Key Points• Volasertib plus low-dose cytarabine increased the response rate and improved survival in AML patients ineligible for intensive treatment.• Volasertib plus low-dose cytarabine resulted in responses across all AML genetic subgroups and had a clinically manageable safety profile.Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC 1 volasertib 350 mg IV days 1 1 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC 1 volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P 5 .052). Responses in the LDAC 1 volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC 1 volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P 5 .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P 5 .047). LDAC 1 volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 1 90. This study was

This study evaluates the 7-year outcome of lumbar disc surgery and the predictive value of pre- and perioperative risk factors. The 7-year follow-up rate of a sample of 122 patients was 93% (n = 114). Six per cent of the patients had undergone repeat surgery. Approximately 90% reported that they were satisfied with having undergone surgery. The clinical outcome was evaluated in 96 patients (54 men and 42 women) by means of patient-scores (VAS) of low back and leg pain, and a Clinical Overall Score (COS). In multivariate regression analyses, women were shown to have poorer outcome than men. Preoperative psychological distress and impaired fibrinolytic activity were predictors of poor 7-year outcome. Age, weight, smoking habits and physical fitness had no statistically significant prognostic value. Whether the patients were operated for one or two herniated discs, or whether surgery involved a full or partial laminectomy, did not influence the outcome significantly.

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411 Background: LDAC is an established treatment option for patients (pts) with AML considered ineligible for intensive remission induction treatment. However, the outlook for pts who receive LDAC remains unsatisfactory, and novel therapeutic strategies are needed to improve clinical outcome in these pts. Plk1 plays a key role in mitosis and cell cycle progression and is an attractive target for novel therapeutic approaches in cancer. Volasertib (V) is a first-in-class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plks. The phase I part of this trial determined the maximum tolerated dose of V in combination with LDAC (V + LDAC) to be 350 mg and demonstrated antileukemic activity of V and V + LDAC in pts with relapsed/refractory AML ineligible for intensive therapy (Bug et al, ASH 2010 and 2011). Here we present preliminary phase II data for the randomized comparison of V + LDAC vs LDAC in pts with newly diagnosed AML ineligible for intensive treatment. Methods: In the phase II part of this open-label study, eligible pts were randomized to receive V (350 mg 1-hr intravenously, days 1, 15 Q4W) + LDAC (20 mg bid subcutaneously, days 1–10 Q4W), or LDAC alone until progression/relapse or intolerance. The primary endpoint was objective response (complete remission [CR] or CR with incomplete blood count recovery [CRi]); secondary endpoints included event-free survival (EFS), overall survival (OS), safety and pharmacokinetics (PK). Results: 87 pts were treated with V + LDAC (n=42) or LDAC (n=45). Pt characteristics (V + LDAC/LDAC) were largely balanced: median age, 75/76 yrs; secondary AML, 40.5%/64.4%; adverse cytogenetic group, 35.7%/33.3%. At time of analysis (February 22 2012) 15 pts were still on treatment (12 with V + LDAC). Pts received a median (range) of 2 (1–12) cycles of V + LDAC and 2 (1–11) cycles with LDAC. A significantly greater proportion of pts who received V + LDAC achieved a CR or CRi compared with pts who received LDAC (31.0% vs 11.1%; odds ratio 3.59 [95% CI: 1.15, 11.18]; P = 0.0277), with a median (range) time to remission of 71 (29–158) days and 69 (34–125) days, respectively. Remissions with V + LDAC were observed across genetic groups, including pts with adverse cytogenetics. A trend for longer median EFS was observed for pts who received V + LDAC compared with those who received LDAC (HR 0.61 [95% CI: 0.35, 1.05]; P = 0.0725; Figure). Follow-up for OS was ongoing at the time of this analysis. Among pts achieving CR/CRi, only 2 had experienced recurrence or death at the time of analysis (1 in each arm after a remission duration of 57 [V + LDAC] or 67 [LDAC] days). For all other pts ongoing in remission, the remission duration was censored after 53–407 days (LDAC + V) or 32–282 days (LDAC), consistent with prolonged duration of remission in some pts. The most frequent all grade adverse events (AEs) in the V + LDAC arm were febrile neutropenia (50%), constipation (45.2%), nausea (40.5%) and anemia (40.5%). In the LDAC arm, the most common all grade AEs were nausea (33.3%), anemia (28.9%), pyrexia (28.9%), and constipation, asthenia and diarrhea (26.7% each). More pts who received V + LDAC experienced ≥ grade 3 AEs than those who received LDAC (95.2% vs 68.9%), particularly for blood and lymphatic system disorders (81.0% vs 44.4%), gastrointestinal disorders (21.4% vs 6.7%), and infections and infestations (45.2% vs 22.2%). The early death rates (V + LDAC/LDAC) at 30, 60 and 90 days were comparable between the two treatment arms: 30 days, 9.5%/8.9%; 60 days, 21.5%/17.8%; 90 days, 28.9%/33.4% (rates calculated using Kaplan-Meier method). PK analyses demonstrated that V is a moderate clearance drug with multi-compartmental PK behavior, a large volume of distribution and a long terminal half-life. Preliminary data suggest no drug-drug interactions following combination of V with LDAC. Conclusions: These preliminary phase II data demonstrate a significantly improved CR/CRi rate and a trend for EFS benefit with V + LDAC compared with LDAC alone in pts with newly diagnosed AML ineligible for intensive treatment. An increased frequency of AEs was observed with the addition of V, which was expected given its myelosuppressive mechanism of action; available data do not suggest increased early mortality for V + LDAC vs LDAC. A confirmatory phase III trial is needed to determine the clinical benefit of V + LDAC in pts with AML ineligible for intensive treatment. Disclosures: Off Label Use: Volasertib is an investigational agent. Fiedler:Pfizer, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bug:Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Tidow:Boehringer Ingelheim: Research Funding. Voss:Boehringer Ingelheim: Employment. Taube:Boehringer Ingelheim: Employment. Fritsch:Boehringer-Ingelheim: Employment. Döhner:Celgene, Amgen, Ambit, Astellas, Lilly: Consultancy.