ALBERT

Description: Introduction: Tumor boards have become a crucial institution in oncology practice to provide paramount interdisciplinary cancer treatment, stream-line patient (pt) entries and to ensure treatment according to clinical pathways (CP). We initiated a weekly MM-TB at our institution in 6/2012. Participating experts are hematologist-oncologists, pathologists/cytogenetic specialists, orthopedists, radiotherapists, immunologists/rheumatologists and, if needed, nephrologists, cardiologists and others. Pt applications to be discussed are centrally organized through our CCCF, with the TB advice being centrally stored within our electronic pt information system. Recommended TB advice is made according to best current literature/knowledge and international CP. The development of mandatory CCCF-CP and transparency of decision making are key quality criteria. Methods: This first analysis focused on a) discussed TB questions, b) given recommendations, c) pt characteristics, d) pts’, referring- and participating-physicians' satisfaction with the TB, e) inclusion of these challenging-to-treat pts in clinical trials (CT) and f) PFS/OS of TB pts as compared to the literature (Kumar SK. Leukemia 2012). Grades of recommendations were assigned using the GRADE criteria (Engelhardt M. Haematologica 2014) and meticulously assessed, as well as whether TB recommendations were pursued. Pts’, referring- and participating-physicians' satisfaction with the TB was evaluated via standardized questionnaires, the aimed sample size being n=100 for consecutive pts and ~n=30 each for participating and referring physicians. Results: From 6/2012-5/2014, 483 pts have been discussed within 90 MM-TB sessions, substantially increasing these from 2011 to 2012, 2013 and 2014 by 12-fold. Of the entire MM cohort seen at our institution, 60% of these challenging-to-treat pts were discussed within the TB in 2012, increasing to 71% in 2013. We have currently assessed 200 TB-protocols for pt characteristics, clinical outcome and adherence to TB decisions. Of those, 2% were presented for explicit diagnosis-finding, 17% had newly diagnosed MM, 41% relapsed/refractory MM and 40% had attained stable disease or better with their last-line therapy and were discussed to resolve their ongoing treatment. Expectedly, most pts (89%) were discussed for their next-line treatment, 43% due to strains with comorbidities, symptom control, side effects, diagnosis finding and MM-staging, and 11% due to various other reasons (multiple entries possible). Mean treatment lines of pts discussed in the TB was 2 (range 0-10), deciding on their 3rd-line-treatment. Within the TB cohort, 70% were presented once, but 30% several times (mean 2, range 2-4). Of these multiple presentations, most pts had relapsed or refractory MM, this rate further increasing towards the 3rd and 4th TB-presentation. The adherence to TB-recommendations was excellent with 93% of decisions being pursued. Reasons for adapted approaches were practicable issues or disagreement of the pt, family or referring physician. Of currently 80/100 interviewed pts, 95% were entirely satisfied with their care, treating oncologists/MM-expert team and very supportively perceived the MM-TB. Of note, 94% considered their cancer care ideally achieved by the TB, 92% that their local physician profited greatly and 88% that their personal preferences were also accounted for. Of 30 interviewed participating physicians, 97% considered themselves well-educated and their time well-spent. Of currently 18 referring physicians, 73% were unconditionally satisfied with all TB-diagnostics and -therapies, with the university centers' cooperation and 65% acknowledged no information loss. Of 288 pts assessed for their CT suitability, 28% were suggested by the TB to be included, with 53% actually being able to enter therein. Thus, 15% of our MM-TB cohort could be included in a CT, which is considerable since these were challenging-to-treat pts who had received extensive prior therapies and showed several comorbidities. This also confirms current CT accrual rates for cancer pts of 5-15%, which can be increased with well-structured TB. Conclusions: Our preliminary results suggest that this MM-TB is a highly relevant exchange platform and allows physicians from different disciplines to intensely and rewardingly collaborate for state-of-the-art cancer care. Disclosures No relevant conflicts of interest to declare.

Description: Key Points The CBL syndrome may predispose to myeloid neoplasias other than juvenile myelomonocytic leukemia. Whole-exome sequencing identifies mutations that possibly cooperate with mutant CBL in AML development.

Description: Introduction The combination of bortezomib, doxorubicin and dexamethasone (BDD) is well tolerated and induces a high overall response rate (ORR). Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma (MM). Methods Patients received escalated vorinostat-doses (provided by MSD) at 100mg (dose level 0), 200mg (dose level +1) and 300mg (dose level+2) on days 1-4, 8-11, 15-18, combined with bortezomib 1.3mg/m2 day 1,8,15 (provided by Janssen), dexamethasone 40mg day 1,8,15,22 and doxorubicin on 9mg/m2 day 1+8. The primary objective was the maximum tolerated dose (MTD; 3+3 dose escalation design). Secondary objectives were safety, response assessed by EBMT and IMWG criteria, progression-free survival and overall survival. Correlative endpoints include prognostic MM-parameters, organ function, QoL-, comorbidity-assessments and translational studies (e.g. HDAC-activity in PB MNCs, Figure 1). Dose limiting toxicities (DLTs) were defined as any possibly drug related adverse events (AEs) ≥grade 3 (CTCAE) within the 1st cycle. After completion of 6 cycles, patients could continue with bortezomib maintenance therapy or proceed to (most often 2nd) ASCT. Results To date, 18/30 patients have been enrolled (median age 63 years [range 54-75], 55% men). The median Karnofsky Performance Status was 90% (range 70-100%). Median prior therapy lines were substantial with 3 (range 1-8): bortezomib, thalidomide or lenalidomide were given in 88% and 24% each, respectively; 94% of patients had undergone prior SCTs. Cytogenetic abnormalities included del(17p) (n=2), t(4;14) (n=2), gain(1q) (n=2), t(11;14) (n=4) and hyperdiploidy (n=7). No DLTs have been observed to date; with 3 patients each being included in dose level 0 and dose level +1 and the following patients safely proceeding to dose level +2. Six SAEs occurred in 4/18 patients (22%): bacteraemia (n=1) and herpes zoster reactivation (n=1) were suspected to be related to all VBDD-drugs. No causal relationship to study drugs was suspected for pneumonia (n=2), 1 syncope and 1 death due to PD with persisting plasma cell leukemia. The ORR (〉PR) and clinical benefit rate (SD, PR, CR) was 65% and 89%, respectively. At a median follow-up of 8 months (range 3-23), there have been only 2 patients with PD (refractory MM + plasma cell leukemia). The analysis of HDAC activity after VBDD initiation demonstrated downregulation in 6/8 (75%) patients (Figure 1). Further analyses will determine, whether HDAC activity and treatment response may correlate and whether this HDAC downregulation may precede and/or indicate depth of response Conclusions VBDD is a well tolerated and effective regimen in heavily pretreated relapsed/refractory MM patients. There have been no observed DLT and the MTD of vorinostat was set at 300mg, with all reported SAEs being in line with the known safety profile of the investigated drugs. Our alternative vorinostat-schedule (dosing of 4 days on and 4 days off) induced excellent tolerability and seems to enhance the antimyeloma response, warranting completion of this study. Disclosures: Kleber: MSD, Janssen-Cilag: Research Funding. Off Label Use: Preclinical studies have demonstrated that vorinostat, a histone deacetylase inhibitor, is synergistic with bortezomib and doxorubicin. The aim of this phase I/II study was to determine the tolerability and activity of the combination of BDD with vorinostat (VBDD) in relapsed/refractory multiple myeloma. Vorinostat is off-label use for MM patients, all other drugs are in label use. Waesch:MSD, Janssen-Cilag: Research Funding. Engelhardt:MSD, Janssen-Cilag: Research Funding.

Description: Introduction: Multiple myeloma (MM) relapse is common and may eventually lead to highly refractory/relapsed MM (RRMM). Therefore, novel treatment combinations are crucially needed for this highly challenging subgroup of patients (pts). The aim of the here presented phase I/II IIT was to test the tolerability and activity of a novel, so-called VBDD schedule within an outpatient regimen for extensively pretreated RRMM pts. In addition to Bortezomib, Doxorubicin and Dexamethason, which are all active and approved drugs in RRMM, Vorinostat has shown promising anti-tumor effects as a histone deacetylase inhibitor (HDACi). It inhibits the enzyme activity of HDAC 1, 2, 3 and 6, thereby allowing the activation of tumor suppressor genes. MM cells have been shown to escape from bortezomib treatment by formation of aggrosomes which desensitize cells to proteasome inhibitors and by microtubule mediated protein shuttling to lysosomes, where proteins are degradaded in order to prevent cytotoxic stress and ultimately escape from apoptosis (Fig.A). Albeit vorinostat has shown moderate activity when given alone, it has promising additive effects when combined with other antimyeloma agents, and was therefore used as an add-on agent within this RRMM regimen as it blocks microtubule coppling and aggrosome building and thereby may antagonize escape mechanisms in bortezomib-refractory pts. Methods: Vorinostat was escalated from 100mg (dose level 0), to 200mg (+1) and 300mg (+2). Primary objectives (MTD; 3+3 dose escalation), secondary objectives (safety, IMWG responses, PFS, OS) and supplementary endpoints (organ function, prognostic factors, QoL, comorbidity and HDAC-activity in PBMCs/BM) were assessed throughout the trial. Dose limiting toxicities (DLTs) were defined as any possibly drug-related adverse event (AEs) ≥grade 3 (CTCAE) during the 1st cycle. After completing 6 cycles, patients could receive either a bortezomib maintenance therapy or next-line treatment (e.g. 2nd ASCT). Results: 34 pts with RRMM with a median age of 63 years (47-78) and KPS of 90% (70-100%) have been enrolled, of which 33 received therapy according to the study protocol (1 pt deceased prior to study start due to aggressive MM progression and was therefore not included in the evaluation). The number of prior therapy lines was substantial with a median of 3 (1-8; with prior bortezomib, SCT and IMiDs in 88%, 94% and 42%, respectively). 3 pts each were treated in dose levels 0 and +1, and the remaining 27 pts in dose level +2. No DLTs were observed. In our current analysis, SAEs amounted to 15 and occurred in 9/33 pts (27%): Amongst them, 2 nonfatal SAEs were judged to be related to the investigational therapy (1 bacteraemia, 1 herpes zoster), for the others, no causal relationship to VBDD was found. The response according to IMWG criteria was rewarding with best ORR (〉PR) and clinical benefit rate (CBR; 〉SD) of 42% and 94% (Fig. B), and end of treatment (EoT) ORREoT and CBREoT of 36% and 88%, respectively (Fig.C). Our data also revealed that the response was independent of the presence or absence of unfavorable cytogenetics. Comorbidity assessments assured no decline in pts' mental or physical condition and pts reported preserved or improved QoL with this well-tolerated 4-agent treatment regimen. Pharmacodynamic analyses in peripheral blood (PB) MCs showed substantial and early HDAC downregulation between VBDD cycles 1 and 2 in 11/16 pts (69%): median HDAC activity decreased to 52% of pre-treatment levels. Thereby, we were able to distinguish 3 groups of pts with substantial, more subtle or no PB HDAC decreases in 8, 3 and 5 pts, respectively. Of note, these HDAC changes correlated well with pts' serological and clinical responses, except in 2 pts. These intriguing results are currently further assessed and will be presented at the meeting. Conclusions: VBDD demonstrated to be an effective and well-tolerated outpatient regimen with promising response rates in heavily pretreated RRMM pts. The employed VBDD regimen, with a continuous, rather than pulsed vorinostat-schedule, constitutes a promising treatment option, expands current standard therapies and, similarly to other HDACi (i.e. panobinostat), suggests HDACi as a valuable add-on within this combination schedule in order to stabilize the disease and/or bridge RRMM patients to next-line treatments (i.e. autologous/allogenic stem cell transplantation) or novel clinical trial drugs. *AK and JW contributed equally Figure 1. Figure 1. Disclosures Off Label Use: We report on results of an Phase I/II IIT, in which the HDACi Vorinostat is used to treat relapsed or refractory Multiple Myeloma pts . Engelhardt:MSD: Research Funding; Janssen-Cilag: Research Funding; Comprehensive Cancer Center Freiburg: Research Funding; German Cancer Aid: Research Funding. Wäsch:German Cancer Aid: Research Funding; Janssen-Cilag: Research Funding; Comprehensiv Cancer Center Freiburg: Research Funding; MSD: Research Funding.

Description: Abstract 4692 Allogeneic hematopoietic cell transplantation (HCT) is the most effective curative therapy in patients acute myeloid leukemia (AML) and myelodisplastic syndromes (MDS). Despite improvements in the clinical management, relapse from the original disease is still one of the main causes of treatment failure. There is scarce available data on the influence of genomic changes in relapsed patients after HCT, in particular in HLA identical transplantation. Selective pressure mediated by T cells can result in genomic changes in the HLA region on chromosome 6, as shown by several animal models and in human haploidentical transplantation. In this study we examined genome wide DNA copy number changes and long contiguous stretches of homozygosity (LCSH) in 21 patients with a diagnosis of AML or MDS/AML undergoing HCT. SNP-chip analysis revealed a total of 162 genomic aberrations (GA) in 21 pairs of samples before allogeneic transplantation and at relapse in patients diagnosed with AML or AML/MDS. Total GA were significantly higher after transplant compared with the pre transplant samples (p

Description: Many efforts are made to treat acute leukemia effectively, but still; new treatment options are urgently needed. In the past, mainly chemically induced and cell line-derived mouse models were used to evaluate the efficacy of new drugs. The high failure rate of 96% in early clinical development illustrates the urgent need for more predictive preclinical models as a major prerequisite for rapid bench-to-bedside translation of investigational anticancer therapies. Transplantable patient-derived xenograft (PDX) models of leukemia offer a strong preclinical tool for drug screening and biomarker development as they represent the complex clinical tumor heterogeneity and molecular diversity of human cancer. Between 2011 and 2015 we collected 91 samples of peripheral blood (PB) or bone marrow (BM) from patients diagnosed with acute myeloid or lymphoblastic leukemia (AML, ALL) and injected them intratibially (i.t.) into NOG (NOD/Shi-scid/IL-2Rγnull) mice (n=1-5/patient sample). Infiltration of human leukemic cells was determined by flow cytometry in murine PB, BM and spleen. If more than 5% of hCD45+, hCD33+, hCD34+, hCD38+, and/or HLA-ABC+ cells were detectable in one sample, it was classified as engrafted. Results were confirmed by histo-pathological examination. FISH analyses confirmed the cytogenetical concordance with the donor patient where available. 8 models were treated with cytarabine and results were compared to patient´s outcome and treatment experiments using cell line derived models of AML. Whole exome sequencing analyses of the transplantable models are underway for a deeper characterization of the respective leukemic clone which adapted to the murine microenvironment. Specimens of 44 female and 47 male patients (median age: 59 years, median BM infiltration: 39%) were collected. The donor patient cohort covered a broad range of different molecular subtypes: amongst others 5 MLL-rearrangements, 1 MLL-Deletion, 2 t(8;21) translocations, 20 cytogenetically normal and 7 complex karyotypes were included. Up to now 12 PDX models were in passage (P) 5 and higher, where P1 represents first implantation of human cells into the murine BM. 15 PDX models grew in P3 - P4, 21 in P2, 36 in P1 and 7 samples showed no engraftment. Engraftment capacity of the leukemic cells did not correlate significantly with any of the patient characteristics. BM engraftment ranged from 30% - 80%. Spleen and PB depicted 5 - 30% of leukemic cells. Infiltration rate in different organs and immuno-phenotypic characteristics of the human cells were specific for a defined model and preserved during serial transplantation. Take rates within one mouse cohort in serial transplantation were ≥98% for all transplantable PDX, similar to cell line derived models thereby qualifying the PDX approach as a suitable preclinical platform. Overall survival (OS) in P1 ranged from 52 to 〉 310 days (d). Models which could be serially transplanted showed model specific median OS ranging from 32 - 150 d. Comparable cell line derived models depicted median OS of 13 - 45 d. Of note, cell line derived models (KG-1, NOMO-1, MOLM-13, THP-1, MV4-11 or HL60, n ≥ 10 mice/cell line) induced hind limb paresis in all recipient mice. These symptoms could not be observed in PDX and most important are not part of the clinical picture. Cytarabine induced a significantly prolonged OS in 8/8 tested PDX models. Respective donor patients showed hematologic response under cytarabine based therapy highlighting the excellent predictivity of the in vivo platform. In contrast none of the investigated cell line derived models showed sensitivity towards cytarabine, although representing similar subtypes of AML as the investigated PDX models. Taken together a constantly expanding panel of well characterized AML/ALL PDX covering a broad range of different subtypes of the disease is available for drug development and tumorbiology studies. The comparison with cell line derived in vivo models revealed significant advantages of the PDX approach as the latter represents the molecular diversity more in detail, mimics the clinical signs of leukemia more realistic and most important mirrors sensitivity towards standard of care in a direct comparison with the donor patient´s clinical outcome. Therefore, we strongly believe that the AML/ALL PDX platform is a robust and predictive tool to address translational challenges in oncology research. Disclosures Oswald: Oncotest GmbH: Employment. Klingner:Oncotest GmbH: Employment. Lenhard:Oncotest GmbH: Employment. Schueler:Oncotest GmbH: Employment.

Description: Introduction: Disease monitoring based on genetics or other molecular markers obtained by noninvasive or minimally invasive methods will potentially allow the early detection of treatment response or disease progression in cancer patients. Investigations in order to identify prognostic factors, e.g. patient's baseline characteristics or molecular markers, contributing to long-term survival potentially provide important information for patients with multiple myeloma. Overall survival (OS) is not very informative for patients who already survived one or more years. To better characterize long-term survival respectively long-term survivors, conditional survival (CS) analyses are useful. Conditional survival (CS) describes probabilities of surviving t additional years given they survived s years and provides information, how prognosis evolves over time. We have demonstrated the use of CS in a large data set of multiple myeloma patients with long-term survival which is mandatory for the calculation of CS (Hieke,... Engelhardt, Schumacher. CCR 2015). Methods: We evaluated 816 consecutive multiple myeloma patients treated at our department from 1997 to 2011 with follow-up until the end of 2011. Patients' data were assessed via electronic medical record (EMR) retrieval within an innovative research data warehouse. Our platform, the University of Freiburg Translational Research Integrated Database Environment (U-RIDE), acquires and stores all patient data contained in the EMR at our hospital and provides immediate advanced text searching capacity. We assessed 21 variables including gender, age, stage and admission period. We calculated 5-years CS and stratified 5-years CS according to disease- and host-related risks. Component-wise likelihood-based boosting and variables selected by boosting were investigated in a multivariable Cox model. Results: The OS probabilities at 5- and 10- years were 50% and 25%, respectively. The 5-year CS probabilities remained almost constant over the years a patient had already survived after initial diagnosis (~50%). According to baseline variables, conditional survival estimates showed no gender differences. The estimated 5-year survival probabilities varied substantially, from 25% for patients ages 70 or older to 65% for patients younger than 60 years. Similarly, patients with D&S stage I have an estimated 5-year survival probability of about 75% compared with 40% for patients with D&S stages II and III. Significant risk factors via Cox proportional hazard model were D&S stage II+III, age 〉70 years, hemoglobin

Description: Introduction: In addition to disease-specific and age-related factors, type and severity of comorbidities play a relevant role, influence the tolerance of anti-MM-treatment and overall survival (OS). We have identified an impaired Karnofsky Performance Status (KPS), lung and renal impairment as significant risk factors for inferior outcome (Kleber,...Engelhardt. BCJ 2011, Kleber,...Engelhardt. CLML 2013, Engelhardt et al. Haematologica 2014). These variables were combined in a comorbidity score (initial Freiburg Comorbidity Index [iFCI]). The objectives of this analysis were to refine the iFCI ('revised FCI' [rFCI]) by adding host- and disease-specific risk factors, cytogenetics, physical function and quality of life. Moreover, we assessed the benefit of a possible weighting of the rFCI, and compared the rFCI to well-established comorbidity indices, namely Charlson Comorbidity Index (CCI), Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and Kaplan-Feinstein (KF). Methods: We assessed 803 consecutive patients (pts) treated at our institution between 1997-2012, determining comorbidities as weighted renal, lung, heart, liver, gastrointestinal diseases, KPS, disability, frailty, infection, pain, secondary malignancies, peripheral neuropathy, thrombosis and disease parameters (e.g. cytogenetics). We divided our cohort into a training (n=553) and validation set (n=250) and performed a multivariate analysis via backward selection. Regression coefficients were used to derive weights for the score. Apart from scoring both iFCI and rFCI, we also assessed the CCI, HCT-CI and KF. Results: Our pts showed a typical median age for a tertiary referral center of 63 years (range: 21-93). 26% revealed less favorable cytogenetics, defined as del(17p13), del(13q14), t(4;14), t(14;16) and chromosome 1 abnormalities. Each half of the pts had received either standard chemotherapy or stem cell transplantation. Frequent comorbidities (〉30%) were KPS, heart, renal, lung impairment, disability and frailty. Univariate analysis revealed age, renal, lung and heart disease, KPS, disability, frailty, pain and infections as significant. Multivariate risks proved to be advanced age (〉70 years), renal, lung, KPS impairment, frailty and cytogenetics with hazard ratios (HR) of 2.2, 1.8, 1.3, 3.2, 1.9 and 1.5, respectively. The rFCI allowed to distinguish low-, intermediate- and high-risk pts with largely different median OS of 11.2, 4.8 and 2.6 years, conclusively confirmed via validation analysis with distinct median OS differences of not reached, 6.5 or 1.4 years, respectively. Weighting of the single risk factors led to a score with maximum points of 39. In order to simplify this score, the single weights were divided by 2 and rounded, which led to a 20-point score (rFCI modified I [mod I]). A 2nd modification led to a 9-point score (rFCI mod II) which was obtained with single risk factors being scored based on their HR. These modified rFCI scores I and II allowed equally well to allocate MM pts in low-, intermediate- and high-risk groups as with the 39-point-rFCI, besides being simpler in their application. Compared to the CCI, HCT-CI and KF, the rFCI remained highly significant. For further comparison, all comorbidity indices in the training and the validation set were divided into two risk groups according to the cut-offs obtained from our initial analyses (BCJ 2011, CLML 2013). Regardless of whether we scored MM pts with the iFCI, rFCI, CCI, HCT-CI or KF, ‘low-risk’ pts had longer median survival than ‘high-risk’ pts. The comparison via median comorbidity indices showed superiority of the rFCI and CCI in the training set and of the rFCI and HCT-CI in the validation set. A further univariate analysis and comparison by dividing the different scores in risk groups based on 25% and 75% quantiles, revealed the highest HR for the rFCI both in the training and the validation set. Conclusions: As comorbidities in MM are frequent, a detailed comorbidity assessment, including host- and disease-specific risk factors, allows an improved risk evaluation in often frail pts. Age, renal, lung, KPS impairment, frailty and cytogenetics are relevant risk factors included in our rFCI. Advantages of the rFCI vs. iFCI are the inclusion of MM-specific risks including cytogenetics, the more accurate assessment of pts' physical conditions, lower prediction errors and its simple clinical applicability. Disclosures No relevant conflicts of interest to declare.

Description: Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of disorders characterized by impaired stem cell function resulting in pancytopenia. Diagnosis of IBMFS presents a major challenge due to limited diagnostic tests and overlapping phenotypes. For that reason, novel and clinical relevant biomarkers and possible targets are urgently needed. Our study defines NIPA as an IBMFS gene, which is significantly downregulated in a distinct subset of MDS-type refractory cytopenia of childhood patients. Mechanistically, NIPA binds FANCD2 and regulates its nuclear abundance. The stabilization of both non- and monoubiquitinated FANCD2 identifies NIPA as an essential player in the Fanconi Anemia (FA) pathway. NIPA thereby prevents MMC hypersensitivity visualized by increased numbers of chromosome radials and reduced cell survival after induction of interstrand crosslinks. To provide proof of principle, re-expression of FANCD2 in Nipa deficient cells restores MMC sensitivity. In a knockout mouse model, Nipa deficiency leads to major cell intrinsic long-term repopulation defects of hematopoietic stem cells (HSCs), with impaired self-renewal in serial transplantations and a bias towards myeloid differentiation. Unresolved DNA damage in Nipa deficient HSCs causes increased sensitivity to cell death and leads to progressive, age-related loss of the HSC pool. Induction of replication stress triggers the phenotypic reduction and functional decline of murine HSCs, resulting in complete bone marrow failure and death of the mice thereby mimicing Fanconi Anemia. Taken together, our study adds NIPA to the short list of FA-associated proteins being essential for a functional DNA repair/FA/BRCA axis and thereby emphasizing its impact as potential diagnostic marker and/or possible target in bone marrow failure syndromes. Disclosures Niemeyer: Celgene: Consultancy.