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Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], 22.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, 26.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843. © 2020 by The American Society of Hematology This study was supported by Bayer AG and Janssen Research and Development.

Absztrakt: Bevezetés: Az allogén vérképző őssejt-transzplantáció (tx) indikációja gyermekkorban a magas szövődményráta és a nem elhanyagolható halálozás miatt csak az életet veszélyeztető betegségekre korlátozódik. A csökkentett toxicitású kondícionáló kezelések bevezetése után célul tűztük ki az egyes a transzplantációs szövődmények, mint graft-versus-host betegség (GVHD), vírusreaktiváció és transzplantációhoz társult thromboticus microangiopathia (TA-TMA) időbeli és egymáshoz viszonyított előfordulásának és a különböző kondícionáló kezelések és a fenti transzplantációs szövődmények összefüggéseinek feltárását. Betegek és módszer: Prospektíven száz (8,5 ± 4,9 év) gyermeket vizsgáltunk, akik malignus (n = 54) és nem malignus alapbetegség (n = 46) miatt részesültek allogén tx-ban. A kondícionáló kezelés megkezdésétől monitoroztuk a korai szövődmények, így az akut GVHD, a vírusreaktivációk, a TA-TMA felléptét, illetve relapszus jelentkezését. Eredmények: A gyerekek kétharmadánál (67%) észleltünk legalább egy korai szövődményt a felsoroltak közül. A leggyakoribb transzplantációs szövődmény a vírusreaktiváció volt (50%). Akut GVHD a betegek 26%-ánál, a medián 31. (10.–174.) napon alakult ki. Az akut GVHD-s esetek 27%-a (7/26) zajlott súlyos (Grade III–IV) formában. A TA-TMA döntően enyhe volt, kizárólag ciclosporin adása során, más transzplantációs szövődményekhez társultan jelentkezett. A TA-TMA kialakulását 5/20 esetben GVHD, 5/20 esetben vírusreaktiváció, és 4/20 esetben vírusreaktiváció és GVHD is megelőzte. A súlyos szövődmények alacsony számával ellentétben a relapszusráta (22/54; 41%) magas volt. A vizsgált betegcsoport összesített túlélése medián 3,8 (1,3–6,5) év követési idő múltán 74%. A nem malignus betegség miatt transzplantált gyermekek összesített túlélése kiváló (43/46; 93,5%). Ezzel szemben a malignus csoportban a halálozási arány – a magas relapszusrátának megfelelően – (17/54, 31,5%) magas. Következtetés: A csökkentett toxicitású kondícionáló kezelések bevezetése óta a súlyos korai transzplantációs szövődmények száma alacsony. A TA-TMA döntően enyhe formában, vírusreaktivációhoz vagy GVHD-hoz társultan jelentkezett. A malignus alapbetegség esetén a halálozás fő oka a relapszusok magas száma.

Myeloid sarcoma according to the WHO 2016 version is an independent subgroup of acute myeloid leukemia, characterized by extramedullary tumor-like proliferation of myeloid precursor cells. Myeloid sarcoma can occur without bone marrow disease, associated with myeloid neoplasias or as a relapse of acute myeloid leukemia, too. In this article we describe the case of a 3 week-old newborn, whose myeloid sarcoma presented with skin symptoms and was successfully treated with AML BMF98 chemotherapy following allogeneic hematopoietic stem cell transplantation. Hereby we also summarize the most important current knowledges of the disease.

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.

Simple Summary The outcome of pediatric AML improved considerably worldwide during the past few decades. Hereby, we summarize the therapeutic results of pediatric AML patients registered between 2012 and 2019 in Hungary. As compared to our previous results, improvement was registered in event-free (EFS) and overall (OS) survival, which can be attributed to the application of contemporary diagnostic and therapeutic guidelines, advanced supportation, and higher efficacy of hematopoietic stem cell transplantation. Between 2016 and 2019, a statistically significant increment of 2-year EFS was confirmed over the period between 2012 and 2015. The most prominent progress was observed in acute promyelocytic leukemia (APL). Multidimensional flow cytometry made possible the prompt introduction of ATRA in two cases with M3v, who also represent the first pediatric APL patients in Hungary to be treated with arsenic-trioxide. Besides joining multinational pediatric AML treatment groups, our future aims include the introduction of centralized treatment centers and diagnostic facilities. Abstract Outcome measures of pediatric acute myeloid leukemia (AML) improved considerably between 1990 and 2011 in Hungary. Since 2012, efforts of the Hungarian Pediatric Oncology-Hematology Group (HPOG) included the reduction in the number of treatment centers, contemporary diagnostic procedures, vigorous supportation, enhanced access to hematopoietic stem cell transplantation (HSCT), and to targeted therapies. The major aim of our study was to evaluate AML treatment results of HPOG between 2012 and 2019 with 92 new patients registered (52 males, 40 females, mean age 7.28 years). Two periods were distinguished: 2012–2015 and 2016–2019 (55 and 37 patients, respectively). During these periods, 2 y OS increased from 63.6% to 71.4% (p = 0.057), and the 2 y EFS increased significantly from 56.4% to 68.9% (p = 0.02). HSCT was performed in 37 patients (5 patients received a second HSCT). We demonstrate advances in the diagnosis and treatment of acute promyelocytic leukemia (APL) in two cases. Early diagnosis and follow-up were achieved by multidimensional flow cytometry and advanced molecular methods. Both patients were successfully treated with all-trans retinoic acid and arsenic-trioxide, in addition to chemotherapy. In order to meet international standards of pediatric AML management, HPOG will further centralize treatment centers and diagnostic facilities and join efforts with international study groups.

Absztrakt: A familiaris myelodysplasias szindroma (FMDS) egy ritka, klinikailag rendkivul heterogen megjelenesű orokletes korkep. Az FMDS hattereben altalaban prediszpozicios szindromak allnak, mel...

The majority of haematological malignancies represent sporadic diseases, but hereditary entities with predisposing genetic alterations have also been described. Diseases of the myeloid and lymphoid cell lineages with genetic predispositions are associated with heterogeneous clinical manifestations, with many symptoms being specific for certain cytogenetic and molecular aberrations. Apart from the myeloid predisposition syndromes with clear Mendelian inheritance patterns, cases with ambiguous predisposing factors are also known, but their role in hereditary leukemogenesis is still poorly understood. The presence of these genetic lesions is usually associated with an increased risk of familial malignancies and often leads to familial disease aggregation. Lymphoid malignancies often lack the disease-associated germline pathogenic variants, with their propensity to familial aggregation being most likely explained by their complex genotype serving as a hereditary base to many sporadic diseases. The heterogeneous clinical features and the large number of potentially affected genes tend to make the diagnosis of hereditary haematological malignancies difficult, however the elevated familial risk caused by predisposing genetic alterations underlines the importance of testing for individuals and families with genetic susceptibility.

Contains fulltext : 219893.pdf (Publisher’s version ) (Closed access) BACKGROUND: Treatment of venous thromboembolism in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. The aim of our study was to compare the efficacy and safety of rivaroxaban versus standard anticoagulants in children with venous thromboembolism. METHODS: In a multicentre, parallel-group, open-label, randomised study, children (aged 0-17 years) attending 107 paediatric hospitals in 28 countries with documented acute venous thromboembolism who had started heparinisation were assigned (2:1) to bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants (heparin or switched to vitamin K antagonist). Randomisation was stratified by age and venous thromboembolism site. The main treatment period was 3 months (1 month in children /=1 dose), were centrally assessed by investigators who were unaware of treatment assignment. Repeat imaging was obtained at the end of the main treatment period and compared with baseline imaging tests. This trial is registered with ClinicalTrials.gov, number NCT02234843 and has been completed. FINDINGS: From Nov 14, 2014, to Sept 28, 2018, 500 (96%) of the 520 children screened for eligibility were enrolled. After a median follow-up of 91 days (IQR 87-95) in children who had a study treatment period of 3 months (n=463) and 31 days (IQR 29-35) in children who had a study treatment period of 1 month (n=37), symptomatic recurrent venous thromboembolism occurred in four (1%) of 335 children receiving rivaroxaban and five (3%) of 165 receiving standard anticoagulants (hazard ratio [HR] 0.40, 95% CI 0.11-1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (p=0.012). Major or clinically relevant non-major bleeding in participants who received >/=1 dose occurred in ten (3%) of 329 children (all non-major) receiving rivaroxaban and in three (2%) of 162 children (two major and one non-major) receiving standard anticoagulants (HR 1.58, 95% CI 0.51-6.27). Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were similar to those in rivaroxaban studies in adults. There were no treatment-related deaths. INTERPRETATION: In children with acute venous thromboembolism, treatment with rivaroxaban resulted in a similarly low recurrence risk and reduced thrombotic burden without increased bleeding, as compared with standard anticoagulants. FUNDING: Bayer AG and Janssen Research & Development. 01 januari 2020

Abstract: Introduction: Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes. Aim: To analyse and compare the results of treatment before and after our joining. Method: A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia. Results: In the whole patient cohort, the time from diagnosis to treatment was median 92 (3–393) days, while in severe aplastic anemia median 28 (3–327) days only. Grade II–IV acute graft versus host disease occurred in 22.6%, grade III–IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1–62.5) months. There was a remarkable increase in overall survival comparing the data before (1992–2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome. Conclusion: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710–1719.

Hematopoietic stem cell transplantation (HSCT)–associated thrombotic microangiopathy (TA-TMA) is a multifactorial complication, and its prediction is largely unresolved. Our aim was to analyze changes of complement profile after HSCT to identify potential markers of TA-TMA development. Thirty-three consecutive pediatric patients (9.6 ± 4.4 years old) who underwent allogeneic HSCT due to malignant (n = 17) or nonmalignant (n = 16) indications were included in this study. Graft-versus-host disease (GVHD) was diagnosed using Glucksberg criteria, viral reactivation was monitored, 5 different TA-TMA diagnostic criteria were applied, and all important clinical and laboratory parameters of TA-TMA activity were registered. Complement pathway activities, components and terminal pathway activation marker (sC5b-9) levels were systematically measured before transplantation and on days 28, 56, and 100 after HSCT. During the first 100 days after HSCT, 1 of 33 patients died (day 50, multiple organ failure), whereas 10 subjects met the criteria for TA-TMA, typically on day 61 (range, 16 to 98 days). TA-TMA was preceded by acute GVHD in 3 of 10 patients, by viral reactivation in 2 of 10, or by both in 4 of 10 cases. Baseline sC5b-9 levels did not differ in patients without (200 [interquartile range, 144 to 266] ng/mL), or with (208 [interquartile range, 166 to 271] ng/mL) subsequent TA-TMA; however, on day 28 significant differences were observed (201 [interquartile range, 185 to 290] ng/mL versus 411 [interquartile range, 337 to 471] ng/mL; P = .004). Importantly, all 10 patients with TMA showed increase in sC5b-9 level from baseline level to day 28, whereas in patients without TMA the same tendency was observed for only 9 of 23 patients (P = .031). No additional complement parameters were closely associated with the development of TA-TMA. Development of TA-TMA occurred in 30% of our patients, typically after GVHD and/or viral reactivation. However, early raise of sC5b-9 activation marker was predictive for later development of TA-TMA, and should therefore be considered as an alarming sign necessitating a careful monitoring of all TA-TMA activity markers. Further studies enrolling a higher number of patients are necessary to determine if terminal pathway activation is an independent predictor of TA-TMA.

Viral reactivation is a frequent complication of allogeneic hematopoietic stem cell transplantation especially in children. For refractory cases, rapid virus-specific T-cell therapy would be ideally implemented within a few days. Over the course of a year in our pediatric cohort of 43 allogeneic transplantation, 9 patients fulfilled criteria for virus-specific T-cell therapy. Viral infections were due to cytomegalovirus (CMV) in 3, Epstein-Barr virus (EBV) in 2, and adenovirus (AdV) in 1 case, whereas >1 virus was detected in 3 cases. Viral diseases necessitating a T-cell therapy were CMV pneumonitis and colitis, AdV enteritis and cystitis, and EBV-induced posttransplantation lymphoproliferative disease. Cells were produced by the CliniMACS Prodigy CCS (IFN-gamma) System within 24 hours after mononuclear leukapheresis. Eight patients became completely asymptomatic, whereas 7 also cleared the virus. Six patients are alive without viral illness or sequelae demonstrating viral DNA clearance in peripheral blood with a median follow-up of 535 (350-786) days. One patient with CMV pneumonitis died of respiratory insufficiency. In 2 cases the viral illness improved or cleared, however, the patients died of invasive aspergillosis. No cases of graft-versus-host disease, rejection, organ toxicity, or recurrent infection were noticed. Virus-specific T-cell therapy implemented by the CliniMACS Prodigy CCS (IFN-gamma) System is an automated, fast, safe, and probably effective way to control resistant viral diseases after pediatric hematopoietic stem cell transplantation.

Abstract: Hematopoietic stem cell transplantation associated thrombotic microangiopathy is a multifactorial complication, and has variable incidence in study populations due to different diagnostic criteria. The diversity of activity parameters, like elevated laktát-dehidrogenáz, hematological parameters and kidney function are not specific variables after stem cell transplantation. Dysregulation of the classical and alternative pathway can play an important role in the pathomechanism of thrombotic microangiopathy, but the understanding of the role of complement activation under transplantation conditions requires further investigation. Monitoring of complement parameters, including terminal complement pathway activation complex during transplantation may help physicians to improve diagnostic strategy, to evaluate therapeutical options and to predict and follow up efficacy of complement blockade methods and supportive therapy. This review focuses on the development of diagnostic criteria and therapeutical options in thrombotic microangiopathy, and presents some preliminary findings while using different diagnostic criteria in pediatric patients. Orv Hetil. 2017; 158(27): 1043–1050.

Although genetic predisposition to haematological malignancies has long been known, genetic testing is not yet the part of the routine diagnostics. In the last ten years, next generation sequencing based studies identified novel germline mutations in the background of familial aggregation of certain haematologic disorders including myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). This is supported by the fact that the myeloid neoplasms with genetic predisposition represent a new category in the revised 2016 World Health Organization classification. According to the new classification, these disorders are subdivided based on the clinical and genetic features, including myeloid neoplasms with germline predisposition alone, or with pre-existing platelet disorder, cytopaenias or other organ failures. The predisposing genetic factors include mutations in the RUNX1, CEBPA, GATA2, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 genes. The genes affected in these syndromes are important regulators of haemopoiesis and are frequently implicated in leukaemogenesis, providing deeper insight into the understanding of normal and malignant haemopoiesis. Despite the growing knowledge of germline predisposing events in the background of familial myeloid malignancies, the germline genetic component is still unknown in a subset of these pedigrees. Here, we present the first study of inherited myeloid malignancies in Hungary. We identified three families with apparent clustering of myeloid malignancies with nine affected individuals across these pedigrees. All tested individuals were negative for CEBPA, GATA2, RUNX1, ANKRD26, ETV6, DDX41, TERC or TERT and SRP72 mutations, suggesting the presence of so far unidentified predisposing mutations.

Erdheim-Chester disease (ECD) is a rare histiocytic disorder, characterized by the xanthomatous infiltration of tissues by CD68-positive and CD1a-/CD100-negative foamy histiocytes. In childhood, ECD is exceptionally rare, and only a dozen cases have been published so far. The cooccurence of Langerhans cell histiocytosis (LCH) and ECD is even rarer. Here, we report a 2-year-old boy, the youngest patient in the literature so far, who was diagnosed with concomitant BRAF mutation-positive LCH and ECD. In his case, conventional LCH treatment proved to be ineffective, but he is the youngest patient who was successfully treated with the BRAF inhibitor vemurafenib.

BACKGROUND AND OBJECTIVES Administration of virus-specific T cells (VSTs) is a viable antiviral treatment strategy after allogeneic HSCT, even if conventional therapies fail. Third-party donors are often chosen for the generation of the VST product. The eligibility of the donor has to be tested in a rigorous donor screening procedure, since the isolation technology only targets pre-existing VSTs. MATERIALS AND METHODS In a period of 3 years, we performed 32 VST treatments for 28 patients. Targeting four different viruses, 284 healthy individuals underwent 417 donor screening procedures. VSTs were counted by flow cytometry detecting interferon-gamma (IFN-γ) producing T cells. Generation of the VSTs was performed from leukapheresis products in a fully automated and closed system using magnetic cell separation. RESULTS The mean circulating VST frequencies ranged from 0·006% to 0·328%. The average yield of viable VSTs in the product was 1·83·106 cells, while the average VST dose calculated for the patient's body weight was 4·63·104 /kg. The mean purity - percentage of VSTs within the T cells - of all T-cell products was 62·9%. Correlation was identified between the frequency of the VSTs in the peripheral blood of the donor and the VST numbers of the end product; the strongest correlation was seen for CMV. CONCLUSION This paper focuses on the T-cell donors, highlighting some key points on the donor selection process. Based on the findings in connection with the CMV therapies, peripheral VST seems to be the best predictor of the VST content of the final product administered to the patient.

Background: Treatment of venous thromboembolism (VTE) in children is based on data obtained in adults with little direct documentation of its efficacy and safety in children. Methods: In a parallel-group open-label randomised study, 500 children aged birth to 17 years with documented acute VTE who had started heparinisation were assigned, in a 2:1 ratio, to receive bodyweight-adjusted rivaroxaban (tablets or suspension) in a 20-mg equivalent dose or standard anticoagulants. The main treatment period was 3 months (1 month in children under 2 years with catheter-related VTE). Symptomatic recurrent VTE and bleeding were centrally assessed unaware of treatment assignment. Repeat imaging was obtained at the end of the treatment period. Findings: Recurrent VTE was the primary efficacy outcome and occurred in 4 of the 335 (1.2%) children allocated to rivaroxaban and in 5 of the 165 (3.0%) children allocated to standard anticoagulants (64.2% of whom received subcutaneous heparins only), for a hazard ratio of 0.40 (95% confidence interval, 0.11 to 1.41). Repeat imaging showed an improved effect of rivaroxaban on thrombotic burden as compared with standard anticoagulants (P=0.012). Major or clinically relevant non-major bleeding was the principal safety outcome and occurred in 10 children (3.0%; all non-major) with rivaroxaban and in 3 children (1.9%; two major and 1 non-major) with standard anticoagulants. Absolute and relative efficacy and safety estimates of rivaroxaban versus standard anticoagulation estimates were comparable those obtained in rivaroxaban studies in adults. Interpretation: In children with acute VTE, treatment with rivaroxaban resulted in a low recurrence risk and a reduced thrombotic burden without increased bleeding, as compared to standard anticoagulants. Trial Registration: This trial is registered with ClinicalTrials.gov, number NCT02234843. Funding Statement: Bayer AG and Janssen Research & Development, LLC. Declaration of Interests: CM reports receiving personal fees and fees, paid to his institution, from Bayer, Bristol-Myers-Squibb, Pfizer and fees, paid to his institution, from BoehringerIngelheim; AWAL being employed by Bayer; RK receiving personal fees from Bayer, CSL Behring, and Kedrion; DB receiving personal fees and grant support from Actelion Pharmaceuticals, Bayer, Eli Lilly, BMS, and Novartis and grant support from AbbVie; PC receiving personal fees from Onyx Health Limited; AKC receiving personal fees from Bayer and fees, paid to his institution, from Bayer, Pfizer, Daiichi Sankyo, and Bristol-Myers-Squibb; GK receiving personal fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo and fees, paid to her institution from Pfizer; SH receiving personal fees from P and fees, paid to her institution, from Bayer, Pfizer, and Daiichi Sankyo; AS receiving personal fees from Bayer, Pfizer, Daiichi Sankyo and Boehringer Ingelheim; PA receiving personal fees and fees, paid to his institution, from Abbvie and Bayer, and fees paid to his institution from Actelion, Novartis, and Daiichi Sankyo; EC receiving personal fees from Boehringer Ingelheim and Bristol-Myers-Squibb, and fees, paid to her institution from Bayer, Pfizer, and Daiichi Sankyo; DLY receiving fees, paid to his institution, from Bayer, Pfizer, and Bristol-Myers Squibb; OL receiving personal fees from Bayer, Pfizer, Boehringer Ingelheim, and Novartis, and fees, paid to her institution, from Bayer; JB-W receiving personal fees and fees, paid to his institution, from Bayer, Daiichi Sankyo, DOASENSE and Portola and fees, paid to his institution, from Pfizer; TTB receiving fees from Boehringer Ingelheim and Bayer, and grant support from Leo Pharma; IM receiving fees from Sanofi and Bayer; MP receiving grant support from Pfizer and Sobi; MPM receiving personal fees from Bayer; GY receiving receiving personal fees from GlaxoSmithKline and Portola and personal fees and fees paid to his institution from Bayer and Daiichi Sankyo; AFP, MM, WTS, SDB, KT, DK being employed by Bayer; JH was employed by Bayer; MC receiving grant support from and serving on a data and safety monitoring board for Bayer, receiving advisory board fees from Shionogi, Octapharma, Bristol-Myers Squibb Canada, and Asahi Kasei, receiving educational funding from Alexion Pharmaceuticals, Pfizer, CSL Behring, and Diagnostica Stago, receiving grant support, paid to his institution, from Leo Pharma, serving on a data and safety monitoring board for Daiichi Sankyo, owning stock in Alnylam Pharmaceuticals, and receiving educational funding and advisory board fees from Servier Canada; MHP receiving personal fees from Bayer; no other potential conflict of interest relevant to this article was reported. Ethics Approval Statement: The protocol was approved by the institutional review board at each participating center. Written permission from a parent or guardian and, when appropriate, child assent, were obtained.

Myelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia. Orv. Hetil., 2016, 157(8), 283–289.

Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes.To analyse and compare the results of treatment before and after our joining.A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia.In the whole patient cohort, the time from diagnosis to treatment was median 92 (3-393) days, while in severe aplastic anemia median 28 (3-327) days only. Grade II-IV acute graft versus host disease occurred in 22.6%, grade III-IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1-62.5) months. There was a remarkable increase in overall survival comparing the data before (1992-2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome.Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710-1719.Absztrakt: Bevezetés: A gyermekkori szerzett csontvelő-elégtelenségek ritka, kezelés nélkül halálos betegségek. Egységes diagnosztikájukat és terápiájukat európai munkacsoport felügyeli. A munkacsoport bevezette a hypocellularis gyermekkori refrakter cytopenia entitást, melyet csökkentett intenzitású kondicionálással transzplantálva lényegesen jobb túlélési eredményeket kaptak. Célkitűzés: A protokollhoz csatlakozás előtt és az azóta eltelt 5 évben kezelt betegek eredményeinek ismertetése. Módszer: A 2013 és 2017 között eltelt 5 évben a Magyar Gyermekonkológiai Hálózat 8 központjában 55 gyermeket kezeltünk (súlyos aplasticus anaemia: 9, myelodysplasticus szindróma: 41, juvenilis myelomonocyter leukaemia: 5). Súlyos aplasticus anaemiában 7 esetben végeztünk őssejt-transzplantációt, egy esetben antithymocytaglobulin-kezelést, egy beteg a diagnózis előtt meghalt. Myelodysplasiában 37 esetben végeztünk transzplantációt, 4 esetben a szoros megfigyelést választhattuk. E transzplantációk 54%-a (20 eset) csökkentett intenzitású kondicionálással történt. A juvenilis myelomonocyter leukaemiában szenvedő 5 betegnél transzplantáció történt. Eredmények: A diagnózis és a kuratív kezelés között eltelt idő medián 92 (3–393) nap volt, súlyos aplasticus anaemia esetén 28 (3–327) nap. Akut graft versus host betegség II–IV. fokozatú súlyossággal 22,6%, III–IV. fokozatú súlyossággal 6,8%-ban jelentkezett, míg betegeink 11,2%-a krónikus graft versus host betegségben szenvedett. A súlyos aplasticus anaemiával kezelt 8 beteg mindegyike teljes remisszióban él (100%). A myelodysplasia miatt transzplantált betegek becsült túlélése 85,1%, juvenilis myelomonocyter leukaemiában 75%. A medián követési idő 30,4 (1,1–62,5) hónap volt. Jelen eredményeinket összevetettük az 1992 és 2012 között kezelt betegek eredményeivel. A túlélés az új szemlélet nyomán jelentősen javult, súlyos aplasticus anaemiában trendszerűen 70%-ról 100%-ra (p = 0,133), myelodysplasticus szindrómában szignifikánsan 31,3%-ról 85,1%-ra (p = 0,000026). Következtetés: Paradigmaváltás történt a gyermekkori szerzett csontvelő-elégtelenségek kezelésében, a betegcsoport túlélése szignifikánsan növekedett. Orv Hetil. 2018; 159(42): 1710–1719.

Primary CNS PTLD is an extremely rare complication after allogeneic HSCT. At our centre, an 11-year-old patient developed nausea, vomiting, and diplopy on day +82 following HSCT. On brain MRI, multiple white matter lesions were seen. Histology showed a diffuse large B-cell lymphoma with high load of EBV in tissue. Despite stopping immunosuppression, treatment with EBV-specific cytotoxic T cells, systemic rituximab, HD-MTX, and intrathecal chemotherapy, progression was observed. With a combination of HD-MTX and cytarabine, only a partial response could be achieved. Having all conventional modalities not only failed but resulted in significant toxicity, a salvage monotherapy with biweekly nivolumab has been instituted. The starting dose was 1.1 mg/kg, later escalated to 2.2 mg/kg. After 8 months of nivolumab therapy, PET-CT showed complete metabolic remission. Subsequently, the patient has been switched to a maintenance dosage of 1.1 mg/kg. No cytopenias, graft failure, GvHD, or any other alloimmune complications were seen during nivolumab therapy. In conclusion, nivolumab may be considered as an effective and safe option for CNS PTLD therapy when all other modalities have failed.

In antithymocyte globulin (ATG) treated patients occasionally bradycardia has been noticed. Therefore, we retrospectively analyzed the occurrence of bradycardia in ATG-treated children. Using medical records between 2007 and 2012 we identified children undergoing a combined therapy with ATG and glucocorticoids (ATG group, n = 22). The incidence of bradycardia was compared to that registered in children treated with glucocorticoids alone (glucocorticoid alone group, n = 21). Heart rates (HR) were registered before and on days 0–3, 4–7 and 8–14 after the ATG or steroid administration. The rate of bradycardic episodes was higher during ATG therapy than in the steroid alone group, while severe bradycardia occurred only in the ATG group (97 versus 32, p = 0.0037, and 13 versus 0, p = 0.0029, respectively). There was an interaction between the time and treatment group on HR (p = 0.046). Heart rates in ATG and steroid alone groups differed significantly on day 0–3 and day 4–7 (p = 0.046, p = 0.006, respectively). Within the ATG group HR was lower on days 4–7 compared to the days before and the days 8–14 values (p

Hematopoietic stem cell transplantation associated thrombotic microangiopathy is a multifactorial complication, and has variable incidence in study populations due to different diagnostic criteria. The diversity of activity parameters, like elevated laktát-dehidrogenáz, hematological parameters and kidney function are not specific variables after stem cell transplantation. Dysregulation of the classical and alternative pathway can play an important role in the pathomechanism of thrombotic microangiopathy, but the understanding of the role of complement activation under transplantation conditions requires further investigation. Monitoring of complement parameters, including terminal complement pathway activation complex during transplantation may help physicians to improve diagnostic strategy, to evaluate therapeutical options and to predict and follow up efficacy of complement blockade methods and supportive therapy. This review focuses on the development of diagnostic criteria and therapeutical options in thrombotic microangiopathy, and presents some preliminary findings while using different diagnostic criteria in pediatric patients. Orv Hetil. 2017; 158(27): 1043-1050.

Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.

The biological therapy of Crohn's disease, such as infliximab is a powerful approach in the therapy of inflammatory bowel diseases. However, in some patients with aggressive disease course, even a combined immunosuppressive therapy will not result in permanent remission. Hematopoietic stem cell transplantation has emerged as a new potential therapeutic tool for inflammatory bowel diseases. The authors report the case of a 15-year-old boy with severe Crohn's disease resistant to combined immunosuppressive therapy. After a 3-years course of unsuccessful conventional therapy including infliximab, autologous hematopoietic stem cell transplantation was performed which resulted in a complete remission. One year after transplantation the patient has relapsed, but he could be treated effectively with conventional therapy regiments. To the best of knowledge of the authors, this is the first report in Hungary presenting hematopoietic stem cell therapy in patient with severe Crohn's disease.A Crohn-betegség pontos oka ismeretlen, így terápiája sem megoldott. Kezelésében az infliximab jelentős áttörést jelentett, a mindennapi gyakorlatban azonban vannak olyan betegek, akik a kombinált immunszuppresszív, illetve biológiai terápia ellenére sem kerülnek remisszióba. Ezekben az esetekben új esélyt jelenthet az őssejt-transzplantáció. A szerzők egy 15 éves fiúgyermek történetét mutatják be, akinél 2008 februárjában súlyos Crohn-betegséget (aktivitási index [PCDAI]: 82,5 – maximumérték: 100) kórisméztek. Konzervatív kezelésének 3 éve alatt a kombinált terápia (immunszuppresszió, antibiotikum, infliximab) ellenére sem került tartós remisszióba. Az ígéretes külföldi esetközlések nyomán autológ őssejt-transzplantációt végeztek, amely a Crohn-betegség remisszióját eredményezte. Egy évvel az őssejt-transzplantáció után az alapbetegség relapsusa jelentkezett, amely a korábbiakhoz képest lényegesen enyhébb, konzervatív terápiával uralható formában zajlott. A szerzők tudomása szerint hazánkban még nem végeztek őssejt-transzplantációt terápiarezisztens Crohn-betegség kezeléseként, amely – noha végleges gyógyulást nem jelentett – terápiás alternatíva lehet súlyos, refrakter esetekben. Orv. Hetil., 2014, 155(20), 789–792.

Background: Inotuzumab ozogamicin (InO) is a CD22-directed monoclonal antibody linked to calicheamicin. It is approved for adults with relapsed/refractory (R/R) CD22+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL) at the dose of 1.8 mg/m2/course fractionated at day 1, 8 and 15 (Kantarjian, NEJM, 2016). The pediatric experience with InO is still limited. Patients (pts) We collected cases of infants and young children diagnosed with R/R ALL and treated with InO via a compassionate access program. Methods: Participating international pediatric oncology centers submitted retrospective demographic, outcome, and toxicity data on infants (age Results: Between 2015 and 2019, 9 infants and 3 children (1.0-2.9 years of age) were diagnosed with ALL and later on received 1-3 cycles of InO due to R/R disease. At the time of InO treatment 1 pt was At the start of InO, 8 (67%) pts had an M3 bone marrow status, 2 (17%) an M2 and 2 an M1 with MRD positivity. CD22 expression was reported in 7/12 pts: in 3 cases >90% of blasts expressed CD22, the others ranging from 52% to 80%. In total 21 courses were administered (60 doses; 3 courses not completed), median administered dose of InO per course 1.74 mg/m2 (divided in 3 weekly doses, with the loading dose at D1 of cycle 1): 6 pts received 1.8 mg/m2 (adult approved dose), 4 intermediate dosages as 1.5 or 1.6 mg/m2, 1 1.4 mg/m2 and 1 1.2 mg/m2. The dose was based on BSA; 0.07 mg/Kg/course was the median pro-Kg dose administered (higher than in adults). 6 pts (50%) achieved a complete remission (CR) (3 after 1 course and 3 after 2-3 courses), 1 additional MRD-positive pt. turned MRD-negative ( Only limited data about toxicity were reported in our records, although hematologic toxicity was the most common (thrombocytopenia in 33% of pts). 1 case of neurotoxicity described as toxic leukoencephalopathy was reported after 1 course of InO, causing death in CR. 1 pt. developed severe veno-occlusive disease (VOD) after HSCT performed in PR, which was fatal. Conclusions: Single agent InO in infants and younger children had a CR rate of 58% in this cohort of heavily pretreated pts. Even with a median dose close to the adult recommended starting dose, InO appeared to be well tolerated, allowing a subsequent HSCT in 5 pts. While taking into account the lower CD22 expression showed by MLL-r pts, further investigation with InO treatment might be valuable in this subgroup of ALL pts with a particular dismal prognosis. Disclosures Pieters: medac: Consultancy; jazz farmaceuticals: Consultancy. Zwaan:Celgene: Consultancy, Research Funding; Roche: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Servier: Consultancy; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Jazz pharmaceuticals: Other: Travel support; Incyte: Consultancy. OffLabel Disclosure: Inotuzumab ozogamicin (InO) is a CD22-directed monoclonal antibody linked to calicheamicin. It is approved for adults with relapsed/refractory (R/R) CD22+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL) at the dose of 1.8 mg/m2/course fractionated at day 1, 8 and 15 (Kantarjian, NEJM, 2016). The pediatric experience with InO is still limited. Patients (pts)

Myelodysplastic syndrome and acute myeloid leukaemia are mainly sporadic diseases, however, rare familial cases exist. These disorders are considered rare, but are likely to be more common than currently appreciated, and are characterized by the autosomal dominant mutations of hematopoietic transcription factors. These syndromes have typical phenotypic features and are associated with an increased risk for developing overt malignancy. Currently, four recognized syndromes could be separated: familial acute myeloid leukemia with mutated CEBPA, familial myelodysplastic syndrome/acute myeloid leukemia with mutated GATA2, familial platelet disorder with propensity to myeloid malignancy with RUNX1 mutations, and telomere biology disorders due to mutations of TERC or TERT. Furthermore, there are new, emerging syndromes associated with germline mutations in novel genes including ANKRD26, ETV6, SRP72 or DDX41. This review will discuss the current understanding of the genetic basis and clinical presentation of familial leukemia and myelodysplasia.

Lesch-Nyhan syndrome (LNS) is a chronic, progressive neurodevelopmental disorder causing motor and behavioral dysfunction due to decreased synthesis of the enzyme hypoxantine-guanine phosphoribosyltransferase (HPRT). Affected boys have mental retardation, delayed development, extrapyramidal motor disturbances and self-injuring behavior. As hematopoietic stem cell transplantation (HSCT) has been shown to be effective in several neurodevelopmental inborn errors, we hypothesized that it could be favorable in LNS as well. Following a myeloablative conditioning regimen (busulphan 3.2 mg/kg/day for 4 days, cyclophosphamide 60 mg/kg/day for 2 days with ATG Thymoglobin 2.5 mg/kg/day for 4 days) an unrelated umbilical cord blood unit was transfused at the age of 2 years. The graft was a 6/6 HLA-matched at HLA-A, B loci by antigen level, and at DRB1 by allelic level typing. Infused total nucleated cell dose was 3.6 × 10e7 per kilogram body weight. Serum HPRT levels reached normal values by the end of the sixth month post transplant. Slow neurodevelopmental improvement seen during the three-year follow-up and the missing self-injuring behavior can be considered as a proof for the presence of enzyme-competent cells behind the blood-brain barrier.

Hereditary predisposition has been ever since implicated in the etiology of childhood myelodysplastic syndromes (MDS). Until recently, GATA2 deficiency prevailed as a major germline cause in pediatric primary MDS. In the past 2 years, we and others identified germline mutations in paralogue genes SAMD9 and SAMD9L residing on chromosome 7q21.2 as new systemic diseases with high propensity for MDS with monosomy 7. Although initially, mutations in SAMD9 and SAMD9L genes were associated with MIRAGE and Ataxia-Pancytopenia syndromes, respectively, with recent reports the phenotypes are becoming more intertwined. Nevertheless, the predisposition to MDS with monosomy 7 (-7) remains a common clinical denominator. Both genes are categorized as negative regulators of cellular proliferation and mutations were shown to be activating. Because of their high evolutionary divergence, classical in silico prediction is erratic, thereby establishing in vitro testing as the current gold standard for pathogenicity evaluation. The objectives of this study were to define the prevalence of SAMD9/9L germline mutations in primary pediatric MDS, and to describe the clinical phenotype and outcome. In addition, we aimed to characterize the somatic mutational architecture and develop a functional scoring system. Within the cohort of 548 children and adolescents with primary MDS diagnosed between 1998 and 2016 in Germany, 43 patients (8%) carried SAMD9/9L mutations that were mutually exclusive with GATA2 deficiency and known constitutional bone marrow (BM) failure. MDS type refractory cytopenia of childhood was diagnosed in 91% (39/43), and MDS with excess blasts in 9% (4/43) of mutated cases. Karyotype at diagnosis was normal in 58%, and -7 was detected in 37% of SAMD9/9L cohort. Within MDS subgroup with -7 (n=74), SAMD9/9L mutations accounted for 22% of patients. Notably, the demographics, familial disease, diagnostic blood and BM findings, overall survival (OS) and the outcome after HSCT were not influenced by mutational status in our study cohort (n=548). At the last follow up, 88% (38/43) of SAMD9/9L MDS patients were alive; 35/43 had been transplanted with a 5-year-OS of 85%. Next, we added 26 additional cases with SAMD9/9L mutations diagnosed in Europe within EWOG-MDS studies. In the total cohort of 69 germline mutated patients we found a total of 75 SAMD9/9L mutations, of which 67 were novel. Of those we tested 47 using a HEK293 cell in vitro system and 45/47 mutants inhibited proliferation. While 53/69 patients carried only single germline mutations (missense in 50/53 and truncating in 3/53), in the remaining 16 patients, 11 additional truncating and 7 missense mutations were found. We did not observe an association between germline mutation and phenotype. Immunological issues (e.g. recurring infections, low Ig) were described in 32%/50% of SAMD9/9L-mutated patients, while physical anomalies were very heterogeneous and reported in ~50% of patients in both mutational groups. Intriguingly, genital phenotypes occurred in 40% of SAMD9L, while neurological problems were present in 30% of SAMD9 - mutational subgroups. To elucidate the somatic mutational landscape, we performed whole exome and deep sequencing of 58 SAMD9/9L patients and identified recurrent somatic mutations in known oncogenes that were earlier associated with pediatric MDS: SETBP1 (10%), RUNX1 (7%), ASXL1 (5%), EZH2 (5%), CBL (3%). The identified somatic mutations occurred in association with monosomy 7 background (18/20). Finally, we utilized the results from functional testing of the 47 SAMD9/9L variants as our test cohort to develop combinatorial in silico scoring. The rationale was to decrease the dependency on functional validation. Based on the results of 20 in silico tools we could concatenate a matrix of 5 algorithms to resolve the pathogenicity of >80% of variants. Using this model, all variants predicted as pathogenic showed also growth-restrictive effect in vitro. In summary, pathogenic SAMD9/9L germline mutations account for 8% of primary pediatric MDS and 22% of MDS/-7. The mutations identified are heterogeneous and their effect can be predicted using a combinatorial in silico - in vitro approach. Finally, the clinical outcome and somatic mutational landscape are not influenced by the mutational status. Disclosures Locatelli: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Niemeyer:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background Germline mutations in the N-terminal of CCAAT/enhancer binding protein α (CEBPA) are a feature of autosomal dominant AML. Despite the strong penetrance of these mutations, the age of disease onset varies considerably and is usually precipitated by acquiring a C-terminal mutation. Although biallelic CEBPA-mutations in sporadic AML are associated with favorable clinical outcomes, little is known about long-term survival or the secondary molecular events linked with familial cases. Aims We sought to establish the long term clinical outcomes in familial CEBPA-mutated AML and to examine the patterns of secondary mutations associated with leukemic transformation. Methods and Results Disease specific and follow up information was collected in 16 affected patients, from 7 pedigrees, published between 2004 and 2011. In 94% of patients (n=15), at least 3 years follow up was achieved. All pedigrees had a germline N-terminal CEBPA mutation and 17 of 18 documented disease episodes had an acquired C-terminal mutation. The age at AML diagnosis varied from 2-39 years (median 24.5 yrs) with a single asymptomatic carrier detected (now 23 yrs). With the exception of 1 patient diagnosed in 1963, all cases received combination chemotherapy at diagnosis. Additional consolidation comprised autologous stem cell transplantation (SCT, n=3) and allogeneic SCT in 1 patient failing to achieve CR post induction therapy. Ten patients had at least 1 further disease episode, the first recurrence presenting after a median of 2.1 years (range 0.5-14 yrs), 5 continued in CR and 1 patient was lost to follow up. In 3 out of 4 patients, where CEBPA was screened at recurrence, the acquired C-terminal mutations differed from diagnosis, signifying new episodes of AML. The median overall survival (OS) for the entire cohort was 20 years (1.1-46 yrs, n=16) and 17.3 years for patients with multiple disease episodes, reflecting durable responses to second line therapies. To identify potential co-operating mutations in CEBPA pedigrees, whole exome sequencing (WES) was performed in 7 tumor samples from 5 patients across 3 pedigrees, all with the germline mutation p.P23fs (Figure 1). All tumor DNA samples were sequenced with matched remission or skin DNA as a germline control. The number of acquired mutations in familial tumors was similar to sporadic disease, with 10-22 (median=14) non-synonymous tier 1 mutations per sample. In addition to the acquired C-terminal CEBPA mutation, these included established AML loci such as EZH2, TET2, WT1, GATA2, NRAS, CSF3R and the recently identified cohesin complex gene, SMC3. Of note, FLT3-ITD, NPM1 and DNMT3A mutations were absent in all tumors. A minimum of 2 established mutations were identified in each tumor and, at present, we can only speculate on which additional mutations are ‘driver' or ‘passenger' events. Reflecting findings in sporadic AML, biallelic CEBPA and GATA2 mutations co-occurred in both siblings from Pedigree 1 and were subsequently identified by Sanger sequencing in the child III.2 (Figure 1). All 3 patients continue in long term remission following chemotherapy. We were able to trace the clonal evolution in patient I.2 (Pedigree 3) by WES of 3 consecutive tumor samples which arose over a 17 year period. At diagnosis (Dx) the patient received induction and consolidation chemotherapy and remained disease free for 14 years. The second disease episode (R1) was treated with chemotherapy followed by autologous SCT and the third presentation (R2) was chemo-refractory. Tumor DNA from R2 was clonally related to Dx, sharing 7 identical mutations, including the original C-terminal CEBPA deletion. In contrast, R1 appeared molecularly distinct from Dx and R2, most likely representing a new clone which was subsequently eradicated with treatment. Conclusion This is the first report of long term clinical outcomes in familial CEBPA-mutated AML. Although many patients experienced disease recurrence, our extended follow up showed that OS remained favorable despite multiple episodes of disease. Assessment of C-terminal CEBPA mutations provided a unique insight into the recurrence of AML, with some patients appearing to develop completely new leukemic episodes. Although the penetrance of germline mutations is high, healthy carriers and late onset disease are noted, emphasizing the need for clinical vigilance and screening of all related potential SCT donors. Disclosures: No relevant conflicts of interest to declare.