ALBERT

Description: Key Points DLBCL patients carrying the HLA-B44 supertype have a worse progression-free and overall survival after R-CHOP-like treatment. The HLA-DRB1*01 allele increases the risk of DLBCL development.

Description: Key Points Melphalan, in combination with bortezomib, should be maintained as one of the standards of care for the treatment of elderly MM patients. Complete response and particularly flow complete response should be an important goal in the treatment of elderly myeloma patients.

Description: Melphalan – Prednisone (MP) has been the Standard of care for elderly multiple myeloma patients in the past 40 years. However, bortezomib and thalidomide-based combinations have demonstrated to improve the efficacy in terms of both response rate and time to events as compared to MP. In two recent Phase II and phase III trials we have shown (Mateos et al. Blood 2006; San Miguel JF et al. EHA 2008) that the combination VMP is highly effective, but it remains to be elucidated which agent is the optimal partner for bortezomib: an alkylating or an immunomodulatory drug. In order to answer this question in April 2006, Spanish Myeloma Group (PETHEMA/GEM) activated a phase III trial comparing VMP versus VTP in untreated MM patients older than 65 years. Patients in the VMP arm received intravenous bortezomib 1.3 mg/m2 twice weekly (days 1, 4, 8, 11; 22, 25, 29 and 32) for one 6-week cycle (8 doses per cycle), followed by once weekly (days 1, 8, 15 y 22) for five 5-week cycles (4 doses per cycle) in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Patients in the VTP arm received the same bortezomib and prednisone regimen, but instead of melphalan they received continuous thalidomide at dose of 100 mg daily. For both groups, treatment continued for a maximum of 6 cycles (31 weeks) unless disease progression or unacceptable treatment-related toxicity occurred. The primary endpoint was overall response rate (ORR) after induction therapy and secondary endpoints included time to progression (TTP), progression-free survival (PFS), overall survival (OS), time to and duration of response, and safety. As of July 30, 2008, 246 out of 260 planned patients have been included in the study and 167 are evaluables for response to induction therapy and adverse events (AEs). Efficacy and toxicity analyses were performed on an intention-to-treat basis. 80 patients were randomly assigned to receive VMP and 87 to receive VTP. Regarding baseline characteristics, including cytogenetic abnormalities, no significant differences were observed in both arms. No significant differences were observed in response rate: ≥ PR in 78% of patients in VMP and VTP groups respectively, with a CR rate of 18% vs 23% (p=NS) and CR/nCR of 38% vs 32% (P= NS). Only one patient prgressed under induction treatment in each arm. Median time to first response was similar in both arms (1,6 months) and there were not differences in the median time to achieve CR (4,4 vs 4,9 months). Regarding haematological toxicity, VMP resulted in higher incidence of ≥G3 neutropenia (34% vs 19%; p=0,009) and thrombocytopenia (21% vs 9%; p=0,01); in contrast, 157 related non-hematological AEs occurred in VTP arm vs 133 in VMP arm (p

Description: Abstract 2680 Introduction: The Human Leukocyte Antigen (HLA) system plays an important role in antitumor immune response. In the last years, different genome-wide association studies have suggested that 6p21.3 (which include HLA system), is a risk region for lymphoma susceptibility. It has been also reported that specific alleles could modify the prognosis in patients diagnosed of lymphoma, including diffuse large B cell lymphoma (DLBCL), treated without Rituximab. Aim: Our hypothesis is that HLA system could play an essential role in disease control of DLBCL. Here, we have evaluated the effect of HLA Class I (A, B and C) and II (DRB1 and DQB1) alleles in DLBCL incidence and survival. Patients and Methods: A total of 251 patients diagnosed of DLBCL according to the 2008 WHO classification were analyzed (68% of them received Rituximab-based regimens). Control population consisted in 1940 healthy donor individuals analyzed for HLA-A, B, and DRB1 alleles and 200 for HLA-C and HLA-DQB1. Overall survival (OS) was calculated from diagnosis until death for any cause. Event-free survival (EFS) was calculated from diagnosis until event defined as death for any cause, relapse or progression of the disease. Allele frequencies and Hardy-Weinberg equilibrium were estimated using the Arlequin software package, version 3.5.1.2. Comparison of allele and phenotype frequencies between populations was performed with the two-sided Fisher's exact test or χ2 test using GraphPad Prism 4.0 (GraphPad Software, Inc. San Diego, CA, USA) or SPSS software (SPSS 15.0, Inc. Chicago, IL, USA). P-value was adjusted applying a Bonferroni correction (Pc). The effect of biological and clinical variables on OS and EFS at five years was analyzed by univariate (two-sided log-rank test) and multivariate (Cox multivariate analysis) methods. Differences were considered to be statistically significant when P〈 0.05. Results: HLA specificities frequencies in patients and controls (Alcoceba et al, Tissue Antigens 2011) were consistent in all cases with the Hardy-Weinberg equilibrium. Phenotypic frequencies showed significant differences in DLBCL patients compared to control population. DRB1*01 frequency was increased in DLBCL patients (28.9% vs. 19.5%, p=0.0009, Pc=0.0117, OR: 1.68; 95% CI: 1.24–2.26). By contrast, DLBCL patients showed a lower frequency in C*03 allele as compared to the control population (6.4% vs. 18.3, p=0.0005, Pc=0.007, OR: 3.2, 95% CI: 1.62–6.3). As far as the outcome of patients was concerned, the presence of B*18 and/or B*44 was significantly associated with a worse EFS (32% vs. 60%, p

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

Description: Abstract 3691 Background. There is currently no established treatment for the management of MALT lymphoma requiring systemic treatment. For patients failing to antibiotics or those with local advanced, refractory or disseminated disease several chemotherapy treatments have been studied. Considering the activity of Bendamustine in relapsed/refractory indolent lymphomas, with or without anti-CD20 antibodies, immunochemotherapy with Bendamustine plus Rituximab (BR) seems very attractive as first-line treatment for MALT lymphoma. Patients and methods. A nation-wide prospective phase II trial (EUDRACT 2008–007725–39) has been carried out in Spain by the GELTAMO group in untreated patients with CD20-positive MALT lymphoma. Patients with lymphoma arisen at any extranodal site and of any stage (Ann Arbor I-IV) could be enrolled. In addition, localized gastric MALT lymphoma previously refractory to H. pylori eradication or those with skin lymphoma not suitable for local therapy or previously treated with selective radiotherapy/surgery were also eligible. Treatment consisted of Bendamustine (90 mg/m2 d1–2) and Rituximab (375 mg/m2 d1), every 28 d. Pts were evaluated after completing 3 cycles: if complete remission (CR), pts received a further cycle (total of 4) and if partial response (PR), pts received 3 more cycles (total of 6). The aims were: feasibility and security of the combination and rate and quality of the responses, and event free survival. From May 2009 to May 2010, 60 patients were enrolled. Clinical characteristics: median age 62 years (range, 26–84); 34 (57%) female; Ann Arbor stage: I in 49%, II in 17% and III-IV in 34%; B-symptoms 5%. 20 patients (33%) had the lymphoma in the stomach, 35 (58%) in extra-gastric sites and the remaining 5 cases (8%) lymphoma was multifocal. The most common extra-gastric sites were lung and ocular adnexa in 11 and 7 patients, respectively. Results. A total of 264 cycles of BR were delivered in the whole population. Only 2 patients received less than 4 cycles. Rituximab dose was no modified at any cycle and only 5 patients required dose reduction of Bendamustine (median dose intensity: 0.98). Only 2 patients have not completed treatment due to toxicity: 1 case after 2 cycles due to severe rituximab-associated toxicity and another one after grade 4 febrile neutropenia in the 5th cycle. Grade 3–4 neutropenia was seen in 18% of patients. A total of 25 grade 3–4 non-haematologic toxicities were documented in 12 patients. Of note, 11 of these episodes were infectious (2 febrile neutropenia, 2 cytomegalovirus enteritis and 7 other).Response after 3 cycles of R was evaluable in 58 patients: 44 achieved CR or uCR and 14 patients PR, for an overall response rate (ORR) of 100% with a CR rate of 76%. CR rate after 3 cycles was higher in patients with gastric origin in comparison with non-gastric (90% vs 64%) (multifocal cases 100%). At the end of treatment, ORR was 100% with CR/uCR of 98%. A remarkable finding was that only 14 pts (23%) required more than 4 cycles of BR. With a median follow-up of 16 months (range, 3–40), one death has been recorded due to a neurologic syndrome and none patient has relapsed. Conclusions. The combination of Bendamustine and Rituximab in first line treatment of MALT lymphoma achieved an ORR of 100% after only 3 cycles. CR rate after completing treatment plan was 98%. Interestingly, a large majority of patients (85%) required only 4 cycles of treatment. This regimen was safe and well accepted by patients, making this response-adapted schedule a foremost therapeutic strategy for this type of lymphoma. Disclosures: Off Label Use: Bendamustine and rituximab are not currently approved for MALT lymphoma in first line, although both are commonly used in the relapse setting.

Description: Background Initial results of the Spanish GEM2005mas65 phase III trial comparing VMP versus VTP as induction therapy in elderly patients with newly diagnosed MM did not show any difference in terms of OS or PFS. The purpose of this study was to update clinical results with a longer follow-up. Secondary objectives were to know the patterns of symptomatic relapse and response to therapy in patients previously exposed to novel agents. Methods GEM2005mas65 trial lasted from March, 2006, and October, 2008. Overall, 260 patients with untreated MM, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or VTP (n=130) as induction therapy followed by maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91). Results With a median follow-up of 53.2 months, median OS of the entire cohort of patients was 42.45 months. Median OS was 62 months in patients receiving VMP versus 42.6 months in patients receiving induction with VTP (P = 0.045) (Figure 1). No differences were observed in PFS, being 31 and 24.4 months in the VMP and VTP groups, respectively. At the time of the study, 167 patients had relapsed or progressed and 92 of them received some kind of post relapse treatment. Front-line therapy and clinical and biological characteristics at the time of relapse in this subgroup of patients are summarized in Table 1. Initial induction treatment consisted of VMP in 40 (43.4%) patients and VTP in 52 (56.5%) patients. Overall, after induction and maintenance therapy 66 (71.7%) patients had been exposed to bortezomib and thalidomide and 26 (28.2%) patients received bortezomib-based therapy without immunomodulatory agents before relapse. At symptomatic relapse, median age was 74 years (range 65-87) and 43 (46.7%) were male. Serum creatine level 〉 2 mg/dL was present in 11.9% of the patients and 4.3 % had hypercalcemia. Extramedullary disease and plasma cell leukemia was present in 17% and 4.4% of patients, respectively. Finally, severe bone disease was observed in 39 the patients. Management of relapse was very heterogeneous. Subsequent drugs used in first clinical relapse included lenalidamide combinations in 40 (43.4%) patients, bortezomib-based therapy in 19 (20.5%) patients, different chemotherapy combinations in 25 (27.1%) patients and bendamustine-prednisone in 2 (2.1%) patients. Six (6.5%) patients received only supportive at time of first relapse. Overall, 45 (52%) patients achieved partial response or better after rescue therapy. Response rates were higher after lenalidomide-based therapy (62.5%) when compared with bortezomib (42.1%) and conventional chemotherapy-based regimens (40.7%),although this difference did not translate into significant PFS advantage. After a median follow-up of 16.4 months (range 0-50.2) from clinical relapse,58 (63%) patients had died. Median PFS and OS were 10 (CI95%; 10.7-50.2) and 15.6 months (CI95%; 8.5-16.5%), respectively. In patients initially treated with VMP (n = 40) and VTP (n =52) median survival from start of subsequent therapy was 15.6 and 15.4 months, respectively. Among characteristics at relapse, only ISS stage had an impact on survival (P= 0.03).There was no difference in OS or PFS from front-line induction and/or maintenance therapies or salvage therapy. Conclusions This updated analysis of the GEM2005mas65trial shows a survival advantage of the VMP arm when compared with patients receiving VTP. Patterns of relapse were similar regardless previous induction and maintenance therapy. Finally, and when analyzing the subgroup of patients receiving active therapy at relapse, only ISS stage seemed to have a prognostic impact on OS. Group A: VMP, group B : VTD Disclosures: Mateos: Janssen, Celgene, Onyx, Millennium, Mundipharma: Honoraria. Oriol:Celgene: Consultancy. Off Label Use: Bendamustine, bortezomib and prednisone is a combination not approved for newly diagnosed myeloma patients.

Description: Maintenance therapy has become a hot field in myeloma, and it may be particularly relevant in elderly patients because the major benefit results from the initial therapy. We report the results of a randomized comparison of maintenance with bortezomib plus thalidomide (VT) or prednisone (VP) in 178 elderly untreated myeloma patients who had received 6 induction cycles with bortezomib plus either melphalan and prednisone or thalidomide and prednisone. The complete response (CR) rate increased from 24% after induction up to 42%, higher for VT versus VP (46% vs 39%). Median progression-free survival (PFS) was superior for VT (39 months) compared with VP (32 months) and overall survival (OS) was also longer in VT patients compared with VP (5-year OS of 69% and 50%, respectively) but the differences did not reach statistical significance. CR achievement was associated with a significantly longer PFS (P 〈 .001) and 5-year OS (P 〈 .001). The incidence of G3-4 peripheral neuropathy was 9% for VT and 3% for VP. Unfortunately, this approach was not able to overcome the adverse prognosis of cytogenetic abnormalities. In summary, these maintenance regimens result in a significant increase in CR rate, remarkably long PFS, and acceptable toxicity profile. The trial is registered at www.clinicaltrials.gov as NCT00443235.

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