Abstract: 8508 Background: High-risk (HR) multiple myeloma (MM) still has a significant impaired prognostic outcome. Addition of CD38 monoclonal antibodies to standard-of-care regimens significantly improved response rates and depth of response in newly diagnosed (ND) and relapsed/refractory MM patients (pts). Here, we report the prespecified end of induction interim analysis (IA) of the investigator-initiated GMMG-CONCEPT trial (NCT03104842), evaluating the quadruplet regimen isatuximab plus carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in HR NDMM pts. Methods: 153 pts with HR NDMM are planned to be included into the trial. HR MM is defined by the presence of del17p or t(4;14) or t(14;16) or 〉 3 copies 1q21 and ISS 2 or 3 stage disease. Pts receive 6 cycles of Isa-KRd induction, 4 cycles of Isa-KRd consolidation and Isa-KR maintenance. Transplant eligible pts (arm A) undergo high-dose therapy. Transplant ineligible pts (arm B) receive 2 additional cycles of Isa-KRd induction. The primary endpoint is MRD negativity measured by next-generation flow after consolidation. This IA reports on overall response rates (ORR) after induction. Additional MRD analysis will be presented. Results: 50 pts (46 arm A, 4 arm B) were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and 〉 3 copies 1q21 in 42%. 39/46 pts in arm A and 4/4 pts in arm B completed induction treatment. ORR was 100%, with 5 pts (10.0%) showing partial response (PR), 22 (44.0%; including 4 in arm B) very good partial response (VGPR) and 23 (46.0 %) complete response (CR). Median stem cell yield was 6.6 × 10 6 CD34+ cells/kg. Grade 3/4 treatment-emergent adverse events (≥ 10%) with Isa-KRd included neutropenia (34.0%), leukopenia (26.0%) and thrombocytopenia (14.0%). Main non-hematologic toxicities grade 3/4 were hypertension (12.0%) and infection (8.0%). Conclusions: To the best of our knowledge, we report for the first time on a trial investigating solely HR NDMM and Isa-KRd quadruplet treatment. Isa-KRd induction induces deep responses in HR MM pts. The overall safety profile of Isa-KRd is expected and consistent with previous reports. The study is ongoing, with pts continuing to be included. Clinical trial information: 03104842 .

Abstract: 3566 Background: Patients (pts) with mCRC progressing on standard chemotherapy have limited therapeutic options. Trifluridine/tipiracil (TAS102) significantly improved survival in patients with refractory mCRC. Ramucirumab (ram) is approved in combination with FOLFIRI for second-line treatment. There is a strong rationale to evaluate the efficacy and safety of ram in combination with TAS102 in pts with refractory mCRC. Methods: This is a randomized, open-label, multicenter, starting as phase IIb and extended to a phase III study in pts with advanced mCRC. Eligible pts were randomized to receive either ram (8 mg/kg on d1+15, q4w) and TAS102 (35 mg/m² on d1-5 and d8-12, q4w, arm A) or TAS102 alone (arm B). The primary endpoint is overall survival. A total of 145 pts were enrolled into phase IIb. Here, we present the data from an interim safety analysis comprising the first 80 treated pts. The trial was extended to phase III including a total of 426 pts. Enrolment of additional 281 pts started in Dec 2020. The trial endpoints remained unchanged. Results: Pts (40 arm A, 40 arm B) received a median of 2.5 treatment cycles in arm A and 2 cycles in arm B; 31 pts in treatment arm A and 32 pts in arm B discontinued participation prematurely, mainly due to cancer progression. Most patients developed adverse events (AEs): grade 3 AEs were observed in 28 pts (70%) in arm A (24 treatment-related) and 27 pts (67%, 17 treatment-related) in arm B. More grade 4 AEs were seen in arm A (13 pts, 32.5%) than in arm B (5 pts, 12.5%). In total, 46 Serious AEs (SAEs) occurred, 27 in arm A (10 treatment-related) and 19 in Arm B (2 treatment-related). Five SAEs (3 in arm A, 2 in arm B) had a fatal outcome (one in arm A treatment-related). Within the analyzed population, no SUSAR occurred. Conclusions: This safety analysis demonstrates a minor increase in AEs in the experimental arm but no unexpected events. There were no excessive toxicity or unacceptable risks. In summary, a favorable risk-benefit-profile was confirmed. Based on these safety results and the ongoing need for efficient treatment in the tested population, the trial was extended to phase III. Clinical trial information: NCT03520946.

Abstract: 10571 Background: Tumor patients (pts.) are considered susceptible to severe COVID-19 after SARS-CoV-2 infection. However, they represent a heterogeneous group of individuals with variable risk. Identification of vulnerable subgroups is important for prioritization of vaccination strategies and possible early therapeutic intervention after infection. Methods: Tumor pts. with PCR-confirmed SARS-CoV-2 infection were included in the multicentric ADHOK registry by 22 institutions. Detailed information about tumor disease and treatment, as well as routine laboratory parameters determined at least 10 days prior to SARS-CoV-2 infection, was collected retrospectively. The primary endpoint was defined as the outcome of the SARS-CoV-2 infection, graded according to the WHO: asymptomatic, mild, moderate, severe, critical, and COVID-19-related death. Results: Until Feb. 5, 2021, 215 pts. (67% with solid tumors, 33% with hematological neoplasms) were included in the registry. 74% of the pts. had an active malignancy. The course of SARS-CoV-2 infection was rather variable: 66% of the pts. remained asymptomatic or showed a mild-to-moderate course, while the rest developed severe or critical disease. The COVID-19-related mortality rate was 24%. Pre-infection routine laboratory values were available for 104 pts., obtained at a median of 21 days before SARS-CoV-2 infection. Compared to COVID-19 survivors, COVID-19 non-survivors showed significantly higher median levels of absolute neutrophil count (ANC: 3.6 vs. 6.4 /nL; p = 0.006, n = 91), neutrophil-to-lymphocyte ratio (NLR: 2.2 vs. 7.2; p = 0.005, n = 75), C-reactive protein (CRP: 9.9 vs. 42.0 mg/L; p = 0.001, n = 104), and lactate dehydrogenase (LDH: 213.0 vs. 267.0 U/L; p = 0.016, n = 78). When categorized by a median split, COVID-19 mortality was significantly higher in pts. with ANC 〉 4.4 /nL (4% vs. 55%, p 〈 0.001), NLR 〉 4.1 (5% vs. 58%, p 〈 0.001), CRP 〉 15.4 mg/L (18% vs. 46%, p = 0.003), LDH 〉 236 U/L (15% vs. 49%, p = 0.003) and lymphocytes 〈 1.3 /nL (41% vs. 11% p = 0.002). In multivariable analysis, ANC and CRP showed a strong and significant association with COVID-19-related death (OR 23.0 and 7.7, p = 0.007 and 0.029, respectively). To develop an easy-to-apply pre-infection score, we combined ANC and CRP and were able to separate three groups of pts. with significantly different COVID-19 outcomes (p 〈 0.001) (Table). Conclusions: Our results unveil subgroups of tumor pts. who may be at increased risk of severe COVID-19 and point to pre-infection routine laboratory parameters with potential prognostic power: ANC and CRP may help identify pts. at risk for severe COVID-19 before SARS-CoV-2 infection.[Table: see text]

Abstract: TPS4158 Background: More than 50% of pts with esophageal cancer have locally advanced or metastatic disease at the time of initial diagnosis. For this group chemotherapy is increasingly used intending local and distant tumor control, improvement of quality of life (QoL) and longer survival. Previous data suggested that EGFR-targeting antibodies may be safely combined with cisplatin and 5-FU, and in addition may increase the efficacy of the standard cisplatin/5-FU regimen [Lorenzen et al, Ann Oncol2009; 20(10): 1667-1673]. Methods: In this open-label, randomized (1:1), multicenter, multinational phase III trial pts with nonresectable, advanced or metastatic ESCC, not eligible for definitive radiochemotherapy, are included. Pts have measurable or non-measurable disease according to RECIST 1.1 and an ECOG PS 0-1. Previous chemotherapy of ESCC in the metastatic setting, concurrent radiotherapy involving target lesions and previous exposure to EGFR-targeted therapy are excluded. Pts receive either CTX (cisplatin 100 mg/m² on day 1 and 5-FU 1000 mg/m²/d on day 1-4) or CTX + P (9 mg/kg on day 1). Cycles are repeated every 3 weeks until progression of disease. Tumor assessment is performed every 9 weeks. The primary objective is to demonstrate superiority of CTX + P over CTX alone in terms of overall survival. Secondary endpoints are progression-free survival, 1-year survival, response rate, safety and tolerability, and QoL. A translational analysis in tumor tissue and serum samples is included. 300 pts are planned to be enrolled for a power of 90% to reject the null hypothesis in which the median overall survival in the control and experimental groups are 6 and 9 months, respectively. 18 pts have been enrolled to date. A Data Monitoring Board will review safety data after 40, 100 and 200 pts. The clinical trial registry number is NCT1627379. Clinical trial information: NCT01627379.

Abstract: The GMMG-CONCEPT trial investigated isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in transplant-eligible (TE) and transplant-noneligible (TNE) patients with newly diagnosed multiple myeloma (NDMM) with exclusively high-risk disease for whom prospective trials are limited, aiming to induce minimal residual disease (MRD) negativity. METHODS This academic, investigator-initiated, multicenter, phase II trial enrolled patients with high-risk NDMM (HRNDMM) defined by mandatory International Staging System stage II/III combined with del17p, t(4;14), t(14;16), or more than three 1q21 copies as high-risk cytogenetic aberrations (HRCAs). Patients received Isa-KRd induction/consolidation and Isa-KR maintenance. TE patients received high-dose melphalan. TNE patients received two additional Isa-KRd cycles postinduction. This prespecified interim analysis (IA) reports the primary end point, MRD negativity ( 〈 10 −5 , next-generation flow), at the end of consolidation. The secondary end point was progression-free survival (PFS). RESULTS Among 125 patients with HRNDMM (TE–intention-to-treat [ITT]-IA, 99; TNE-ITT, 26) of the IA population for the primary end point, the median age was 58 (TE-ITT-IA) and 74 (TNE-ITT) years. Del17p was the most common HRCA (TE, 44.4%; TNE, 42.3%); about one third of evaluable TE/TNE patients presented two or more HRCAs, respectively. The trial met its primary end point with MRD negativity rates after consolidation of 67.7% (TE) and 54.2% (TNE) of patients. Eighty-one of 99 TE-ITT-IA patients reached MRD negativity at any time point (81.8%). MRD negativity was sustained for ≥1 year in 62.6% of patients. With a median follow-up of 44 (TE) and 33 (TNE) months, median PFS was not reached in either arm. CONCLUSION Isa-KRd effectively induces high rates of sustainable MRD negativity in the difficult-to-treat HRNDMM population, regardless of transplant status, translating into a median PFS that was not yet reached after 44/33 months.

Abstract: Introduction: The German-Speaking Myeloma Multicenter Group (GMMG) has initiated a randomized multicenter phase III trial on the effect of elotuzumab in VRD (bortezomib, lenalidomide, dexamethasone) induction/consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma (GMMG-HD6 trial, NCT02495922). The study compares four cycles induction therapy with VRD vs. VRD + elotuzumab, followed by standard intensification (i.e. mobilization and stem cell transplantation), two cycles consolidation with VRD/VRD + elotuzumab and lenalidomide maintenance +/- elotuzumab. The primary endpoint is determination of the best of four treatment strategies regarding progression-free survival. Here we present a first analysis of stem cell mobilization within this study. Patients and Methods: We performed a retrospective analysis of collection data on all patients who underwent peripheral blood stem cell (PBSC) collection between trial initiation in June 2015 and June 2016. Only patients with completely available datasets in respect of mobilization were considered (n=111). The vast majority of 99 patients (89%) received chemomobilization with CAD (cyclophosphamide, adriamycin, dexamethasone) followed by 5-10 µg G-CSF /kg body weight (bw) /d (starting day +9 until completion of PBSC collection), while in one case (1%) dexamethasone was omitted and in 10 cases (9%) cyclophosphamide mono was administered. One patient underwent steady-state mobilization with G-CSF only (10µg /kg bw /d). 55/111 patients received VRD (50%), whereas the remaining patients received VRD + elotuzumab. According to the recommendations of the study group, PBSCs for three stem cell transplants were to be collected. One transplant ideally consisted of ≥2.5 x10^6 CD34+ cells /kg bw, but in the event of poor mobilization as low as ≥2.0 x10^6 CD34+ cells /kg bw would be considered acceptable. Results: The median number of collected CD34+ cells was 10.4 x10^6 /kg bw (range 2.88 to 23.01 x10^6 /kg bw). Overall, 92 patients (83%) collected ≥7.5 x10^6 CD34+ cells /kg bw and another 12 patients (11%) collected between 6.0 and 7.5 x10^6 CD34+ cells /kg bw, resulting in three transplants, respectively. Only 7 patients (6%) collected below 6.0 x10^6 CD34+ cells /kg bw; 5 of them had been treated in the VRD-arm without elotuzumab. Due to insufficient PBSC mobilization after conventional treatment, 14 patients (13%) received a rescue mobilization with plerixafor, from which 12 patients collected ≥6.0 x10^6 CD34+ cells /kg bw. Overall, 7 serious adverse events (SAEs) occurred during mobilization phase, 4 of them in the study arm with elotuzumab. Conclusions: Cyclophosphamide-based chemomobilization after induction therapy with VRD is feasible. Efficient PBSC collection of ≥6.0 x10^6 CD34+ cells /kg bw could be performed in 104 of 111 patients (94%), with a low incidence of SAEs. The need for rescue mobilization was not higher than that of comparable previous GMMG treatment protocols. The addition of elotuzumab during induction phase did not impede PBSC collection. Disclosures Wuchter: Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bertsch:Janssen: Research Funding; Celgene: Research Funding; Chugai: Research Funding. Munder:Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Fenk:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Research Funding; Sanofi: Research Funding. Raab:Novartis: Consultancy, Research Funding; BMS: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ho:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Medac: Other: Travel, accomodations or expenses; Baxalta: Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel, accomodations or expenses; Janssen: Consultancy, Honoraria; Celgene: Other: Travel, accomodations or expenses; BMS: Consultancy, Honoraria. Weisel:Onyx: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldschmidt:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: During the past decade, prognostic tools and outcomes of patients with newly-diagnosed multiple myeloma (NDMM) markedly improved. Data from clinical trials evaluating early morbidity and mortality including patients with transplant-eligible NDMM treated with novel agents are scarce. Thus, we aimed to analyze early morbidity and mortality in this patient cohort, devise and validate a predictive score to identify patients at risk. Patients and methods: Between July 2005 and January 2018, 1333 patients with transplant-eligible NDMM from three subsequent phase III trials, HD4, MM5 and HD6 from the German-speaking Myeloma Multicenter Group (GMMG), received a novel agent-based induction therapy with either bortezomib (BTZ) / doxorubicine / dexamethasone (DEX; PAD: n=192, HD4; PAd: n=296, MM5), BTZ / cyclophosphamide / DEX (VCD: n=300, MM5), BTZ / lenalidomide / DEX (VRD: n=272, HD6) or elotuzumab / VRD (ELO-VRD: n=273, HD6). Severe infections (SI) were defined as any infection grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE). SI and early deaths were counted on and up to 30 days post induction therapy. Uni-/multivariable logistic regression models were used to assess predictive factors for SI and early death and to account for trial effects. Data from the European Myeloma Network (EMN) 02 / Dutch-Belgian Cooperative Trial Group for Hematology Oncology Foundation (HOVON) 95 phase III trial including 1497 patients with transplant-eligible NDMM receiving induction therapy with VCD were used to validate a predictive score for SI and early mortality. Results: Overall, early mortality during induction therapy was low (n=24, 1.8%) in the GMMG cohort. SI were the most common cause for early deaths (n=15, 62.5%) as compared to MM progression-related death (n=5, 20.8%) and other causes (n=4, 16.7%). Rates of SI during induction therapy were 11.9% (n=159) and decreased in subsequent trial generations: HD4-PAD: 27.1%, MM5-PAd: 10.8%, MM5-VCD: 9.3%, HD6-VRD: 7.3% and HD6-ELO-VRD: 9.9% of patients. In the EMN02/HO95 trial, early mortality was 1.7% (n=25) and rates of SI were 6.8% (n=101). A multivariate model including patient and disease baseline characteristics identified four major risk factors for SI and/or early death on induction therapy in the GMMG cohort: age ( & gt;60 years; odds ratio [OR]=1.70, 95% confidence interval [95% CI] : 1.21-2.40, p=0.002), International Staging System (stage III; OR=1.92, 95% CI: 1.22-2.94, p=0.005), platelet count ( & lt;150/nl; OR=2.03, 95% CI: 1.27-3.30, p=0.004) and World Health Organization (WHO) performance status ( & gt;1; OR=1.82, 95% CI: 1.10-3.06, p=0.022). A sum score based on these four risk factors (one risk factor = one point) was built and included 519 (39.5%), 550 (41.9%) and 245 (18.6%) patients with a score of 0, 1 and ≥2 points. A higher score gradually predicted an increasing risk for SI and/or death during induction therapy: 0 points=7.9%, 1 point=11.5% and ≥2 points=23.2% (p & lt;0.001, Figure 1A); SI only: 0 points=7.7%, 1 point=10.9% and ≥2 points=21.6% (p & lt;0.001, Figure 1B) and early death only: 0 points=0.4%, 1 point=1.3% and ≥2 points=5.7% (p & lt;0.001, Figure 1C). In the EMN02/HO95 cohort, 673 (45.6%), 587 (39.7%) and 217 (14.7%) patients had a score of 0, 1 and ≥2 points. The score was successfully validated in the EMN02/HO95 cohort: SI and/or death during induction therapy: 0 points=5.0%, 1 point=8.3% and ≥2 points=11.9% (p & lt;0.001); SI only: 0 points=4.5%, 1 point=7.0% and ≥2 points=10.0% (p=0.006) and early death only: 0 points=0.5%, 1 point=2.2% and ≥2 points=2.5% (p=0.01). Conclusions: To date, this is the largest pooled analysis of individual patient data on early morbidity and mortality in patients with transplant-eligible NDMM treated with novel agent-based induction therapy. Our analysis highlights a decreasing incidence of SI and early mortality and proposes a validated, easy-to-use score to identify patients at excessive risk for SI and/or early death during induction therapy. This allows the implementation of intensive monitoring, preventive and supportive strategies for this subgroup of patients in further clinical trials and also routine care. Figure 1 Figure 1. Disclosures Mai: Celgene / BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Glaxo Smith Kline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations and expenses, Research Funding. Salwender: AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Oncopeptides: Honoraria; Chugai: Honoraria; Pfizer: Honoraria. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munder: GSK: Consultancy; BMS: Consultancy, Honoraria; Abbvie: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Honoraria; Sanofi: Consultancy; Janssen: Consultancy, Honoraria; Incyte: Research Funding. Pantani: Janssen: Honoraria; Amgen: Honoraria. Brossart: BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; MSD: Honoraria. Beksac: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy. Raab: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Abbvie: Consultancy, Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Dürig: Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Besemer: Takeda: Honoraria; Janssen: Honoraria; GSK: Honoraria. Fenk: GSK: Honoraria; Amgen: Honoraria; Janssen: Honoraria; BMS/Celgene: Honoraria; Takeda: Honoraria. Haenel: Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. Metzler: Takeda: Consultancy; BMS: Consultancy; GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy. Graeven: Amgen: Honoraria; Sanofi Aventis: Honoraria; Celgene: Honoraria, Research Funding; Johnson and Johnson: Honoraria; Astra Zeneca: Honoraria; MSD: Consultancy; Boehringer Ingelheim: Honoraria; BMS: Honoraria; Fujifilm: Honoraria; Roche: Research Funding; Gilead: Research Funding; Ipsen Bioscience: Research Funding; MacroGenics: Research Funding. Boccadoro: Janssen and GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and AbbVie: Honoraria; Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol-Myers Squibb, and Mundipharma: Research Funding. Scheid: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dimopoulos: Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Beigene: Honoraria. Weisel: Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sonneveld: SkylineDx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Goldschmidt: Mundipharma: Research Funding; Incyte: Research Funding; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grant; Molecular Partners: Research Funding; MSD: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, 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.