ALBERT

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

Description: Abstract 1886 Poster Board I-909 Background: Approximately 30% of patients with multiple myeloma (MM) present with baseline renal impairement, with 1% to 13% having renal failure requiring dialysis support. The severity of renal impairment significantly affects the prognosis of patients with MM and has been associated with shorter survival or early death. Lenalidomide is an immunomodulating agent indicated for the treatment of MM patients after one prior therapy. Lenalidomide is primarily excreted unchanged by the kidney, adjustements to the starting dose are recommended in patients with moderate or severe renal impairement and in patients on dialysis. For patients with end stage renal disease (CLCr 〈 30 mL/min) requiring dialysis, the recommended starting dose is 5 mg/day. However, experience in patients with MM and dialysis support is limited. To further examine the safety and activity of lenalidomide-based therapy in these patients, we underwent a retrospective analysis in patients with MM who required dialysis at the time of lenalidomide administration. Methods: Fifteen patients (10 M/5 F; median age, 70 years, range 55–77) with relapsed MM from 10 Spanish hospitals received lenalidomide-based therapy between 2007 and 2009. All patients were on dialysis at the time of lenalidomide administration. Median (range) number of therapies previously administered was 2 (1–4) and median time between diagnosis and lenalidomide treatment was 14 months (range, 5–50). Eighty-seven percent of patients received lenalidomide at a dose of 15 mg/day three times weekly after dialysis given in combination with dexamethasone. Patients were given a median of seven 28-day cycles (range, 1–22 cycles) of lenalidomide treatment. Antithrombotic prophylaxis was administrated in fourteen patientes and consisted of low molecular weight heparin (five cases, 36%), oral anticoagulation (four cases, 29%), antiplatelet therapy (three cases, 21%), and combination of the above agents (two cases, 14%). Results: Overall, 13 (87%) patients experienced adverse events, with grade 3 neutropenia as the most common (8 patients). Seven patients (47%) developed grade 3–4 infectious complications (3 bacteremias, 1 infection of arterio-venous fistula, 1 septic arthritis, 1 central venous line infection, and two pneumonias in the remaining patient). No patient developed thromboembolic complications. Fourteen patients were evaluable for response: 4 had complete response (29%), 1 a very good partial response (7%), and 3 partial response (21%). In addition, 4 patients had stable disease (29%) and 2 (14%) did not respond. One patient became independent of dialysis following lenalidomide-based treatment. As of July 2009, seven (47%) patients have died, four due to infectious complications and three as a result of progressive disease. Eight patients are still alive, six of them continue on lenalidomide treatment and two discontinued therapy due to liver toxicity (1 case) and progressive disease (1 case). Conclusion〉: These results suggest that lenalidomide-based regimens can be used in MM patients requiring dialysis, with a good response rate. The high incidence of neutropenia and infectious complications highlights the need of a close monitoring of these patients. Currently ongoing studies will more formally evaluate the impact of lenalidomide-based regimens in this patient population. Disclosures: No relevant conflicts of interest to declare.

Description: Despite improvement in the treatment of advanced classical Hodgkin lymphoma, approximately 30% of patients relapse or die as result of the disease. Current predictive systems, determined by clinical and analytical parameters, fail to identify these high-risk patients accurately. We took a multistep approach to design a quantitative reverse-transcription polymerase chain reaction assay to be applied to routine formalin-fixed paraffin-embedded samples, integrating genes expressed by the tumor cells and their microenvironment. The significance of 30 genes chosen on the basis of previously published data was evaluated in 282 samples (divided into estimation and validation sets) to build a molecular risk score to predict failure. Adequate reverse-transcription polymerase chain reaction profiles were obtained from 262 of 282 cases (92.9%). Best predictor genes were integrated into an 11-gene model, including 4 functional pathways (cell cycle, apoptosis, macrophage activation, and interferon regulatory factor 4) able to identify low- and high-risk patients with different rates of 5-year failure-free survival: 74% versus 44.1% in the estimation set (P 〈 .001) and 67.5% versus 45.0% in the validation set (P = .022). This model can be combined with stage IV into a final predictive model able to identify a group of patients with very bad outcome (5-year failure-free survival probability, 25.2%).

Description: A variable degree of immune impairment is present in lymphomas, either as a cause or a consequence of the disease. There is preliminary evidence that this immune status is related to disease control and survival. Our objective was to analyze the relationship of the immune status with the main clinical prognostic variables in DLCL. Seventeen patients with DLCL de novo were prospectively included in the study, receiving an homogenous induction treatment based on CHOP-R regimen. Median age was 60 (29–74); ECOG PS 〉 1 in 65%; Ann-Arbor stage 〉 II in 53%; B-symptoms in 47%; more than one extranodal site in 47%; bulky mass present in 59%; high LDH in 65%; high beta-2-microglobulin in 56%. Levels of B, T and NK subpopulations were assessed at diagnosis by flow cytometry, including general populations as well as cytotoxicity, costimulation and adhesion phenomena. This was compared with main clinical prognostic variables included in the adjusted-IPI (a-IPI) and MD. Anderson Tumor Score (TS) by U of Mann-Whitney non parametric test or Kaplan Meier survival analysis. Worst a-IPI patients (2–3 scores) (59%) showed significant lower levels of total lymphocytes as well as of the following populations: General T lymphoid markers (CD2 and CD3); expression of adhesion molecules (CD3+CD11a+, CD4+CD11a+ and CD8+CD11a+); expression of costimulatory molecules (CD4+CD28+ and CD8+CD28+); cytotoxicity in CD56+ cells (CD56+ Perforin+). Worst TS patients (3–4 scores) (59%) showed significant lower levels of the following populations: Activated or regulatory lymphoid subsets (CD3+CD25+); expression of costimulatory molecules (CD4+CD152+ and CD8+CD152+); cytotoxicity in CD56+ cells (CD56+ Perforin+). With a median follow-up of 16 months we observed a better overall survival and progression-free survival data in patients with levels above median of CD56+ and expression of perforin by T and NK cells. We conclude that worst prognostic groups of a-IPI and TS in DLCL are associated with a worst immune status, based on T and NK immune phenomena analysis. Perforin expression by NK and T CD56+ cells was associated with outcome in DLCL.

Description: Introduction: Mantle cell lymphoma (MCL) is mostly incurable. The current standard therapy achieves a high rate of complete remission (CR), but the pattern of continuous relapses still marks this disease as a challenge. We previously reported the efficacy of GemOx-R, a combination regimen of gemcitabine, oxaliplatin and rituximab, in patients with refractory and relapsing MCL. Our aim is to confirm our previous results in a larger retrospective series and evaluate the efficacy of each component of GemOx-R in a panel of MCL cell lines and in patient-derived primary cells. Methods: Between 2003 and 2015, 30 patients with MCL were included in a retrospective study of treatment with GemOx-R from the University Hospital Son Espases: 10 cases frontline and 20 in the salvage setting. Frontline cohort was consolidated with radioimmunotherapy and received maintenance therapy with rituximab. The translational study was performed in established cell lines as well as primary MCL lines from patients by cell viability, cell cycle, apoptosis and western blot analysis. Drug synergy was determined by the isobologram and combination index methods. Results: This is a high risk series of patients: median age 70 years, 87% stage IV and 86% intermediate or high risk MIPI. Overall response rate and CRR was 80% and 60% in the frontline cohort as well as 85 % and 60% for salvage patients, respectively. Median progression-free survival was 28 months in the entire series: 66 and 22 months, respectively, for the two cohorts. Median overall survival was 34 months in the entire series: not reached and 20 months, respectively, for the two cohorts. Grade 3 and 4 toxicity was as follows: neutropenia (63%), anemia (34%) and thrombocytopenia (30%) as well as 24% of grade 1 and 2 neurotoxicity. Cell viability and apoptosis analysis showed that oxaliplatin is the most effective drug in this regimen in contrast to the poor responses induced by gemcitabine and rituximab. Oxaliplatin had a profound effect on cellular viability, consistent with the induction of caspase activityand the downregulation of pro-survival proteins. We further present synergistic efficacy of oxaliplatin combined with cytarabine in MCL cells. Conclusions: (1) GemOx-R shows excellent results in MCL both in the frontline and salvage settings considering the high risk patients included. (2) Oxaliplatin is the most effective drug in GemOx-R; (3) oxaliplatin has a robust in vitro activity comparable to that of cytarabine, and the combination of both oxaliplatin and cytarabine shows a significant synergism; (4) taken together, our findings suggest that oxaliplatin alone or combined with cytarabine could constitute a new or alternative backbone for promising new regimens in MCL. Disclosures No relevant conflicts of interest to declare.

Description: This work reports the molecular genetic study of a patient who suffered from Glanzmann thrombasthenia (GT). Structural analysis of the glycoprotein (GP) IIb and GPIIIa genes showed the presence of a homozygous G1846→T transversion in exon 11 of GPIIIa that changes Glu616→Stop. Cytometric and immunochemical analysis indicated that platelet GPIIb-IIIa was absent in the proband but present at normal levels in the heterozygous relatives. The following observations indicate that this mutation is responsible for the thrombasthenic phenotype of the proband. (1) We failed to detect mutations other than [T1846]GPIIIa in the coding region of both GPIIb and GPIIIa genes. (2) The G1846→T mutation was observed in either parent and a brother of the proband, but none of 100 unrelated individuals carried this defect. (3) Pulse-chase and immunoprecipitation analysis of GPIIb-IIIa complexes in cells transiently cotransfected with cDNAs encoding normal GPIIb and [T1846]GPIIIa showed neither maturation of GPIIb nor complex formation and surface exposure of GPIIb-▵GPIIIa. These observations indicate that the sequence from Glu616 to Thr762 in GPIIIa is essential for heterodimerization with GPIIb. Polymerase chain reaction-based analysis demonstrated the presence of normal levels of full-length GPIIIa-mRNA in the proband and in heterozygous relatives. In addition, a shortened transcript, with a 324-nucleotide deletion, resulting from in-frame skipping of exons 10 and 11, was detectable upon reamplification of the DNA. Thus, unlike other nonsense mutations, [T1846]GPIIIa does not lead to abnormal processing or reduction in the number of transcripts with the termination codon.

Description: Background: Nodal aggressive PTCL have a poor prognosis with conventional chemotherapy regimens for aggressive non-Hodgkin lymphomas. Therefore innovative approaches are needed. Among them, strategies including consolidation with high-dose chemotherapy and autologous stem cell transplantation in front line therapy may improve the outcome of these diseases. Aim: To report the experience of a national cooperative group in 26 patients with aggressive nodal PTCL who underwent treatment including ASCT as consolidation of front line therapy. Patients and Methods: Twenty-six patients Gallium scan positive with nodal PTCL entered into the study: 11 cases of PTCL-unspecified (42%), 8 ALCL (31%) and 7 AIL (27%). Patients received three courses of MegaCHOP and subsequently were evaluated by CT scan and Gallium scan. Those patients Gallium scan negative received another course of MegaCHOP and then the transplant. Those patients Gallium scan positive after 3 courses of MegaCHOP received 2 courses of the IFE regimen (Ifosfamide 3.3g/m2 days 1–3 and Etoposide 300 mg/m2 days 1–3) and if at least achieved a partial response received the transplant otherwise they are out of the study. Median age was 44 years, 96% of the patients presented Ann Arbor stage III or IV; 54% presented B symptoms; 31% bone marrow involvement and 72% of the patients presented 2–3 factors of the a-IPI. Results: Thirteen patients (50%) achieved a CR after 3 courses of MegaCHOP and 12 patients received IFE as salvage therapy. Twenty patients out of the 26 initial patients were able to proceed to the transplant. After the transplant 85% of patients achieved a CR. The 6 patients who did not received the transplant was due to progression of the disease in 4 cases, lethal toxicity in one case and refusal in another case. With a median follow up of 35 months for alive patients, the overall survival (OS) and progression-free survival (PFS) at 3 years were 73% and 53%, respectively. OS, PFS and disease-free survival for the 20 patients who underwent the ASCT consolidation was 84%, 53% and 63%, respectively. Conclusion: Early salvage therapy for patients not in CR after 3 courses of chemotherapy and ASCT consolidation for chemosensitive patients may improve the outcome of patients with nodal aggressive PTCL. Larger series and longer follow up are needed to confirm this promising approach.

Description: Background DLBCL is the more common non Hodgkin lymphoma. This is an aggressive lymphoma that is treated with a standard chemotherapy regimen: R-CHOP. In the last years attempts have been done to improve the outcome both increasing dose-density (DD) (CHOP14) or intensity (CHOEP, ACVBP, frontline high dose therapy followed by autologous stem cell transplantation). Although phase 2 studies of these interventions suggested promising results, when randomized phase 3 trials have been conducted, there is no demonstrated benefit of these higher toxicity approaches when compared with R-CHOP alone. Only addition of rituximab to CHOP has proved a survival advantage. This has allowed setting R-CHOP administered every 21 days (R-CHOP21) as the standard treatment for DLBCL patients. The purpose of this study is further analyzing the prognostic impact of DD delays in two cohorts of DLBCL patients treated with R-CHOP21 or R-CHOP14. Methods All patients diagnosed between 1999 and 2013 of DLBCL in University Hospital Son Espases were identified from Pathology Department registry. Only patients treated with R-CHOP21 or R-CHOP14 +/- radiotherapy were included. Patients receiving other chemotherapy regimens or consolidations were excluded. DD delay was calculated as follows: DD delay = real number of days from first to last cycle of chemotherapy / expected number of days from first to last cycle in every regimen. Results A total of 166 cases were identified: considering inclusion and exclusion criteria finally 111 cases were selected (71 in the R-CHOP21 cohort and 40 in the R-CHOP14 cohort). Respectively for R-CHOP21 and R-CHOP14, 61% and 37% were older than 60 years (p=0.02), 26% and 35% had an ECOG PS higher than 1 (p=0.3), 49% and 62% had an Ann Arbor stage III-IV (p=0.09), 44% and 51% an a-IPI higher than 1 (p=0.47). Median DD delay was 2% versus 14% for R-CHOP21 and R-CHOP14 groups (p

Description: Background Cyclooxygenase-2 (COX-2) is an inflammatory enzyme involved in the pathogenesis and prognostic of Hodgkin lymphoma. We previously reported that expression of COX-2 on Reed-Sternberg cell is a major independent, unfavorable prognostic factor in patients with early Hodgkin lymphoma treated with ABVD (Blood 2012; 119: 6072). The relationship between COX-2 expression and poor prognosis has been associated with pathogenic phenomena such as induction of angiogenesis, chemoresistance through induction of antiapoptotic mechanisms such as up-regulation of bcl-2 or resistance to Fas, or promotion of invasion through induction of some metalloproteinases. As patients in our series were treated with ABVD +/- radiotherapy, we aim to analyze the role of radiotherapy on the adverse prognostic factor of COX-2 RS expression. Methods In the present study, we investigated the prognostic value of COX-2 expression in a large (N = 143), uniformly treated early Hodgkin Iymphoma (HL) population from the Spanish Network of HL using tissue microarrays. Univariate and multivariate analysis was done, including the most recognized clinical variables and the potential role of administration of adjuvant radiotherapy. Results Median age was 31 years; there was B-symptoms or bulky disease in 30% of patients; ECOG PS 〉 1 in 6%, EORTC score 〉 1 in 84% and 66% received radiotherapy. The expression of COX-2 defined a subgroup with significantly worse prognosis. Accordingly, the 46 (32%) COX-2+ patients had a PFS at 5 years of 72% versus 86% of COX-2- patients (P = .017). Similarly, the OS at 5 years also differed for both groups, with 82% and 94% for COX-2+ and COX-2-, respectively (P = .004). By multivariate analysis, COX-2 expression (HR = 2.76), B symptoms (HR = 2.34), and administration of RT (HR = 0.32) were independently associated with PFS, whereas only ECOG PS (HR = 9) and COX-2 RS expression (HR = 4.81) were independently associated with OS. Considering patients COX-2+, those that received RT had a significantly better 5y-PFS (80% versus 54% if no RT; p = .008). In contrast, COX-2- patients only had a modest non-significant benefit from RT in terms of 5y-PFS (90% versus 79%; p=0.13). When compared the outcome of patients receiving RT considering the expression of COX-2 on RS we found a non-significant 10% difference in terms of PFS between COX-2+ and COX-2- patients (p=0.09) while this difference between the two groups was important (25%) in patients non receiving RT (p=0.04). Conclusions COX-2 RS expression is an adverse independent prognostic factor in early HL. Radiotherapy overcome the worse prognosis associated to COX-2 expression on RS acting in a chemotherapy-independent way. COX-2 RS expression may be useful to determine patients with early HL candidates to receive consolidation with RT. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4845 Hodgkin lymphoma (HL) represents 10–15% of all types of lymphoma. At present, more than 70% of patients can be cured with current strategies based on chemotherapy with or without radiotherapy. However, one third of the cases finally relapses and needs salvage regimens usually consolidated with high dose chemotherapy and autologous stem cell transplantation. The number of regimens and drugs available are limited and new protocols that increase the efficacy with manageable toxicity are needed. In the present communication we report the results of a retrospective study using the GemOx schema that combines the efficacy of gemcitabine in Hodgkin lymphoma with oxaliplatin, a less toxic and effective platinum-based drug. Patients and methods: Patients were eligible for this retrospective study, according to the following criteria: diagnosis of HL, which relapsed or failed to achieve complete remission after induction treatment. They received GemOx regimen that consisted of gemcitabine 1000mg/m2 and oxaliplatin 100mg/m2 on day 1. Treatment was given every 15 days if feasible or every 21 days. To evaluate response and toxicity Cheson criteria and OMS toxicity scale were used respectively. Results: Between 2003 and 2012, 29 patients with Hodgkin lymphoma were retrospectively included in this study. All patients had recurrent (n=17) or refractory (n=12) disease. Median age was 24 (14–76) years and 50% had an International Prognosis Score (IPS) higher than 2. Patients received a mean of 2.79 previous regimens and 79% more than 1 regimen before GemOx with 48% relapsing after a prior autologous stem cell transplant (ASCT). Median follow-up was 41 months. 76% of patients responded (31% complete responses; CR). Responses were better in the relapsed setting or partial response (PR) (85% with a 45% of CR) compared to the truly refractory cases (55% PR) (p=0.037). Main prognostic factors for HL were assessed to view their impact on survival. Factors related with progression- free survival (PFS) and overall survival (OS) were age lower than 45 years, response to GemOx and consolidation with stem cell transplantation (p=0.001). Presence of B-symptoms at diagnosis also influenced OS. Neurologic toxicity was present in 9% of patients, all of them grade I or II. Hematologic toxicity was also common, including grade 3 or 4 neutropenia in 23% of patients, and grade 3 or 4 thrombocytopenia in 33%. Nausea and vomiting occurred in all the patients at grade 2, or lower. At last follow-up, 13 patients (45%) are alive and remain free of progression. However, 16 patients (54%) had died: 12 (41%) due to progression of disease, 3 (10%) due to complications due to a subsequent allogenic transplant (graft versus host disease, thrombotic thrombocytopenic purpura and bleeding) and 1 due to pneumonia. PFS was better in patients consolidated with autologous or allogeneic transplantation (100%) compared with patients not consolidated (14%) (p=0.009). PBSC collection after GemOx and G-CSF was successful for all of candidates. Conclusions: 1) GemOx regimen is effective in relapsed or refractory Hodgkin lymphoma with manageable toxicity; 2) Results are better in relapsed or chemosensitive disease compared to truly refractory cases; 3) No mobilization failures were observed; 4) Consolidation after response is needed. Disclosures: No relevant conflicts of interest to declare.