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Introduction It is postulated that the improvement in the overall treatment outcome in adult Ph-negative ALL came from the implementation of more aggressive pediatric-like protocols and higher portion of allogeneic HSCT. Here we report the results of the adult (15-55 yy) Ph-negative ALL protocol based on the opposite approaches: less intensive but non-interruptive treatment with low numbers of allo-HSCT. The study is registered on the ClinicalTrials.gov public site; NCT01193933. Patients and Methods The ALL-2009 is based on: (1) the replacement of prednisolone (Pdn) 60 mg/m2 with dexamethazone (Dexa) 10 mg/m2 if blast cells are >25% in b/m after prephase (7d); (2) de-intensified but non-interruptive 5 months induction/consolidation treatment (5 wks prd/dexa with 3 instead of 4 dauno/vncr pulses, 4 weeks of 6MP with 5 L-asp, 2 instead of 4 ARA-C blocks, 1 instead of 2 Cph injections during induction; induction-like 3 consolidations for 3wks, 2wks, 4wks-continuously without intervals), followed by (3) 2 late (at 6 mo) intensifications- with 1 day HD MTX and with 1 d HD ARA-C, both with L-asp and 3 ds dexa and (4) 2-yrs continuous 6MP/MTX maintenance with doses modification according to myelosuppression with monthly 3-days dexa/vncr/L-asp pulses (∑ L-asp = 590.000 IU/m2). The protocol was identical for all risk groups. Allo-HSCT was indicated only for extremely high-risk BCP-ALL (t(4;11),L>100). No central MRD monitoring was performed. Since Apr 2009 till June 2015 20 centers had recruited 168 BCP-Ph-negative ALL pts with a median age 28 years (15-54), 84f/84 m. Full cytogenetics was available in 67,3% (n=113), 43,4% of them (n=49) had normal karyotype (NK), 10% (n=9%) had no mitosis, 47,6% (n=54) - different abnormalities (hypoploid-1, hyperploid-12, t(11q23)/MLL-8, del11q23-2, t(1;19)-2, t(12;21)-1;others-28). 26,7% of pts (n=45) were in the standard risk (SR) group (WBC 30; EGIL BI, LDH > 2N; late CR; t(4;11)-positive), 28 patients (n=16,8%) were not qualified by the risk. The analysis was performed in June 2015. 158 pts were available for analysis. Results CR rate in 158 available for analysis pts was 87,7% (n=139), induction death occurred in 9,1% (n=14), resistance was registered in 3,2% (n=5). The majority of CR pts (87,8%) achieved it after prephase (12,2%, n=17) and the 1st phase of induction (75,6%, n=105). Late responders constituted 12,2% (n=17). Allogeneic BMT was performed only in 9 of 144 patients who survived induction (6,2%). Totally 31 pts (22,3%) had relapsed. At 60 mo OS for the whole group constituted - 50%, DFS - 51.3%. In a univariate analysis among various risk factors (age <> 30y, initial risk group, WBC, LDH, immunophenotype, late response >35d, PRD resistance) age (>30 y) became statistically significant for OS, DFS and relapse probability (RP) (pic.1), abnormal karyotype - for DFS (30% vs 68%, p=0,04) and RP (42% vs 19%, p= 0,04). In a multivariate analysis no common risk factors were significant. Conclusions Our data demonstrate that the proposed treatment approach is rather effective. We believe that constant non-interruptive treatment without intensive highly myelosuppressive consolidation courses and high portion of allogeneic HSCT may become an alternative and reproducible approach in adult Ph-negative ALL, though we have to stress that it should be very strict compliance of the pts to the protocol. All pts, mostly from the region hospitals who refused prolonged and constant treatment (~5%), relapsed. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction Intensive “pediatric oriented” treatment with heavy cytostatic load, incorporation of allogeneic HSCT is now considered a backbone approach in adult ALL therapy. Highly myelosuppressive treatment is more toxic and less reproducible, so RALL has initiated non-intensive but non- interruptive protocol “ALL-2009”and started a prospective multicenter trial for adult Ph-negative ALL based on: 1) the replacement of prednisolone (Pdn) 60 mg/m2 with dexamethazone (Dexa) 10 mg/m2 if blast cells are >25% in bone marrow after 7 days of prephase; 2) de-intensified but non-interruptive treatment with doses modification according to the myelosuppression with total treatment duration of 127 weeks; 3) prolonged implication of L-asparaginase (total proposed dose 590.000 IU/m2); 4) autologous hematopoietic stem cell transplantation (HSCT) after non-myeloablative BEAM conditioning followed by prolonged maintenance – for T-cell ALL patients. Allo-BMT was an option for high risk patients with sibling donors. The study is registered on the ClinicalTrials.gov public site; NCT01193933. Methods and patients From Jan 2009, till June 2014, 30 centers enrolled 250 pts: median age 30 years (15-60 years), 115f/135 m; in 2,4% phenotype was unknown (n=6), B-lineage ALL - 63,2% (n=158), T-lineage ALL - 34% (n=85), biphenotypic - 0,4% (n=1). Cytogenetics was available in 62,4% of patients (n=156) and 41% of them (n=64) had normal karyotype (NK). 25,2% of patients (n=63) were in the standard risk (SR) group (WBC 30 for B-lineage, >100 for T-lineage; EGIL BI, T-I-II-IV; LDH > 2N; late CR; t(4;11)-positive), 39 patients were not qualified by risk group. The analysis was performed in June 2014. The median time of follow-up was 26,1 mo. Results Prednisolone was replaced with dexamethazone after prephase in 68,1% of patients (135 of 198). The portion of non-responders to PRD in SR and HR groups was 54% and 67%, respectively (p=0,06). CR rate in 228 available for analysis patients was 87% (n=198), induction death occurred in 10,5% (n=24), resistance was registered in 2,5% (n=6). The majority of CR patients (91%) achieved it after prephase (7,1%, n=16) and the 1st phase of induction (83,9%, n=164). Late responders constituted 9% (n=18). None of those factors (PRD sensitivity, initial risk group, immunophenotype, late response) influenced overall (OS) or disease-free survival (DFS). OS rate in older ALL patients (>30) was substantially less than in younger ones (52,7% vs 73,6%, p=0,0009). DFS was comparable - 61,2% vs 71,5%, p=0,1. 24 of 75 (32%) CR T-ALL patients underwent autologous BMT after BEAM conditioning at a median time of 6 mo from CR and proceeded to further maintenance. No relapses were registered in this group so far. Allogeneic BMT was performed only in 14 patients (Ò-ALL-7, B-ALL-7) on the protocol. Totally 47 patients (20,6%) relapsed (16 with T-lineage, 31 with B-lineage ALL). At 48 mo OS for the whole group constituted - 65,6%, DFS - 69,3%. OS and DFS differed in B-ALL patients with NK in comparison with abnormal karyotype: 80% vs 57%,(p=0,01) and 81% vs 61%, respectively (p=0,02), but not in T-ALL patients. Conclusions Our data demonstrate that the proposed treatment approach is rather effective and reproducible. OS and DFS did not depend on various common risk factors (initial risk group, WBC, LDH, immunophenotype, late response, PRD resistance). The only independent risk factor for OS was age (>30 y). In B-cell ALL abnormal karyotype became an independent adverse risk factor for OS, DFS, relapse incidence. Fig.1 Overall survival (A) according to age in the whole cohort and disease-free survival (B) in B-cell ALL according to karyotype Table 1 (A) OS in different age groups (B) DFS in B-cell ALL Figure Figure. (A) OS in different age groups Figure Figure. (B) DFS in B-cell ALL Disclosures No relevant conflicts of interest to declare.

Introduction. The vast majority of AML clinical trials incorporate high-dose ARA-C (HDARA-C) as a basic approach. Though it was recently proved by a controlled prospective comparison that different treatment strategies in patients with AML did not show clinically relevant outcome differences (Th.Buchner, JCO, 2012), the RALSG initiated a randomized multicenter AML-10 trial (ClinicalTrials.gov Identifier: NCT01587430) aiming to evaluate the necessity of HDARA-C in consolidation in the context of high total dose of different anthracyclines/anthracenedione (660-720 mg/m2). Materials and methods. The patients aged 16-60 yy with de novo AML (except APL) were randomized before treatment start to different types of consolidation after two induction 7+3 with daunorubicin 60 mg/m2x3 and ARA-C 100 mg/m2 bid iv (1-7d) in the 1st course and 200 mg/m2/d (1-7d) continuous infusion in the 2nd course: (1st arm) two courses of 7+3 with Idarubicin (Ida) 12 mg/m2x3 and with Mitoxantrone (Mito) 10 mg/m2x3, in both ARA-C 100 mg/m2 bid iv (1-7d); (2nd arm) two courses of HDARA-C 1g/m2 bid iv 1-3 days with Ida 8 mg/m2 3-5 days and Mito10 mg/m2 3-5 days. After consolidation all pts proceeded to the maintenance 5+5 courses (ARA-C 100 mg/m2 bid iv 1-5 days with 6-mercaptopurine 50 mg/m2 1-5 days). Allogeneic HSCT was indicated to patients from intermediate and poor cytogenetic risk groups, late CR, WBC > 100*109/l. Results. From Jan 2010 till Jan 2014, 250 AML patients from 20 centers were randomized: (1st arm) 125 pts (m.age 45 y, 17-59 yy; 73f / 52m; LDH=674 IU (128-6653); cytogenetics favorable - 17,3%, intermediate - 66,7%, poor - 16%) and (2nd arm) 125 pts (m.age 43y, 16-60yy; 69f/56m; LDH=704 IU (123-8159); cytogenetics favorable - 20%, intermediate - 58,6%, poor - 21,4%). No molecular testing in cytogenetically normal pts was done. The analysis was performed in May 2014. The follow-up data were available in 199 pts. CR was achieved in 72,9% (n=145), early death was registered in 12,7% (n=25) and refractory disease - in 12,4% (n=24). Death in CR did not differed in a randomized groups (1st) 13,9% and (2nd) 13,7%. 17% of CR pts (n=20) were withdrawn from the protocol due to refusals (3,5%), infectious complications (13,5%). No relevant cardiotoxicity was registered on both arms. 12% (8 pts on the 1st arm, 9 - on the 2nd) were transplanted in 1st CR from HLA-identical donors. 3-years OS and DFS by intent-to-treat analysis were identical on both arms: (1st arm) 43% and 62%, (2nd arm) - 38% and 51%, respectively. For those patients in whom consolidation was fulfilled the comparison of DFS in different cytogenetic groups demonstrated equal efficacy of each consolidation arm: favorable - 85% (1st) and 85% (2nd), intermediate -65% (1st) and 57% (2nd), poor - 20% (1st) and 22% (2nd). In a multivariate analysis only cytogenetic group (HR=3,01, p=0,005) and CR achievement after the 2nd induction course (HR=2,83, p=0,0007) adversely influenced DFS. As the land-mark (5 mo of CR) analysis have shown, the bad prognosis of late CR could be modified by allo-HSCT in 1st CR: DFS of transplanted patients = 86%, non-transplanted=27% (p=0,03). Conclusion. Our interim analysis has demonstrated that conventional 7+3 consolidation is equal in long-term outcome to high dose ARA-C in case of the high total doses of different anthracyclines/ anthracenedione in induction/consolidation. CR after the 2nd induction became independent adverse prognostic factor (even inside cytogenetic risk groups) defining patients who should be transplanted in 1st CR. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.