Abstract: Background: Standard therapy of acute promyelocytic leukemia has long relied on the combination of All-trans-retinoic acid (ATRA) and chemotherapy. The introduction of arsenic trioxide (ATO) in APL treatment has allowed achievement of similarly high remission and survival rates coupled with significantly reduced myelosuppression. Recent results of the APL0406 trial by the GIMEMA-AMLSG-SAL study groups showed that the combination of ATRA and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in front-line therapy of low/intermediate risk acute promyelocytic leukemia (APL). The implications of these results for the clinical practice of APL patients in Germany have been uncertain given the fact that ATO is not formally licensed for front-line therapy of APL. Aim:In order to provide evidence and a reflection of the clinical reality of APL patient care in Germany an intergroup APL registry (National acute promyelocytic leukemia (APL) observational study, NAPOLEON) was recently initiated by several AML study groups. Methods:Eligible patients are adults at least 18 years of age with newly diagnosed or relapsed APL not beyond the first year of diagnosis. Here we report the first analysis on the series of patients prospectively enrolled into this registry. The study was conducted in accordance with the Declaration of Helsinki, received IRB approval by all participating centers and was registered at ClinicalTrials.gov (NCT02192619). Results: As of August 1st 2016, 88 patients have been included into the study with a median age of 57 years (range 22-87). All had newly diagnosed APL (100%) with 66% (n=58) being of low/intermediate risk according to the Sanz score. Out of those patients 76% (n=44) received an ATO-ATRA based induction regimen followed by a median of 4 courses of consolidation (according to the APL 0406 study).Of 41 patients evaluable for response to induction, 40/41 (98%) patients achieved complete remission (CR) with the ATRA-ATO arms. Early death rate within 30 days of therapy was 2% (1/44). After a median follow-up of 12 months, the event-free survival, cumulative incidence of relapse and overall survival at 12 months for these patients were 97%, 0% and 97%, respectively. Therapy was well tolerated and no new safety signals have been obtained. Conclusion:These real life data from a prospective German registry provide further evidence for the safety and sustained anti-leukemic efficacy of ATRA-ATO in low/intermediate risk APL. These results further support ATRA-ATO as the new standard of care in this clinical setting. Table Demographic, clinical and laboratory characteristics of the eligible patients. Table. Demographic, clinical and laboratory characteristics of the eligible patients. Disclosures Platzbecker: TEVA: Honoraria, Research Funding. Greiner:BMS: Research Funding. Thiede:AgenDix: Employment, Other: Ownership. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding.

Abstract: 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.