Kurzfassung: Background and Aim. In the current WHO classification, marginal zone B-cell lymphomas (MZL) have been divided into three distinct subtypes (extranodal, EMZL; nodal, NMZL; splenic, SMZL) according to clinical, pathological and cytogenetic features, however the relationship between any of the different subtypes is still unclear. We thus performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question. Materials and Methods. DNA extracted from frozen samples of MZL was analyzed with Affymetrix Human Mapping 250K SNP arrays. Results. Samples from 193 patients with MZL (23 NMZL, 63 EMZL, 84 SMZL and 23 not better specified MZL) from 15 Institutions were analyzed. Among EMZL, main primary sites were orbital adnexa in 28%, GI-tract in 16%, lung and salivary glands 5% each. Overall, MZL displayed more recurrent deletions than gains. Gains of 3q and 18 gains were common to all three MZL subtypes as were losses at 1p32.3-pter, 7p22.1-pter, 7q11.21–q11.23, 9q33.3-qter, 16p, 17p and 19. EMZL had significantly more gains at 3p14.2-pter, 6p and 7q31.3-qter and losses at 6q15, 6q23.3 and 14q11.2 than SMZL. Conversely, the latter had deletions of 7q31.32-qter and 14q23.3–q32.13 more frequently than EMZL. NMZL profiles showed the EMZL-specific 6q losses and the SMZL-related 7q losses at very low frequency while presented recurrent gains of chromosome 11, which was unique of NZML among the three subtypes. The 6q23.3 region contains the gene coding for TNFAIP3/A20, a negative regulator of the NFkB pathway. In SMZL a minimal deleted region was observed in 7q32.1. Regarding chromosome 3, gains targeted the whole chromosome in EMZL while, in SMZL and NMZL, the long arm was more commonly affected. Conclusions. EMZL, NMLZ and SMLZL share genetic alterations, which differ from other B-cell lymphomas. However subtype-specific genetic lesions are observed. In particular, gains of 6p and losses of 6q23.3 (TNFAIP3) are specific for EMZL, and 7q31-qter for SMZL.

Kurzfassung: Marginal zone B-cell lymphomas (MZLs) have been divided into 3 distinct subtypes (extranodal MZLs of mucosa-associated lymphoid tissue [MALT] type, nodal MZLs, and splenic MZLs). Nevertheless, the relationship between the subtypes is still unclear. We performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question. Samples from 218 MZL patients (25 nodal, 57 MALT, 134 splenic, and 2 not better specified MZLs) were analyzed with the Affymetrix Human Mapping 250K SNP arrays, and the data combined with matched gene expression in 33 of 218 cases. MALT lymphoma presented significantly more frequently gains at 3p, 6p, 18p, and del(6q23) (TNFAIP3/A20), whereas splenic MZLs was associated with del(7q31), del(8p). Nodal MZLs did not show statistically significant differences compared with MALT lymphoma while lacking the splenic MZLs-related 7q losses. Gains of 3q and 18q were common to all 3 subtypes. del(8p) was often present together with del(17p) (TP53). Although del(17p) did not determine a worse outcome and del(8p) was only of borderline significance, the presence of both deletions had a highly significant negative impact on the outcome of splenic MZLs.

Kurzfassung: Introduction: IELSG32 is an international randomized phase II trial with 2 key clinical questions in pts with PCNSL. The first question focused on optimal induction therapy, and results of the 1st randomization have demonstrated that MATRix combination (methotrexate (MTX), cytarabine (ARAC), thiotepa, rituximab (R)) is associated with significantly better outcome [Ferreri AJ, et al. Lancet Haematol 2016]. The second question addresses the efficacy and neurotolerability of ASCT, as an alternative to WBRT as consolidation. Herein, we report the results of the 2nd randomization (NCT01011920). Methods: HIV-neg pts 18-70 ys and ECOG PS ≤3 with new histology-proven PCNSL and measurable disease were randomly assigned to receive 4 courses of MTX-ARAC (arm A); or R-MTX-ARAC (arm B); or MATRix (arm C). ASC were collected after 2nd c. Pts with responsive or stable disease were further randomized between WBRT 36 ± 9 Gy (arm D) and BCNU-thiotepa conditioned/ASCT (arm E). Stratification parameters were induction arm and response . Primary endpoint of the 2ndrandomization was 2-year PFS. To demonstrate a 2-yr PFS improvement from 65% (P0) to 85% (P1), 52 pts/arm (one-sided; α 5%; β 95%) were required. Consolidation arm would be considered effective if ≥40 pts were progression-free survivors at 2 ys. Analyses were performed on an intention-to-treat (ITT) basis. Effects of consolidation treatments on neurocognitive functions and quality of life (QoL) were assessed with the IPCG tests panel and EORTC-QLQ at baseline, after treatment and every 6 months afterwards. Results: 227 pts were enrolled in 52 centers of 5 countries; 219 assessable pts were referred to 1st randomization (arm A 75; B 69; C 75). 167 pts had responsive or stable disease after induction: 49 pts were excluded from 2nd randomization (poor mobilization, poor condition or patients' refusal); 118 pts were thus randomized (59 pts/arm) and constitute the study population (median age 58 ys; range 18-70). 15 (13%) pts had high IELSG risk, 3 pts had ocular disease and 20 pts had meningeal disease; with the exception of a higher male prevalence in arm D, there were no differences in clinical presentation between two arms; There were 6 protocol violations: 4 pts randomly allocated to arm D were treated with ASCT and 2 pts randomly allocated to arm E were treated with WBRT; 5 pts (D 2; E 3) refused consolidation. Therefore, per-protocol (PP) groups consisted of 55 pts treated with WBRT and 58 with ASCT. Both consolidation therapies were well tolerated. Grade 4 toxicity was uncommon (≤5% of pts); as expected, hematological toxicity was more common in arm E (neutropenia 5% vs. 71%; p=0.00001 - thrombocytopenia 2% vs. 72%; p=0.00001). There were 2 toxic deaths (infections), both in arm E. Neuropsychological tests showed a significant impairment of attention/executive functions and a non-significant trend to impaired memory among pts treated with WBRT, whereas pts treated with ASCT exhibited improved functions. Both consolidation therapies were associated with significant improvement in language and QoL. Both WBRT and ASCT were active and resulted in significant improvement in CR rate: from 54% after induction to 95% (95%CI: 90-100) after consolidation in arm D, and from 53% to 93% (95%CI: 87-99) in arm E. After a median follow-up of 40 months (range 24-76), there were 20 events (16 relapses, 2 PDs, 2 off-therapy deaths) in arm D, and 25 events (18 relapses, 2 PDs, 2 toxic deaths, 3 off-therapy deaths) in arm E. Importantly, WBRT and ASCT were both effective, with a number of progression-free survivors at 2 ys equal to the pre-determined efficacy threshold: 40 among both the first 52 arm-D and 52 arm-E pts. There were no significant differences in PFS between WBRT and ASCT; on ITT basis, the 2-yr PFS was 80 ± 5% after WBRT and 70 ± 6% after ASCT; per protocol, the 2-yr PFS was 76 ± 6% and 75 ± 6%, respectively. In multivariate analysis, IELSG risk group, number of lesions and induction arm were independently associated with PFS; gender, CSF cytology status and consolidation arm were not. Forty-two pts randomized to arm D and 37 randomized to arm E are alive, with 2-year OS of 85 ± 5% and 71 ± 6% (p=0.12), respectively. Conclusions: WBRT and ASCT are both feasible, active and effective as consolidation therapies after high-dose-MTX-based chemoimmunotherapy in pts ≤70 ys with PCNSL. Potential impairment of specific neurocognitive functions after WBRT should be considered at the time of therapeutic decision. Disclosures Ferreri: Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Research Funding, Speakers Bureau; Italfarmaco: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adienne: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees. Fox:Adienne: Honoraria, Research Funding; Takeda: Honoraria, Other: travel funding; Gilead: Honoraria, Other: travel funding; Janssen: Honoraria, Other: travel funding; AbbVie: Consultancy. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Johnson:Celldex Therapeutics: Research Funding. Linton:Takeda: Research Funding. Hess:Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Celgene: Honoraria; Pfizer: Honoraria. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau. Rummel:Roche Pharma AG: Other: Personal fees, Research Funding; Mundipharma GmbH: Other: Personal fees, Research Funding. Illerhaus:Riemser: Honoraria; Amgen: Honoraria.

Kurzfassung: There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m 2 /d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m 2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

Kurzfassung: Abstract 3939 Poster Board III-875 The available clinical information on MALT lymphoma is mostly based on retrospective series. In 2003 the International Extranodal Lymphoma Study Group launched the IELSG-19 study to compare Chlorambucil alone versus the combination of Chlorambucil and Rituximab. Because of the excellent initial recruitment, a third arm with Rituximab alone was later introduced. The study is still ongoing and at the end of July 2009, 403 patients (pts) of the 450 planned have entered. The Italian Lymphoma Intergroup and the French GELA group were the main contributors to this study together with Cancer Research UK, the Catalan Hematology Group and the Oncology Institute of Southern Switzerland. All the MALT lymphoma pts with localized disease at any extranodal site who do not respond or are not suitable to local therapy, the H.pylori-negative gastric lymphomas or those who failed antibiotic therapy are eligible, as well as those with disseminated or multifocal MALT lymphoma. Histology review of all cases is underway. A planned interim analysis was performed in April 2009 on the first 320 pts, 169 men (53%) and 151 women (47%); 292 pts (91%) had no previous treatment. The treatment was completed in in 86% of the 320 analysed pts, in 64% without dose changes or time delay. The primary MALT lymphoma site was the stomach in 138 pts (43%);182 pts (57%) had a non-gastric presentation. The most common non-gastric sites were the lungs (N=42, 13%), the ocular adnexa (N=32; 10%), the intestine (N=29; 9%), the salivary glands (N=26; 8%), and the skin (N=21; 7%). In 95 pts (30%) the lymphoma involved more than 1 extranodal site. Lymph node involvement was present in 118 pts (37%); 181 pts (58%) had localized disease (Ann Arbor stage I-II) while 129 (42%) had advanced stage. The ECOG performance status was 0 in 230 pts (74%). According to the international prognostic index (IPI) 190 pts (59%) had a low risk, 68 (21%) a low-intermediate risk, 54 (17%) an intermediate-high risk, and only 8 (2.5%) a high risk score. B-symptoms were present in 33 pts (11%) and LDH levels were higher than normal in 31 (10%). The median age is 61 year (range, 26-81). At a median follow-up of 40 months, overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) are 96%, 88%, and 62%, respectively. Among the main clinical characteristics, the presence of B-symptoms, elevated LDH, more than one extranodal site, advanced stage, poorer performance and unfavourable IPI scores were significantly (p 〈 0.05) associated with shorter OS, PFS and EFS. The presence of lymph nodal involvement was significantly associated with shorter PFS and EFS but did not affect the OS. Patient younger than 60 years had longer OS and PFS but age had no effect on the EFS. Differently from previous series, there were no differences in outcome between pts with gastric and non-gastric localization; this finding is likely due to the fact that H. pylori-positive gastric MALT lymphoma pts still responding to antibiotics were excluded from the study. This is by far the largest prospective study ever conducted in MALT lymphomas; further analyses are in progress. Disclosures: Zucca: Mundipharma: Research Support; Johnson & Johnson: Research Support; Roche: Research Support.