ALBERT

Description: Background: The therapeutic effect of DNA-hypomethylating agents (HMAs) in AML/MDS is discussed to be via its effects on aberrant gene silencing by reactivation (e.g. through promoter hypomethylation). While this has been broadly studied in cell line models, only very few studies have addressed the global effects of HMAs in primary blasts serially isolated from AML patients (pts) undergoing HMA treatment (Claus et al., Leuk. Res. 2013, Klco et al., Blood 2013, Welch et al., N. Engl. J. Med. 2016). We therefore conducted prospective serial methylome and transcriptome analyses on AML blasts from pts of the DECIDER trial (NCT00867672), hypothesizing that both random and non-random effects of the HMA may be observed in vivo. Patients, Materials and Methods: Of a total of 200 newly diagnosed AML pts included into the DECIDER randomized phase II trial (Decitabine/DAC treatment, 20 mg/m2 intravenous 1-hour infusion over 5 days, with add-on drugs Valproic acid and/or ATRA added at day 6; Grishina et al., BMC Cancer 2015), serially obtained peripheral blood (pb) samples from a total of 28 pts yielded sufficient numbers of purified blasts at 3 timepoints (days 0, 8 and 15 from DAC treatment start) to allow a "triplet analysis" of these matched samples. Baseline pt characteristics: median WBC 11,900/µl (range 1,200 - 53,800), median pb blasts 37.5% (range 1% - 93%). Blasts were sorted using anti-CD34, CD117 MACS microbeads, respectively (median purity 〉90%). Methylomes were obtained using Infinium Human Methylation 450 BeadChip arrays (Illumina). For expression analyses, GeneChip Human Gene 2.0 ST arrays were used. A linear-model based approach was used to identify the differentially methylated CpGs and expressed genes post vs. prior to treatment. Results: To address in vivo methylation changes occurring at day 8 and 15 from DAC treatment start, complete "triplets" of DNA preparations (thus from purified pb blasts of all 3 time points) were interrogated. Significant hypomethylation at day 8 (Δβ

Description: Introduction In older patients (pts), host factors such as functional deficits, comorbidities and other age-related factors are increasingly recognized as predictors for outcome of leukemia treatment. Thus, prospective clinical trials increasingly implement functional studies (often termed geriatric assessment) in their pretreatment diagnostic workup. In older, fit AML pts receiving standard chemotherapy, Klepin et al. demonstrated a predictive value of this approach for overall survival (OS) in a single-center study (Blood 2013). We also developed a Frailty Score, assessed at 3 study centers and predicting OS of elderly AML/MDS pts receiving either hypomethylating agents (n=66) or sole best supportive care (n=35; Deschler et al., Haematologica 2013). To validate this score, which is composed of performance status (PS), activities of daily living (ADL) and fatigue, we prospectively assessed these parameters in the DECIDER trial (AMLSG 14-09, NCT00867672). Methods In the DECIDER trial, 200 non-fit AML pts aged 〉60 years (yr) were randomized between four treatment arms with either decitabine (DAC) alone, or DAC plus all-trans retinoid acid (ATRA) or DAC plus valproic acid (VPA) or DAC plus ATRA and VPA. We assessed PS via ECOG, ADL via Barthel index and fatigue via the EORTC QLQ-C30 questionnaire, which were available for 200, 175 and 156 pts, respectively. Pts with missing ADL and/or fatigue assessments tended to have a lower PS than those with complete data, which may explain at least in part why the assessments could not be performed. The Frailty Score was calculated using ECOG PS as a substitute for the Karnofsky Index (KI, as applied when establishing this score), with ECOG 0-1 taken as corresponding to KI ≥80, and ECOG 2-3 to KI

Description: 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

Description: Introduction The inclusion of "novel" agents including proteasome inhibitors or IMiD-derivatives in the treatment of multiple myeloma significantly improves patient survival. Results of several study groups suggest incorporating at least one "novel agent" in first-line treatment before and after high-dose chemotherapy (HDT) followed by autologous stem cell transplantation. Here we address four main questions: First, what determines (excellent) long-term survival for different treatment regimen? Second, can we show benefit of novel agents for all patients and molecular subentities, including low risk? Third, can the prognostic impact of molecular entities be explained by different association with response, proliferation, and renal impairment? Fourth, does it matter regarding long-term survival by which agents, i.e. "old" vs. "new", a response was reached? Patients and Methods Patients were included in the prospective phase III HOVON-65/GMMG-HD4-trial (German part, n=354) randomizing VAD-induction, autologous tandem-transplantation and thalidomide-maintenance vs. PAD-induction, tandem-transplantation and bortezomib-maintenance. Plasma cells after CD138-purification were subjected to interphase fluorescence in-situ hybridization and gene expression profiling using Affymetrix U133 2.0 DNA-microarrays. Median follow-up (time to censoring) was 93 months. Results Low proliferation, revised-ISS I and cyto-ISS I delineate excellent long-term survival (70-75% after eight years, both arms). Molecular entities are associated with proliferation-rate, i.e. higher (del17p13, del8p21, del13q14, 1q21+, t(4;14)) or lower proliferation (hyperdiploidy), and response: bad response/survival in case of del17p, bad response/no survival impact (t(11;14)), and good response/bad survival (1q21+, t(4;14), and del13q), depending on the treatment regimen. Thus, it does not hold true that good response = good survival if patients are substratified according to their molecular background. Renal insufficiency is associated with 1q21+, del17p13, and t(4;14). For patients with ≥1 of the chromosomal aberrations del17p13, t(4;14), 1q21+ (i.e. cytogenetic high risk, 27.5% of patients) or renal insufficiency (10.6%), risk is abrogated; in absence of these risk features, no benefit could be shown. Patients reaching a near complete remission or better (≥nCR) with VAD-based regimen, HDT followed by thalidomide maintenance show significantly better survival compared to those reaching ≥nCR after bortezomib-based induction/HDT followed by bortezomib maintenance treatment. Conclusions Taken together, adversely prognostic molecular entities are associated with proliferation but can show association with better or adverse remission. Bortezomib-based upfront treatment abrogates chromosomal high-risk aberrations and renal insufficiency; however, no long-term survival-benefit is evident for those without these risk factors or low proliferation, i.e. the majority of patients. Responses achieved by different regimen are not equal in transmission in long-term survival. Responses (≥nCR) are not equivalent regarding their biological and prognostic role in patients with different molecular background and different treatment regimen. Disclosures Seckinger: Celgene: Research Funding; Sanofi: Research Funding; EngMab: Research Funding. Salwender:Novartis: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Janssen: Honoraria, Other: travel support, Research Funding. Scheid:Celgene: Honoraria; Janssen: Honoraria. Knauf:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy; Roche: Consultancy; Amgen: Consultancy, Honoraria; Mundipharma: Consultancy. Duehrsen:AbbVie: Consultancy, Honoraria; Amgen: Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Consultancy, Honoraria. Dürig:Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Celgene: Honoraria. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Haenel:Novartis: Honoraria; Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria. Raab:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Blau:Celgene: Other: Advisory board, Research Funding; Janssen: Other: Advisory board, Research Funding; Amgen: Other: Advisory board; Takeda: Other: Advisory board; Novartis: Other: Advisory boards; BMS: Other: Advisory board. Hillengass:Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; amgen: Consultancy, Honoraria, Other: Advisory Board; Sanofi: Research Funding; Janssen: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; 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. Goldschmidt:Chugai: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Hose:Celgene: Honoraria, Research Funding; EngMab: Research Funding; Sanofi: Research Funding.

Description: 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 (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.