ALBERT

Description: Primary NHL of the CNS (PCNSL) carries a poor prognosis despite initial response to steroids and radiotherapy (RT). Addition of methotrexate (MTX) to RT has improved the prognosis of patients (pts) with PCNSL, but a significant proportion of patients are still not cured. To improve relapse free survival and to reduce neurotoxicity we initiated a multicenter phase II study with early dose intensified chemotherapy (CT) and PBSCT followed by hyperfractionated whole-brain radiation (WBRT) for pts aged under 65yrs. The use of high-dose (HD) lipophilic blood-brain-barrier-penetrating agents (BCNU, Thiotepa) in addition to maximum doses of water-soluble agents (MTX, AraC) is a novel approach in the treatment of PCNSL. To reduce the risk of delayed neurotoxicity, intrathecal chemotherapy was completely avoided and CT was administered before RT. Induction treatment included 3 repetitive cycles of HD-MTX (8g/m2). AraC (2x 3g/m2) and thiotepa (40mg/m2) followed by rG-CSF were used for stem-cell-mobilisation. The conditioning regimen included BCNU (400mg/m2) and thiotepa (2x5mg/kgBW) prior PBSCT. Additional hyperfractionated WBRT (45 Gy, 2x1Gy/d) was administered as consolidation. From 1999 to 2003 thirty pts (age under 65y) have been enrolled in the study (median age 54, range 30–64y). 21 of 30 pts responded to HD-MTX (6 CR, 15 PR). 22/30 pts received high dose CT and autologous PBSCT according to the protocol. Four pts refractory to MTX proceeded to RT directly and 1 patient died from PD subsequently. One patient died because of treatment-related liver toxicity after High-Dose MTX. Beside cytopenia no severe acute toxicities [WHO Grade 3 or 4] were observed after high-dose chemotherapy. After intention-to-treat analysis the response-rate was 89%. All patients that completed the protocol obtained CR (22/22). Three of these pts died, two died during follow-up due to relapse after 1 or 5 years respectively, the third patient died after 25 mo due to progressive heart failure. With a median follow-up of 42 months (range 3–84 mo) the overall survival of all pts included and pts that fulfilled the protocol is 71,3% and 86,5%, respectively. We conclude that sequential systemic application of high-dose differential acting cytostatic agents with consolidating hyperfractionated radiotherapy is very effective and well tolerable. In a new multicenter phase II study, pts will be treated with more intensive high dose CT and PBSCT omitting consolidating radiotherapy.

Description: Background: Lenalidomide with low-dose dexamethasone (Rd) is an emerging treatment option for newly diagnosed multiple myeloma patients with higher age. However, many older patients also remain candidates for autologous transplantation especially with age-adjustment of high-dose melphalan. Potentially, high-dose therapy could add to the benefit of Rd, alternatively the effect of high-dose therapy could be more or less redundant in this setting. The DSMM XIII trial is a multicenter, open-label, phase III trial comparing the safety and efficacy of continuous Rd versus Rd induction followed by age-adjusted tandem high-dose melphalan with autologous transplantation and lenalidomide maintenance. Methods: Patients with newly diagnosed multiple myeloma with symptomatic and measurable disease of age 60-75 years were randomly assigned to either (A1) lenalidomide (25 mg po d1-21/28d) with low-dose dexamethasone (Rd) (40 mg po d1, d8, d15, d22/d28) for 3 cycles followed by stem cell mobilization and continued Rd until progression or (A2) 3 cycles of Rd, followed by stem cell mobilization, tandem high-dose melphalan 140 mg2 (MEL140) with autologous blood stem cell transplantation and lenalidomide maintenance 10 mg daily until progression. At randomization, patients were stratified according to age (≤70 years vs 〉70 years) and ISS stage (I, II vs III). Antithrombotic prophylaxis with low molecular weight (LMW) heparin or aspirin was recommended. The primary endpoint was progression-free survival (PFS), and secondary endpoints included safety, responses, overall survival and others. We report the results of the planned first interim analysis after occurrence of one third of events as pre-specified. Results: Since March 2010, 253 patients have been randomized and data of 251 patients were available for analysis. The median age was 68 years (range 59-75), 30% were older than 70 years, 34% had ISS stage I, 37% ISS stage II, and 29% ISS stage III. The median PFS for the whole study population (A1 and A2) was 37.3 months. The comparison of PFS by randomization arm did not meet the formal criteria for early termination of the trial. The overall response rate after 3 cycles of Rd (A1 and A2) was 75%, with 2% demonstrating complete response (CR), 21% very good partial response (VGPR) and 52% partial response (PR). A further 20% of patients had stable disease and 6% of patients progressive disease. The 3-year-survival rate is 75% (95% confidence interval, 68-84) for all patients and with respect to ISS stage amounted to 90% (CI: 81-99, ISS stage I), 78% (CI: 66-91, ISS stage II) and 51% (CI: 35-74, ISS stage III). For the two age groups, the 3-year-survival was 73% (CI: 64-84) in patients with age ≤70 years and 80% (CI: 68-94) in patients with age 〉70 years. So far, 8 (3%) second primary malignancies (SPM) were observed, 4 skin tumors and 4 other solid tumors, but no hematological SPM was documented. Conclusion: In our trial, lenalidomide with low-dose dexamethasone (Rd) was found to be associated with a favorable median progression-free survival at 3 years. The survival in patients 〉70 years was not inferior compared to younger patients. The potential advantages and disadvantages of combining lenalidomide with high-dose melphalan and autologous transplantation in comparison to continous Rd are addressed by this ongoing trial and further data will be presented at the meeting. Disclosures Straka: Celgene: Consultancy, Honoraria, Research Funding. Off Label Use: Lenalidomide for first-line treatment.

Description: 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.