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Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.

Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are among the most frequent alterations in acute myeloid leukemia (AML) and can be found in ∼20% of patients at diagnosis. Among 4930 patients (median age, 56 years; interquartile range, 45-66) with newly diagnosed, intensively treated AML, we identified IDH1 mutations in 423 (8.6%) and IDH2 mutations in 575 (11.7%). Overall, there were no differences in response rates or survival for patients with mutations in IDH1 or IDH2 compared with patients without mutated IDH1/2. However, distinct clinical and comutational phenotypes of the most common subtypes of IDH1/2 mutations could be associated with differences in outcome. IDH1-R132C was associated with increased age, lower white blood cell (WBC) count, less frequent comutation of NPM1 and FLT3 internal tandem mutation (ITD) as well as with lower rate of complete remission and a trend toward reduced overall survival (OS) compared with other IDH1 mutation variants and wild-type (WT) IDH1/2. In our analysis, IDH2-R172K was associated with significantly lower WBC count, more karyotype abnormalities, and less frequent comutations of NPM1 and/or FLT3-ITD. Among patients within the European LeukemiaNet 2017 intermediate- and adverse-risk groups, relapse-free survival and OS were significantly better for those with IDH2-R172K compared with WT IDH, providing evidence that AML with IDH2-R172K could be a distinct entity with a specific comutation pattern and favorable outcome. In summary, the presented data from a large cohort of patients with IDH1/2 mutated AML indicate novel and clinically relevant findings for the most common IDH mutation subtypes.

Background Double induction using two subsequent 7+3 regimens of cytarabine plus anthracycline is commonly performed in AML patients with an adequate performance status in order to maximize dose intensity upfront. However, for patients with a good early response at day 15 of first induction, there is no prospective randomized evidence on the necessity or value of a second induction cycle. Aims In order to answer the question if good responders of the first 7+3 induction could be spared a second induction cycle, we set up randomized-controlled SAL DaunoDouble trial. The study prospectively assesses the outcome of patients with a good early response with respect to the number of induction cycles (single versus double). We assumed non-inferiority of single induction in terms of complete remission (CR/CRi) rate, based on a margin of 7.5%. Here, we present the results of the planned interim analysis. Methods Patients (pts) 18-65 years with newly diagnosed AML, normal cardiac and organ function received a first induction cycle with seven days of cytarabine plus three days of daunorubicin ("7+3"). Response assessment in bone marrow was done on day 15 after the initiation of chemotherapy and confirmed by central review. A blast count Results Between 2014 and 2020, 624 evaluable pts were enrolled and received the first induction cycle with 7+3. A marrow blast clearance below 5% on day 15 was achieved in 298 pts (48%), providing eligibility for randomization. Of these patients, 150 were randomized into arm S and 148 into arm D, respectively. Median age was 52 years, 92% had de novo AML, NPM1 mutation was present in 53%, FLT3-ITD in 25% of pts. Favorable, intermediate and adverse risk (ELN 2017) were present in 56%, 34% and 10% of pts, respectively. CR/CRi rates at the end of induction were 86% after single induction and 85% after double induction. The CR/CRi rates in 224 pre-defined per-protocol pts were 88% versus 91%, resulting in a CR difference of 3% (95%-CI -0.047-0.111; p for non-inferiority test 0.145). After a median follow-up time of 24 months, RFS was slightly but not significantly lower after single induction with a 3-year RFS of 53% versus 64% (HR 1.4, p=0.125), whereas no differences were seen in 3-year OS, with a of rate of 74% versus 75% (HR 1.1, p=0.645) after single versus double induction. Conclusion The interim analysis results show that in good responders, the difference between CR rates after single versus double induction was even smaller than the predefined 7.5% margin, suggesting a trend for non-inferiority of single induction, although statistical significance was not reached. The trial continued recruitment. These findings suggest that in good responders, it may be safe to omit a second induction cycle if a second cycle poses a high risk. Figure. CR + CRi, RFS and OS after randomization to single versus double induction. Disclosures Alakel: Pfizer: Consultancy. Jost:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; JAZZ: Other: travel support; Celgene: Other: travel support. Novak:Roche: Consultancy; Janssen: Other: Travel expenses; Takeda: Consultancy; Amgen: Consultancy, Other: Travel expenses; Pfizer: Consultancy; Novartis: Consultancy. Krause:Takeda: Honoraria; Celgene: Other: Travel Support; MSD: Honoraria; Pfizer: Honoraria; Siemens: Research Funding; Gilead: Other: Travel Support. Held:Roche: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy; Acrotech: Research Funding; Spectrum: Research Funding; Amgen: Research Funding. Platzbecker:AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.

Summary Background Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients. Methods The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK–NUP214, RUNX1–RUNX1T1, CBFb–MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1–7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov , number NCT01462578 , and finished recruitment on Aug 21, 2018. Findings Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44–72) of 53 patients were relapse-free and alive (p Interpretation Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes. Funding Celgene Pharma, Jose Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.

Mobilization and collection of peripheral blood stem cells is part of the standard treatment procedure for non-Hodgkin’s lymphoma patients eligible for high-dose chemotherapy with autologous stem cell transplantation. Mobilization is usually achieved with chemotherapy and/or cytokines, but plerixafor might be added in case of poor mobilization. Due to the high cost several institutions have developed their own management pathway to optimize use of plerixafor. Such models are however rarely generalizable; in a multi-center, European, non-interventional study, evaluating the impact of plerixafor in poor mobilizers, country specific differences in patient treatment and cost structure were obvious. For German centers, there was a non-significant reduction in the number of apheresis sessions carried out and in apheresis costs. In contrast to other European countries the majority of German Plerixafor patients were very poor mobilizing patients with initial CD34+ cell count ≤ 10/µl (40/51). In this group the number of apheresis sessions decreased from 2.1 to 1.6 sessions per patient (p = 0.01) and costs decreased from €6246 to €4758 (p = 0.01). Our results show that preemptive plerixafor use has a strong effect in poor mobilizers with an initial CD34+ cell count ≤ 10 cells/µl. CA extern

Background In newly diagnosed acute myeloid leukemia (AML) with FLT3 mutations (FLT3-mut), the tyrosine kinase inhibitor midostaurin (MIDO) in combination with intensive chemotherapy (IC) is considered standard of care (SoC). Subgroup analyses from the ALFA 0701 trial indicate that the addition of the conjugated CD33 antibody gemtuzumab ozogamicin (GO) to IC increases efficacy in the FLT3-ITD subgroup of patients (pts), providing a rationale for the combined use of MIDO plus GO with IC in newly diagnosed FLT3-mut AML. On the other hand, there is evidence that the subgroup of core-binding factor (CBF) AML benefits from the inhibition of the tyrosine kinase KIT with respect to survival end points. In this respect, MIDO is a more powerful KIT inhibitor as compared to dasatinib which has been applied in previous studies. While the combination of IC plus GO in induction treatment is considered SoC in patients with CBF AML the addition of MIDO to SoC seems promising to further improve treatment outcomes in the CBF subgroup. We therefore set up the clinical trial MOSAIC composed of a phase-I part to prospectively assess the feasibility of combining MIDO plus GO with IC (MODULE), followed by a randomized phase-II part evaluating the benefit of adding GO to SoC in FLT3-mut AML (MAGMA) and of adding MIDO to SoC in CBF AML (MAGNOLIA). Here, we report the results of the phase-I part (MODULE). Methods MODULE is a dose escalation phase-I trial following a 3+3 design. Eligibility criteria include newly diagnosed AML harboring either FLT3 or CBF mutations, and fitness for IC. Standard 7+3 IC using cytarabine 200 mg/m 2 continuous infusion over 7 days plus daunorubicin 60 mg/m 2 on 3 days was combined with increasing doses of MIDO and GO in three dose levels: 1 st dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 25 mg MIDO p.o. BID days 8-21); 2 nd dose level (GO 3 mg/m 2 i.v. QD on day 1+4 plus 50 mg MIDO p.o. BID days 8-21); 3 rd dose level (GO 3 mg/m 2 i.v. QD on day 1+4+7 plus 50 mg MIDO p.o. BID days 8-21). Based on the 3+3 design, each dose cohort consisted of three but maximal six pts. The protocol predefined the maximal tolerable dose (MTD) as reached if ≤2 dose-limiting toxicity events (DLTs) would occur in maximum six evaluable pts who received ≥80% of the planned study therapy. Results From September 2020 to July 2021, 11 pts were enrolled. In the 1 st dose level, three pts completed the regular study period without DLT, whereas treatment had to be discontinued in one patient on day 6 before commencement of MIDO due to infusion related reaction CTC grade 4. This patient was subsequently replaced. In the 2 nd dose level, one of three enrolled pts experienced neutropenic colitis CTC grade 3 on day 14 of treatment, which was classified as DLT. The colitis fully recovered by day 27 after commencement of treatment. As a result of the DLT, the dose cohort was subsequently extended by three additional pts. Of those, one patient developed signs of sinusoidal obstruction syndrome (SOS) CTC grade 3 starting on day 13 of treatment. SOS was classified as DLT. The patient was treated with defibrotide and supportive care until recovery on day 28. Another patient had to discontinue treatment on day 14 due to inability of swallowing MIDO. This patient was replaced as the target dose of MIDO was not reached. As predefined in the study protocol, the occurrence of 2 DLTs in six evaluable pts precluded further dose escalation to the 3 rd dose level and defined the 2 nd dose level as safe and feasible. A total number of 5 serious adverse events (SAEs) were observed among all 11 pts who completed the DLT evaluation period: infusion related reaction, colitis, parvo-B19 infection, prolonged neutropenia CTC grade 4, and SOS. An unexpected increase in frequency of common AML adverse events was not observed. The 30-day mortality among all enrolled pts was 0%. After blood count recovery, remission assessment showed complete remission (CR) in 7 pts, CR with incomplete hematologic/platelet recovery (CRi/CRp) in 3 pts and primary refractory disease in one patient. Conclusion GO standard dose on days 1 + 4 and MIDO standard dose on days 8-21 of induction treatment is defined as MTD which can be safely combined with standard IC in newly diagnosed AML. In the phase-I cohort of the MOSAIC trial, CR/CRi/CRp rates of 91% were reached. Based on the results of this dose finding trial the MTD of combined MIDO and GO will be defined as phase-II dose for the randomized phase-II studies in CBF and FLT-mut AML. Figure 1 Figure 1. Disclosures Röllig: Jazz: Honoraria; Amgen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Fransecky: Novartis: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria; Medac: Honoraria. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding.

Objective Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma (RMM). Methods Peripheral blood stem cells (PBSCs) were mobilized with high dose cyclophosphamide (2 g/m2 daily on days 1 and 2) and G-CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the ReLApsE trial of the German-Speaking Myeloma Multicenter Group (GMMG). Results Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G-CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (≥2×106 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3×106 vs 17×106 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events (SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock). Conclusions These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic.

Background: Monitoring of measurable residual disease (MRD) in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who achieve complete remission (CR) can predict hematological relapse. Recently published data from the first cohort of the RELAZA2-trial have shown that pre-emptive therapy with azacitidine (AZA) can prevent or substantially delay an overt relapse in MRD-positive pts with MDS or AML (Platzbecker et al. Lancet Oncol. 2018). Aims: To evaluate outcome of the entire patient cohort of the RELAZA2-trial and determine whether MRD-guided pre-emptive AZA treatment could prevent relapse in molecularly defined cohorts. Methods: Between 12/2011 and 07/2018 380 pts with advanced MDS or AML, who had achieved CR after conventional chemotherapy or allogeneic hematopoietic stem-cell transplantation (allo-HCT) were prospectively screened for MRD in monthly intervals either in bone marrow (BM) or peripheral blood (PB). A total of 94 pts (AML, n=83; MDS, n=11) became MRD positive during 24 months from baseline by either quantitative PCR (qPCR) or analysis of CD34+ donor-chimerism and entered the treatment phase. Preemptive MRD-triggered treatment consisted of AZA 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for up to 24 cycles. After six cycles, MRD status was reassessed and pts with MRD negativity were eligible for treatment de-escalation. Primary endpoint was relapse-free survival (RFS) six months after start of pre-emptive treatment. For mutational analysis next generation sequencing (NGS) with a panel of 54 genes was performed (Illumina Trusight Myeloid). Results: Median age was 60 yrs (range: 22-80 yrs); 52 (55%) of the pts were female. Prior therapy consisted of chemotherapy in 42 (45%) and allo-HCT in 52 (55%) of the pts. Cytogenetics could be analyzed in 93 (99%) of the 94 pts. Risk categorization according to ELN 2017 was favorable in 30 (37%), intermediate in 31 (38%) and adverse in 21 (26%) of the AML pts, respectively. Type of MDS was advanced in all 11 pts and all were previously transplanted. Fifty-two (61%) of 85 pts with available NPM1 status were positive. NGS on 64 (68%) pts with available DNA at the time of first diagnosis revealed additional mutations in DNMT3A (n=25), TET2 (n=15), FLT3-ITD (n=12), IDH1 (n=9), FLT3-TKD (n=8), ASXL1, NRAS, TP53 (n=7, each), IDH2 (n=6), PTPN11, WT1 (n=5, each), GATA2, U2AF1 (n=4, each), CBL (n=3), CEBPA, CSFR3, CUX1, EZH2, KIT, RAD21, RUNX1, SF3B, STAG2, ZRSR2 (n=2, each), and KRAS (n=1). MRD data were correlated with outcome in 45 pts for NPM1, in 3 for RUNX1-RUNX1T1, whereas CD34-donor-chimerism was analyzed in 39 pts (missing, n=7). There was a significant faster and deeper decline of MRD in PB as compared to BM (P=0.03). The same held true with regard to the increase of donor-chimerism, which was achieved faster in PB as compared to BM (P=0.05). Secondary molecular abnormalities (MAs) had no impact on MRD response as measured by qPCR, which was also true if MAs were categorized functionally. Similarly, additional chromosomal abnormalities had no impact on MRD response in both MRD methods. However, in pts with measurement of donor-chimerism ASXL1 mutations were a negative factor for MRD response (P Conclusions: AZA as a pre-emptive therapy was effective in delaying hematological relapse of advanced MDS or AML pts, regardless of the underlying genetic signature. Based on these encouraging results, intensifying treatment with AZA in combination with pembrolizumab is currently investigated as MRD-guided treatment in NPM1 positive AML (PEMAZA; ClinicalTrials.gov Identifier: NCT03769532). Disclosures Wolf: Celgene: Honoraria, Research Funding. Bug:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hexal: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Eurocept: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Jazz: Honoraria; Neovii: Other: Travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sanofi: Other: Travel. Götze:Celgene: Research Funding. Stelljes:Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Subklewe:Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Seattle Genetics: Research Funding; Morphosys: Research Funding; Janssen: Consultancy; AMGEN: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy, Honoraria, Research Funding. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Rollig:Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Müller-Tidow:Pfizer: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; BiolineRx: Research Funding; Janssen-Cilag GmbH: Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. OffLabel Disclosure: Off-label: treatment with azacitidine to prevent or substantially delay an overt relapse in MRD-positive patients with MDS or AML

Managing acute myeloid leukemia (AML) is often hampered by repeated failure to achieve complete remission as well as recurrent relapse that causes an emergent need for alternative salvage therapies. The efficacy of most salvage therapies is based on anthracycline combinations. In highly pretreated patients who are not eligible for anthracycline-based protocols therapeutic alternatives are limited. For this particular group we evaluated the efficacy and safety of fludarabine, cytarabine, granulocyte colony-stimulating factor (FLAG) in combination with etoposide (FLAG-Eto) in 36 patients. The complete remission rate (CR) was 25.7% with a median overall survival of 6 months (95% CI 4.5–7.7). The median disease-free survival for CR/CRi/MLFS (CR/CR with incomplete he­matological recovery/morphologic leukemia-free state) patients was 8 months (95% CI 0.6–15.5). The mortality rate on day 30 was 8% and increased on day 60 to 17%. Our results show meaningful anti-leukemic activity of the FLAG-Eto regimen with a moderate toxicity profile in heavily pretreated relapsed/refractory AML patients enabling consolidating allogeneic stem cell transplantation.

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia–Acute Myeloid Leukemia (SAL-AML) registry. All registered non–acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.

Background Although children, adolescents and young adult patients with ALL have in general a good prognosis relapses occur and patients with a second relapse, a relapse after allogeneic SCT or patients with primary refractory disease have a poor prognosis. In this patient group several studies using second generation CD19 chimeric antigen receptor T- cells (CAR-T cells) demonstrated high efficacy with survival rates of up to 65%. Here we report our first results using commercially available CAR-T-cell product Tisagenlecleucel in patients with ALL. Methods, Patients Between May 2016 and August 2019 twenty-six patients received a peripheral blood apheresis for CAR-T cell generation. Twenty-four patients had relapsed after allogeneic HSCT (92%), one patient suffered from second r/relapse (4%) or from primary r/ALL (4%). In 23/26 (88%) patients CAR-T cell production was possible after first apheresis, in 2 patients (4%) a second apheresis was necessary after failure of the first transduction. Patients' median age was 13.5 years (range: 1.1-33.2 years). Between apheresis and start of lymphodepleting chemotherapy (LDC) 24 patients received low dose maintenance chemotherapy according to the FRAPOSTALL protocol (Willasch et al. 2016) and two patients were treated with inotuzumab. Disease status at start of LDC was CR w/o MRD (n=12), and persistence of blasts (n=11). Results CAR-T cells could be transfused to 23/26 patients at a median dose of 1.5 Mio/kgBW (range 0.145 to 8.5) /kgBW. In two patients (8%) CAR-T cell production was not possible and in one patient, in whom a second viral transduction procedure was necessary, CAR-T cell transfusion could not be performed because of diseases progression and deterioration of the patients' general condition. Cytokine release syndrome (CRS) grade I-IV was observed in seven patients (30%); 14/23 patients (70%) did not develop CRS. Cytokine related encephalopathy syndrome (CRES) grade II was observed in 4/23 patients (17%). At day +28 17/23 patients (74%) achieved MRD negative CR. Three patients (13%) did not respond and three patients died before day +28. Thereof two patients (8%) with progressive disease at time of LDC who did not respond, and unfortunately one patient (4%) died in CR based on infection before day +28. As of 8/20/2019 median follow-up was 9.5 months. Patients with Conclusion These results confirm that commercial available CAR-T cell product Tisagenlecleucel (Kymriah®) showed high efficacy in ALL patients. Response to bridging chemotherapy and level of residual diseases prior to CAR-T infusion might impact the pEFS and survival of the patients.

Acute myeloid leukemia (AML) is characterized by a high failure rate to achieve complete remission as well as high relapse rates that cause an emergent need for efficient and tolerable salvage therapies. The combination of FLAG with idarubicin (FLAG-Ida) is a widely used protocol. However, its efficacy has been analyzed in only a limited number of studies with majorly small patient cohorts. Here, we analyzed 132 patients with largely primary refractory or first-time relapsed AML treated according to the FLAG-Ida protocol. The overall complete remission rate (CR + CRi) was 56% with a median overall survival of 15 months (95% CI, 5.7-25.1). The median disease-free survival for CR/CRi-patients was not reached. The mortality rate on day 30 was 9% and increased on day 60 to 16%. Our results show in relapsed/refractory AML patients a high efficacy and compatibility for the FLAG-Ida regimen.

This multicenter, randomized, open-label, phase 3 trial evaluated azacitidine efficacy and safety vs conventional care regimens (CCRs) in 488 patients age ≥65 years with newly diagnosed acute myeloid leukemia (AML) with >30% bone marrow blasts. Before randomization, a CCR (standard induction chemotherapy, low-dose ara-c, or supportive care only) was preselected for each patient. Patients then were assigned 1:1 to azacitidine (n = 241) or CCR (n = 247). Patients assigned to CCR received their preselected treatment. Median overall survival (OS) was increased with azacitidine vs CCR: 10.4 months (95% confidence interval [CI], 8.0-12.7 months) vs 6.5 months (95% CI, 5.0-8.6 months), respectively (hazard ratio [HR] was 0.85; 95% CI, 0.69-1.03; stratified log-rank P = .1009). One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively (difference, 12.3%; 95% CI, 3.5%-21.0%). A prespecified analysis censoring patients who received AML treatment after discontinuing study drug showed median OS with azacitidine vs CCR was 12.1 months (95% CI, 9.2-14.2 months) vs 6.9 months (95% CI, 5.1-9.6 months; HR, 0.76; 95% CI, 0.60-0.96; stratified log-rank P = .0190). Univariate analysis showed favorable trends for azacitidine compared with CCR across all subgroups defined by baseline demographic and disease features. Adverse events were consistent with the well-established safety profile of azacitidine. Azacitidine may be an important treatment option for this difficult-to-treat AML population. This trial was registered at www.clinicaltrials.gov as #NCT01074047.

High-dose chemotherapy alongside peripheral blood stem cell (PBSC) infusion has become the standard of care in different hematologic malignancies. The goal of PBSC mobilization is to allow collection of sufficient CD34+ cells to proceed to transplantation. The current mobilization regimen with granulocyte colony-stimulating factor (G-CSF), alone or in combination with chemotherapy, still fails in 10-25% of patients. Plerixafor is able to rescue most of these patients from mobilization failure. In this study, we investigated the impact of plerixafor on the cost and time spent on apheresis in patients who were considered poor mobilizers, with

Background In newly diagnosed acute myeloid leukemia (AML), the general recommendation is to start treatment immediately after the diagnosis has been made. This paradigm is based both on the observation that untreated acute leukemia has a poor prognosis and on retrospective analyses demonstrating a shorter survival in younger AML patients (pts) in whom treatment was delayed by more than 5 days (Sekeres et al., 2009). A more recent single-center analysis came to a different conclusion, showing no prognostic effect for the time from diagnosis to treatment (TDT; Bertoli et al., 2013). We explored the relationship between TDT and prognosis on a large set of real-world data from the AML registry of the Study Alliance Leukemia (SAL) and compared it to the published cohorts. Methods The SAL runs a transregional AML registry in 46 treatment centers across Germany (NCT03188874). All registered patients with an intensive induction treatment, a minimum follow-up time of 12 months and no acute promyelocytic leukemia were selected (n=2,200). Treatment start was defined by the first day of cytarabine, whereas single agent hydroxyurea (HU) was labeled as pretreatment. We analyzed the influence of TDT on complete remission (CR), early death (ED) and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0-5, 6-10, 11-15 and >15 days of TDT, and by using the restricted cubic spline (RCS) method for data modelling. In order to adjust for the influence of established prognostic variables on the outcomes, we used multivariable regression models and propensity score weighting. The influence of HU pretreatment on outcomes was investigated by introducing an interaction term between TDT and the presence of HU pretreatment. Results The median age was 59 years (y) (IQR 50-68), the proportion of pts with favorable, intermediate and adverse genetic risk according to ELN was 27%, 53%, and 20%; >95% of pts received induction treatment with standard 7+3. HU pretreatment was administered in 4% of pts. The median TDT was 3 days (IQR 2-6). Descriptive statistics after grouping of pts showed the highest median age and the lowest proportion of NPM1 mutated and favorable risk in the TDT group 11-15. Of all pts, 79% achieved a CR/CRi; unadjusted CR rates for the patient groups with TDT of 0-5, 6-10, 11-15 and >15 days were 80%, 77%, 74% and 76%, respectively (p=0.317). In multivariable analysis accounting for the influence of ELN risk, age, WBC, LDH, de novo versus secondary AML and ECOG, the OR for each additional day of TDT was 0.99 (95%-CI, 0.97-1.00; p=0.124). Four percent of pts died within the first 30 days from treatment start. The respective rates in the four TDT categories were 4.0%, 3.8%, 5.1% and 4.1% (p=0.960). In multivariable analysis, the OR for TDT was 1.01 (95%-CI, 0.98-1.05; p=0.549). After a median follow-up of 40 months, the 2-y OS of all pts was 51%. The unadjusted 2-y OS rates stratified by TDT of 0-5, 6-10, 11-15, >15 days were 52, 49, 46, and 51% (see Table 1 and Figure 1). The hazard ratio (HR) for each day of treatment delay was 1.00 (95%-CI; 0.99-1.01; p=0.317). In multivariable Cox regression analysis, the HR for TDT as continuous variable was 1.00 (95%-CI, 0.99-1.01; p=0.689). When OS was analyzed separately stratified for age ≤60 and >60 ys and for high versus lower initial WBC defined by a threshold of 50 x 109/L, no significant differences between TDT groups were observed. Multivariable models using TDT as a grouped variable or with RCS did not provide evidence for a significant influence of TDT on outcomes. Propensity score matching of pts in the four TDT groups did not reveal an influence on outcomes. The use of HU was not associated with CR, ED nor OS. Conclusion Our study on 2,200 newly diagnosed registry pts receiving consistent intensive induction with standard-dose cytarabine plus daunorubicin (7+3) suggests that TDT is not related to response or survival, neither in younger nor in older pts. Despite multivariable analyses, a bias towards longer TDT intervals in pts judged to be clinically stable by the treating physician cannot be excluded entirely. As treatment stratification in intensive first-line treatment of AML evolves, the TDT data suggests that it may be a safe and reasonable approach to wait for genetic and other laboratory test results in order to assign clinically stable pts to the best available treatment option before the start of intensive treatment. Disclosures Krämer: Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hänel:Roche: Honoraria; Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board. Jost:Daiichi: Honoraria; Sanofi: Honoraria; Gilead: Other: travel grants; Jazz Pharmaceuticals: Honoraria. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Kiani:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Middeke:Sanofi: Research Funding, Speakers Bureau; Roche: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau; MSD: Consultancy. Thiede:AgenDix GmbH: Employment, Equity Ownership; Novartis: Research Funding, Speakers Bureau; Bayer: Research Funding; Daiichi-Sankyo: Speakers Bureau. Stoelzel:JAZZ Pharmaceuticals: Consultancy; Neovii: Other: Travel funding; Shire: Consultancy, Other: Travel funding. Platzbecker:Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Background: Measurable residual disease (MRD) can identify patients (pts) with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in complete hematological remission (CR) at high risk of relapse even after allogeneic hematopoietic stem cell transplantation (HSCT). We have recently shown in 53 pts treated within the first cohort of the RELAZA2 trial that pre-emptive therapy with azacitidine (AZA) at the time of MRD-positivity (MRDpos) can successfully prevent imminent hematological relapse (Platzbecker et al. Lancet Oncol. 2018). We now report on the results of the second cohort of 41 pts undergoing MRD-guided treatment in the RELAZA2 trial (ClinicalTrials.gov NCT01462578) by the Study Alliance Leukemia (SAL). Methods: Between 2015 and 2018, 166 MDS/AML pts were screened and centrally monitored for MRD in bone marrow or peripheral blood at monthly intervals for a period of 2 years prospectively in 9 centers in Germany. Of these 166, 41 pts with either advanced MDS (n=6) or AML (n=35) in CR after either conventional chemotherapy only (n=13) or consecutive allogeneic HSCT (n=28) developed MRD above a threshold defining imminent hematological relapse. Still being in morphological CR, these pts pre-emptively received 6 cycles of AZA (75mg/m2, s.c. days 1-7), which was followed by a risk-adapted AZA-maintenance therapy based on MRD-response for up to 18 additional months. Pts developing a hematological relapse went off study. MRD was detected by either the quantification of NPM1 mutation level (n=19), leukemia-specific fusion genes DEK-NUP214 (n=1) or RUNX1/RUNX1T1 (n=2) or a sensitive donor chimerism analysis of sorted CD34(+)/CD117(+) peripheral blood cells (n=28) in pts undergoing allogeneic HSCT. Here, we report the analysis of the primary endpoint of the 41 pts in the second cohort as well as the data for the entire 94 pts who entered the treatment phase of the RELAZA-2 study. Results: At a median of 110 days (range 28-476) after start of screening, 41 (25%) out of 166 prospectively screened pts became MRDpos as defined by either a decrease of CD34(+)/CD117(+) donor chimerism to 1% (NPM1 n=18) while being still in hematological CR. All of these MRDpos pts started AZA-based pre-emptive treatment to prevent imminent hematological relapse. Six months after start of MRD-guided therapy, 25 out of 41 pts were still in CR (61%, 95%-CI 45-76%, p Conclusion: These multicenter prospective data provide further strong evidence that continuous MRD monitoring is feasible and can identify MDS/AML pts at high risk of hematological relapse. Pre-emptive MRD-guided therapy with AZA is an effective treatment to prevent or at least substantially delay hematologic relapse in these pts. Disclosures Platzbecker: Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Wolf:Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Krämer:Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding. Bug:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Hexal: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Other: travel grants; Celgene Neovii: Other: travel grant. Götze:AbbVie: Membership on an entity's Board of Directors or advisory committees. Stelljes:Novartis: Honoraria; Amgen: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; MDS: Consultancy. Subklewe:AMGEN: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Miltenyi: Research Funding; Oxford Biotherapeutics: Research Funding; Janssen: Consultancy; Roche: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Morphosys: Research Funding. Hänel:Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Amgen: Honoraria; Roche: Honoraria. Dührsen:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Takeda: Consultancy, Honoraria; Teva: Honoraria; Celgene: Research Funding; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; CPT: Consultancy, Honoraria. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Thiede:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; AgenDix GmbH: Employment, Equity Ownership.

Background Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. Discussion This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24). Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2321-2) contains supplementary material, which is available to authorized users.

Purpose Mutations of the isocitrate dehydrogenase-1 (IDH1) and IDH2 genes are one of the most frequent alterations in acute myeloid leukemia (AML) and can be found in ~20% of patients at diagnosis. Several IDH inhibitors are currently in late stage clinical development with Enasidenib, an IDH2 inhibitor, being recently approved by the FDA. Previous analyses have reported differential impact on response to chemotherapy and outcome, depending on the IDH-mutation type, co-occurring mutations and cytogenetic abnormalities, as well as the variant allele frequency (VAF) of IDH mutations. In order to better understand its prognostic role, we analyzed newly diagnosed AML patients enrolled in prospective trials of the Study Alliance Leukemia (SAL) to investigate the impact of IDH1/2 mutations on outcome. Patients and Methods All AML patients consecutively enrolled into intensive AML treatment protocols of the SAL or into the SAL registry were included in this analysis. Next-generation sequencing (NGS) on an Illumina MiSeq-system was performed to detect IDH1/2 mutations using pre-treatment samples. Overall survival (OS) and response to therapy were analyzed for all patients with intensive treatment and according to the mutational status. Results Overall, samples of 3898 patients were analyzed. The median follow-up was 91 months (95% CI 87.2 - 93.9). Patients' characteristics are shown in Tbl.1. Three-hundred twenty-nine patients (8.4%) had IDH1 mutations and 423 (11%) had IDH2 mutations; both mutations were found in 12 pts, so the overall mutation rate in IDH1 and 2 was 19% (740/3898 patients). Of the IDH1 variants, the most common ones were the R132C found in 143 patients (43%) and R132H in 137 patients (42%). For IDH2, 324 patients had the R140Q (77%) and 80 patients the R172K (19%) variant. According to the two main variants of the more common IDH2 mutations, as reported before, the IDH2 R172K was mutually exclusive with NPM1 and/or FLT3-ITD mutations. Overall, there was a trend for increased OS for patients with IDH2 R172K (26 vs. 15 months) as compared to those with R140Q. Considering only patients with a normal karyotype and no NPM1/FLT3-ITD mutation, these patients (n=27) had a highly significant better OS than patients with IDH2 R140Q (46.3 vs. 13.1 months, p=.012), supporting the findings published by Papaemmanuil et al. (NEJM 2016). In IDH1-mutated patients, we observed statistically significant differences in baseline characteristics between the two most common mutation types, IDH1 R132C and R132H. Patients carrying the R132C mutation were older (62 vs. 55 years, p=.001), had lower WBC (3.6 vs. 21 Gpt/L, p≤.001) and were less likely to have a normal karyotype (43% vs. 66%, p=.002), NPM1 (23% vs. 66%, p= In univariate testing, the CR rate was also statistically significant lower in patients with IDH1 R132C (53% vs. 72%, p≤.001), with a median OS of 12.9 months compared to 17.4 months for patients with R132H variant (p=.08). In multivariate analysis including age, WBC, NPM1 and FLT3 status, and ELN risk, the CR rate was significantly lower in patients with the IDH1 R132C variant (p=.038). The median IDH VAF was 38% (range, 0.1 - 58) with no difference according to the different types of mutation. Patients with a VAF > 30% had a significantly higher BM blast count (73% vs 40% for VAF≤5%) and WBC (21.2 Gpt/L vs. 3.7 Gpt/L) at baseline, but there was no clear impact on CR rate or OS found in multivariate analysis. Conclusion In this large cohort of AML patients with IDH1/2 mutations, we found significant and so far not reported differences for one of the two most prominent mutations types of IDH1. The R132C variant was associated with increased age, lower WBC, and lower NPM1 and/or FLT3 co-mutation rate. Further, these patients had lower CR rates and a trend for shorter OS. For IDH2 we were able to reproduce findings on co-mutations and showed a favorable outcome for intensively treated patients with a normal karyotype and no NPM1/FLT3-ITD mutation and the IDH2 R172K variant, providing additional evidence for classification as a separate AML entity. Disclosures Middeke: Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Scholl:Alexion: Other: Travel support; Abbivie: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; MDS: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Brümmendorf:Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Novartis: Consultancy, Research Funding. Burchert:Novartis: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Takeda: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Johnson & Johnson: Research Funding; Roche: Research Funding; Eisai: Research Funding; Affimed: Research Funding; Novartis: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Schetelig:Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria; Sanofi: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Stoelzel:Neovii: Speakers Bureau.

Introduction The ReLApsE trial compared lenalidomide (LEN)/dexamethasone (DEX; Rd) re-induction, salvage high dose chemotherapy (HDCT), autologous stem cell transplantation (ASCT) and LEN maintenance with continuous Rd in relapsed multiple myeloma. Landmark (LM) analyses from salvage HDCT were performed due to the fact that ~30% of patients in the HDCT arm did not receive salvage HDCT/ASCT. These analyses showed a survival benefit in patients actually undergoing salvage HDCT/ASCT. Median PFS and OS from LM were 23.3 vs. 20.1 months (HR 0.74; p=0.09) and not reached vs. 57 months (HR 0.56; p=0.046) favoring the salvage HDCT/ASCT arm. Multivariate LM analyses showed significant associations of the salvage HDCT/ASCT arm with superior PFS (HR 0.6; p=0.01) and OS (HR 0.39; p=0.006). The present analysis aims to dissect treatment efficacy in relevant subgroups and provide clues for treatment stratification. Methods The ReLApsE trial (ISRCTN16345835) compared 3 Rd (LEN 25 mg, d1-21; DEX 40 mg, d1,8,15,22; 4 week cycles) re-induction cycles, HDCT (melphalan 200 mg/m2), ASCT and LEN maintenance (10 mg/d) until PD (arm B, n=139) with Rd until PD (arm A, n=138). Key inclusion criteria were 1-3 prior therapy lines, age ≤ 75, time to PD in case of front-line HDCT/ASCT (TTP1) ≥ 12 months and WHO PS ≤ 2. Exploratory subgroup analyses were performed in the ITT population for PFS/OS using an LM at HDCT (B; n=103) and the contemporaneous Rd cycle 5 (A; n=114). The median interval from randomization to LM was 117/122 days in arm B/A. Heterogeneity of treatment effect was assessed by cox regression with interaction term between treatment and subgroup factor. Results No significant differences in the PFS/OS benefit between arms were observed in subgroups according to baseline ISS (I/II/III; interaction p[i-p]=0.5/0.66), age (1; i-p=0.37/0.22), single vs. tandem front-line HDCT/ASCT (i-p=0.34/0.56), and TTP1 (12-24 vs. 24-48 vs. >48 months; i-p=0.91/0.21). The subgroups according to front-line HDCT/ASCT (yes/no) differed significantly with regard to PFS/OS benefit in arm B (i-p=0.006/0.001). A significant benefit was observed in patients with front-line HDCT/ASCT treated in arm B regarding PFS (HR 0.68, p=0.03; n=107[A]/98[B]) and OS (HR 0.43, p=0.009). Patients without front-line HDCT/ASCT constituted a very small subgroup with imbalances in baseline parameters adversely affecting arm B and had expectably inferior survival in arm B (PFS: HR 4.35, p=0.08; OS: HR 19.83, p=0.0078; n=7[A]/5[B]). The subgroup with baseline LDH upper limit of normal (ULN) differed significantly in PFS benefit in arm B (i-p=0.03) but not in OS benefit (i-p=0.46). Patients with LDHULN (PFS: HR 1.54, p=0.31; n=16[A]/18[B]). The subgroups according to baseline cytogenetic risk and R-ISS showed a trend towards a differential benefit in arm B regarding OS (i-p=0.05 and 0.09) but not PFS (i-p=0.5 and 0.88). Patients with low risk cytogenetics (i.e. absence of t(4;14), del17p, +1q>3 copies and t(14;16)) had significantly superior OS in arm B (HR 0.21; p=0.01; n=57[A]/35[B]), whereas patients with high risk cytogenetics had no significant difference in OS according to trial arm (HR 0.82, p=0.67; n=25[A]/28[B]). Patients with R-ISS I had significantly superior OS in arm B (HR 0.08; p=0.02; n=33[A]/25[B]), whereas no significant difference in OS according to trial arm was seen in patients with R-ISS II (HR 0.72, p=0.42; n=52[A]/43[B]) and R-ISS III (HR 0.65, p=0.6; n=3[A]/5[B]). Conclusions The ReLApsE trial is the first RCT of salvage HDCT/ASCT vs. continuous novel agent treatment. In the absence of a significant survival benefit for the primary endpoint, LM analyses indicated a significant PFS/OS benefit in patients actually undergoing HDCT/ASCT. No heterogeneity of treatment effect was observed according to ISS, age, renal function, response to re-induction, prior therapy lines, single vs. tandem front-line HDCT/ASCT, and TTP1. Subgroup effects regarding PFS and/or OS benefit from HDCT/ASCT were seen favoring patients with front-line HDCT/ASCT and patients with low risk according to LDH, cytogenetics and R-ISS. Disclosures Baertsch: Takeda: Consultancy; Novartis: Consultancy, Research Funding. Raab:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Hillengass:Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; amgen: Consultancy, Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Sanofi: Research Funding. Graeven:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Fenk:Bristol-Meyers Squibb: Honoraria, Other: travel grant; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Travel grant, Research Funding. Haenel:Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Honoraria. Scheid:Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Salwender:Janssen: Honoraria, Other: travel support, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding; Novartis: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

Introduction Salvage high dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is used in fit patients with relapsed multiple myeloma (RMM) in clinical practice. However, the role of this approach in the era of continuous novel agent based treatment has not been defined in randomized trials. The ReLApsE trial compared lenalidomide/dexamethasone (Rd) re-induction, salvage HDCT/ASCT and lenalidomide (R) maintenance with standard continuous Rd in a randomized controlled multicenter trial. Methods Between 2010 and 2016, 282 patients were randomized of whom 277 constituted the intention-to-treat (ITT) population (arm B/A n=139/138). Arm B received 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, 22; 4 week cycles) re-induction, HDCT (melphalan 200 mg/m2), ASCT and R maintenance (10 mg daily) until progression (PD). Arm A was treated with Rd until PD. In both arms stem cells were harvested after the 3rd Rd cycle if no back-up transplant was available. Key inclusion criteria were 1-3 prior therapy lines, age ≤ 75 years, time to PD ≥ 12 months in case of front-line HDCT/ASCT and WHO PS ≤ 2. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS), response rates and toxicity. ISRCTN16345835, Eudra CT-No: 2009-013856-61. Results Arm B and A were balanced regarding age (median 61.3 vs. 62.2 years), ISS (I/II/III in 62.6/24.4/13% vs. 59.7/31/9.3%) and WHO PS (0/1/2 in 69.1/30.9/0% vs. 76.1/23.2/0.7%). Almost all patients had only 1 prior therapy line (arm B: 94.2% vs. arm A: 93.5%) and had received front-line HDCT/ASCT (92.8% vs. 94.2%). More patients in arm B had high risk cytogenetic aberrations (HR-CA; 42.9% vs. 31.6%) based on a higher frequency of t(4;14) (20.2% vs. 10.1%). The overall response rate (≥ partial response; ORR) for arm B and A was 77.9% and 74.6% (p=0.57) with 49.3% and 47.1% (p=0.81) achieving ≥ very good partial response as best response. Within a median follow up of 36.3 months, 183 PFS events and 76 deaths occurred. Median PFS in the ITT population was 20.7 months in arm B and 18.8 months in arm A without a statistically significant difference (HR 0.87; 95% CI 0.65-1.16; p=0.34). Median OS was not reached (NR) in arm B vs. 62.7 months in arm A (HR 0.81; 95% CI 0.52-1.28; p=0.37). In arm B, 41 patients (29.5%) did not receive the planned HDCT/ASCT. Thus, exploratory landmark (LM) analyses from HDCT and the contemporaneous Rd cycle 5 in arm A were performed (median interval from randomization to HDCT/Rd cycle 5: 117/122 days; n=103[B]/114[A]). They showed a trend towards superior PFS (23.3 vs. 20.1 months; HR 0.74; p=0.09) and significantly superior OS (NR vs. 57 months; HR 0.56; p=0.046) in arm B vs. A. Multivariate analyses revealed significant associations of treatment in arm B with superior LM PFS (HR 0.6; p=0.01) and LM OS (HR 0.39; p=0.006). Other factors in the LM multivariate models showing significant associations with survival were HR-CA (PFS, OS), number of prior therapy lines (PFS), and age (PFS). The ORR in arm B after HDCT/ASCT was significantly higher than in arm A after Rd cycle 5 (82.3% vs. 69.6%; p=0.04). Grade ≥3 adverse events were reported in 83% (arm B) and 74.5% (arm A; p=0.11). Grade ≥3 leukopenia/neutropenia was reported in 61.5 vs. 24.8% (p Conclusions This is the first RCT comparing salvage HDCT/ASCT with continuous novel agent based treatment. No significant PFS or OS difference was observed in the overall trial population. However, HR-CA were more frequent in the HDCT/ASCT arm and ~30% of patients did not receive the planned HDCT/ASCT. Landmark analyses from the time of HDCT indicate superior PFS and OS in patients actually undergoing salvage HDCT/ASCT. Salvage HDCT/ASCT was safe with an expected increase in hematological as wells as gastrointestinal toxicity but without treatment-related mortality in patients up to the age of 75 years in this multicenter trial. However, the number of patients not undergoing salvage HDCT/ASCT and the approval of more active Rd-based triplet regimens after the initiation of this trial prevents definite conclusions on the role of salvage HDCT/ASCT. Disclosures Goldschmidt: Amgen: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Chugai: Honoraria, Research Funding. Baertsch:Takeda: Consultancy; Novartis: Consultancy, Research Funding. Raab:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Hillengass:Novartis: Honoraria, Other: Advisory Board; Sanofi: Research Funding; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; amgen: Consultancy, Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding. Graeven:AbbVie: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees. Fenk:Takeda: Honoraria; Bristol-Meyers Squibb: Honoraria, Other: travel grant; Celgene: Honoraria, Other: Travel grant, Research Funding; Janssen: Honoraria; Amgen: Honoraria. Haenel:Novartis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Scheid:Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Salwender:Celgene: Honoraria, Other: travel suppport, Research Funding; Janssen: Honoraria, Other: travel support, Research Funding; Novartis: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square meter per day in non–Hodgkin's lymphoma patients led to an elimination of target cells in blood. Partial and complete tumor regressions were first observed at a dose level of 0.015 milligrams, and all seven patients treated at a dose level of 0.06 milligrams experienced a tumor regression. Blinatumomab also led to clearance of tumor cells from bone marrow and liver. T cell–engaging antibodies appear to have therapeutic potential for the treatment of malignant diseases.

DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.

Purpose Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome–negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Patients and Methods This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m2/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. Results Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m2/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m2/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m2/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days). Conclusion In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m2/day. Single-agent blinatumomab showed antilymphoma activity.

Summary Background Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger. Methods This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18–60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0–2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1:1) to receive two cycles of induction therapy with daunorubicin (60 mg/m 2 on days 3–5) plus cytarabine (100 mg/m 2 on days 1–7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m 2 twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10–19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40). Findings Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35·5–38·1), median event-free survival was 9 months (95% CI 4–15) in the placebo group versus 21 months (9–32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13–32) in the placebo group versus 40% (29–51) in the sorafenib group (hazard ratio [HR] 0·64, 95% CI; 0·45–0·91; p=0·013). The most common grade 3–4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1·54, 95% CI 1·04–2·28), diarrhoea (RR 7·89, 2·94–25·2), bleeding (RR 3·75, 1·5–10·0), cardiac events (RR 3·46, 1·15–11·8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4·06, 1·25–15·7). Interpretation In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease. Funding Bayer HealthCare.

Objective Resistance to chemotherapy-induced apoptosis and a multidrug-resistance phenotype is the major problem in the treatment of acute myeloid leukemia (AML). Patients and Methods We recently demonstrated that the coexpression of at least two proteins, including P glycoprotein, multidrug resistance-related protein, bcl-2 (flow cytometry), p53 (luminometric immunoassay), and heat shock protein 27 (Western blotting), was predictive for response to induction therapy in de novo AML comparing leukemic blasts of 20 responders with 20 nonresponders. After long-term follow-up, we now present our evaluation on the prognostic significance of these proteins in leukemic blasts of 124 untreated AML patients with regard to the probability of remission (PoR) and overall survival (OS). Results Analyzing leukemic blasts obtained from bone marrow samples, we found that no single protein significantly correlated with PoR or OS. In contrast, the coexpression of at least two of these proteins was predictive for reduced OS in univariate as well as multivariate analysis. Although we could not identify any particular protein combination predictive for reduced OS, those patients with no or only one protein expressed in their leukemic blasts had a survival probability of 48% in contrast to 24% in those patients with the coexpression of two or more proteins. Among the clinical markers, only response to chemotherapy had a significant effect on OS and age was of prognostic relevance for PoR. Conclusion We conclude that overexpression of only one protein possibly involved in resistance, is not sufficient to influence the prognosis for long-term survival in AML, whereas the expression of more than one protein is predictive for reduced OS. Protein combination seems to be individually different, and targeting only one protein in further clinical trials may not help to overcome multifactorial resistance.

Background: The addition of sorafenib to standard induction and consolidation therapy in newly diagnosed patients (pts) ≤60 years (yrs) with acute myeloid leukemia (AML) led to significant prolongation of event-free survival (EFS) and relapse-free survival (RFS) in the randomized placebo-controlled SORAML trial (NCT00893373). After a median follow-up of 3 yrs, a benefit for sorafenib treated pts was observed also in overall survival (OS), but this difference was not significant. Here, we present updated survival data and information on relapse treatment and outcome. Methods: In the SORAML trial, 267 newly diagnosed untreated fit AML pts up to 60 yrs of age and irrespective of FLT3 mutation status received two cycles of induction chemotherapy with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Allogeneic stem cell transplantation (SCT) was scheduled for all intermediate-risk pts in first complete remission (CR) with a sibling donor and for all high-risk pts with a matched related or unrelated donor. At study inclusion, pts were randomized to receive either sorafenib (2x400 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Study medication was given on days 10-19 of DA I+II, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months (mos) after the end of consolidation. The primary endpoint of the trial was EFS. The results after follow-up of 3 yrs were presented at ASH 2014 (Röllig et al., Blood 2014; 124: 6) and fully published (Röllig et al., Lancet Oncol 2015; 16: 1691-9). Here, we present the results after prolonged follow-up. For this analysis, information on remission and survival status, mode and outcome of relapse treatment including SCT were collected for all randomized pts and analyzed by standard statistical methods. Results: Of 267 treated pts, 134 were randomized in the sorafenib arm and 133 in the placebo arm with a resulting CR rate of 60% and 59%, respectively. After a median observation time of 78 mos, the primary study endpoint EFS in the placebo vs sorafenib arm was 9 mos vs 26 mos (HR 0.68, p=0.01) in univariate Kaplan Meier analysis. The beneficial effect of sorafenib on EFS was confirmed in multivariate Cox regression analysis with a HR of 0.61 (p=0.005). Median RFS in the placebo vs sorafenib arms was 22 vs 63 mos, corresponding to a HR of 0.64 (p=0.033). Exploratory analyses were performed in the 70 relapsing pts (40 after placebo vs 30 after sorafenib treatment). Among relapsing pts, 82% vs 73% achieved a second CR. In these two groups, 88% and 87% of pts received a SCT as part of salvage treatment. A lower proportion of pts in the placebo arm received a second SCT as salvage treatment (5% vs 13%). In the context of salvage SCT, the proportion of haploident donors in the placebo and sorafenib group was 3% vs 15% and the incidence of Grade 3/4 GVDH was 17% vs 0%. SCT-related non-relapse mortality (NRM) was similar in both groups, but the cumulative incidence of second relapse (CIR) was higher in the sorafenib group (35% vs 54% after 48 mos). Therefore, median OS from relapse in the placebo vs sorafenib groups were 27 mos vs 10 mos, corresponding to a HR of 1.68 (p=0.098). The projected median OS from randomization is 83 mos in the placebo arm and was not reached for the sorafenib arm, corresponding to a 5-year OS of 52% vs 61% (HR 0.81, p=0.263). Conclusion: Mature follow-up data confirms the antileukemic efficacy of sorafenib in younger AML pts with and without FLT3 mutation. The addition of sorafenib to standard chemotherapy resulted in a significantly longer EFS and clinically relevant 36% risk reduction for relapse or death. Five pts need to be treated (NNT) to prevent one relapse or death at 3 years and six pts at 5 yrs. Exploratory analyses in relapsing pts show that survival after relapse is shorter after sorafenib which might be due to i) a higher rate of second SCTs and a higher incidence of haploidentical SCT despite the lower frequency of severe GVHD, most likely by chance and not explainable by systematic reasons and ii) a lower response to salvage treatment after sorafenib therapy. Despite these observations, primary sorafenib treatment led to an OS benefit with a 19% risk reduction for death which was not statistically significant since this phase II trial was not adequately powered to detect OS differences. Figure Figure. Disclosures Rollig: Bayer: Research Funding; Janssen: Research Funding. Hüttmann: Gilead, Amgen: Other: Travel cost; Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria. Giagounidis: Acceleron: Consultancy; Celgene: Consultancy. Mackensen: AMGEN: Research Funding. Hänel: Roche: Honoraria; Novartis: Honoraria. Thiede: Roche: Consultancy; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Agendix: Employment. Schetelig: Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria.

Background: NVP-HDM201 is a selective inhibitor of the p53-HDM2 interaction and has demonstrated potent single-agent activity in various in vitro and in vivo tumor models, dependent on wild-type (wt) TP53. This study aims to determine the optimal dose and schedule of NVP-HDM201 for treating patients (pts) with TP53 wt tumors for further clinical study. Here we focus on pts with advanced, TP53 wt acute leukemias. Methods: In this multicenter, open-label, dose-finding, Phase I study, pts with advanced, TP53 wt tumors who had relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were treated with single-agent oral NVP-HDM201. Four treatment regimens were explored: two high-dose intermittent regimens (reg), Reg 1A and 1B (1A: Day 1 of a 3-week [wk] cycle; 1B: Days 1 and 8 of a 4-wk cycle) and two low-dose extended regimens, Reg 2A and 2C (2A: once daily for the first 2 wks of a 4-wk cycle; 2C: once daily for the first wk of a 4-wk cycle). Results: As of Dec 07, 2016, a total of 37 pts, comprising 35 pts with AML and 2 pts with ALL, had been enrolled in the study (Reg 1A n=16; Reg 1B n=6; Reg 2A n=7; Reg 2C n=8); treatment is ongoing in 3 pts (2 in Reg 1B and 1 in Reg 2C). The most common Grade 3/4 adverse events (AEs) suspected to be treatment-related (occurring in ≥25% of pts; Reg 1A; Reg 1B; Reg 2A; Reg 2C) were thrombocytopenia (50%; 50%; 29%; 50%), tumor lysis syndrome (TLS; 44%; 0; 14%; 13%), neutropenia (38%; 17%; 0; 25%), anemia (25%; 33%; 29%; 38%), febrile neutropenia (25%; 33%; 29%; 38%), and decreased white blood cell count (0; 0; 14%; 25%). Six dose-limiting toxicities (DLTs) were observed in 4 pts at 400 mg in Reg 1A: G4 hypophosphatemia (n=2), G3 infection (n=1), G3 chronic graft versus host disease (n=1), G3 stomatitis (n=1), and G4 subarachnoid hemorrhage (n=1). One DLT each occurred in Reg 1B (G4 acute kidney injury at 150 mg) and Reg 2C (G4 TLS at 45 mg). Importantly, there were no dose-limiting gastrointestinal (GI) toxicities. NVP-HDM201 also showed approximate dose-proportional pharmacokinetics (PK) and pharmacodynamics. Investigator-assessed overall response rate (CR + CRi + PR) for all pts with AML who had ≥1 post-baseline assessment (n=34) was 20.6% (95% confidence interval: 8.7-37.9%). There were 3 CRs (2 in Reg 1A; 1 in Reg 2C) and 4 CRis (1 in Reg 1B; 3 in Reg 2C). CRs/CRis were observed in pts receiving a cumulative dose of 250 mg within the first wk of treatment. Conclusions: Across all regimens, the AEs reported were overall expected and manageable, with no dose-limiting GI toxicities. The recommended dose for expansion (RDE) was declared as 45 mg in Reg 2C, based on the manageable safety profile, therapeutically relevant exposures determined by PK modeling, and meaningful antitumor activity seen at this dose level of NVP-HDM201. RDE determination for Reg 1A and Reg 1B is ongoing. Preliminary anti-leukemic activity is promising in these pts and warrants further study of this agent in AML. Citation Format: Eytan Stein, Joerg Chromik, Daniel J. DeAngelo, Manik Chatterjee, Richard Noppeney, Filip de Vos, Hironobu Minami, Sébastien Jeay, Christophe Meille, Ensar Halilovic, Luisa Mariconti, Matthieu Klopfenstein, Nelson Guerreiro, Rajkumar Radhakrishnan, Emil T. Kuriakose, Cecilia Carpio. Phase I dose- and regimen-finding study of NVP-HDM201 in pts with advanced TP53 wt acute leukemias [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT152. doi:10.1158/1538-7445.AM2017-CT152

Purpose The prognosis of elderly patients with acute myeloid leukemia (AML) is still dismal even with intensive chemotherapy. In this trial, we compared the antileukemic activity of standard induction and consolidation therapy with or without the addition of the kinase inhibitor sorafenib in elderly patients with AML. Patients and Methods All patients received standard cytarabine and daunorubicin induction (7+3 regimen) and up to two cycles of intermediate-dose cytarabine consolidation. Two hundred one patients were equally randomly assigned to receive either sorafenib or placebo between the chemotherapy cycles and subsequently for up to 1 year after the beginning of therapy. The primary objective was to test for an improvement in event-free survival (EFS). Overall survival (OS), complete remission (CR) rate, tolerability, and several predefined subgroup analyses were among the secondary objectives. Results Age, sex, CR and early death (ED) probability, and prognostic factors were balanced between both study arms. Treatment in the sorafenib arm did not result in significant improvement in EFS or OS. This was also true for subgroup analyses, including the subgroup positive for FLT3 internal tandem duplications. Results of induction therapy were worse in the sorafenib arm, with higher treatment-related mortality and lower CR rates. More adverse effects occurred during induction therapy in the sorafenib arm, and patients in this arm received less consolidation chemotherapy as a result of higher induction toxicity. Conclusion In conclusion, combination of standard induction and consolidation therapy with sorafenib in the schedule investigated in our trial is not beneficial for elderly patients with AML.

We describe 20 patients with myeloma and 1 with primary amyloidosis from 15 centres, all with advanced renal failure, most of whom had PBSC mobilised using plerixafor following previous failed mobilisation by conventional means (plerixafor used up-front for 4 patients). For 15 patients, the plerixafor dose was reduced to 0.16 mg/kg/day, with a subsequent dose increase in one case to 0.24 mg/kg/day. The remaining six patients received a standard plerixafor dosage at 0.24 mg/kg/day. Scheduling of plerixafor and apheresis around dialysis was generally straightforward. Following plerixafor administration, all patients underwent apheresis. A median CD34+ cell dose of 4.6 x 10(6) per kg was achieved after 1 (n=7), 2 (n=10), 3 (n=3) or 4 (n=1) aphereses. Only one patient failed to achieve a sufficient cell dose for transplant: she subsequently underwent delayed re-mobilisation using G-CSF with plerixafor 0.24 mg/kg/day, resulting in a CD34+ cell dose of 2.12 x 10(6)/kg. Sixteen patients experienced no plerixafor toxicities; five had mild-to-moderate gastrointestinal symptoms that did not prevent apheresis. Fifteen patients have progressed to autologous transplant, of whom 12 remain alive without disease progression. Two patients recovered endogenous renal function post autograft, and a third underwent successful renal transplantation. Plerixafor is highly effective in mobilising PBSC in this difficult patient group. Bone Marrow Transplantation (2012) 47, 18-23; doi: 10.1038/bmt.2011.9; published online 28 February 2011

Background Chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival (OS) of ≤1 year. Elderly patients often present with cardiac comorbidity. Gemtuzumab ozogamicin (GO) is active in elderly (≥60 years) patients with relapsed AML with low cardiac toxicity. Patients and methods This randomized phase II study compared a standard combination of ara-C and daunorubicin (DNR; 7+3) versus ara-C plus gemtuzumab ozogamicin (7+GO) as the first course of induction therapy. Primary objectives were comparison of blast clearance on day 16, event-free survival (EFS), and remission duration. OS, complete remission (CR), and tolerability were secondary objectives. Results One hundred and nineteen patients with de novo AML, treatment-related AML, AML with a history of myelodysplastic syndrome (MDS), or high-risk MDS entered the study. Median age of 115 patients (intent-to-treat population) was 69 years. Protocol outlined a second course 7+3 for patients without blast clearance and two courses of high-dose ara-C consolidation upon CR. Both treatments were equally effective in blast clearance, CR, EFS, remission duration, or OS (median: 7+3, 9 months; 7+GO, 10 months). Induction death rate was higher in the GO group due to veno-occlusive disease. Conclusion The study did not show significant superiority of 7+GO over standard 7+3.

Background XIAP (X-linked inhibitor of apoptosis protein) is an inhibitor of caspases 3 and 9 that is overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report an open-label randomized phase II trial of reinduction chemotherapy with and without the XIAP antisense oligonucleotide AEG35156 in patients with AML who did not achieve remission with initial induction chemotherapy. Methods Twenty-seven patients with AML who were refractory to initial induction chemotherapy were randomized and treated with AEG35156 (650 mg) in combination with high-dose cytarabine and idarubicin. Thirteen patients were randomized and treated with high-dose cytarabine and idarubicin alone. The rates of response and toxicity were determined. Results Of the 27 patients assigned to AEG35156 in combination with high-dose cytarabine and idarubicin, 3 died during reinduction chemotherapy, 5 achieved complete remission (CR), and 6 achieved CR with incomplete platelet count recovery (CRp), for an overall response rate of 41%. Of the 13 patients assigned to the control arm of the study, none died during reinduction, 6 achieved CR, and 3 achieved CRp, for an overall response rate of 69%. The differences in response rates between patients in the AEG35156 and control arms were not statistically different ( P = 0.18 by the χ 2 test). Conclusions The addition of AEG35156 to reinduction chemotherapy was well tolerated but did not improve rates of remission. Therefore alternative therapeutic strategies should be explored in patients with AML refractory to induction chemotherapy.

Abstract 335 Purpose. Standard chemotherapy for elderly patients with acute myeloid leukemia (AML) results in a median overall survival of only 60 years) patients with relapsed AML and shows low cardiac toxicity. The purpose of the randomized phase II study reported here was to compare the antileukemic activity of a standard combination of ara-C (100 mg/m2/day c.i., days 1–7) and DNR (60 mg/m2 i.v., on days 3–5) (7+3) versus ara-C plus GO (6 mg/m2 i.v. on days 1 and 8) (7+GO) as the first course of induction therapy in AML patients at the age of 60 years and older. Patients and Methods. On the basis of the data from the AMLCG (JCO 27: 61–69, 2009) the study was powered to detect an increase of median event free survival (EFS) from 90 to 160 days and a prolongation of the median overall survival (OS) from 9 to >16 months with a power of 80% (alpha= .05), in order to obtain information as a basis for potential further phase III randomized studies. Primary objectives of the study were the achievement of blast clearance (< 5%) on day 16 after induction therapy onset and EFS. OS, complete response (CR) and tolerability were among the secondary objectives. 112 pts. entered the study, suffering from de novo AML, treatment-related secondary AML, AML with a history of MDS, and high-risk MDS. Median age of the patients was 69 years (range 60–83). Study protocol outlined a second induction course 7+3 in those pts. without blast clearance on day 16 and 2 courses of consolidation therapy with high-dose ara-C (1 g/m2 q 12 hours i.v., days 1, 3, 5) for patients in CR. We looked for balance of AML standard risk factors between both arms of the study. Results. The study was approved by the Ethical Board of the University of Muenster and the other participating institutions and written informed consent was obligatory by every pt. prior to entry on study. 58 pts. were randomized to induction therapy with 7+3 as the first course, whereas 54 pts. were randomized to receive 7+GO. All parameters evaluated are for the intent-to-treat population. There were no statistically significant differences between treatment arms in blast clearance (< 5%) on day 16 after treatment onset (7+3: 18 pts., 7+GO: 19 pts.), complete response (CR) rate (7+3: 53.5%, 7+GO: 61.1%), EFS (median for 7+3: 67 days, median for 7+GO: 172 days), or OS (median for 7+3: 9 months, median for 7+GO: 15 months). Toxicity profiles of the protocols were different with 4 pts. developing severe veno-occlusive disease in the 7+GO group. Conclusion. The study did not show a significant advantage of 7+GO over 7+3 as the first course of induction treatment in elderly pts. with AML. Ara-C and GO and ara-C and DNR have comparable antileukemic activity as the first course of induction. Ara-C and GO may represent an alternative, replacing non-targeted anthracyclines for induction therapy of elderly AML patients e.g. with significant cardiac comorbidities. Disclosures: Berdel: Wyeth: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Mylotarg as first-line treatment in AML.

BACKGROUND: The use of autologous peripheral blood progenitor/stem cells as part of dose-intensified treatment protocols for patients with acute myeloid leukemia (AML) is under current clinical investigation. METHODS: We analyzed the frequency of CD 34 + 38 - and CD 34 + DR - subpopulations, clonogenic cells and long-term culture-derived clonogenic cells (LTC-DC) in peripheral blood (PB) samples from patients with AML after chemotherapy and G-CSF given for mobilization in comparison to a control population of patients with non-hematological malignancies. RESULTS: We observed a lower number of CD 34 + cells (31.2 ± 14.8 vs. 114 ± 36 /μl) and a reduction to less than 15 % for clonogenic progenitors (CFU) and LTC-DC in peripheral blood mononuclear cells from AML patients after consolidation therapy. In contrast, the quality of these CD 34 + cells was not significantly impaired after consolidation therapy determined by a moderately reduced frequency of CFU/CD34 + cells (5.0 ± 1.5 % vs. 10.0 ± 2.8 %), a nearly identical frequency of LTC-DC/CD34 + cells (0.5 ± 0.1 % vs. 0.6 ± 0.2 %), and a higher percentage of CD 34 + 38 - cells/CD34 + cells (8.4 ± 1.8 % vs. 3.8 ± 1.1 %) in comparison to the control population. CONCLUSION: Our data confirm that it is possible to mobilize CD 34 + cells into the peripheral blood of AML patients using chemotherapy and G-CSF. Nevertheless, the low absolute number of CFU and LTC-DC after high-dose ara-C treatment for AML has to be taken into consideration for the design of treatment protocols using autologous progenitor/stem cell transplantation.

Introduction Aberrant DNA methylation is a common feature of acute myeloid leukemia (AML) and increases with age. DNMT inhibitors such as Azacitidine (AZA) can induce meaningful responses and remissions in AML as monotherapy. The combination of AZA with standard chemotherapy (7+3) has not been tested in a randomized trial. Patients and study design The AML-AZA trial compared AZA directly followed by standard induction therapy, AZA followed by standard consolidation, and further Azacitdine maintenance with standard induction and consolidation without AZA in older patients with AML. All patients received standard Cytarabine (100 mg/sqm) and Daunorubicin (60 mg/sqm) induction (“7+3”) and up to two cycles of intermediate dose Cytarabine (1 g/sqm q12hr days 1, 3, 5) as consolidation therapy. AZA (75 mg/sqm for 5 days) preceded each therapy cycle in the AZA arm. In addition, AZA maintenance for up to 1 year was also scheduled for patients in the AZA arm. 105 patients were randomized to receive AZA plus Cytarabine plus Daunorubicin as induction therapy (AZA + 7+3) and 109 patients to receive 7+3 only (control group). Median age was 70 years in both treatment arms. Patient cohorts were well balanced with regard to blast counts in bone marrow, secondary versus de novo AML and molecular genetics risk group. More patients in the AZA + 7+3 arm (39/105; 37.1%) than in the control group (25/109; 22.9%) showed high risk cytogenetics (p=0.057). Event free survival (EFS) was the primary end point. Secondary endpoints were overall survival (OS), complete remission (CR) rate, toxicity and different treatment response according to molecular markers. Results Overall, 214 of 216 planned patients were enrolled into the AML-AZA trial. Due to a higher number of severe adverse events (SAE), AZA administration was stopped after recruitment of 214 patients whereas chemotherapy was continued as planned. Percentages of patients in the AZA arm with AZA doses as initially planned were as follows: 99% for first induction cycle, 72% for the second induction cycle. AZA as maintenance therapy for at least one cycle was delivered to 18% of patients in the AZA group. At least one SAE occurred in 51% of AZA + 7+3 patients compared to 31% of 7+3 patients (p=0.005). Cardiac disorders with CTCAE grade 3-5 occurred more frequently in the AZA + 7+3 arm (n = 15) than in the 7+3 arm (n = 6) (not significant). Leukopenia was prolonged by one day (median 23 vs 22 days) in the AZA + 7+3 group (p=0.043), whereas time of thrombocytopenia was not different. The early death rates at 30, 60 and 90 days did not differ significantly between treatment groups. Efficacy analyses were performed on an intention-to-treat basis. Median EFS as the primary endpoint was 6 months in both treatment arms (p=0.96). Median OS was 16 months for patients treated with AZA + 7+3 and 21 months for 7+3 (p=0.35). Median relapse free survival was 12 months in both treatment arms (p=0.95). 48 of 100 patients (48%) in the AZA + 7+3 arm achieved complete remission (CR) after induction therapy versus 57 of 109 patients (52%) in the 7+3 arm (p=0.58). DNMT3A exon 23 mutations were detected in 30 out of 162 analyzed patients. Exploratory analyses were performed to detect a potential interaction between AZA + 7+3 response and DNMT3A mutation status. Trends for improved EFS and OS were noted for AZA + 7+3 treatment in DNMT3A mutated patients. Conclusion AZA as addition prior to standard induction and consolidation chemotherapy does not prolong EFS and OS in unselected older AML patients and it is more toxic. However, a trend towards better efficacy in patients with DNMT3A mutation was observed and should be further explored. Disclosures Müller-Tidow: Celgene: Honoraria, Research Funding. Thiede:AgenDix GmbH: Equity Ownership, Research Funding; Illumina: Research Support, Research Support Other. Kiehl:Roche: Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Ehninger:GEMoaB GmbH: Consultancy, Patents & Royalties.

Background: Sorafenib is a multi-kinase inhibitor with activity against several oncogenic kinases that may play a role in the pathogenesis of acute myeloid leukemia (AML). In-vitro data and results from non-randomized clinical trials suggest that sorafenib might be an effective drug for the treatment of AML. We present the results of the randomized placebo-controlled SORAML trial testing sorafenib versus placebo as add-on to standard induction and consolidation treatment in AML patients ≤60 years. Patients and Methods: Between March 2009 and October 2011, 276 patients from 25 centers were enrolled in the SORAML trial (NCT00893373). The main eligibility criteria were newly diagnosed AML, age from 18 to 60 years and suitability for intensive therapy. The treatment plan for all patients included two cycles of induction with DA (daunorubicin 60 mg/m2 days 3-5 plus cytarabine 100 mg/m2 cont. inf. days 1-7), followed by three cycles of high-dose cytarabine consolidation (3 g/m2 b.i.d. days 1, 3, 5). Patients without response after DA I received second induction with HAM (cytarabine 3 g/m2 b.i.d. days 1-3 plus mitoxantrone 10 mg/m2 days 3-5). Allogeneic stem cell transplantation was scheduled for all intermediate-risk patients in first complete remission with a sibling donor and for all high-risk patients with a matched related or unrelated donor. At study inclusion, patients were randomized to receive either sorafenib (800 mg/day) or placebo as add-on to standard treatment in a double blinded fashion. Block randomization at a ratio of 1:1 was performed within cytogenetic and molecular risk strata, allocation was concealed and treatment was double blinded. Study medication was given on days 10-19 of DA I+II or HAM, from day 8 of each consolidation until 3 days before the start of the next consolidation and as maintenance for 12 months after the end of consolidation. The primary endpoint of the trial was event-free survival (EFS) with an event being defined as either failure to achieve a complete remission (CR) after induction, relapse or death. Secondary endpoints were relapse-free survival (RFS), overall survival (OS), CR rate and incidence of adverse events (AE). We present the results of the final analysis of the primary endpoint EFS (intent to treat) after the occurrence of 134 events. Results: Out of 276 enrolled patients, 267 received study treatment, 134 in the sorafenib arm and 133 in the placebo arm. Demographic and disease characteristics were equally distributed between the two arms; the incidence of FLT3-ITD was 17%. The median cumulative dose of administered study medication was similar in both arms. The CR rates were 59% versus 60% in the placebo versus sorafenib arm (p=0.764). After a median observation time of 36 months, the median EFS was 9.2 months in the placebo arm and 20.5 months in the sorafenib arm, corresponding to a 3-year EFS of 22% versus 40% (p=0.013). Median RFS after standard treatment plus placebo was 23 months and not yet reached after sorafenib treatment, corresponding to a 3-year RFS of 38% and 56%, respectively (p=0.017). The median OS had not been reached in either arm; the 3-year OS was 56% with placebo versus 63% with sorafenib (p=0.382). In 46 FLT3-ITD positive patients, no difference in EFS, but a trend for prolonged RFS and OS in favor of sorafenib was observed. The most common reported AEs Grade ≥3 were fever (40%), infections (22%) and bleeding events (2%). The risk for fever, bleeding events and hand-foot syndrome was significantly higher in the sorafenib arm while the incidence of all other AEs showed no significant differences. Conclusions: In younger AML patients, the addition of sorafenib to standard chemotherapy in a sequential manner is feasible and associated with antileukemic efficacy. We observed a higher incidence of infections and bleeding events under sorafenib. Whereas OS in both treatment arms was similar, sorafenib treatment resulted in a significantly prolonged EFS and RFS. Figure 1: Event-free survival Figure 1:. Event-free survival Disclosures Off Label Use: sorafenib for treatment of aml. Serve:Bayer HealthCare: Research Funding. Ehninger:Bayer HealthCare: Research Funding.