healthy randomly selected controls to evaluate susceptibility to developing B-CLL. Six polymorphisms were evaluated: rs1109324, rs1547651, rs3025039 (+936 C>T), rs833052 of the VEGFA gene, rs1449683 (c.233C>T) of the bFGF gene and (−710 C>T) of the VEGFR1 gene. The association between clinical parameters and patient outcome was analyzed. Carriers of the CT/TT variants of rs3025039 showed a significant protective effect against developing B-CLL. The CT/TT variants of rs1449683 show a tendency towards the development of the disease and the same variants associated significantly with higher genetic risk and with reduced disease free survival. Moreover, the association persisted in the early-stage disease subgroup. Our study provides evidence of the protective effect of the T/- rs3025039 VEGFA variant against B-CLL development and the association of CT/TT variants of the rs1449683 bFGF gene with genetic risk and an adverse survival.

INTRODUCTION Lymphomas represent the fourth most frequent type of cancer, 90% of them arising from B cell lymphocytes. Despite their high prevalence, around 40% remain incurable because of refractoriness to current chemoimmunotherapy or disease relapse after obtaining response (Li et al., 2018; Meng et al., 2020). The cell of origin is a B lymphocyte with a unique B cell receptor (BCR). The BCR is an immunoglobulin composed of two heavy chains (IgH) and two light chains (IgL) whose genes have multiple coding segments that through rearrangement first and further somatic hypermutation in the germinal center, generate a unique sequence that could be used to monitor the treatment response (Seifert et al., 2019; Wang et al., 2020). This project studies the use of next-generation sequencing (NGS) to characterize and monitor such IgH clonality. The use of liquid biopsy samples would provide a minimally invasive method to identify refractory or relapse-risk patients since all of them will have residual tumor cells after treatment. METHODS The sample size of the study was 53 patients with several types of B-cell lymphomas. The IgH gene of the tumor clone was characterized from DNA of tumor samples at diagnosis by NGS and Sanger. The monitoring of this clone was studied by NGS from DNA and circulating tumor nucleic acids (ctNAs) during and after receiving treatment and at different times after clinical response was stablished (CR or PR). Relapse samples were analyzed by NGS and Sanger. RESULTS Characterization of the tumor clone IgH rearrangement is achieved in 45 of the 53 patients with B-cell lymphoma included in the study. As shown in Figure 1, after the two different amplification PCRs results are similar. In contrast, after sequencing the results obtained by Sanger and NGS are very different. In NGS, thanks to the massive amplification prior to sequencing, it is identify the tumor clone in approximately 80% of the samples. It is shown that the effectiveness in characterization is dependent on the origin of the DNA sample, with fresh material samples being the optimal (Figure 1). In monitoring, samples of different origin are used as shown in Figure 2. About 50% of these samples are plasma ctNAs whose average efficiency in the detection of IgH gene rearrangement is 73.3%, with a clear positive correlation between the sensitivity and the toal volume of plasma processed more starting plasma used (2 mL efficiency of 84.09%). Monitoring makes it possible to classify patients into three different groups (Figure 3): patients with complete remission, patients refractory to the different lines of treatment and patients with apparent complete response and subsequent relapse. In patients with complete response, the tumor clone decreases during treatment and at the end of the line it is no longer detectable, nor in subsequent follow-up samples. With respect to refractory patients, it is observed that the tumor clone remains present despite subsequent lines of treatment. Finally, in patients achieving CR with subsequent relapse, the clone can be detected in a small percentage at the end of the treatment schedule and remains present until relapse. A section of patients under treatment is also shown (Figure 3) to demonstrate the application of the study to clinical practice. Two patients with apparent complete response, one of them in complete remission and the other with a high risk of relapse, requiring a more exhaustive follow-up. The monitoring results obtained by flow cytometry are shown being these, in general, concordant. In some cases NGS shows greater sensitivity. CONCLUSION The use of NGS and liquid biopsy samples provides a minimally invasive method to monitor the IgH gene rearrangement of the tumor clone of patients with B-cell lymphomas. In our experience,, patients in remission can be clearly differentiated from those who are refractory or at risk of relapse. facilitating their treatment strategy and clinical decision making. Figure 1 Figure 1. Disclosures Ferrer Lores: Janssen: Membership on an entity's Board of Directors or advisory committees. Terol: BMS: Consultancy; Hospital Clinico Valencia: Current Employment; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel.

The T-cell non-Hodgkin lymphomas continue to be an area of unmet need for new therapies that offer novel mechanisms of action. Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). Tipifarnib inhibits farnesylation of key regulatory proteins involved in CXCL12 production (Gualberto et al, EHA 2019). CXCL12 is a chemokine that is essential for T-cell homing to lymphoid organs and bone marrow, and for the maintenance of immune cell progenitors via its receptor CXCR4 (Susek et al, Front Immunology, 2018). Angioimmunoblastic T-cell lymphoma (AITL) is associated with high levels of CXCL12 expression, which is also a negative prognostic factor (Witzig et al, Blood, 2019). Additionally, Peripheral T-Cell lymphoma Not Otherwise Specified (PTCL-NOS) patients with the CXCL12 rs2839695 A/A wildtype genotype (PTCL-CXCL12+) have also been found to have elevated levels of CXCL12. Therefore, there is strong rationale for targeting these subsets of PTCL with tipifarnib. This Phase 2 study (NCT02464228) was a multi-institutional, single-arm, open-label trial determining the efficacy, safety, and potential predictive biomarkers for tipifarnib in adult patients with relapsed or refractory (R/R) PTCL. Patients received tipifarnib 300 mg orally twice daily on Days 1-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. The primary objective of the study was to determine the antitumor activity by overall response rate (ORR) per Lugano Classification. Secondary objectives included safety, duration of response (DoR) and progression-free survival (PFS), and exploratory analyses included overall survival (OS) and identification of potential biomarkers associated with tipifarnib activity. Sixty-five R/R PTCL patients (38 AITL, 14 PTCL-NOS, 11 PTCL-CXCL12+, 2 other (1 ALCL-ALK negative, 1 PTCL-subtype not specified) were treated with tipifarnib. The population was heavily pretreated with a median of 3 prior regimens (range 1-8). All patients had at least one treatment-emergent adverse event (TEAE); most patients (87.7%) had at least one treatment-related TEAE, and 18 (27.7%) patients had at least one treatment-related serious TEAE. The most frequently observed (≥20%) treatment-related TEAEs (all grades) were hematological (neutropenia, thrombocytopenia, anemia,) and gastrointestinal (nausea, diarrhea), as well as fatigue, which is consistent with the known safety profile of tipifarnib. Fifty-eight patients were efficacy evaluable and had an associated ORR of 39.7% (23/58) with most responses observed in the AITL and PTCL-CXCL12+ cohorts. In the 32 patients with AITL, the ORR was 56.3% (18/32), including 9 complete responses (CR) and 9 partial responses (PR). In the 10 patients with PTCL-CXCL12+, the ORR was 40.0% (4/10), including 1 CR and 3 PR. The median OS for patients with AITL was 32.8 months, and the median OS had not been reached for patients with PTCL-CXCL12+. Previously, a strong association between KIR3DL2 C336R/Q386E mutation and the activity of tipifarnib was observed and reported in AITL patients (Witzig et al, EHA 2020). Extensive gene expression and gene variant analyses of samples from the study population is currently ongoing to evaluate this correlation and explore other potential predictors of response. Final data will be presented at the time of the conference. Overall, the results from this Phase 2 study with tipifarnib demonstrated very encouraging efficacy in patients with CXCL12-expressing subtypes of PTCL (AITL and PTCL-CXCL12+) and showed a tolerable safety profile. Disclosures Witzig: Karyopharm Therapeutics, Abbvie/Genentech, Seattle Genetics, Celgene/BMS, Incyte, Epizyme, Cellectar, Tessa Therapeutics, Portola Pharmaceuticals, MorphoSys, ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Kim: IGM Biosciences: Research Funding; Kyowa Kirin: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Johnson & Johnson: Research Funding; Eisai: Research Funding. de la Cruz Vicente: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Marin Niebla: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kiowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Terol: BMS: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bendris: Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Ahsan: Gilead: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Kura Oncology: Current Employment, Current equity holder in publicly-traded company. Leoni: Kura Oncology: Current Employment. Foss: Daiichi Sankyo: Honoraria; Mallinckrodt: Honoraria; Acrotech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Kyowa: Honoraria; Kura: Honoraria.

Introduction: The BCL-2 inhibitor venetoclax (Ven) has been approved on monotherapy or combined with rituximab in relapsed/refractory CLL patients (pts) and combined with obinutuzumab in previously untreated CLL pts. However, evidence from clinical trials can be difficult to generalize to real-world patient populations. The VENARES study assesses the real-world use of Ven following approval to inform of subpopulations underrepresented in clinical trials. Methods: This is Spanish non-interventional retrospective, multicenter post-marketing observational study. The main objective was to evaluate the effectiveness of Ven in adult CLL pts by the overall response rate (ORR) at 9 months (mo) after the first Ven dose administration. Secondary objective was to evaluate the effectiveness for the Ven monotherapy and the Ven combined with rituximab subpopulations. Consecutive adult pts with diagnosis of CLL who have initiated Ven at least 9 mo before the inclusion in the study were included. Data of pts are retrospectively reviewed until the date of last follow-up or death. Results: 125 pts diagnosed with CLL and who met the eligibility criteria were analyzed. The median age was 72 years (67 - 77) with 76.8% being older than 65 years. Most patients were male (68.8%), had a concurrent disease (65.6%). ECOG PS was recorded in 76 pts: 40 pts (32%) had PS 0, 30 pts (24%) PS 1 and 6 pts (4.8%) PS 2. Pts had received a median of 4 prior lines of therapy (range 1-13 lines). At baseline, among the 92 pts with known Binet stage, 31 (33.7%) had stage C and 38 (41.3%) had stage B; bulky nodes ≥ 5 cm were present in 20 of 87 pts; 49 pts (39.2%) had an absolute lymphocyte count ≥ 25 x 10 9/L and 33 of 54 pts (61%) baseline beta-2 microglobulin value above of 3500 ng/mL. In total, 29 of 90 patients (32%) assessed had Cr 17p deletion, 28 of 86 patients (32%) tested had TP53 mutations, and 46 of 56 patients (82%) who were tested had unmutated immunoglobulin heavy-chain variable (IGHV) status. Ven was administered as monotherapy in 71 pts (57.6%), combined with rituximab in 36 pts (28.8%), combined with obinutuzumab in 5 pts (4%) and combined with other drugs in 13 pts (10.4%). 83 of 125 patients included were evaluable for the primary objective of the study: the ORR at 9 mo was 84.3% (70 patients): CR/CRi in 44 (53%) pts, PR/nPR in 26 pts (31.3%), SD in 9 pts (10.8%) and PD in 4 pts (4.8%). By treatment, in the evaluable patients, ORR at 9 months were 79.2% (38 of 48 patients) in the Ven monotherapy group, with 45% of CR/CRi, and 92.3% (24 of 26 patients) in the Ven combined with rituximab, with 61% CR/Cri. The median duration of PFS was not reached at the time of the analysis (1-June-2021). Kaplan-Meier estimates of the probability of PFS at 24 mo was 75.4% (95% CI, 58.2 - 86.3). Disease progression occurred in 21 pts. Assessment of minimal residual disease (MRD) was available for 32 patients (25.6%) on the basis of peripheral-blood samples, bone marrow or both. Best undetectable MRD was reached in fourteen patients (43.8%). uMRD was more common in pts treated with Ven combined with R (83.3%, 5 of 6 pts) than in pts treated with Ven monotherapy (33.3%, 7 of 21 pts). Adverse events (AEs) were reported during Ven therapy in all 125 patients, 93 of these pts reported AEs related to Ven. Related to Ven, 67 patients (53.6%) experienced at least one AE: 52 pts (41.6%) had neutropenia being grade 3 and 4 in 22 (42.3%) and 9 (17.3%) pts, respectively. 9 pts (7.2%) had febrile neutropenia. Thrombocytopenia and anemia were less common occurring in 5.6% and 2.4%, respectively. Tumor lysis syndrome (TLS) occurred in 4 of 125 pts during ramp-up (3 laboratory and 1 clinical), 2 of them were related to Ven both lab TLS. None of the pts discontinued therapy due to TLS. Richter transformation was observed in 6 pts (4.8%). Other common AEs was diarrhea (10.4%), but most cases were mild. Conclusions: Our first real-world data show that Ven monotherapy or combined with rituximab is effective in highly pre-treated CLL patients, ORR at 9 mo was 84.3% in all population and PFS estimate at 24 mo was 75.4% with similar outcomes to those in the pivotal clinical trials. The safety profile of Ven was consistent with prior experience of Ven in monotherapy or combined with rituximab and no new safety signals were detected. Disclosures Baltasar: Janssen, Abbvie: Consultancy. Terol: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; BMS: Consultancy; Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Hospital Clinico Valencia: Current Employment. Moreno: Janssen, Abbvie: Research Funding; Abbvie, Janssen, AstraZeneca: Speakers Bureau; Abbvie, Janssen, AstraZeneca, Beigene: Membership on an entity's Board of Directors or advisory committees. Osorio: Janssen, Abbvie, Roche: Consultancy. De la Cruz: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirkin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Serna: AbbVie, AstraZeneca, Roche: Speakers Bureau; ABBVIE, ASTRAZENECA,ROCHE: Research Funding; AbbVie, AstraZeneca, Beigene, Gilead, GSK, Janssen, Jazzpharma, Novartis, Roche: Consultancy. Arguiñano: Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Speakers Bureau; Takeda, Sanofi, Janssen, BMS-Celgene, Abbvie: Consultancy. Loscertales: Janssen, Abbvie, Roche, Gilead: Speakers Bureau; Janssen, Abbvie, Astra-Zeneca, Beigene, Roche, Gilead: Consultancy. García: Janssen, Roche, Gilead, Celgene: Consultancy; Janssen, AbbVie: Research Funding; Janssen, Roche, Gilead, AbbVie, Celgene: Other: medical meetings funding. Pérez Persona: BMS/Celgene: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Amgen: Consultancy, Other: Support for attending meetings and/or travel, Speakers Bureau; Takeda: Speakers Bureau; AbbVie: Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; GSK: Consultancy; Incyte: Consultancy. Pérez-Encinas: Janssen: Consultancy. Caballero: Celgene, Janssen, Novartis, Abbvie: Speakers Bureau; Celgene, Janssen, Amgen: Consultancy. Ruiz-Zorrilla: Abbvie: Current Employment. Moreno: abbvie: Current Employment. Ferrà: Janssen, Roche, Gilead, Takeda, Abbvie: Consultancy; Janssen, Roche, Gilead, AbbVie: Other: medical meetings funding.

Introduction: Among the genetic lesions described in chronic lymphocytic leukemia (CLL), TP53 and IGHV mutational status are well-established prognostic biomarkers. While mutations resulting in dysregulation of TP53 are associated with chemo-resistance, mutated IGHV (IGHV-M) identifies a good prognosis and unmutated (IGHV-UM) is associated with an aggressive clinical outcome. Thus, molecular assessment of TP53 and IGHV mutational status is recommended to make treatment decisions. Moreover, 30% of CLL patients have a highly homologous complementarity-determining region 3 (CDR3), allowing their classification in subsets based on the stereotypical B-cell receptor immunoglobulins (BcR IG), which have been associated with different clinical features and outcomes. This study aimed to assess the mutational status of TP53 and IGHV and the frequency of stereotypical BcR IG subsets, including CLL#2 and CLL#4 associated with poor and good prognosis, respectively, in a large series of CLL patients in Spain. Methods: Observational, retrospective, cross-sectional, multicentric study of data from the RED53 project, a collaborative network between the Spanish Group of CLL (GELLC) and Janssen for the characterization of TP53 and IGVH mutational status in naïve CLL candidate patients to receive treatment. Blood samples from 225 institutions were collected between May 2016 and March 2021. Included patients had confirmed diagnosis of CLL and required first-line treatment. Basic demographic variables, leukocyte and lymphocyte counts, and the number of clonal CD5 +/CD19 + lymphocytes were recorded at sample extraction. Clonotypic IGHV-IGHD-IGHJ gene rearrangements and exons 4 to 10 of TP53 were amplified by PCR and sequenced (Sanger). Four analytical reference centers qualified by the European Initiative for CLL (ERIC) determined the mutational status following the ERIC guidelines. Results: A total of 1097 samples from patients with a median (range) age of 70.0 (27-97) years were analyzed. At sample extraction, patients had a median (range) of 54.5 (2-516) x10 9 leukocytes/mL and 46.1 (0-8810) x10 9 lymphocytes/mL, of which a median (range) of 80.0 (1-100) % (n=754) were clonal CD5 +/CD19 + lymphocytes. The most frequent indications for treatment initiation were progressive/tumoral adenopathy (n=525, 50.4%), progressive lymphocytosis (n=429, 41.2%), cytopenia (n=369, 35.4%), and systemic constitutional symptoms (n=252, 24.2%). Median (IQR) age was 63.0 (55.0, 71.0) years at diagnosis and 70.0 (62.0, 77.0) years at treatment onset. Median (range) time from diagnosis to treatment was 2.7 (0.6-6.1) years. Among 1097 patients, 100 (9.2%) had TP53 mutations with 103 variants, of which only 3 (3.0%) had 2 mutations. Of the 103 mutations, 91 (88.3%), 9 (8.7%), and 3 (2.9%) were pathogenic, likely pathogenic, and of uncertain significance, respectively. Fig. 1 shows mutation localization and type. IGHV was UM in 58% (471/812) and M in 33.1% (269/812) of patients, and unknown/undetermined in 1.8% (15/812), non-productive in 3.2% (26/812), and borderline in 3.8% (31/812) of patients. IGHV rearrangements were undetected in 25.6% (279/1091) of patients and 65.7% (717/1091), 8.5% (93/1091), and 0.2% (2/1091) had 1, 2, and 3 rearrangements, respectively . Of the 30 patients with IGHV3-21 rearrangements, 18 had available data, of which all had CLL#2 subset and, of the 15 patients with IGHV-M, 5 (33.3%) had CLL#2. Minor subsets were found in 7 (46.7%) and 17 (33.3%) of IGHV-M and UM, respectively. The most frequent stereotyped BcR IG subsets were CLL#2, CLL#1, and CLL#6, in 24.3% (18/74), 23% (17/74), and 10.8% (8/74) of patients, respectively. Among the 60 patients with mutated TP53 and IGHV mutational study available, 66.7% (40/60) had IGHV-UM. Conclusions: In our real-world experience, results regarding TP53 M and IGHV UM (9.2% and 58.0% of patients, respectively) are similar to those reported in previous series of patients requiring first-line treatment, with a slightly higher predominance of IGHV-UM over IGHV-M cases. Subset CLL#2 was the most frequently identified, whereas the frequency of CLL#6 was higher than that reported before. Considering the difficulties associated with the analysis of TP53 and IGHV mutational status of most laboratories diagnosing CLL, the RED53 network allows access to these determinations to naïve CLL patients with active disease by a simple, fast, and standardized method. Figure 1 Figure 1. Disclosures Terol: Roche: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; BMS: Consultancy; Hospital Clinico Valencia: Current Employment. Ferrer Lores: Janssen: Membership on an entity's Board of Directors or advisory committees. Bosch: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: Travel. Gonzalez Diaz: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Crespo: Janssen: Consultancy; Astra Zeneca: Research Funding; Roche/Genentech: Research Funding. Alcoceba: Janssen: Consultancy. Esteve: Janssen: Current Employment. Loriente: Janssen: Current Employment. Villanueva: Janssen: Current Employment.

Introduction. Patients with relapsed/refractory classical Hodgkin's lymphoma (RRHL) still represent a therapeutic challenge. Consolidation with autologous stem cell transplantation (auto-HCT) is the standard of care in this setting. The achievement of a metabolic complete remission (mCR) with salvage chemotherapy (CT) improves long-term outcome after auto-HCT. The introduction of new drugs has significantly changed the landscape of RRHL. Our cooperative group (GELTAMO) has already demonstrated that brentuximab vedotin (BV) + ESHAP (BRESHAP, García-Sanz R et al, Ann Oncol 2019) is able to achieve a mCR rate of 70% before auto-HCT in patients with RRHL. Nevertheless, the superiority of BV + CT vs CT alone has never been tested in prospective randomized clinical trials. Additionally, it is unknown if consolidation treatment with BV could eventually spare auto-HCT in a good risk group of RRHL patients. Objectives. We have conducted a phase IIb prospective clinical trial (BRESELIBET, ClinicalTrials.gov ID: NCT04378647) that evaluates the efficacy of salvage therapy with BRESHAP vs ESHAP in patients with RRHL, followed by BV consolidation (instead of auto-HCT) in those who attained a mCR after salvage therapy. Methods. 150 adult patients with classical RRHL after one line of therapy were to be included and randomized 1:1 in an open label design to receive either BRESHAP [BV (1.8 mg/m 2 iv, D1), etoposide (40 mg/m 2/day iv, D1-4), Solumedrol (250 mg/day iv, D1-4), Ara-C (2 g/m 2 iv, D5) and cisplatin (25 mg/m 2/day iv, D1-4)] (x3 cycles) or ESHAP (x3 cycles). Primary efficacy endpoint of the trial was mCR [Deauville Score (DS) of 1-2]. Those patients in mCR went on to receive up to a 16 doses of BV (1.8 mg/kg iv every 3 weeks) unless unacceptable toxicity or disease progression. Patients not achieving a mCR went off the trial. Herein we are reporting preliminary results of the first 43 patients treated within the trial. Results. As of June 2021, 47 patients have been enrolled; 3 of them have been screening failures and one patient is still under screening. Among the remaining 43 patients [28 males, age at inclusion of 42 (18-64) years, median (range)], 15 were primary refractory, 15 had an early relapse (1 st CR Conclusions. BRESELIBET trial is a randomized trial that tries to demonstrate the superiority of BRESHAP vs ESHAP in RRHL as well as the feasibility of a non-transplant option in patients achieving a stringent CR assessed by PET-CT. These initial results provide safety data as possible support for these two hypotheses and the trial enrollment continues. Disclosures Sureda: Takeda: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Honoraria; Mundipharma: Consultancy. Núñez: Tekada: Consultancy; Incyte: Consultancy. De la Cruz: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirkin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Eva: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Terol: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Roche: Consultancy; BMS: Consultancy; Hospital Clinico Valencia: Current Employment. Cordoba: ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Romero: Takeda: Honoraria; Alexion: Honoraria.

Patients with postransplant lymphoproliferative disease (PTLD) who are refractory to rituximab-based regimens have extremely poor prognosis. Data is lacking in the setting of solid organ transplantation (SOT)-related PTLD treated with chimeric antigen receptor T-cell (CAR-T) therapy. Moreover, limited information is available on the influence of concomitant immunosuppressive drugs on CAR-T function. Here, we describe the clinical outcome in one PTLD patient and propose a strategy for tailoring immunosuppressive treatment and organ monitoring in patients with kidney allografts after CAR-T infusion. This report also reviews the limited published data in the setting of SOT-related PTLD treated with CAR-T, which appears to be a feasible treatment in this clinical scenario, without severe toxicity and capable of inducing sustained responses. A noteworthy finding is that in most reported cases patients underwent complete or partial discontinuation of immunosuppressive drugs, with only one documented case of allograft rejection.

Background There is a lack of clinical information regarding the usefulness of plasma Epstein-Barr virus (EBV) DNA load kinetics analyses in the management of EBV infections in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Namely, it remains unknown whether this type of analysis can help physicians to anticipate the development of high-level EBV DNAemia episodes requiring rituximab treatment or predict the risk of recurrent EBV DNAemia or post-transplant lymphoproliferative disorders (PTLDs). Study design Unicentric, retrospective, observational study including 142 consecutive patients undergoing T-cell replete allo-HSCT. The plasma EBV DNA load was monitored on a weekly basis using the artus® EBV PCR kit. Results Fifty-five of the 142 patients (38.7%) developed at least one episode of EBV DNAemia; 13 of the 55 initial EBV DNAemia episodes (23.6%) were preemptively treated with rituximab, 7 patients had a recurrent episode of EBV DNAemia, and biopsy-proven PTLDs were diagnosed in 4 patients. The initial plasma EBV DNA load was not significantly different (P = 0.269) in episodes of self-resolving EBV DNAemia, those requiring rituximab treatment, or those leading to PTLDs. The plasma EBV DNA load doubling times were similar across all the groups (P = 0.799), and the EBV DNA-load half-life was not associated with the occurrence of recurrent EBV DNAemia (P = 0.550). Conclusion Plasma EBV DNA-load kinetics analyses are unlikely to be useful in predicting the occurrence of high-level EBV DNAemia, PTLD, or recurrent EBV DNAemia.

Introduction. Ibrutinib is a first-in-class, oral, once-a-day Bruton's tyrosine kinase inhibitor that achieves high overall response rates and durable remissions in patients with chronic lymphocytic leukemia (CLL) including those with high-risk features (unmutated IGHV, TP53 abnormalities, 11q deletion). Survival with continuous single-agent ibrutinib in previously-untreated CLL patients is comparable to an age-matched general population (Figure 1). IBRORS is an observational, retrospective, multicentre study to describe the characteristics and clinical outcomes of patients with CLL treated with single-agent ibrutinib in routine clinical practice in Spain. This present analysis reviews the subset of patients in IBRORS who received ibrutinib as the first-line of treatment. This series includes a significant number of patients with high risk cytogenetic/molecular alterations (del17p/TP53 M), which corresponds with the approved indication for first-line CLL patients in Spain at the time. Methods. Adult patients diagnosed with CLL treated with single-agent ibrutinib in first-line, or at first or second relapse since its commercialization in Spain (between January 2016 to January 2019) were included in the IBRORS study. Clinical characteristics of patients, efficacy and tolerability of ibrutinib as first-line treatment were analyzed here. A Kaplan-Meier analysis was performed for overall survival (OS) and progression-free survival (PFS). Results. 84 patients, from a total of 269 included in IBRORS, received single-agent ibrutinib as first-line treatment. The median age was 71.3 years (range 63-77) at the time of ibrutinib initiation. 56.3% of patients presented with an intermediate/high-risk Rai-Binet stage, and the majority of patients (98.6%) had an ECOG PS of 0-1. 91.7% of patients had at least 1 high risk molecular cytogenetic factor (unmutated IGHV, TP53 abnormalities, 11q deletion or complex karyotype) described in table 1. Baseline comorbidities of patients are described in table 2. Concomitant medication included anticoagulants (9.5% patients; vitamin K antagonist [n=4], Apixaban [n=1] and LMWH [n=3] patients), antiplatelet agents (11.9% patients), and antihypertensives (50% patients). The overall response rate (ORR) was 79.5%; 14/84 (16.6%) achieved a complete response (CR), 14/84 (16.6%) achieved CR unconfirmed, 27/84 (32.14%) achieved a partial response (PR) and 12/84 (14.2%) a PR + lymphocytosis. The median PFS and OS were not reached, and the estimated PFS at 24 months was 84.5% (73.4-95.6%). OS and PFS curves are represented in figure 2. The PFS of each patient subgroup with high-risk cytogenetic characteristics was similar to that of all patients in the first-line cohort: del17p/TP53 mutation (HR = 0.963 [95% CI 0.188-4.928]; p = 0.964), del11q (HR = 0.042 [95% CI 0.000-682.736]; p=0.521), unmutated IGHV (HR = 0.391 [95% CI 0.110-1.394]; p = 0.148). The median duration of exposure to ibrutinib was 17.3 (11.9-25.6) months. Dose reduction of ibrutinib occurred in 17/84 (20.2%) patients, 8/84 (9.52%) due to toxicity (4 hematologic toxicity and 4 non-hematologic toxicity). 27/84 (32.1%) patients had temporary interruption of treatment. 15/84 (17.8%) patients permanently discontinued ibrutinib including 6 (7.14%) patients due to progression, 4 (4.76%) due to toxicity and 5 for other reasons. Safety: 49/84 (58.3%) patients developed at least one adverse event (AE), while 12/84 (14.2%) patients developed at least one serious adverse event (SAE). Twelve (14.3%) patients reported at least one haematological toxicity while 53 patients (63.1%) recorded at least one non-haematological toxicity. Only 1 patient experienced grade 3 atrial fibrillation, which did not lead to discontinuation. The most common AEs are described in table 3. Conclusion. This population of previously-untreated CLL patients, enriched for high-risk genomic features, reflects the initial approval of ibrutinib for the treatment of first-line patients with del17p in Spain. Single-agent Ibrutinib as the first-line treatment in this real world population was effective regardless of risk factors and well tolerated, with a low rate of discontinuation due to toxicity. Findings are consistent with those reported in clinical trials. Disclosures Loscertales: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Arguiñano:AbbVie: Honoraria; Janssen: Honoraria; BMS-Celgene: Honoraria; Novartis: Honoraria. Hernandez-Rivas:Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Pérez Persona:Amgen: Consultancy; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Jannsen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy. Loriente:Janssen Cilag: Current Employment. Villanueva:Janssen Cilag: Current Employment.

BACKGROUND Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), non-candidates for autologous stem-cell transplantation (ASCT), have few treatment options. Ibrutinib is an oral Bruton's tyrosine kinase inhibitor that has shown increased antitumor activity in patients with DLBCL of different subtype from germinal center B-cell like (non-GCB). In the present phase II clinical trial (NCT02692248), we investigated the efficacy and toxicity of the combination of Ibrutinib with the R-GEMOX-D regimen (rituximab, gemcitabine, oxaliplatin and dexamethasone), in patients with non- GCB DLBCL. METHODS We included patients with histological diagnosis of non-GCB DLBCL (according to Hans algorithm), with relapsed or refractory disease after at least 1 line of immunochemotherapy and non-candidates for ASCT. Patients received an induction treatment consisting of 6 (in case of complete remission [CR] after cycle 4) or 8 (in case of partial response [PR] or stable disease after cycle 4) cycles of R-GEMOX-D at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate (ORR) after 4 cycles, and the secondary objectives were: CR rate, progression-free survival (PFS), overall survival (OS) and toxicity. Analyses were performed in the intention to treat population (data cut-off 10th April 2020). RESULTS Sixty-four patients (59.4% male) were included between March 2016 and November 2018. Median age was 67 (25-84) years. Patients had received a median of 2 previous lines of treatment; 56.3% were refractory ( Of the 64 patients who started study treatment, 44 and 35 patients, respectively, were evaluated for response after 4th cycle and at the end of induction. Twenty-four (37%) patients started maintenance with ibrutinib, 7 of whom continue or have completed it. Causes of withdrawal from the trial (n=57) were progression (n=40), adverse event (n=6), transplantation (n=5), withdrawal of consent (n=3) and other causes (n=3). ORR and CR rate after 4th cycle were 53.2% and 35.9%, respectively. Patients with relapsed disease had significantly higher ORR (67.9% vs 41.7%, p=0.037) and CR rate (57.1% vs 19.4%, p=0.002) than patients with refractory disease. At the end of induction, ORR and CR rate were 35.9% and 29.7%, respectively. After a median follow-up of 22 months (range: 1 to 39 months), the estimated 2-year PFS and OS were 21% and 25%, respectively (Figure 1A and 1B), being significantly better in patients with relapsed disease (Figure 1C and 1D). In the multivariate analysis, status of lymphoma at study entry significantly influenced PFS (HR 0.45; 95% CI 0.25-0.82; p=0.009) and OS (HR 0.51; 95% CI 0.27-0.94; p=0.0031) independently from the IPI and the number of previous treatment lines. The most frequent adverse events (AE) (present in at least 20% of patients) were thrombocytopenia (67.2%), diarrhea (51.6%), neutropenia (46.9%), anemia (37.5%), fatigue (34.4%), nausea (29.7%) and paresthesia (20.3%). The most frequent grade 3-5 AE (present in at least 10% of patients) were thrombocytopenia (46.9%), neutropenia (35.9%), diarrhea (15.6%) and anemia (14.1%). Three patients presented a grade 5 AE, two of them related (aspergillosis and pneumonia, respectively) and one unrelated (heart failure). CONCLUSIONS The combination of ibrutinib with R-GEMOX-D as salvage therapy for patients with non-GCB DLBCL is associated with high response rates, especially in relapsed patients. The vast majority of refractory patients progress very early, so this regimen could be considered as a bridge to other consolidation therapies. Biological studies analyzing cell of origin by gene expression profiling, minimal residual disease and mutational spectrum are in progress. Disclosures Abrisqueta: Roche: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Giné:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. Grande:Janssen: Research Funding. Caballero:Roche: Other: travel; Gilead: Other: travel; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: travel; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Other: travel; Takeda: Other: travel; Kite: Membership on an entity's Board of Directors or advisory committees. Martin Garcia-Sancho:Roche, Celgene, Janssen, Servier, Gilead: Honoraria; Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy. OffLabel Disclosure: Off-label use of a new combination in the context of a clinical trial. New combination (Ibrutinib + R-GEMOX)

The management of recurrent/refractory (R/R) Hodgkin lymphoma (HL) remains challenging. Previously published data have shown some efficacy of rituximab in this setting. The purpose of this phase II trial was to investigate the activity of ofatumumab in combination with etoposide, steroids, cytarabine and cisplatin (O-ESHAP) in 62 patients with R/R classical HL. Treatment consisted of ESHAP plus ofatumumab 1000 mg on days 1 and 8 of the first cycle and day 1 of the second and third cycles. O-ESHAP was well tolerated with only 3% of patients requiring treatment discontinuation because of adverse events. Overall response rate was 73% (44% complete metabolic response). In multivariate analysis, early relapse (P < 0.001), bulky disease (P < 0.001) and B symptoms (P < 0.001) were the most important prognostic factors for response. No failures of stem cell mobilization were observed. The high response rate, particularly the complete metabolic response rate, the low toxicity profile, and the high mobilizing potential of the O-ESHAP regimen suggest that patients with R/R HL may benefit from this salvage regimen. However, with the encouraging results observed with other new therapeutic agents in HL, the O-ESHAP regimen could be restricted to patients failing these agents or to those with R/R nodular lymphocyte-predominant HL.

Angiogenesis process contributes to the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) being the levels of VEGFA and bFGF higher in patients than in healthy controls. Our aim was to evaluate the implication of angiogenesis factors genetic variants in the predisposition to B-CLL and their association with clinical factors and survival. We performed a population-based case-control study in 224 Spanish B-CLL patients and 476 healthy randomly selected controls to evaluate susceptibility to developing B-CLL. Six polymorphisms were evaluated: rs1109324, rs1547651, rs3025039 (+936 C>T), rs833052 of the VEGFA gene, rs1449683 (c.233C>T) of the bFGF gene and (−710 C>T) of the VEGFR1 gene. The association between clinical parameters and patient outcome was analyzed. Carriers of the CT/TT variants of rs3025039 showed a significant protective effect against developing B-CLL. The CT/TT variants of rs1449683 show a tendency towards the development of the disease and the same variants associated significantly with higher genetic risk and with reduced disease free survival. Moreover, the association persisted in the early-stage disease subgroup. Our study provides evidence of the protective effect of the T/- rs3025039 VEGFA variant against B-CLL development and the association of CT/TT variants of the rs1449683 bFGF gene with genetic risk and an adverse survival.

Introduction. Despite the high proportion of prolonged remissions obtained with ibrutinib in patients with CLL, complete responses (CR) are rarely observed. For the purpose of increasing the deepness of response, ibrutinib has been tested in combination with other drugs that exert a different mechanism of action. Thus, monoclonal antibodies (mAbs) have been concomitantly combined with ibrutinib in untreated or R/R CLLs. Nonetheless, several data derived from both in vitro and clinical studies do not support a synergistic effect of the concomitant administration of ibrutinib with anti-CD20 mAbs. Herein, we present the preliminary results of a multi-center, non-randomized phase 2 study aimed to determine the efficacy and safety of the sequential treatment of CLL patients with ibrutinib followed, in those not attaining CR, by a consolidation phase with ofatumumab (GELLC-7, EudraCT number 2016-004937-26). Patients and methods. Patients aged ≥18 years, physically fit (CIRS score < 6) with treatment-naïve CLL were enrolled in this study. Patients received an induction phase consisting of 12 cycles (28-day) of ibrutinib in monotherapy at 420 mg once daily. Patients attaining a CR after this induction phase were kept on ibrutinib until progression. In contrast, patients not obtaining a CR also continued on ibrutinib but received a consolidation treatment with 7 doses of ofatumumab (300 mg D1 and 1000mg D8 of C13, 1000 mg D1 of C14-C18). The primary endpoint of the study was the CR rate assessed after 20 cycles of treatment (2 months after completing ofatumumab consolidation). Results. 84 patients with a median age 69 years (range 38-84 yrs), 71% male, were included in this study. At inclusion, 83.3% had Binet stage B/C, 61% unmutated IGHV status, and 19% high risk genetic aberrations (7.6% 17p deletion and/or TP53mut, and 11.4% 11q deletion). At the interim data cut-off (June 2019), 7 patients had discontinued the study (progression to Richter transformation, n=1; patient withdrawal, n=3; adverse events [AE], n=3, including one G5 AE), 5 of them during the first 12 cycles of treatment. Sixty-seven patients received the induction phase with 12 cycles of ibrutinib, whereas 22 patients completed 20 cycles of treatment and were evaluable for the primary endpoint of the study. After 12 cycles of ibrutinib, 3 patients (4.5%) were in CR, 54 patients (80.5%) in PR, 6 patients (9%) in PR with lymphocytosis, and 4 patients (6%) in SD. In 20 patients receiving the consolidation with ofatumumab an improvement in response was observed, with 8/20 patients (40%) attaining a CR (7 patients converted PR to CR, and one patient SD to CR), whereas the remaining 12 patients were classified as PR. Two patients that were already in CR at cycle 12 maintained the CR under ibrutinib monotherapy. MRD was undetectable in blood ( Grade ≥3 adverse events (AEs) were experienced by 26 patients (31%), whilst 22 serious AEs were observed in 16 patients (19%) (14 infections, 1 febrile neutropenia, 3 dyspnoea, 1 anemia, 1 edema/pleural effusion, 1 renal insufficiency, 1 squamous carcinoma). The most common G3/4 AEs were hematological toxicity (neutropenia [7.1%], anemia [4.5%], thrombocytopenia [2.4%]) and infections (8.5%). The Gr 5 AE consisted of a severe peripheral edema and pleural effusion leading to death. The great majority of SAEs (67%) and G3/4 AEs (66%) were observed during the first 12 cycles of treatment with ibrutinib monotherapy. Conclusions. The preliminary analysis of the GELLC7 trial showed that the addition of consolidation with ofatumumab after 12 cycles of prior treatment with ibrutinib was well tolerated and elicited a deeper response. These results support the potential role of a sequential therapeutic strategy in CLL, where the addition of a consolidation with mAbs in patients with low tumor burden might improve the quality of the response. Finally, more mature results will be further presented at the meeting. Disclosures Abrisqueta: Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. González-Barca:Kiowa: Consultancy; Celgene: Consultancy; Takeda: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celtrion: Consultancy. Terol:Roche: Consultancy; Janssen: Consultancy, Research Funding; Abbvie: Consultancy; Astra Zeneca: Consultancy; Gilead: Research Funding. Baltasar Tello:GILEAD: Honoraria; JANSSEN: Consultancy, Honoraria; ABBVIE: Honoraria; ROCHE: Honoraria. de la Serna:Roche, AbbVie, Gilead, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, AbbVie, Janssen, Gilead: Speakers Bureau. 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. Bosch:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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; AstraZeneca: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Ibrutinib followed by Ofatumumab Consolidation

We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 x 10(9)/l and >20 x 10(9)/l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.

Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous group of lymphomas that can be divided in two gene expression profiles by means of microarray gene expression profiling (GEP), germi...

The use of immunochemotherapy has improved the outcome of follicular lymphoma (FL). Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression-free survival. This study aimed to analyse the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age-matched Spanish general population (relative survival; RS). The training series comprised 263 patients consecutively diagnosed with FL in a 10-year period who needed therapy and were treated with rituximab-containing regimens. An independent cohort of 693 FL patients from the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO) group was used for validation. In the training cohort, 188 patients were in CR30, with a 10-year overall survival (OS) of 53% and 87% for non-CR30 and CR30 patients, respectively. Ten-year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Multivariate analysis indicated that the FL International Prognostic Index was the most important variable predicting OS in the CR30 group. The impact of CR30 status on RS was validated in the independent GELTAMO series. In conclusion, FL patients treated with immunochemotherapy who were in CR at 30 months showed similar survival to a sex- and age-matched Spanish general population.

Primary Thyroid Lymphoma (PTL) is an uncommon disease, although its incidence is of 5%. Ultrasound and Fine Needle Aspiration Cytology (FNAC) usually do not provide the diagnosis. Surgery is one of the treatment options because it enables histological diagnosis and can also relieve compression symptoms in patients with rapid growth cervical mass. We present 7 cases of PTL diagnosed in the last 10 years in our unit. Five were female (71.4%) and 2 were male (28.6%). The mean age was 64.2 (range: 40 - 81); 4 patients (57.1%) had associated Hashimoto’s Thyroiditis (HT). One patient (14.2%) had concomitant Graves disease. 5 cases presented with compressive symptoms and cervical mass. Ultrasound was not diagnostic in any case. FNAC was diagnostic only in one patient (14.3%). Five patients underwent total thyroidectomy (71.4%). All the cases were diagnosed with lymphoma postoperatively. Two interventions consisted of left hemithyroidectomies (28.6%). No complications appeared. 5 patients (71.4%) were classified as Mucosa-Associated Lymphoid Tissue (MALT) lymphoma. We also observed 1 Follicular grade I lymphoma and 1 Burkitt case. When the extension study was done, 1 patient was at stage IIIE (14%), 2 at IIE (28.5%) and 4 at IE (57.14%). Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) and Iphosphamide, ethoposide and high dose Cytarabine (IVAC) were the treatment scheme when chemotherapy was used (in three cases). Two cases were treated only with total thyroidectomy, and 2 with total thyroidectomy and rituximab, and the latter was MALT. Complete Remission (CR) was achieved in all patients in the first year. All are still alive and in CR. In our experience, PTL diagnose can be challenging before surgery. Although surgery is not the gold standard for treatment, when it is done, it should be curative in MALT lymphomas confined to the thyroid.

CLL remains an incurable disease in spite of the many new compounds being studied. Arsenic trioxide (ATO) induces apoptosis in all CLL cell types and could constitute an efficient therapy. To further explore this, we have studied the influence of stromal cells, key components of the CLL microenvironment, on the response of CLL cells to ATO. Bone marrow stromal cells induced CLL cell resistance to 2 μM ATO and led to activation of Lyn, ERK, PI3K and PKC, as well as NF-κB and STAT3. Mcl-1, Bcl-xL, and Bfl-1 were also upregulated after the co-culture. Inhibition experiments indicated that PI3K and PKC were involved in the resistance to ATO induced by stroma. Moreover, idelalisib and sotrastaurin, specific inhibitors for PI3Kδ and PKCβ, respectively, inhibited Akt phosphorylation, NF-κB/STAT3 activation and Mcl-1 upregulation, and rendered cells sensitive to ATO. Mcl-1 was central to the mechanism of resistance to ATO, since: 1) Mcl-1 levels correlated with the CLL cell response to ATO, and 2) blocking Mcl-1 expression or function with specific siRNAs or inhibitors overcame the protecting effect of stroma. We have therefore identified the mechanism involved in the CLL cell resistance to ATO induced by bone marrow stroma and show that idelalisib or sotrastaurin block this mechanism and restore sensibility to ATO. Combination of ATO with these inhibitors may thus constitute an efficient treatment for CLL.

We report the outcome of 30 consecutive patients with Hodgkin disease (HD) who underwent single-unit UCBT. Most (90%) patients had failed previous autologous hematopoietic stem cell transplantation. The conditioning regimens were based on combinations of thiotepa, busulfan, cyclophosphamide or fludarabine, and antithymocyte globulin. The cumulative incidence (CI) of myeloid engraftment was 90% [95% confidence interval (C.I.), 74-98%] with a median of 18 d (range, 10-48). CI of acute graft-versus-host disease (GvHD) grades II-IV was 30% (95% C.I., 17-44%), while the incidence of chronic GVHD was 42% (95% C.I., 23-77%). The non-relapse mortality (NRM) at 100 d and 4 yr was 30% (95% C.I., 13-46%) and 47% (95% C.I., 29-65%), respectively. EBV-related post-transplant lymphoproliferative disease (EBV-PTLD) accounted for more than one-third of transplant-related death, with an estimate incidence of 26% (95% C.I., 9-44). The incidence of relapse at 4 yr was 25% (95% C.I., 9-42%). Four-year event-free survival (EFS) and overall survival (OS) were 28% and 30%, respectively. Despite a high NRM and an unexpected high incidence of EBV-PTLD, UCBT in heavily pretreated HD patients is an option for patients lacking a suitable adult donor, provided the disease is not in refractory relapse.

Background: The use of immunochemotherapy has substantially increased the outcome of patients with follicular lymphoma (FL). Nowadays, life expectancy for those reaching a durable response is excellent. Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression-free survival. The aim of this study was to analyze the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age-matched Spanish general population (relative survival; RS). Methods: 263 patients consecutively diagnosed with FL in a 10-year period, needing therapy and treated with rituximab-containing regimens, constituted the training series. An independent cohort of 693 FL patients from the GELTAMO group was used for validation. Findings: In the training cohort, 188 patients (71%) were in complete response at 30 months, with a 10-year overall survival of 53% and 87% for non-CR30 and CR30 patients, respectively. Ten-year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Follicular Lymphoma International Prognostic Index (FLIPI), beta2-microglobulin and response to induction, but not maintenance therapy or PET/CT assessment after induction, predicted RS in the CR30 patients group. FLIPI was the most important variable predicting overall survival in the CR30 group in the multivariate analysis. The impact of CR30 status on RS was validated in the independent GELTAMO series. Interpretation: Follicular lymphoma patients treated with immunochemotherapy who were in complete remission at 30 months showed similar survival to that of the sex- and age-matched Spanish general population. Funding: Instituto de Salud Carlos III, Ministerio de Salud, Espana, Ministerio de Economia y Competitividad, Espana, CIBERONC, the program "Fellowship de Gilead Sciences", Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO). Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: All the patients gave informed consent to participate in the study according to the declaration of Helsinki and the ethical standards of the Ethic Committee of the Hospital Clinic de Barcelona and in each participating centre in accordance with institutional standards.

This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (de novo or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m2) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 [43.9%; 90% confidence interval (CI:) 30.6-57.9%]. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at: clinicaltrials.gov identifier: 01472887). ispartof: HAEMATOLOGICA vol:103 issue:8 pages:1351-1358 ispartof: location:Italy status: published

Sirolimus appears to protect against cytomegalovirus (CMV) in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation recipients remains unexplored. By means of multivariate continuous-time Markov model analyses, we identified 3 independent covariates that significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure, and sirolimus exposure. CMV-seropositive recipients with CMV-seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by 40% (from 40% to 80%), whereas this probability decreased by 25% (from 40% to 15%) when trough concentrations of sirolimus increased from 0 to 16 ng/mL. Sensitivity analysis showed that sirolimus exposure between 0 and 6 ng/mL has no or negligible effect on CMV DNAemia, but levels >8 ng/mL significantly decreased the number of detectable CMV DNAemia cases (the risk ratios decreased from 0.68 to 0.21 when whole blood sirolimus concentrations changed from 8 to 18 ng/mL, P < .01). In conclusion, we used a pharmacometric statistical tool to provide the first clinical evidence that fewer CMV DNAemia events become detectable as sirolimus exposure increases.

Highlights • Human coronavirus are common after allogeneic stem cell transplantation and can progress to LRTDs, and in some cases this leads to hospitalization and requires supportive care. • Human bocavirus are quite rare after allogeneic stem cell transplantation and are commonly detected in conjunction with other viral co-pathogens., Epidemiologic data about coronaviruses (CoVs) and human bocavirus (HBoV) in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are scarce. We conducted a prospective longitudinal study on respiratory viral infections (RVIs) in allo-HSCT recipients with respiratory symptoms from December 2013 until June 2016. Respiratory virus in upper and/or lower respiratory tract (URT and LRT) specimens were tested using Luminex xTAG RVP Fast v1 assay. Seventy-nine consecutive allo-HSCT recipients developed a total of 192 virologically documented RVI episodes over 30 months. The median follow-up after RVI was 388 days (range, 5 to 923). CoV or HBoV was detected in 27 of 192 episodes (14%); 18 of 79 recipients (23%) developed a total of 21 CoV RVI episodes, whereas 6 recipients (8%) had 1 HBoV RVI episode each. Fourteen CoV RVI episodes were limited to the URT, whereas 7 affected the LRT. Co-pathogens were detected in 8 (38%) CoV cases. Type OC43 CoV was the dominant type (48%) followed by NL63 (24%), KHU1 (19%), and 229E (9%); the CoV hospitalization rate was 19%, whereas mortality was 5% (1 patient without any other microbiologic documentation). Among the 6 recipients with HBoV (3%), only 1 had LRT involvement and no one died from respiratory failure. In 5 cases (83%) HBoV was detected along with other viral co-pathogens. CoV RVIs are common after allo-HSCT, and in a significant proportion of cases CoV progressed to LRT and showed moderate to severe clinical features. In contrast, HBoV RVIs were rare and mostly presented in the context of co-infections.

The hallmark of mantle cell lymphoma (MCL) is the t(11;14)(q13,q32) translocation, which leads to the juxtaposition of CCDN1 to the IgH promoter locus, resulting in cyclin D1 overexpression. However, studies from transgenic mouse show that additional secondary genetic events are required for oncogenic transformation. Epigenetic dysregulation is an important mechanism of oncogenesis and tumour progression, but there are only few genome-wide studies of DNA methylome in MCL and mainly focused on promoter regions. In an elegant article published in Cancer Cell , Queiros et al 1 studied the genome-wide methylation profiles of 82 MCL cases using microarray containing approximately 450 000 CPG sites across the genome. They developed a novel computational strategy to isolate tumour DNA methylation changes from normal cells, in a so called ‘in silico purification’. Based on this strategy, the MCL samples were clustered into two groups—C1 and C2, which display similar methylation patterns to normal germinal centre (GC) inexperienced and GC experienced B cells, respectively, indicating a different B-cell origin. Both groups were highly heterogeneous and this also translated into distinct clinical–biological features, as IgVH mutational status, SOX11 expression, nodal presentation and worse survival for C1 patients. To identify tumour-specific alterations (TSA) from their normal counterpart, the authors compared data obtained from the MCL tumour cells with those coming from different B-cell subpopulations, ranging from haematopoietic progenitor cells to plasma cells. They found that 61%–79% of methylation changes CpGs overlapped with those acquired during B-cell differentiation and were enriched for enhancer elements, whereas the rest of 21%–39% were strictly tumour specific. Overall, hypomethylation in MCL in both the B-cell-related …

Mutations in Toll-like receptor (TLR) and myeloid differentiation primary response 88 (MYD88) genes have been found in chronic lymphocytic leukemia (CLL) at low frequency. We analyzed the incidence, clinicobiological characteristics, and outcome of patients with TLR/MYD88 mutations in 587 CLL patients. Twenty-three patients (3.9%) had mutations, 19 in MYD88 (one with concurrent IRAK1 mutation), 2 TLR2 (one with concomitant TLR6 mutation), 1 IRAK1, and 1 TLR5. No mutations were found in IRAK2 and IRAK4. TLR/MYD88-mutated CLL overexpressed genes of the nuclear factor κB pathway. Patients with TLR/MYD88 mutations were significantly younger (83% age ≤50 years) than those with no mutations. TLR/MYD88 mutations were the most frequent in young patients. Patients with mutated TLR/MYD88 CLL had a higher frequency of mutated IGHV and low expression of CD38 and ZAP-70. Overall survival (OS) was better in TLR/MYD88-mutated than unmutated patients in the whole series (10-year OS, 100% vs 62%; P = .002), and in the subset of patients age ≤50 years (100% vs 70%; P = .02). In addition, relative OS of TLR/MYD88-mutated patients was similar to that in the age- and gender-matched population. In summary, TLR/MYD88 mutations identify a population of young CLL patients with favorable outcome.

Introduction: Genomic studies of chronic lymphocytic leukemia (CLL) have uncovered >80 potential driver mutations. The vast majority of these mutations affect coding regions, and just two potential drivers have been identified in non-coding elements. Aim: To describe the biological and clinical impact of a recurrent A>C mutation at the third base of the small nuclear RNA U1, the non-coding component of the spliceosome involved in the recognition of the 5' splice site (5'SS). Methods: Whole-genome sequencing (WGS) and RNA-seq from 318 CLL patients were used to identify and characterize a highly recurrent A>C point mutation occurring at position 3 of the U1 snRNA gene (g.3A>C mutation). The U1 wild-type and mutant forms were introduced into three CLL cell lines (JVM3, HG3, MEC1) to validate in vitro the predicted effect of this alteration. We screened two independent cohorts including a total of 1,314 CLL patients for the presence of the mutation using the rhAmp SNP genotyping assay, and integrated the U1 mutational status with well-known driver alterations, IGHV and epigenetic subgroups, and clinical parameters. Results: The U1 mutation was found in 8/78 (10.3%) CLL cases analyzed by WGS. Given its role in 5'SS recognition by base-pairing, we reasoned that this mutation was likely to alter the splicing and expression patterns of CLL. We were able to confirm widespread specific alterations in the transcriptome by comparing RNA-seq data between wild-type and g.3A>C mutated samples. Applying this knowledge to an algorithm aimed to infer the U1 mutational status from expression data, we were able to identify 4 mutated cases among 240 additional cases that had RNA-seq but no WGS. In total, 12/318 (3.8%) CLL patients analyzed by WGS and/or RNA-seq harbored this mutation. This g.3A>C U1 mutation changes the preferential A-U base-pairing between U1 and 5'SS to C-G base-pairing, creating novel splice junctions and altering the splicing pattern of 3,193 introns in 1,519 genes. In addition to altered splicing, 869 genes were differentially expressed between mutated and wild-type cases. We identified specific cancer genes (e.g. MSI2, POLD1, or CD44) and pathways (B-cell receptor signaling, promotion of apoptosis, telomere maintenance, among others) altered by the U1 mutation. To confirm a causal link between this mutation and splicing changes, we introduced exogenous U1 genes with or without the mutation into three cell lines. Subsequent RNA-seq of these cell lines recapitulated the altered splicing and expression patterns observed in CLL patients. We next screened for the presence of the U1 mutation 1,057 patients (cohort 1) using the rhAmp assay and it was found in 30 (2.8%) cases. The distribution of the mutation was similar in Binet stages and CLL vs monoclonal B-cell lymphocytosis. However, the U1 mutation was almost always found in IGHV unmutated CLL (29/30, p=9.0e-11) and within the naïve-like CLL epigenetic subgroup (p=3.7e-7). None of the U1 mutated cases had mutations in the SF3B1 splicing factor. Considering only pre-treatment CLL samples, U1 mutation was associated with a shorter time to first treatment independently of the Binet stage, IGHV mutational status, epigenetic subgroups, and mutations in the well-known CLL drivers SF3B1, NOTCH1, ATMor TP53. In cohort 2 (n=257), this mutation was found in 13 (5.1%) patients, confirming its enrichment in IGHV unmutated cases, naïve-like epigenetic subgroup, and splicing modulation. Despite the relatively small number of pre-treatment samples carrying the U1 mutation (7/178) and short follow-up of the patients (median 2.6 years), the effect of this mutation on time to first treatment in cohort 2 was compatible with the one observed in cohort 1. Finally, we screened for the U1 mutation a cohort of diffuse large B-cell lymphoma (n=108), mantle cell lymphoma (n=101), follicular lymphoma (n=87), splenic marginal zone lymphoma (n=12), acute myeloid leukemia (n=52), and myelodysplastic syndrome (n=67). The mutation was not present in any of the samples analyzed. Conclusions: Here we have reported that the third base of the small nuclear RNA U1 is recurrently mutated in CLL, proved its effect in splicing and gene expression, and shown that this mutation is independently associated with faster disease progression. The g.3A>C U1 mutation represents a novel non-coding driver alteration in CLL with potential clinical and therapeutic implications. Disclosures Ramirez Payer: GILEAD SCIENCES: Research Funding. Terol:Astra Zeneca: Consultancy; Gilead: Research Funding; Abbvie: Consultancy; Janssen: Consultancy, Research Funding; Roche: Consultancy. Lopez-Guillermo:Celgene: Consultancy, Research Funding; Janssen: Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding.

Background and objective. Specific immunochemotherapy is the standard treatment of patients with Burkitt leukemia or lymphoma (BL/L). The BURKIMAB08 trial showed 3-yr overall survival (OS) probability of 72% (Ribera JM et al, Cancer. 2013; 119:1660-8). However, the toxicity was high, and 11% of patients died in complete response (CR). In the BURKIMAB14 trial, dose-intensity of chemotherapy blocks was reduced in patients ≤55 years who achieved CR, with the aim to decrease the death rate without impact on efficacy. We present the results of this trial in 80 patients with BL/L and compare them with those of the BURKIMAB08 trial. Patients and method. All patients received a pre-phase with cyclophosphamide, prednisone and rituximab. Patients in localized stages (I-II non-bulky) received 4 blocks of immunochemotherapy (A1, B1, C1, A2), with 33% reduction of doses of iphosphamide, methotrexate and ARA-C in patients ≤55 years in CR (assessed by PET-CT) after B1 cycle. Patients in stages III-IV and mature B-ALL received 6 immunochemotherapy blocks (A1, B1, C1, A2, B2, C2), with the same dose reduction in cycles C1, A2, B2, C2 in patients ≤55 years in CR after B1 cycle. Patients >55 years received reduced intensity chemotherapy (as in BURKIMAB08) in both induction and post-induction cycles. The CR rate, cumulated incidence of relapse (CIR) and OS were analyzed and compared with those from the BURKIMAB08 trial. Results. From 2014-2019, 80 patients with BL/L were enrolled. Median age (range): 48 (17-80) years, 57 (71%) ≤55 years, 61 males (76%), 15 (19%) patients in stages I-II non-bulky and 65 (81%) in stages III-IV, 25 of whom (38%) had mature B-ALL. 18 patients (23%) were HIV positive, 13 (17%) showed CNS involvement at diagnosis and 23 (31%) bulky mass (>10 cm). 45 patients (60%) had intermediate-high or high IPI. All patients in stages I-II non-bulky showed CR. 4/65 patients in stages III-IV or mature B-ALL are receiving induction therapy, 1/65 withdrew the trial, 7/60 (12%) died in induction, 2/60 (3%) were resistant and 51/60 (85%) achieved CR. Of them, 6 relapsed, 3 withdrew the trial and 3 died in CR (one in the group of localized stage). OS probability at 3 years was 74% (95%CI: 64%-84%) (localized stages 100% [NE], advanced stages 68% [56%-80%], p=0.047, without difference in patients in stages III-IV vs. mature B-ALL, Figure 1). Patients >55 years showed a significantly lower probability of OS (61% [41%-81%] vs. 80% [68%-92%], p=0.022, Figure 2). A lower but non-statistically significant OS probability was observed in HIV-infected vs. non-HIV-positive patients (61% [36%-86%] vs. 78% [67%-89%], p=0.310). The CIR for patients in advanced stage/mature B-ALL was 13% (3%-28%)A trend for lower death rate in CR was observed in BURKIMAB14 vs. BURKIMAB 08 trial (3/62 vs. 16/151, p=0.180), without differences in CIR (9% [3%-21%] vs. 12% [6%-20%]) or in OS (74% [64%-84%] vs. 72% [65%-79%], respectively). Conclusions. The results of the BURKIMAB14 trial are promising, especially for patients in localized stages and for those Supported in part with the grants PI14/01971 FIS, Instituto Carlos III, SGR 288 (GRC) y Fundación "La Caixa". Figure 1. OS according to stage (I-II, vs. III-IV vs. mature B ALL) Figure 2. OS according to age (≤55 y vs >55 y) Figure 1 Disclosures Abrisqueta: Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, expenses, Speakers Bureau. Fernandez:Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Terol:Roche: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Research Funding. Gimeno Vázquez:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Sancho:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Other: Advisory board; Novartis: Honoraria; Kern Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Celltrion: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squib: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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 Results: Forty patients (Gender M 29/ F 11; median age 65.7 years; low-risk MIPI 22% and intermediate/high MIPI 78%) were enrolled in the study up to data cut-off on 15 MAY 2019 (Consort diagram). The median observation time for the patients before treatment was of 7.6 months (range:3-107) and median follow-up was of 19 months. Efficacy data of the first 33 patients evaluable after 12 cycles of treatment are reported here, including two patients who were discontinued before cycle 12 due to related toxicity. A total of 27 patients achieved a response with an 82% overall response rate (ORR) and 75% CR. Among CR patients with evaluable MRD (N=23), the rate of undetectable MRD achieved after 12 cycles was 87%. Only 1 patient eventually became MRD positive at cycle 24, whereas 12 remained MRD negative and accordingly, nine of them discontinued ibrutinib as per protocol whereas 3 had interrupted treatment earlier because of intolerance. At data cut-off, all responding patients maintained the response with a median follow-up of 25 months (12-35). Only one patient progressed at one year of therapy. This particular case had shown intolerance to full-dose ibrutinib, received different salvage therapies and died of progressive disease. The estimated 15 month progression-free survival was 96% (CI95%: 89-100). Four patients withdrew the study because of serious adverse events, including cutaneous rash, severe aplastic anemia, pancreatic adenocarcinoma and lumbar fractures. Twenty-one additional G3 and G4 AEs related to Ibrutinib have been recorded including hematological toxicity in 7 patients, gastro-intestinal intolerance in 4 patients, arthralgias, atrial fibrillation and asthenia in one patient each. Conclusion: In indolent clinical forms of MCL frontline ibrutinib in combination with rituximab has a high efficacy, including undetectable MRD in the majority of cases, with a predictable toxicity profile. Figure Disclosures Gine: Roche: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Janssen: Other: Travel expenses, Research Funding. Martín:Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Teva: Research Funding; Roche: Consultancy, Honoraria, Other: Travel Expenses; Servier: Honoraria, Other: Travel Expenses; iQone: Consultancy; Janssen: Honoraria, Other: Travel Expenses, Research Funding; Kiowa Kirin: Consultancy. Terol:Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy; Roche: Consultancy; Gilead: Research Funding; Abbvie: Consultancy. González-Barca:AbbVie: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Kiowa: Consultancy; Roche: Consultancy, Honoraria; Celtrion: Consultancy; Takeda: Honoraria. Lopez-Guillermo:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Introduction: Determination of the mutational status of rearranged immunoglobulin heavy chain variable (IgHV) genes in patients with Chronic Lymphocytic Leukaemia (CLL), is considered one of the most important prognostic factors: patients with unmutated IgHV (UM; ≥98% of identity to the germline) genes have a more aggressive disease course and develop more frequently unfavourable genetic deletions or mutations than patients with mutated IgHV (M; ≤98%). Mutational status, is currently determined by Sanger sequencing (Sseq) that allows the analysis of the major clone, however, international guidelines recommend caution in assigning mutational status in cases with "Borderline" IgHV identity (97-97.9%), and cases with double rearrangements with discordant mutational status. Objective: Analyze and determine the mutational status of the IgHV locus by High-throughput sequencing (HTS), in a cohort of CLL patients (n=51) with unclassifiable Sseq results: borderline status (n=22); double rearrangements (n=27) with discordant mutational status (n=2). Methods: We included 51 DNA samples extracted from peripheral blood of patients diagnosed of CLL according to the National Cancer Institute Working Group guidelines in our institution between 1986 and 2019 (median absolute lymphocytes 11.4x109/L [2,8-239,5x109/L]). Sseq amplification and analysis of IgHV rearrangements were performed on DNA conforming to the updated ERIC recommendations. In all the cases we were able to determinate the IGVH identity. To switch high-throughput sequencing to the clinical practice, we assessed the reliability of different library preparation methods to sequence IGH locus in patients with CLL. Amplification was performed using the Sequencing Multiplex Kit based on IGH FR (forward primers) and consensus JH (reverse primer) multiplex. PCR products were purified using Magsi-NGS Prep magnetic beads (Magnamedics Diagnostics), normalized and pooled to create a library for sequencing using a MiSeq equipment. To simplify and make automatic the analysis of the same we developed a specific bioinformatic pipeline that covers from preprocessing to final data summarization and interpretation. The backbone of the analysis includes read preprocessing, mapping against IMGT reference sequences, consensus IgHV reads pairwise alignment to determine mutational status and read classification into rearrangements. Results: This approach led to the identification of a dominant clone IgHV in all cases (n=51). Instead, the percentage of identity calculated by HTS analysis varies in: - 15/22 borderline cases whose mutational status could be recalculated into 10 MM and 5 UM. The rest 7 remaining in borderline group. - We could identify both clones in 29 double rearrangements cases, with concordant mutational status except 2/29 undetermined cases, included in UM group regarding HTS results. Our tool led to the identification of a dominant clonotypic IgHV in all cases, and when compared the HTS sequence/mutational status for the most abundant clone with Sseq and for the IgHV status determination, 15 out of 22 (68,18%), could be reclassified. This case showed a major clone with productive rearrangement mutated by Sseq but unmutated by HTS. Conclusions: Analyze and determine the mutational status of the IgHV locus by HTS, would potentially reveal multiple rearrangements and increase the prognostic precision of IgHV mutation analysis. IgHV-HTS classification is able to precisely classify patients with borderline status or/and multiple IgHV rearrangements for which Sseq is inconclusive. In this case, it has been possible to improved prognostication for 17 out of 24 patients. This is helping us to discover the advantages of the data obtained by HTS compared with current Sseq standard technique. Samples were provided by the INCLIVA Biobank. Funded by Gilead Felowship 257/17 Disclosures Terol: Abbvie: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Research Funding; Roche: Consultancy; Astra Zeneca: Consultancy.

Introduction: The negative minimal residual disease (MRD) after treatment has been recently accepted as endpoint for Chronic Lymphocytic Leukaemia (CLL) clinical trials. Conventionally, MRD can be detected by using multi-color Flow Cytometry (FC) with high sensitivity. Determination of the clonal immunoglobulin gene rearrangement can be a useful monitoring marker in a broad range of B-cell lymphoproliferative neoplasms. Moreover, the mutational status of immunoglobulin heavy chain variable (IgHV) rearrangement is considered one of the most important prognostic factors in CLL. Therefore, the identification of the IgHV rearrangement can be a useful marker both at diagnostic and as monitoring marker for MRD. Nowadays, high-throughput sequencing (HTS) technologies has enabled highly sensitive cancer genomic testing in clinical laboratories. There are same initiatives based on HTS to use IgHV rearrangement as marker for MRD monitoring in Acute lymphoblastic leukemia or multiple myeloma, but it remains unharmonized for application on CLL in the clinical laboratory. Objective: We evaluated the performance and clinical applicability of HTS assay for IgHV rearrangement in CLL MRD monitoring in 69 samples from 19 CLL patients treated. Methods: The libraries including IGH locus were performed using the Sequencing Multiplex Kit on IGH consensus primers. To simplify and make automatic the analysis of the data obtained, we developed a specific bioinformatic pipeline that covers from preprocessing to final data summarization and interpretation. The backbone of the analysis includes read preprocessing, mapping against IMGT reference sequences, consensus IgHV reads pairwise alignment to determine mutational status and read classification into rearrangements. Assessment of IgHV mutational status by Sseq, genomic DNA (gDNA; 50-100 ng), were used for IgHV analysis. gDNA was amplified using locus-specific primer sets for IgHV designed to allow for the amplification of all known alleles of the germline IgH sequence, as described previously. Inmunophenotypic studies were performed on erythrocyte-lysed whole PB samples according to Euroflow procedures. PB white blood cells (WBC) was systematically stained with the eight color combination panel recently proposed by the ERIC group for MRD detection (Rawstron AC et al. 2016). Data acquisition was performed on a FACSCanto II flow cytometer Becton-Dickinson Biociences using the FACSDiva software (V8.0; BD). For data analysis, the Infinicyt softwareTM (Cytognos SL, Salamanca, Spain) was used. The MRD levels were reported as fraction of CLL cells of all nucleated cells. MRD negativity was define as a fraction Results: Patient demographics and the results of IGH clonality tests are summarized in Table 1. Interpretable results were obtained with higher sensitivity compared with Sseq at diagnosis stage (19/19 samples), and we are able to determine the same clone at subsequent samples. Among 50 follow-up samples, 44 MRD were positive in both techniques (HTS and FC); 3 follow-up samples, were negative in both determinations (HTS and FC); in contrast, 3 follow-up samples, were negative by FC but positive by HTS (8.3, 17.2, 18.2 samples). This is the case of Patient 8, in which the last follow-up sample, the detection of the primary clone is positive by HTS, while by FC is undetected (Figure 1). In addition, it was possible to detect IgHV clone in all Patient 7 samples. It was under long-term monitoring by HTS and FC, and 17 months after initial diagnosis and first line of treatment (7.5 sample), it was detected a loss of response (Figure 2.). Conclusions: We evaluated an HTS IgHV assay using initial and follow-up samples of 19 CLL patients. Using our pre-designed primer set in library preparation, and developed our specific bioinformatic pipeline that covers from preprocessing to final data summarization and interpretation, we were able to demonstrate that our method was more sensitive than FC in detecting positive follow-up samples and could be able to propose it for MRD monitoring in CLL. However, the prognostic impact of these low-level MRD detected by HTS should be validated with further investigations. Samples were provided by the INCLIVA Biobank. Funded by Gilead Felowship 257/17 Disclosures Ortiz: GILEAD SCIENCES: Research Funding. Terol:Abbvie: Consultancy; Gilead: Research Funding; Janssen: Consultancy, Research Funding; Astra Zeneca: Consultancy; Roche: Consultancy.

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 Conclusion The AITL and wt CXCL12 3'UTR cohorts met pre-specified statistical hypotheses supporting proof-of-concept for tipifarnib in PTCL. AITL histology, KIR3DL2 and CXCL12 genotype provided robust tools for the selection/stratification of PTCL subjects treated with tipifarnib. Extended enrollment of AITL patients continues and an update on enrollment and outcomes will be provided at the time of the presentation. Disclosures Sokol: EUSA: Consultancy. Foss:Mallinckrodt: Consultancy; Eisai: Consultancy; Spectrum: Other: fees for non-CME/CE services ; Acrotech: Consultancy; Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; miRagen: Consultancy. Kim:Donga: Research Funding; Celltrion: Research Funding; J&J: Research Funding; Roche: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; Mundipharma: Research Funding. Jacobsen:Kura Oncology: Research Funding. Advani:Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Kura: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; Stanford University: Employment, Equity Ownership; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Research Funding; Millennium: Research Funding. Roncero:Kura Oncology: Research Funding. Terol:Janssen: Consultancy, Research Funding; Roche: Consultancy; Gilead: Research Funding; Astra Zeneca: Consultancy; Abbvie: Consultancy. Domingo-Domenech:Bristol-Myers Squibb: Other: Travel expenses; Roche: Other: Travel expenses; Seattle Genetics: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses. Piris:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Lecture Fees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding. Rodriguez:Kura Oncology: Research Funding. Bolognese:Kura Oncology: Consultancy. Kessler:Kura Oncology: Employment. Mishra:Kura Oncology: Employment. Curry:Kura Oncology: Employment. Kurman:Kura Oncology: Employment. Scholz:Kura Oncology: Employment, Equity Ownership, Patents & Royalties. Gualberto:Kura Oncology: Employment, Equity Ownership, Patents & Royalties.