Abstract: The acute respiratory distress syndrome (ARDS) is a life-threatening condition. In special situations, these critically ill patients must be transferred to specialized centers for escalating treatment. The aim of this study was to evaluate the quality of inter-hospital transport (IHT) of ARDS patients. Methods We evaluated medical and organizational aspects of structural and procedural quality relating to IHT of patients with ARDS in a prospective nationwide ARDS study. The qualification of emergency staff, the organizational aspects and the occurrence of critical events during transport were analyzed. Results Out of 1234 ARDS patients, 431 (34.9%) were transported, and 52 of these (12.1%) treated with extracorporeal membrane oxygenation. 63.1% of transferred patients were male, median age was 54 years, and 26.8% of patients were obese. All patients were mechanically ventilated during IHT. Pressure-controlled ventilation was the preferred mode (92.1%). Median duration to organize the IHT was 165 min. Median distance for IHT was 58 km, and median duration of IHT 60 min. Forty-two patient-related and 8 technology-related critical events (11.6%, 50 of 431 patients) were observed. When a critical event occurred, the PaO 2 /FiO 2 ratio before transport was significant lower (68 vs. 80 mmHg, p  = 0.017). 69.8% of physicians and 86.7% of paramedics confirmed all transfer qualifications according to requirements of the German faculty guidelines (DIVI). Conclusions The transport of critically ill patients is associated with potential risks. In our study the rate of patient- and technology-related critical events was relatively low. A severe ARDS with a PaO 2 /FiO 2 ratio  〈  70 mmHg seems to be a risk factor for the appearance of critical events during IHT. The majority of transport staff was well qualified. Time span for organization of IHT was relatively short. ECMO is an option to transport patients with a severe ARDS safely to specialized centers. Trial registration NCT02637011 (ClinicalTrials.gov, Registered 15 December 2015, retrospectively registered)

Abstract: Introduction: For physically fit CLL pts with low comorbidity burden FCR is the standard frontline regimen in advanced CLL. The CLL10 study, an international phase III study evaluated the efficacy and tolerance of BR in comparison to FCR in frontline therapy of fit pts without del(17p). Methods and Patients: 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) registered 688 CLL pts for central screening including immunophenotyping, FISH, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance 〉 70 ml/min and without del(17p) were enrolled between 10/2008 and 6/2011. Pts were randomly assigned 1:1 to receive 6 courses of FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days) or BR (N=280; B 90mg/m² i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days). A general prophylactic use of antibiotics or growth factors was not recommended. Three patients (2 FCR, 1 BR) were excluded because of deferred treatment. The median CIRS score was 2. There was no difference in median age (61.6 years (yrs) for all pts), but a significantly higher proportion of pts ≥ 70 yrs was included in the BR arm (22% vs 14%, p=0.020). Binet A was present in 22%, Binet B in 38 % and Binet C in 40 %. Unmutated IGHV status was not balanced between both groups (68% in BR versus 55% in FCR arm; p=0.003). All other characteristics showed no differences. The mean number of administered FCR courses was 5.27 courses vs 5.41 BR course (p=0.017). Results: The median observation time for all patients was 35.9 months (mo). 547 pts (FCR 274 ; BR 273) were evaluable for response and all pts (282 FCR ; 279 BR) included for progression-free survival (PFS) and overall survival (OS) analysis. The overall response rate in both arms was 97.8% (p=1.0). The complete response (CR) rate according to IWCLL and confirmed by central bone marrow immunohistology was 40.7% with FCR compared to 31.5% with BR (p=0.026). Four-colour-flow MRD data from peripheral blood (sensitivity 10-4) were available from 355 pts (185 FCR; 170 BR) at final staging. In the FCR arm 74.1% and 62.9% in the BR arm respectively of all evaluated pts were MRD negative (p=0.024). Bone marrow samples, available in 129 FCR and 98 BR pts, were MRD negative in 58.1% and 31.6% of pts, respectively (p 〈 0.001). At 12 mo follow-up 58.2% of the pts in the FCR arm (46/79) were still MRD negative in comparison to 26.3% (20/76) after BR (p 〈 0.001). At 18 mo there were 53.8% (35/65) MRD negative cases versus 24.6% (16/65; p=0.006). Median PFS was 53.7 mo in the FCR arm and 43.2 mo in the BR arm (HR=1.589, 95% CI 1.25-2.079; p=0.001). While PFS was statistically not significant different between both arm in pts with mutated IGHV, pts with unmutated IGHV status had a median time to progression of 43.9 mo after FCR compared to 34.0 mo after BR (p=0.015). Physically fit subgroups (CIRS max 3, only one CIRS item, age 〈 65 yrs) benefited most from FCR therapy. The difference in PFS was statistically not significant between both arms in pts ≥ 65 years, CIRS 4-6 or 〉 1 CIRS item. Multivariate analysis identified treatment arm, age ≥ 65 yrs, male sex, high serum TK, del(11q), absence of del(13q) and IGHV status as independent prognostic factors for PFS. No difference in OS was observed (at 36 mo 90.6% for FCR vs 92.2% for BR; HR=1.030, 95% CI 0.618-1.717; p=0.910). For OS male gender, age ≥ 60 yrs, high serum TK and IGHV status were assessed as independent prognostic factors. Severe neutropenia was more often observed in the FCR arm (87.7% vs 67.8%, p 〈 0.001), but no significant difference in the incidence of anemia (14.2% vs. 12.0%; p=0.46) or thrombocytopenia (22.4% vs 16.5%; p=0.096) was documented. Severe infections occurred significantly more frequent (39.8% vs 25.4%, p=0.001) in the FCR arm during treatment phase until 6 months follow-up, especially in older pts (48.4% vs 26.8%; p=0.001). Treatment related mortality was 3.9% (FCR) and 2.1% (BR), respectively. Conclusion: The final analysis of the CLL10 study shows that FCR remains the standard therapy in very fit CLL patients, because it yields higher CR rates, more MRD negativity and longer PFS in comparison to BR. However, in elderly fit pts high toxicity rates and infection rates result into dose reductions leading to similar efficacy between both arms. Elderly fit pts or pts with previous infections might benefit from BR as alternative regimen. Disclosures Eichhorst: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant Other; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grant, Travel grant Other; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy. Off Label Use: The Combination of Bendamustine and Rituximab is not approved for frontline chemoimmunotherapy of CLL. Fink:Celgene: Other. Maurer:Mundipharma: Travel grant Other. Kiehl:Roche: Membership on an entity's Board of Directors or advisory committees. Gregor:Roche: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria. Trneny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fischer:Roche: Other. Döhner:Roche: Research Funding. Kneba:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Wendtner:Mundipharma: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Klapper:Hoffmann-La Roche: Research Funding; Takeda/Millenium: Research Funding. Kreuzer:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Böttcher:Roche: Honoraria, Research Funding, Travel grant Other. Hallek:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding.

Abstract: Introduction: FCR is still the standard frontline regimen for physically fit CLL pts without TP53 alteration. The international phase III CLL10 study demonstrated the inferiority of BR in comparison to FCR in this population. In order to evaluate long-term outcome and toxicity we performed an updated analysis after extended observation time. Methods and Patients: 561 pts were randomized as previously published (Eichhorst B et al., Lancet Oncol 2016). 282 and 279 pts were randomized to receive either 6 courses of FCR or BR respectively. After the end of treatment pts were followed 3-monthly for 2 years (yrs) and 6-monthly for 3 yrs, and afterwards annually until progressive disease (PD). After PD annual visits were documented either within the study or within the registry of the GCLLSG. Health related quality of life (HRQOL) was evaluated by using the EORTC C30 questionnaire, which was completed at baseline, after 3, 6 and 12 months and then annually until year 5. Results: After a median observation time of 58.2 months (mo) (range, 0 - 88 mo), the median progression-free survival (PFS) for FCR was 57.6 mo versus (vs) 42.3 mo for the BR arm [Hazard ratio (HR)=1.593 (95% confidence interval (CI), 1.271-1.996); p 〈 0.0001]. While PFS was statistically significant different in younger pts [≤ 65 years (yrs)] (median PFS 57.6 vs 38.2 mo.; p 〈 0.0001), the difference was statistically not significant in elderly pts [ 〉 65 yrs] (57.6 vs 42.3; p=0.134). Richter transformation (RT) was assessed as PD and occurred in 5 pts (1.8%) after FCR and 8 pts (2.9%) after BR. 77 (27.3%) pts following FCR and 108 (38.7%) following BR treatment received at least one subsequent therapy. BR was the most common second line therapy after prior FCR (42 pts), while BR re-exposure after frontline BR was performed in 31 pts. 33pts switched to FCR after BR first line therapy. So far, only 3 pts after FCR and 2 pts after BR received kinase inhibitors. 51 pts (18.1%) of the FCR arm and 54 (19.4%) pts of the BR arm deceased so far. Main cause of death in the FCR arm were secondary malignancies (14 pts; 5.0%), followed by CLL including RT (11 pts incl. 2 RT; 3.9%), infections (7 pts; 2.5%) and concomitant diseases (6 pts; 2.1%). In the BR arm CLL was the most common cause of death (15 pts incl. 6 pts with RT; 5.4%) followed by infections (12 pts; 4.3%) and concomitant disease and secondary malignancies (10 pts each; 4.3% each). Other causes of deaths were distributed similarly (incl. adverse events to frontline or relapse treatment or unknown). No differences in overall survival (OS) were observed (OS at 5 yrs, 80.9% for FCR vs 80.1% for BR; HR=1.108, 95% CI 0.755-1.627; p=0.599). The difference in OS for younger pts was statistically not significant (OS at 5-yrs 85.6% for FCR vs 81.1% for BR; p=0.119). Otherwise, 5-yrs OS was 78.8% for pts 〉 65 yrs receiving BR and 70.9% for those receiving FCR (p=0.238). Multivariate analysis identified treatment arm, male sex, high serum thymidine kinase (TK), del(11q) and unmuated IGHV status, but not age as independent prognostic factors for PFS. For OS only high serum TK and unmutated IGHV status were assessed as independent prognostic factors. Secondary neoplasia was documented in 49 (17.6%) of 279 FCR treated pts and 35 (12.5%) of 278 BR treated pts. No difference in the incidence rate of secondary solid tumors was observed between both arms (for FCR 28 (10.0%) and for BR 25 (9.1%)). Secondary MDS and/or AML occurred more frequently after FCR therapy (12 [4.3%] vs 2 [0.7%] ), particularly in pts 〉 65 yrs (6 [7.0%] vs 1 [0.9%] ). 540 of 561 pts (96.3%) were evaluable for HRQOL analysis, 272 pts of the FCR and 268 pts of the BR arm. No differences between both arms were detected with respect to global health status or any functional or symptom scale. As compared to an age- and sex-matched normal population functional scale values were impaired mostly during treatment phase and symptom scales also during follow-up. However, after the end of therapy and during follow-up global health status was improved. Conclusion: Long-term follow-up data of the CLL10 study confirm the superiority of FCR regimen in young (≤ 65 yrs) and fit CLL patients. However, importantly these data support the recommendation of using BR in fit elderly pts. This particular group of pts had both a very good outcome after BR and compared to FCR a decreased risk of secondary MDS and/or AML. Disclosures Eichhorst: Novartis: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding, Speakers Bureau. Bahlo:F. Hoffman-La Roche: Honoraria, Other: Travel grant. Maurer:Mundipharma: Other: Travel grants. Kiehl:Roche: Consultancy, Other: Travel grants, Speakers Bureau. Fischer:Roche: Other: travel grants. Kneba:Amgen: Research Funding; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants; Glaxo-SmithKline: Other: Travel grants; Janssen-Cilag: Consultancy, Honoraria, Other: Travel grants. Wendtner:Hoffmann-La Roche, Mundipharma, Janssen, Gilead, Abbvie, Servier, Morphosys: Consultancy, Other: Travle grants, Research Funding. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Kreuzer:Roche Pharma GmbH and Mundipharma GmbH: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Research Funding, Speakers Bureau. Böttcher:Celgene: Research Funding; Hoffmann-LaRoche: Honoraria, Other: Travel grants, Research Funding; AbbVie: Honoraria, Research Funding. Stilgenbauer:GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding. Fink:Celgene: Research Funding; Roche: Honoraria, Other: Travel grants; Mundipharma: Other: Travel grants; AbbVie: Other: Travel grants. Hallek:Celgene: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; GSK: Research Funding; Mundipharma: Research Funding; Janssen: Research Funding.

Abstract: Introduction FCR is the current standard first line treatment regimen in advanced CLL (Hallek et al., Lancet, 2010), but is associated with significant side effects. The GCCLSG initiated an international phase III study in order to test the non-inferiority regarding efficacy and potentially better tolerability of BR compared to FCR in first-line therapy of physically fit pts without del(17p). Methods and Patients 688 CLL pts from 158 sites in five countries (Germany, Austria, Switzerland, Denmark and Czech Republic) were screened centrally for immunophenotype, genomic aberrations by FISH, IGHV sequenzing, comorbidity burden and renal function. 564 CLL pts with CIRS score ≤ 6, creatinine clearance 〉 70 ml/min and without del(17p) were enrolled between October 2008 and June 2011. Pts were randomly assigned to receive 6 courses of either FCR (N= 284; F 25mg/m2 i.v. d1–3, C 250 mg/m2 i.v. d1–3, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days) or BR (N=280; B 90mg/m2 i.v. d1+2, R 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent courses; q 28 days). The intent-to-treat population consisted of 561 pts, because three patients were excluded due to deferred treatment (1 pt decision, 1 treatment before randomization, 1 misdiagnosis). 22 % were Binet A, 38 % Binet B and 40 % Binet C. The median age was 62 years (yrs) (range 33 to 82), median CIRS score 2 (range 0-6). There were significantly more pts with unmutated IGVH in the BR arm (68%) in comparison to the FCR arm (55%; p=0.003). All other characteristics including median age were well balanced. A mean number of 5.27 courses was given in the FCR arm versus 5.41 courses in the BR arm (p=0.022). 70.6% (FCR) and 80.3% (BR) of pts received 6 courses (p=0.008). Dose was reduced by more than 10% in 27.3% (FCR) and 31.6% (BR) of all courses given (p = 0.012). Results The median observation time was 27.9 months (mo) in all pts alive. While response evaluation was missing in 14 pts, 547 pts (274 FCR; BR 273) were evaluable for response and all 561 pts (282 FCR; 279 BR) for progression-free survival (PFS), event-free survival (EFS) and OS. The overall response rate was identical in both arms with 97.8% (p=1.0). The complete response rate (CRR) (confirmed by central immunhistology) with FCR was 47.4% as compared to 38.1% with BR (p=0.031). MRD data were available at interim analysis from 192 pts (99 FCR; 93 BR) of the first 300pts. 71.7% of pts in the FCR and 66.7% in the BR arms achieved MRD-levels below 10-4 in peripheral blood at final staging (p=0.448). The complete MRD data set will be available by November. PFS was 85.0% at 2 yrs in the FCR arm and 78.2% in the BR arm (p=0.041). EFS was 82.6% at 2 yrs in the FCR arm and 75.7% in the BR arm (p=0.037).There was no difference in OS rate for the FCR vs BR arm (94.2% vs 95.8% at 2 years p=0.593). Hazard Ratio for PFS, EFS and OS was 1.385, 1.375 and 0.842 respectively. PFS was assessed in pts 〈 65 yrs and ≥ 65 yrs. While there was a significant difference in pts 〈 65 yrs between both treatment arm (median PFS for BR 36.5 mo vs not reached for FCR; p=0.016), the difference disappeared in elderly pts (not reached vs. 45.6 mo; p=0.757). A multivariate analysis including treatment arm, Binet stage, age, sex, comorbidity, serum TK, serum beta2-microglobulin (Beta2M), del(11q) and IGHV status identified treatment arm, Beta2M, del(11q) and IGHV as independent prognostic factors for PFS and EFS. FCR treated pts had significantly more frequent severe, CTC grade 3 to 5, adverse events during the whole observation period (90.8% vs 78.5%; p 〈 0.001). Especially severe hematotoxicity was more frequent in the FCR arm (90.0% vs 66.9%, p 〈 0.001). The higher rate of severe neutropenia (81.7% vs 56.8%, p 〈 0.001) resulted in a significantly higher rate of severe infections (39.0% vs 25.4%, p=0.001) in the FCR arm, especially in the elderly (FCR: 47.4% vs BR: 26.5%; p=0.002). Treatment related mortality occurred in 3.9% (n=11) in the FCR and 2.1% (n=6) in the BR arm. Conclusion The results of this planned interim analysis show that FCR seems more efficient than BR in the first-line treatment of fit CLL pts with regard to higher CRR, as well as longer PFS and EFS. These advantages might be balanced by a higher rate of severe adverse events, in particular neutropenia and infections, associated with FCR. In light of these results, no firm recommendation of one regimen over the other can be given at the present time regarding the first-line use in CLL pts with good physical fitness. Disclosures: Eichhorst: Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding. Gregor:Roche: Consultancy, Honoraria, Travel Support Other; Mundipharma: Travel Support, Travel Support Other. Plesner:Mundipharma: Research Funding. Trneny:Roche: Honoraria, Research Funding. Fischer:Roche: Travel grants Other; Mundipharma: Travel grants, Travel grants Other. Kneba:Roche: Consultancy, Research Funding. Wendtner:Roche: Consultancy, Research Funding; Mundipharma: Consultancy, Research Funding. Kreuzer:Roche: Honoraria; Mundipharma: Honoraria. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Böttcher:Roche: Honoraria, Research Funding. Hallek:Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding.

Abstract: For curative treatment of younger patients with acute myeloid leukemia (AML) double induction with two cycles of intensive cytarabine/ anthracycline based chemotherapy 21 days apart is the current standard of care. In the prospective randomized AML-CG 2008 trial we asked question whether current results could be improved on by a dose-dense regimen (S-HAM – Sequential High-dose cytArabine and Mitoxantrone) in which the interval between cycles was minimized to 3 days. A prior large one-armed study (AML-CG 2004) had demonstrated a high antileukemic efficacy and shortened neutropenia of the S-HAM regimen as compared to a historical control of standard double induction treatment. The first clinical results of the randomized comparison are presented here. Methods All patients with first diagnosis of a de-novo or secondary AML (excluding APL) that were deemed fit for intensive induction chemotherapy by their treating physician were eligible for this study. Younger patients in the standard arm were treated with one cycle of TAD-9 (standard dose cytarabine and daunorubicine 60mg/m2 for 3 days) and a mandatory second cycle of HAM (high dose cytarabine and mitoxantrone) starting at day 21. Elderly patients were treated with one cycle of HAM followed by a second cycle of HAM only in case of residual leukemia in the day 16 bone marrow aspirate. Patients in the experimental arm all received S-HAM (two sequential cycles of high-dose cytarabine on days 1+2, mitoxantrone days 3+4) with a 3 days interval. Patients in the age cohort 60 – 69 could be allocated to the “younger” or “elderly” cohort according to their biological fitness at the discretion of the treating physician. However high-dose cytarabine dosages were allocated according to chronological age with patients 〈 60 years receiving 3g/m2 cytarabine per dose and patients 60+ years receiving 1g/m2. The primary endpoint was the overall response rate (i.e. CR + CRirate), secondary endpoints were duration of critical neutropenia, overall survival amongst others. Postremission treatment consisted of recommended early allogeneic transplantation in high risk patients and conventional postremission treatment according to the AML-CG standard (one cycle of TAD-9 consolidation followed by up to 3 years of maintenance treatment) in patients with low risk disease. Results 396 patients were randomized into the study with an age range of 18 to 86 years (median 58). The 387 evaluable patients (184 standard, 203 experimental) were well balanced according to their clinical characteristics, cytogenetics, molecular genetics and overall risk profile. For the primary endpoint a higher ORR of 77% for S-HAM could be found as compared to 72% in the standard arm which was however not significant because a 15% difference had been postulated for the study. Non-hematological toxicities did not show any significant differences. However this was in clear contrast to hematological toxicities: Importantly the duration of critical neutropenia was highly significantly reduced by more than 2 weeks from 45 days (standard) to 29 days (S-HAM) counted from day 1 of treatment. Similarly critical thrombocytopenia was reduced by 13 days from 46 days to 33 days. The early death (ED) rate between both arms was identical between both arms. However a subgroup analysis demonstrated a significantly reduced ED rate in patients receiving 1g/m2 S-HAM as compared to all other treatment groups. The respective ED rates for the various time intervals (always counted from day d1 of treatment) for the 1g/m2S-HAM group were as follows: Interval d1-14 1%, d1-30 3%, d1-60 5%, d1-90 10%. Data for overall survival will be available in November 2013. Conclusion The dose-dense induction regimen S-HAM was highly feasible in patients up to the 8th age decade. The antileukemic efficacy was high with an ORR of 77% for the whole group of unselected patients. As compared to standard double induction dose-dense S-HAM reduced critical neutropenia by more than two weeks. Moreover the subgroup of patients receiving the 1g/m2 S-HAM regimen experienced the lowest ED rate ever reported in the AML-CG trials. This underlines that in contrast to our general expectations the concept of dose-density is able to combine high antileukemic efficacy with significantly reduced haematological toxicity in AML, characterising this approach as first candidate for the next standard arm for future trials of the study group. Disclosures: Lengfelder: TEVA/ Cephalon: Research Funding.

Abstract: Background: A European Marketing Authorization Application for ivosidenib (IVO) is currently under review for the indication of mutant isocitrate dehydrogenase 1 (mIDH1) R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) in adult patients (pts) who have received ≥ 2 prior regimens, including ≥ 1 standard intensive chemotherapy (IC) regimen, or are not candidates for IC and have received ≥ 1 prior non-intensive regimen. IVO is an oral, potent, targeted inhibitor of mIDH1 and was approved by the FDA for the treatment of mIDH1 R/R AML in 2018, and in newly diagnosed AML in adults ≥ 75 years of age or pts ineligible for IC in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study. Aims: To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, UK, and Spain. Methods: Individual pt data from Arm 1+ of the AG120-C-001 study (n = 159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n = 127) and the RWD (n = 148). A medical review was conducted to identify Arm 1+ IVO pts in the AG120-C-001 study and HC pts who fell within the proposed EU indication. Treatment with IVO was compared with the most recent therapy received by HC pts. HC pts treated with IC as their most recent therapy were excluded, as IVO pts, based on the AG120-C-001 study's eligibility criteria, were not considered candidates for IC. Propensity score-based matching/weighting methods were used to adjust for imbalances in baseline prognostic factors between the 2 cohorts (optimal full matching and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 6 baseline prognostic factors for estimation of propensity scores (age, history of hematopoietic stem cell transplantation, number of prior regimens for AML, nature of AML, cytogenetic risk, and primary refractory status). Balance between populations was assessed pre- and post-match via comparison of (weighted) standardized differences (SDs) for each covariate. Time-to-event data were summarized via Kaplan-Meier (KM) estimators with 2-sided 95% confidence intervals (CI). Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HR) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Complete remission (CR) rates were also compared between IVO pts and RWD non-IC HC pts (AMLSG pts were excluded as the response data did not allow for identification of CRs distinct from other response types). Results: One hundred and nine IVO pts and 60 HC pts fell within the proposed EU indication. The IPTW-matched dataset was selected for analysis, as it more strongly minimized the absolute weighted SDs between cohorts as compared with optimal full matching, with all SDs & lt; 0.05. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with IVO compared with 2.9 mo (95% CI: 1.9, 4.5) in the HC pts. The HR for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favor of IVO (p & lt; 0.0001). There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). Conclusion: IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population. Disclosures Paschka: Amgen: Other; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Astex Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy, Speakers Bureau; BerGenBio ASA: Research Funding. Dombret:Novartis: Consultancy; Cellectis: Consultancy; Sunesis: Consultancy; Abbvie: Consultancy; Immunogen: Consultancy; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shire: Honoraria; Otsuka: Consultancy, Honoraria; Menarini: Honoraria; Daiichi Sankyo: Consultancy, Other: travel, accommodation expenses; Incyte: Consultancy, Other: travel, accommodation expenses; Celyad: Consultancy. Montesinos Fernandez:Abbvie: 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, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Kreuzer:Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Grifols: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Hexal: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Biotest: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau. Heuser:Karyopharm: Research Funding; Janssen: Consultancy; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Bayer: Consultancy, Research Funding; PriME Oncology: Honoraria. Metzeler:Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Astellas: Honoraria. Quesnel:Abbvie: Other: travel expenses; Daichii Sankyo: Other: travel expenses, Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. De Botton:Pierre Fabre: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Celgene: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria. Döhner:Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Astellas Pharma: Consultancy; Astex Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Agios: Consultancy; Novartis: Honoraria, Research Funding; Abbvie: Consultancy. Milkovich:RJM Group LLC: Current Employment. Reitan:RJM Group LLC: Current Employment. MacDonald:IQVIA: Current Employment. Casso:IQVIA: Current Employment. Storm:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Liu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Kapsalis:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Attar:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Döhner:Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Sunesis: Other, Research Funding.