Background Genomic aberrations affecting the repair of DNA double-strand breaks by homologous recombination (HR) are found in various cancers and result in sensitivity to inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP). DNA double-strand breaks and activation of PARP can be induced by trabectedin, a cytotoxic agent used in soft-tissue sarcoma. In HR-deficient cancers that depend on PARP activity, trabectedin may thus increase the effect of PARP inhibitors such as olaparib. Next-generation sequencing techniques allow rapid identification of mutations in DNA repair pathways and mutational signatures that are generated by these aberrations. Trial design We present a randomized phase II trial comparing a combination of trabectedin and olaparib with treatment of physician’s choice in adult patients with advanced or metastatic tumors with genomic imprints of defective HR DNA repair (“BRCAness”), as determined by whole-exome or genome sequencing. A dedicated BRCAness score incorporates germline and somatic mutations in HR-relevant genes, mutational signatures, and measures of genomic instability; scores equal or above 3 allow for inclusion. Main exclusion criteria are hematologic and primary brain cancers, progressive/symptomatic brain metastases, ECOG PS > 1, severe organ insufficiencies, and prior treatment with a PARP inhibitor. Patients are randomized 1:1 to treatment with trabectedin (day 1) and olaparib (days 1-21) in a 21-day cycle vs. physician’s choice, both until disease progression. Cross-over upon disease progression is allowed. The primary endpoint is disease control (including CR, PR and SD according to RECIST v1.1) after 16 weeks. Secondary endpoints are tumor response, PFS, OS and quality of life. Efficacy evaluation involves a 2-group comparison between treatment arms in 102 patients. The statistical test used is a one-sided test of differences in disease control rates (alpha = 0.025). An interim analysis for futility will be conducted after 30% of patients are evaluable for the primary endpoint. The trial is active within the German Cancer Consortium, and thus far nine patients have been randomized. Clinical trial identification EudraCT: 2017-001755-31; NCT03127215. Legal entity responsible for the study Heidelberg University Hospital, Heidelberg, Germany. Funding AstraZeneca, ParmaMar and German Cancer Research Center (DKFZ). Disclosure C.E. Heilig: Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Teva; Honoraria (institution), Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Novartis. H. Kopp: Advisory / Consultancy: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck-MSD; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Boehringer-Ingelheim. K.H. Metzeler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jazz; Research grant / Funding (institution): Agios. S. Richter: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly. B. Hermes: Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Lilly. N. von Bubnoff: Honoraria (self): AstraZeneca; Honoraria (self): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self): BMS. T. Kindler: Advisory / Consultancy: Novartis; Travel / Accommodation / Expenses: PharmaMar. J. Siveke: Advisory / Consultancy: Baxalta; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Shire; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Research grant / Funding (self), Travel / Accommodation / Expenses: BMS. S. Wagner: Advisory / Consultancy: Takeda. S. Ochsenreither: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca. B. Brors: Research grant / Funding (institution): SAP. D. Jager: Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: CureVac; Advisory / Consultancy: Definiens; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. C. Von Kalle: Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Shareholder / Stockholder / Stock options: Genewerk. H. Glimm: Honoraria (self), Research grant / Funding (self): Bayer. S. Frohling: Honoraria (self), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bayer. R.F. Schlenk: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Daiichi Synkyo. All other authors have declared no conflicts of interest.

Synovial sarcoma (SySa) is a rare soft-tissue malignancy occurring predominantly in the lower extremities of young adults. It is driven by a unique SS18::SSX fusion gene. In locally advanced/metastatic SySa, treatment options are limited, and it is of high interest to identify targetable molecular alterations. Within the MASTER precision oncology program of DKFZ, NCT Heidelberg/Dresden, and DKTK (ClinicalTrials.gov Identifier: NCT05852522), patients with advanced SySa were analyzed by whole-genome/exome (WGS/WES) and RNA sequencing to inform the care of individual patients and provide starting points for interventional clinical trials in adolescents and young adults. Median age at the time of molecular analysis was 37 years (range, 22–65 years), and 45% of patients were female. Median time between diagnosis and molecular analysis was 29 months (range, 2–288 months). Median follow-up for survival was 89 months. Between 2013 and 2022, 69 patients were studied. Median survival and 3-year survival rate after molecular analysis were 14 months (95% confidence interval [CI], 12–19 months) and 8% (95% CI, 3–22%), respectively. Molecular profiling included WES (n=33) or WGS (n=32) as well as RNA sequencing (n=56). Beyond SS18::SSX fusions, the most common somatic and germline single-nucleotide variants and small insertions/deletions affected TTN (17%), NIPBL (9%), CTNNB1 (8%), ATM, TAF1L, TP53, MADD, and COL7A1 (each 6%). Based on the presence of a significant single-base substitution signature 3 (SBS3), two patient groups could be distinguished (group 1, SBS3 present, 28 patients; group 2, SBS3 absent, 37 patients). The most frequent genomic gains involved chromosomes 8 and 12; the most frequent deletions involved chromosomes 3 and 11. Comparative analysis of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 expression between the SySa cases (n=56) and the entire MASTER cohort (n=3,023) revealed significant differences for SSTR2, SSTR4, and SSTR5, with top 10% expression in 13, 31, and 22 patients, respectively. Our study demonstrates the utility of broad molecular profiling in patients with advanced SySa for identifying subgroups of patients, whose molecular profiles may inform the design of future clinical trials.

Desmoplastic small round cell tumor (DSRCT) is an ultra-rare soft-tissue sarcoma characterized by an EWSR1::WT1 gene fusion that affects predominantly male adolescents and young adults. Despite intensive multi-modality treatment outcomes remain dismal, with only 25% of patients being alive after five years. Beyond conventional therapies, novel, molecular mechanism-aware therapies are urgently needed. Patients with advanced DSRCT underwent multilayered molecular profiling as part of NCT/DKFZ/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a prospective, multicenter observational study that applies whole-genome/exome, transcriptome, methylome, and – more recently – mass spectrometry-based (phospho-)proteome analysis in young adults with advanced malignancies and patients with rare cancers to inform clinical decision-making and the design of molecularly stratified clinical trials. Between 2013 and 2022, 29 patients with DSRCT were analyzed with a median follow-up of 17 months (range, 0–48). The median age at the time of molecular analysis was 30 years (range, 18–56). The median time between diagnosis and molecular analysis was 12 months (range, 1–216). The median survival and the 4-year survival rate from registration were 2.4 years (95% confidence interval [CI], 1.4–3 years) and 7.4% (95% CI, 1.2–45.2%), respectively. In 8 of 9 samples with available proteomics data, we observed pronounced activation of ERBB (also called HER) signaling and high ERBB2 mRNA expression levels, providing a rationale for personalized therapy with ERBB2-specific antibody-drug conjugates. In addition, selected somatostatin receptor family members, i.e., SSTR3 and 5, were highly expressed in all patients with available transcriptome data, providing the basis for treatment with pasireotide, a novel multireceptor-targeted somatostatin receptor ligand, within an academic clinical trial, which is currently being prepared. We describe the molecular profiles of patients with DSRCT enrolled in MASTER and demonstrate the utility of broad molecular profiling for the clinical management of this disease, including the application of targeted treatment strategies.

Molecular techniques have improved cancer diagnosis and treatment. Due to limited availability and costs, broad molecular profiling, i.e., analysis of whole genomes/exomes, transcriptomes, and methylomes, is rarely performed upfront in clinical practice and mostly confined to research settings. However, in contrast to more readily available focussed analyses of, e.g., the few genes seemingly relevant for a suspected diagnosis, broad molecular profiling may yield unsuspected findings pertinent to diagnosis and/or treatment. This analysis is based on patients enrolled in the MASTER program of DKFZ, NCT Heidelberg/Dresden, and DKTK, a nationwide precision oncology network applying genome/exome, transcriptome, methylome, and – more recently – proteome analysis in young adults with advanced malignancies and patients with rare cancers to inform clinical decision-making and the design of molecularly stratified clinical trials. Cases with molecular findings suggestive of an alternative diagnosis are subjected to clinical, molecular, and pathologic revaluation. In 99 of 3,092 patients (3.2%), the molecular profile warranted revaluation of the clinical diagnosis. The most frequent presenting diagnoses were cancer of unknown primary (n=21); various sarcomas (n=50), e.g., sarcoma not otherwise specified (n=4), malignant peripheral nerve sheath tumor (n=5), and undifferentiated sarcoma (n=6); and melanoma (n=4). Molecular findings suggesting an alternative diagnosis were based on genome/exome, transcriptome, and methylome analysis in 30, 78, and 41 cases, respectively. Potential clinical consequences were classified as changes in diagnosis without relevance for treatment (n=22), relevant for routine treatment (n=58), and prompting molecular alteration-specific treatment (n=19). The molecularly suspected diagnosis was confirmed in a major subset of cases for which sufficient material for histopathologic review was available. The clinically most relevant findings were EWSR1::WT1 fusions and diagnosis of desmoplastic small round cell tumor (n=9) and druggable gene fusions involving FGFR2 (n=4), ALK (n=4), and NTRK3 (n=1). Broad molecular profiling is a useful adjunct to routine cancer diagnostics, especially in rare entities.

CRAFT (Continuous ReAssessment with Flexible ExTension in Rare Malignancies) is an open-label, 7-arm, cross-entity phase 2 trial investigating the efficacy of combinations of molecularly targeted agents and PD-L1 inhibition with atezolizumab in cancers with targetable molecular alterations (PMID: 34808524). We report the interim efficacy analysis of ipatasertib and atezolizumab in cancers with increased PI3K-AKT pathway activity. Adult patients with locally advanced/metastatic cancer refractory to ≥1 medical treatment and selected molecular tumor characteristics (arm 1: BRAF V600E/K mutations; arm 2: ERBB2 amplification/overexpression, activating ERBB2 mutations; arm 3: ALK rearrangements/ALK mutations; arm 4: aberrations predicting increased PI3K-AKT pathway activity; arm 5: activating PIK3CA mutations; arm 6: aberrations predicting increased RAF-MEK-ERK pathway activity; arm 7: alterations predicting anti-PD-L1/anti PD-1 sensitivity) were eligible. Main exclusion criteria were hematologic/primary brain cancers. In arm 4, ipatasertib 400 mg q.d. was given in a 21-days-on/7-days-off schedule, and atezolizumab was administered every 3 weeks. Statistics are based for each arm on a Simon’s optimal 2-stage design with 14 patients accrued in stage 1 and 11 additional patients if ≥4 patients achieve the primary endpoint, i.e., disease control (complete/partial remission [PR] or stable disease [SD]) at day 110. Until 04/2023, 51 patients were registered, and 28 were treated. Thirteen patients with various cancers and PI3K-AKT-activating alterations (PTEN deletion/loss-of-function mutation: n=8; activating PIK3CA mutation: n=2; activating AKT1 mutation: n=3) were enrolled in arm 4. One patient with breast cancer and a homozygous AKT1 E17K and one patient with prostate cancer and PTEN loss achieved a PR and SD, respectively. None of the remaining 11 patients reached the endpoint. Toxicity was mainly gastrointestinal and manageable. Ipatasertib and atezolizumab were ineffective in this patient population with PI3K-AKT-altered tumors. More stringent molecular selection criteria and an addition trial arm were implemented (arm 5).

The aim of this randomized clinical trial was to evaluate the impact of all- trans retinoic acid (ATRA) in combination with non-intensive chemotherapy in older unfit patients (> 60 years) with newly diagnosed NPM1 -mutated acute myeloid leukemia. Patients were randomized (1:1) to low-dose chemotherapy with or without open-label ATRA 45 mg/m 2 , days 8–28; the dose of ATRA was reduced to 45 mg/m 2 , days 8–10 and 15 mg/m 2 , days 11–28 after 75 patients due to toxicity. Up to 6 cycles of cytarabine 20 mg/day s.c., bid, days 1–7 and etoposide 100 mg/day, p.o. or i.v., days 1–3 with (ATRA) or without ATRA (CONTROL) were intended. The primary endpoint was overall survival (OS). Between May 2011 and September 2016, 144 patients (median age, 77 years; range, 64–92 years) were randomized (72, CONTROL; 72, ATRA). Baseline characteristics were balanced between the two study arms. The median number of treatment cycles was 2 in ATRA and 2.5 in CONTROL. OS was significantly shorter in the ATRA compared to the CONTROL arm ( p = 0.023; median OS: 5 months versus 9.2 months, 2-years OS rate: 7% versus 10%, respectively). Rates of CR/CRi were not different between treatment arms; infections were more common in ATRA beyond treatment cycle one. The addition of ATRA to low-dose cytarabine plus etoposide in an older, unfit patient population was not beneficial, but rather led to an inferior outcome. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2010-023409-37, first posted 14/12/2010).

BACKGROUND:Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS:Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS:Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS:Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Background: Ruxolitinib (RUX) alleviates disease-associated symptoms including splenomegaly in patients (pts) with myelofibrosis (MF). However, management of cytopenia remains challenging. Aims: As single-agent pomalidomide (POM) improved cytopenia in 14-29% of MF pts in our previous MPNSG-0109 trial, we sought to investigate the combination of RUX plus POM in MF pts with anemia (Hb <10 g/dL and/or RBC transfusion dependency [RBC-TD]). Methods: MPNSG-0212 is a multicenter, open-label, phase-Ib/II trial (NCT01644110) comprising 39 pts in cohort 1 (co1, recruited 2013-2017) and 52 pts in co2 (2017-2021). Co1 pts received RUX 10 mg BID plus POM 0.5 mg QD, while POM was intended to be increased in co2 to 1 and 2 mg QD after 3 and 6 28-day-cycles, respectively. Primary endpoint was response according to IWG-MRT and RBC-TI criteria at end of cycle 12 (EOC12). In addition, genomic landscape was characterized in all pts using targeted NGS of 269 candidate genes (Illumina NextSeq550). Results: Co1 and co2 pts had similar characteristics: median age was 71 years (range 49-86), median Hb level 8.6 g/dL (5.4-11.7), and median spleen size 17.5 cm (11.4-36); 30% were RBC-TD, 66% intermediate-2, and 25% high-risk according to DIPSS; mutations (muts) in JAK2, CALR, or MPL were identified in 57%, 23%, and 20%, respectively; 55% had ≥1 high-molecular risk (HMR) mut, with ASXL1 being the most common (41%), followed by SRSF2 (24%), EZH2 (10%) and IDH2 (9%). Of note, pts in co2 were more frequently pre-treated with RUX compared to co1 (44% vs 15%; p=.006). Median treatment time at data cut-off was 12 cycles in co1 (2-98) and co2 (3-46); 3 pts of co2 have not yet reached EOC12. In co1, 8/39 pts (21%) achieved response at EOC12: partial remission (PR, n=1), clinical improvement (CI, n=6), or RBC-TI (n=1); 18/39 pts (46%) were treated for >12 cycles due to response (n=8), clinical benefit (CB, n=5) defined as Hb increase ≥1 g/dL or >50% improvement of ≥1 quality of life (QoL) symptom according to MPN-SAF, or stable disease (SD, n=5). Median Hb level at EOC12 was 9.3 g/dL; 15/39 pts (38%) were on treatment for >30 cycles, and 3 pts remained on long-term treatment (cycle 76, 97, and 98). In 73% and 40% of pts in co2, POM dose was increased to 1 mg and 2 mg QD after cycle 3 and 6, respectively. 5/49 pts (10%) showed response at EOC12 (CI, n=3 and RBC-TI, n=2), while 14 additional pts (29%) had CB; median Hb level at EOC12 was 8.6 g/dL; 22/49 pts (45%) were treated for >12 cycles; 3 pts were still on treatment (cycle 21, 36, and 46). Targeted NGS did not reveal a distinct mutational pattern associated with treatment response. Median overall survival (OS) of co1 and co2 was 3.6 and 2.6 years, respectively (p=.66). Among all, CALR, but not JAK2 or MPL muts were associated with better OS (p=.04), whereas HMR muts were in trend prognostically adverse (p=.057). Pts with more than 3 muts had a worse median OS (1.2 vs 4 years, p=.002). Combination therapy was well tolerated in both cohorts. Most common grade 1/2 adverse events (AE) were dyspnea (28%) and fatigue (23%), while the most frequent grade 3 AE was worsening of anemia (32%) in the first weeks of combination treatment not limiting therapy. Summary/Conclusion: Treatment with RUX and POM was safe and feasible in our study of advanced MF with an adverse genetic profile. Almost half of co1 and co2 pts were treated >12 cycles due to clinical benefit of the combination therapy with a subset of 38% of pts in co1 receiving treatment for >30 cycles. Dose increase of POM in co2 did not result into better anemia response or improvement of OS. Authors FS and EJ contributed equally.

Background: Anemia remains one cardinal symptom associated with reduced quality of life (QoL) in patients (pts) with myelofibrosis (MF) which is normally not being addressed by ruxolitinib (RUX). In our previous MPNSG-0109 trial, single-agent pomalidomide (POM) improved cytopenia in 14% (POM 0.5 mg QD) and 29% (POM 2.0 mg QD) of MF pts, respectively. In the MPNSG-0212 study, we sought to investigate the potential synergism of RUX plus POM to improve anemia and QoL in MF pts. Study Design: MPNSG-0212 is an ongoing multicenter, open-label, single-arm phase-Ib/II trial with a target population of 90 pts following a two-stage design (NCT01644110). Pts 1-40 in cohort 1 (co1) were treated with RUX (10 mg BID) plus low-dose POM (0.5 mg QD), while pts 41-90 in cohort 2 (co2) receive a step-wise dose increase of POM from 0.5 mg to 1 mg and 2 mg QD after 3 and 6 28-day-cycles, respectively. Primary endpoints are safety of the combination therapy, anemia response after 12 cycles (according to IWG-MRT and RBC transfusion independence [RBC-TI] criteria), and clinical benefit (CB) defined as stable disease plus i) hemoglobin (Hb) increase ≥1 g/dL in pts with RBC-TI or ii) doubling of RBC transfusion intervals and/or iii) significant (>25%) improvement of QoL as measured by the MPN-SAF questionnaire. Main inclusion criterion is MF with anemia (Hb <10 g/dL and/or RBC transfusion dependence [RBC-TD]). Pts suitable for allogeneic transplantation and pts with low platelet counts (<100/nL) are excluded. Results: At data cut-off (31-May-2019), 79 pts were included. Data from 67 pts were available for evaluation (co1, n=40; co2, n=27). Baseline characteristics of the pts were as follows: median age 72 years (range 49-84), prior treatment in 53% (RUX in 22%, POM in 4%), median Hb level at study start 8.6 g/dL (range 5.4-11.7), RBC-TD in 28%, median spleen diameter measured by ultrasound 17.7 cm (range 12-36), presence of constitutional symptoms in 76%, and 91% intermediate-2 (61%) or high-risk (30%) pts according to DIPSS; 55% of pts in co1 had ≥1 high molecular risk mutation (ASXL1, SRSF2, EZH2, and/or IDH1/2). Median number of cycles until data cut-off was 12 (range 2-63) in co1 and 11 (range 2-21) in co2. In total, 502 adverse events (AE) mainly grade 1/2 were recorded: AE grade 1/2 in >20% of pts were fatigue (in 27% of pts), dyspnea (24%), diarrhea (22%), and muscle cramps (21%); AE grade ≥3 in >3% of pts was Hb decrease in the first weeks of treatment occurring in 25% of pts. In total, 87 serious AE (SAE), were recorded: most common SAE (in ≥3 pts) were pneumonia (in 15% of pts), leukemic transformation (9%), worsening of general condition (6%), CNS ischemia, and sepsis (4% each); 7 SAE (in 10% of pts) were grade 5. Number or severity of (S)AE was not increased in co2. Treatment interruptions of RUX and/or POM were necessary in 11 pts (27%) of co1 and 3 pts (11%) of co2; 2 pts stopped treatment permanently due to hematotoxicity. Increase of the POM dose to 1 mg and 2 mg QD was feasible in the majority of pts after 3 and 6 cycles, respectively. In co1, 18/40 pts (45%) continued treatment beyond cycle 12 because of an objective anemia response (7/40, 18%: clinical improvement [CI, Hb increase ≥2 g/dL] n=5, partial remission and RBC-TI n=1 each) or CB (11/40, 27%): Hb increase ≥1 g/dL and/or doubling of RBC transfusion intervals (n=4) or improvement of QoL according to MPN-SAF (n=7). In co2, 17/27 pts (63%) reached cycle 12 and 10/17 (59%) continued treatment: 2/10 (20%) experienced CI, whereas 8/10 (80%) fulfilled the CB criterion; 19/27 pts (70%) were still on treatment at the time of data cut-off. Among all 67 pts analyzed, 42% (28/67) were on treatment for more than 12 cycles and 24% (16/67) for more than 24 cycles; 3 pts (4%) were treated for more than 60 cycles due to sustained response or CB. Of note, mean Hb increased from 8.7 g/dL at baseline to 9.6 g/dL at end of cycle 18 and remained stable thereafter (Figure 1). Conclusions: Combination treatment using RUX plus POM is feasible in pts with poor-risk MF and resulted in an objective anemia response rate of 18% in co1. Of note, 42% of pts were treated with >12 cycles and showed a longer lasting stabilization of their disease with sustained improvement of Hb and QoL. Step-wise increase of the POM dose in co2 is safe and feasible with 70% of pts still on study treatment. Updated efficacy results of co2 with longer follow-up data will be presented at the meeting. Figure 1 Disclosures Stegelmann: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Koschmieder:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Foundation: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Isfort:Novartis: Consultancy, Honoraria, Other: Travel reimbursement; Pfizer: Consultancy, Honoraria, Other: Travel reimbursement; Ariad: Consultancy, Honoraria; BMS: Honoraria; Hexal: Other: Travel reimbursement; Amgen: Other: Travel reimbursement; Mundipharma: Other: Travel reimbursement; Roche: Other: Travel reimbursement; Alexion: Other: Travel reimbursement. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Göthert:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel support; Incyte: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support; Proteros Biostructures: Consultancy; AOP Orphan Pharmaceuticals: Honoraria, Other: Travel support. Schafhausen:Incyte: Consultancy, Equity Ownership, Honoraria; Novartis: Consultancy, Honoraria. Radsak:Daiichi Sankyo: Other: Travel Support, Advisory Boards; Novartis: Other: Travel Support, Advisory Boards; JAZZ: Other: Travel Support; Celgene: Other: Travel Support, Advisory Boards; Takeda: Other: Advisory Boards; Otsuka: Other: Advisory Boards. von Bubnoff:Novartis: Research Funding. Reiter:Blueprint: Consultancy, Honoraria, Other: Travel reimbursement; Novartis: Consultancy, Honoraria, Other: Travel reimbursement, Research Funding; Deciphera: Consultancy, Honoraria, Other: Travel reimbursement. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding. Griesshammer:Novartis: Consultancy, Honoraria, Speakers Bureau. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria.

Background: Acute myeloid leukemia (AML) with t(8;21)(q22;q22.1) resulting into the RUNX1-RUNX1T1 gene fusion defines a distinct entity within the category ‘AML with recurrent genetic abnormalities’ of the World Health Organization classification and is considered as a favorable AML subset in the 2017 risk stratification by the European LeukemiaNet (ELN). Although most patients (pts) achieve complete remission (CR) following intensive chemotherapy, relapse occurs in about 50% of the cases and is associated with poor prognosis. In this AML subset monitoring of measurable residual disease (MRD) has been shown to identify pts at higher risk of relapse. Aims: To assess the prognostic impact of MRD monitoring in bone marrow (BM) and peripheral blood (PB) in a large cohort of 155 homogeneously treated and clinically well-annotated patients with t(8;21)-AML. Methods: Quantification of RUNX1-RUNX1T1 transcript levels (TL) was performed by RT-qPCR. TL were reported as normalized values of RUNX1-RUNX1T1 per 106 transcripts of the housekeeping gene B2 M. Samples were analyzed in triplicate, the sensitivity of our assay was up to 10−6. Results: While pretreatment RUNX1-RUNX1T1 TL did not impact prognosis, both reduction of RUNX1-RUNX1T1 TL and achievement of MRD negativity (MRDneg) at defined time points were of significant prognostic importance. First, achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after cycle 2 were significantly associated with a reduced risk of relapse (P = 0.034 and P = 0.028, respectively). Second, after completion of therapy, achievement of MRDneg in both, BM and PB, was an independent favorable prognostic factor for cumulative incidence of relapse (4-year CIR BM: 17% vs 36%, P = 0.021; PB: 23% vs 55%; P = 0.001) and overall survival (4-year OS rate BM: 93% vs 70%, P = 0.007; PB: 87% vs 47%; P < 0.0001). Finally, during follow-up serial RT-qPCR analyses allowed prediction of relapse in 77% of pts exceeding a cut-off of 150 RUNX1-RUNX1T1 TL in BM, and in 84% of pts with > 50 RUNX1-RUNX1T1 TL in PB, respectively. KIT mutation observed in 28% of pts predicted for lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TL during treatment. Virtually all relapses occurred within one year after end of treatment (EOT) with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this period. Based on our data we suggest a refined practical guideline for MRD assessment in RUNX1-RUNX1T1-positive AML: Along with the current ELN MRD recommendations, BM and PB should be analyzed after each treatment cycle. According to MRD at EOT and during follow-up we suggest MRD monitoring as follows: (i) MRDneg: PB monthly can be used, (ii) MRDpos (TL < 150 in BM and < 50 in PB): BM 3-monthly and PB monthly, and (iii) MRDpos (TL >150 in BM and/or >50 in PB) or increase of MRD >1-log or conversion from MRDneg to MRDpos: BM and PB, both monthly, should be analyzed. Summary/Conclusion: RUNX1-RUNX1T1 MRD monitoring allows for the discrimination of pts at high and low risk of relapse. MRDneg in both, BM and PB, after completion of therapy was the most valuable independent favorable prognostic factor for relapse risk and OS. During follow-up, serial MRD analyses allowed the definition of cut-offs predicting relapse. Moreover, considering that virtually all relapses occurred within one year after EOT with a very short latency from molecular to morphologic relapse, MRD assessment at shorter intervals during this period is indispensable.