Abstract: Background and Aim: Deletion of 5q is the most frequent cytogenetic aberration in MDS and is associated with distinct clinical characteristics, disease course and sensitivity to lenalidomide. The serine-threonine kinase CSNK1A1 is located in the commonly deleted region at 5q32 and has been described as a tumor-suppressor gene in colon cancer and acute myeloid leukemia through regulation of ß-catenin and p53. Recently, missense mutations in CSNK1A1 have been described in individual patients with del(5q) MDS. The aim of our study was to characterize the frequency and potential prognostic impact of CSNK1A1mutations in MDS and AML following MDS. Methods: 192 patients with MDS or AML following MDS (sAML) and deletion of chromosome 5q and 406 patients with MDS/sAML without deletion of chromosome 5q were included in the current analysis (n=598 in total). Patients with MDS (n=442) or sAML (n=156) were cytogenetically characterized by chromosome banding analysis and molecularly analyzed for mutations in exon 3 and 4 of CSNK1A1, the region critical for the kinase function, by Sanger sequencing. Patients with mutated CSNK1A1 were also analyzed for mutations in TP53 by next-generation or Sanger sequencing. Results: CSNK1A1 mutations were found in 17 (8.9%) of 192 MDS patients with del(5q). The mutation frequency was similar between patients with isolated del(5q) (n=153) and patients with concurrent cytogenetic aberrations or missing additional cytogenetic information (n=39)(9.2% vs 7.7%, P=.7). No mutation of CSNK1A1 was found in any of 406 MDS/sAML patients without del(5q). Thirteen patients (76%) had missense mutations affecting amino acid E98 in exon 3 of CSNK1A1. Of these, the glutamic acid to lysin substitution was the most frequent amino acid substitution (n=7). All mutations of glutamic acid 98 had a high probability to be damaging to the protein based on PolyPhen2 predictions (scores 0.922 to1). One patient had an Asn86Tyr mutation concurrently with the Glu98Ala mutation. Four patients (24%) had missense mutations affecting aspartic acid 140 in exon 4 of CSNK1A1. These mutations had moderate PolyPhen2 prediction scores (0.558-0.798). Three of the 17 CSNK1A1 mutated patients had additional cytogenetic aberrations besides del(5q), i.e. one trisomy 8, one trisomy 11, and one monosomy 7. None of the CSNK1A1 patients had a concurrent TP53 mutation. Del(5q) patients with wildtype or mutated CSNK1A1 had a similar median age (73.3 vs 77.5 years, P=.15). 70% and 59% of wildtype and mutated CSNK1A1 patients had female sex, respectively (P=.33). The WBC count was similar between wildtype and mutated CSNK1A1patients (3.9 vs 4.6, P=.47). Survival information was available for 155 patients with del(5q) (81%) including 16 patients (94%) with mutated CSNK1A1. Median follow-up from the time of sample harvest was 2.02 years. The probability of survival at 2 years was 41% for CSNK1A1 mutated and 72% for CSNK1A1wildtype patients (P=.059, log-rank test), suggesting a potential negative prognostic impact of CSNK1A1 mutations in del(5q) MDS patients. Conclusion: CSNK1A1 mutations are highly specific for MDS patients with del(5q) and are one of the most frequent recurrent genetic aberrations in these patients. Our survival analysis suggests that CSNK1A1 mutations have an unfavorable prognostic effect in patients with MDS and del(5q); however, the prognostic impact has to be confirmed in additional patients. Mutation analysis of exon 3 and 4 of CSNK1A1 should be included in the routine workup of MDS patients with deletion of 5q. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Kobbe:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Haferlach:MLL: Equity Ownership.

Abstract: Non‐alcoholic fatty liver disease and particularly liver fibrosis are related to cardiovascular disease and may indicate an increased risk for atrial fibrillation (AF), but this association has not yet been systematically investigated in a cohort of ischemic stroke patients. Methods We analyzed data from a prospective single‐center study enrolling all consecutive ischemic stroke patients admitted to our stroke unit over a 1‐year period. All patients received a thorough etiological workup. For evaluation of liver fibrosis, we determined the Fibrosis‐4 (FIB‐4) index, a well‐established noninvasive liver fibrosis test. Laboratory results were analyzed from a uniform blood sample taken at stroke unit admission. Results Of 414 included patients (mean age 70.2 years, 57.7% male), FIB‐4 indicated advanced liver fibrosis in 92 (22.2%). AF as the underlying stroke mechanism was present in 28.0% (large vessel disease: 25.6%, small vessel disease: 11.4%, cryptogenic: 29.2%). Patients with FIB‐4 ≥ 2.67 had higher rates of AF (53.3% vs. 20.8%, p   〈  0.001), and this association remained significant after correction for established AF risk factors (odds ratio 2.53, 95% confidence interval 1.44–4.46, p  = 0.001). FIB‐4 was further associated with worse functional outcome 3 months ( p   〈  0.001) and higher mortality 4 years post‐stroke ( p   〈  0.02), but these relationships were no longer present after correction for age and initial stroke severity. Moreover, FIB‐4 was not associated with long‐term recurrent vascular events. Conclusions Liver fibrosis assessed by the FIB‐4 index is independently associated with AF in acute ischemic stroke patients. Further studies should evaluate whether adding the FIB‐4 index to AF risk scores increases their precision.

Abstract: Gene mutations independent of BCR::ABL1 have been identified in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase, whereby mutations in epigenetic modifier genes were most common. These findings prompted the systematic analysis of prevalence, dynamics, and prognostic significance of such mutations, in a clinically well-characterized patient population of 222 CML patients from the TIGER study (CML-V) by targeted next-generation sequencing covering 54 myeloid leukemia-associated genes. In total, 53/222 CML patients (24%) carried 60 mutations at diagnosis with ASXL1 being most commonly affected ( n  = 20). To study mutation dynamics, longitudinal deep sequencing analysis of serial samples was performed in 100 patients after 12, 24, and 36 months of therapy. Typical patterns of clonal evolution included eradication, persistence, and emergence of mutated clones. Patients carrying an ASXL1 mutation at diagnosis showed a less favorable molecular response to nilotinib treatment, as a major molecular response (MMR) was achieved less frequently at month 12, 18, and 24 compared to all other patients. Patients with ASXL1 mutations were also younger and more frequently found in the high risk category, suggesting a central role of clonal evolution associated with ASXL1 mutations in CML pathogenesis.

Abstract: Introduction: The TIGER (CML V)-study (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon alpha2b (Peg-IFN) and the option to discontinue therapy after Peg-IFN maintenance as first line therapy for chronic myeloid leukemia (CML) patients in chronic phase. Methods: Recruitment started in August 2012 with a pilot phase, aiming to validate the recommended dose of PEG-IFN. 25 pilot phase patients (pts) were treated with the combination of NIL 2*300 mg daily and PEG-IFN (30-50μg/week according to tolerability and commenced after 〉 6 weeks NIL monotherapy). During the main phase of the study, newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/PEG-IFN combination in accordance with the approach which was confirmed to be feasible during the pilot phase. After at least 2 years NIL based induction therapy and achievement of major molecular remission (MMR, BCR-ABL transcript level ≤0.1% according to the international scale, IS), maintenance therapy (NIL vs PEG-IFN) started. Requirements for treatment discontinuation were treatment duration of at least 3 years with stable MR4 (BCR-ABL ≤0.01%) for at least one year. NIL therapy was reinitiated in case of molecular recurrence, defined as loss of MMR. The major co-endpoints of the study are (i) rate of MMR at 18 months (NIL vs NIL+PEG-IFN), and (ii) rate of continuous MMR 12 and 24 months after discontinuation of NIL vs PEG-IFN. Efficacy and safety data are presented without specification of the randomized therapy during the ongoing study. Results: Within 5 years, a total of 717 pts (429 male; median age 51, range 18-85 years; 13.3% EUTOS high risk) were recruited from 111 sites in Germany, Switzerland, and the Czech Republic. Median observation time since recruitment was 30.3 months. 396 pts concluded the induction phase and reached the maintenance phase of the study. 138 pts achieved and maintained MR4 (BCR-ABL ≤0.01% IS) for at least one year during the maintenance phase and discontinued all therapy. With regard to efficacy in the two treatment arms, 79.5% reached MMR at 12 mo. (95% confidence interval (CI): [76.1-82.7%]), 84.9% at 18 mo. (95% CI: [81.4-88.0%] ), and 89.4% at 24 mo. (95% CI: [86.0-92.2%]) after randomization. Probabilities of adverse events of grade 1-5 after 12 mo. of therapy were 83.7 (95% CI: [79.2-87.3%] ) and 90.0% (95% CI: [85.8-93.0%]), and of grade 3-5 after 3 years 39.6 (95% CI: [33.4-45.7%] ) and 49.5% (95% CI: [42.7-56.0%]) for the two treatment arms. Twelve pts progressed to accelerated phase or blast crisis; four of them died from blast crisis. A total of 13 patients received 14 allogeneic stem cell transplantations in chronic phase (n=7) or blast crisis (n=7). In total, 19 pts died, five related to CML, three from vascular complications. Conclusions: This interim analysis demonstrates feasibility of 1st-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Molecular response during the first 24 mo. favourably compares with data from recent NIL based studies (ENESTnd, NCT00471497; ENEST1st, NCT01061177) and permits access to the maintenance phase (NIL vs PEG-IFN monotherapies) for the majority of patients - with the potential of treatment-free remission. The study was conducted by the German CML Study Group in cooperation with the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO). Figure. Figure. Disclosures Hochhaus: Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Saussele:Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding. Baerlocher:Novartis: Research Funding. Brümmendorf:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Research Funding. La Rosée:Novartis: Research Funding. Hasford:Novartis: Research Funding. Heim:Novartis: Research Funding. Krause:Novartis: Research Funding. le Coutre:Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Niederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding. Mayer:Novartis: Research Funding; Amgen: Research Funding. Lange:Novartis: Research Funding. Haenel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria. Gil:Novartis: Research Funding. Ernst:Novartis: Research Funding. Fabisch:Novartis: Research Funding. Pfirrmann:Novartis: Research Funding.

Abstract: Introduction Based on improvement of overall survival (OS), lenalidomide (R) maintenance after up-front autologous stem cell transplantation has recently been approved for multiple myeloma (MM) patients (pts). Conversely, in transplant non-eligible (TNE) pts R maintenance after R-based induction improved progression free survival (PFS) but had no impact on OS. First-line treatment with VMP is considered a standard of care for newly diagnosed (ND) TNE pts, but whether maintenance therapy with R after VMP induction can further improve PFS and OS is currently unknown. Aims The prospective phase IIb GERMAIN trial (EudraCT-No: 2012-003023-38) aimed to evaluate the role of R maintenance after VMP induction in ND TNE MM pts. The trial, which planned to include 286 ND TNE MM pts, closed early in December 2017 due to insufficient accrual and high discontinuation rate. The present analysis focuses on the reasons for the high drop out rate. Methods After induction with 6 courses of VMP (Mateos et al., Lancet Oncology 2010), pts achieving at least a partial response (PR) were randomized 1:1 to R 10 mg or placebo (PCB) daily until progression (PD) or unacceptable toxicity. Pts with 〈 PR could receive second line therapy with R 25 mg/day (three weeks on, one week off) and low dose dexamethasone until PD in the observational arm of the study. Pts with poor performance status (ECOG ≥3), creatinine clearance 〈 15 ml/min, or other concomitant serious medical conditions were excluded, but no upper age limit was applied. Results From May 2014 to December 2017 85 pts were enrolled. Median age was 75 years (range 63-87). A significant proportion of pts presented with at least one concomitant illness: 75% were hypertensive, 29% had a cardiac disorder, 37% a metabolic disorder and 19% a chronic kidney disease. Induction was completed by 53 pts and 40 pts entered maintenance randomization (Figure 1). Of patients completing induction therapy 77% achieved at least a PR, including 11% of sCR/CR and 26% of VGPR. Overall 70% of pts discontinued the study; main reasons for trial discontinuation were PD (24%), unacceptable toxicity (17%), investigator decision (16%) and withdrawal of informed consent (12%). Of pts discontinuing treatment, 27 pts (47%) stopped during induction, and in 71% of these cases discontinuation was due to unacceptable toxicities (26%) or investigator (26%) and patients (19%) decision. Only one pt discontinued due to insufficient response during induction. In total 745 adverse events (AE) and 71 serious AEs (SAE) were reported; of these 814 had complete data and were analyzed. During induction 571 AE occurred, of which 110 (19%) were of grade ≥3. Seventy-one pts (86%) reported at least one AE, and 49 (59%) at least one grade ≥3 AE. The most common grade ≥3 AE were: leukopenia (25%), thrombocytopenia (20%), cardiac toxicity (10%), infections (8%), peripheral neuropathy (6%), anemia and gastrointestinal toxicity (5% each). The cumulative probability of development of a grade ≥3 AE at 6 months was 59% (95% CI: 47 to 69%). SAEs during VMP were 54; 39% of pts experienced at least one SAE during induction. The cumulative probability for an SAE at 6 months was 41% (95% CI: 30 to 51%). During induction 4 deaths were recorded, all within the first month of treatment. Of the pts randomized to maintenance treatment 37 received at least one dose of R/PCB and were considered evaluable. Twenty-one pts (36%) discontinued the study during maintenance. Main reason for discontinuation was PD (11 pts, 4 in R and 9 in PCB arm); only 2 pts (both in R arm) discontinued due to AE 2 and 21 months after start of maintenance, respectively. Of the AE recorded during maintenance (n=157, 92 in the R and 65 in the PCB group) 17% were grade ≥3 and 12 were considered SAE. At least one AE and at least one SAE were reported in 29 (78%) and 8 pts (22%), respectively. Four secondary malignancies (1 basal cell carcinoma, 1 AML, 1 bladder cancer and 1 lung cancer) were reported, 1 during VMP induction and 3 during maintenance. Conclusions In comparison to other studies focusing on ND TNE MM pts, our study investigated a remarkably elderly and frail population. In the cohort investigated, treatment with VMP resulted in increased toxicity and higher rate of discontinuation. Nevertheless, in those pts able to complete induction a promising ORR was observed. In elderly and frail MM pts, regimens other than VMP should be considered for induction. Disclosures Brioli: Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria. Hänel:Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Pfirrmann:Novartis: Research Funding. von Lilienfeld-Toal:Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Fabisch:Novartis: Research Funding. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria.

Abstract: Introduction: The TIGER (CML V)-study* (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon α2b (Peg-IFN) 30-50μg/week as first line therapy for chronic myeloid leukemia (CML) patients (pts) in chronic phase and discontinuation of therapy after Peg-IFN maintenance (Figure). Methods: In August 2012, recruitment started with a pilot phase, aiming to validate the recommended dose of Peg-IFN. 25 pilot phase patients were treated with the combination of NIL 2*300 mg daily and Peg-IFN (30-50μg/week according to tolerability and commenced after ≥6 weeks NIL monotherapy). During the main phase of the study, 692 newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/Peg-IFN combination according to the outcome of the pilot phase. Results: Within 5 years, a total of 717 pts (429 male; median age 51 years, range 18-85; 12.9% EUTOS high risk) were recruited from 109 sites in Germany, Switzerland, and the Czech Republic. 702 pts with typical BCR-ABL1 transcripts (97.9%) were eligible for molecular follow-up assessments according to the international scale (IS). Fifteen pts (2.1%) expressed atypical BCR-ABL1 transcripts. 692 pts were randomized after EUTOS risk stratification to receive NIL monotherapy (n=353) or NIL/PEG-IFN combination therapy (n=339). Median observation time since recruitment was 41 months. Up to now, 477 pts concluded the induction phase by achieving a confirmed major molecular response, MMR (BCR-ABL1 transcript levels ≤0.1% IS, which qualified for entering the maintenance phase of the study using NIL or Peg-IFN monotherapy. During the maintenance phase, 199 pts achieved or sustained MR4 (BCR-ABL1 ≤0.01% IS) for at least one year and then discontinued all therapy. While the rate of MMR at 12 and 18 mo - the first primary endpoint of the study - was not different between the treatment arms, adding Peg-IFN to upfront NIL significantly improved rates of MR4 and MR4.5, BCR-ABL1 ≤0.0032% IS) (Table). In competing risk analysis, median time to MMR was 5.7 vs 5.4 mo, to MR4 20.9 vs 12.5 mo, and to MR4.5 33.8 vs 23.2 mo for NIL vs NIL/Peg-IFN, respectively. After NIL discontinuation, during Peg-IFN maintenance therapy, rate of molecular recurrence (BCR-ABL1 & gt;1% IS) after 18 mo was 28%. From 199 pts who discontinued all therapy, 63 experienced a molecular relapse (BCR-ABL1 & gt;0.1%). Relapse free survival by 18 mo after treatment discontinuation was 61% in the total cohort. By protocol, it is too early to assign relapse rates to the randomized treatment arm. Frequencies of adverse events after 24 mo of therapy were 90 and 92% (grade 1-5) and 36 and 42% (grade 3-5) for NIL vs NIL/Peg-IFN, respectively. Adverse events of special interest (all grades) were fatigue in 34.6 vs 40.4%, thrombocytopenia in 13.3 vs 18.9% and elevation of the alanin aminotransferase (ALAT) in 11.0 vs 18.9% of pts in the NIL vs NIL/Peg-IFN arms, respectively. Fifteen pts (2.1%) progressed to accelerated phase or blast crisis; 22 pts (3.1%) received an allogeneic stem cell transplantation, 10 of them after disease progression. In total, 22 pts (3.1%) died, 16 during the induction phase, 4 in the maintenance phase and 2 in treatment free remission. Four deaths were related to CML, 3 to vascular complications. Conclusions: This per protocol interim analysis demonstrates feasibility of the first-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Peg-IFN, when added upfront to NIL further increases the rates of MR4 and MR4.5, which may translate into higher rates oftreatment free remission. *The study is being conducted on behalf of the German CML Study Group, the Swiss Group for Clinical Cancer Research (SAKK) and the East German Study Group on Hematology and Oncology (OSHO). Disclosures Hochhaus: Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Burchert:Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria. Baerlocher:Novartis: Research Funding. Brümmendorf:Janssen: Consultancy; Ariad: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy, Research Funding. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Heim:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Lange:Novartis: Research Funding. Fabarius:Novartis: Research Funding. Hänel:Novartis: Honoraria; Amgen: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board; Roche: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Hasford:Novartis: Research Funding. Hehlmann:Novartis: Research Funding. Ernst:Novartis: Research Funding. OffLabel Disclosure: Combination of Nilotinib and PEG-IFN alpha is being tested is off-label and being tested in the TIGER study.