Browsing by Subject "AML"

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  • Singh, Abhishek A.; Mandoli, Amit; Prange, Koen H. M.; Laakso, Marko; Martens, Joost H. A. (2017)
    Chromosomal translocations are one of the hallmarks of acute myeloid leukemia (AML), often leading to gene fusions and expression of an oncofusion protein. Over recent years it has become clear that most of the AML associated oncofusion proteins molecularly adopt distinct mechanisms for inducing leukemogenesis. Still these unique molecular properties of the chimeric proteins converge and give rise to a common pathogenic molecular mechanism. In the present study we compared genome-wide DNA binding and transcriptome data associated with AML1-ETO, CBFB-MYH11 and PML-RARA oncofusion protein expression to identify unique and common features. Our analyses revealed targeting of oncofusion binding sites to RUNX1 and ETS-factor occupied genomic regions. In addition, it revealed a highly comparable global histone acetylation pattern, similar expression of common target genes and related enrichment of several biological pathways critical for maintenance of AML, suggesting oncofusion proteins deregulate common gene programs despite their distinct binding signatures and mechanisms of action.
  • Løhmann, Ditte J. A.; Asdahl, Peter H.; Abrahamsson, Jonas; Ha, Shau-Yin; Jónsson, Ólafur G.; Kaspers, Gertjan J. L.; Koskenvuo, Minna; Lausen, Birgitte; De Moerloose, Barbara; Palle, Josefine; Zeller, Bernward; Sung, Lillian; Hasle, Henrik (2019)
    Background Associations between body mass index (BMI), outcome, and leukemia-related factors in children with acute myeloid leukemia (AML) remain unclear. We investigated associations between pretherapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML. Methods We included patients, age 2-17 years, diagnosed with de novo AML from the five Nordic countries (2004-2016), Hong Kong (2007-2016), the Netherlands and Belgium (2010-2016), and Canada and USA (1995-2012). BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Kaplan-Meier estimator, Cox regression, and logistic regression were used to investigate associations. Results In total, 867 patients were included. The median age was 10 years (range 2-17 years). At diagnosis, 32 (4%) were underweight, 632 (73%) were healthy weight, 127 (15%) were overweight, and 76 (9%) were obese. There was no difference in relapse risk, treatment-related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age, and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1-3.4) and 2.8 (95% CI 1.3-5.8), respectively, compared to healthy weight patients. Conclusions This study did not confirm previous reports of associations between overweight and increased treatment-related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status.
  • Olgac, Ezgi (Helsingin yliopisto, 2022)
    Background– The BCL-2 protein family members are major regulators of apoptosis, and the anti-apoptotic (pro-survival) members of the family is commonly targeted with BH3 mimetic drugs in haematological cancers. However, these treatments have not been very impactful when administered as single agents and they have long been investigated for combination therapy with other agents. Acute myeloid leukaemia (AML) is one of the difficult-to-cure haematological malignancies. A recently approved therapy for AML consists of the combinatorial administration of venetoclax (a selective BCL-2 inhibitor) and a DNA methyltransferase (DNMT) inhibitor such as azacitidine or decitabine. Although this novel therapy has shown promising clinical results, the majority of the patients still relapse under this treatment. These relapsed patients typically become highly resistant to treatment and have poor prognosis, emphasising the need for new effective drug combinations. Apart from BCL-2, other family members like BCL-xL and MCL1 are also common targets of BH3-mimetic drugs. This project thus aims to understand and characterise the resistance against BH3-mimetics and investigate new therapeutic approaches to overcome the challenges of resistance. Aims– This study aims (i) to characterise BH3-resistant AML cell lines for uncovering the mechanisms of drug resistance, and (ii) to identify possible combination treatment options for overcoming drug-resistance. Methods– Viability assays with Cell Titer Glo® (CTG) and Drug Sensitivity and Resistance Testing (DSRT). The long-term effectiveness of venetoclax, azacitidine and talazoparib (a PARP inhibitor) as single agents, double combinations and triple combination were investigated with Time-to-Progression (TTP) assay. For the resistant cell line models, underlying resistance mechanisms were assessed by checking protein expression of pro- and/or anti-apoptotic members of the BCL-2 family members with western blot (WB). Real-time quantitative PCR (RT-qPCR) and WB were carried out for transcriptional and translational expression analyses of certain DNA damage-associated genes in PARP inhibitor-resistant cell lines. Results– Drug screening with DSRT has revealed promising results for two combination treatments of a BCL-xL inhibitor (A-1331852) (i) with an Aurora kinase A inhibitor (alisertib) and (ii) with an MCL1 inhibitor (S63845) for BCL-xL inhibitor-resistant cells. WB analyses of BCL-2 family members showed translational upregulation of un-inhibited members of the anti-apoptotic proteins in BH3-mimetic-resistant cell lines. A venetoclax-resistant AML cell line showed increased levels of the DNA damage marker P-γ-H2Ax upon treatments containing venetoclax, as well as increased levels of cleaved-PARP1, indicating induction of apoptosis. RT-qPCR analyses revealed increased mRNA expression of PARP1 in two resistant cell lines, whereas no significant expression changes in other DNA repair mechanism genes on the transcriptional level. Conclusions– In BH3-mimetic-resistant AML cell lines, apoptosis is avoided through translational upregulation of un-inhibited anti-apoptotic members of the BCL-2 family, and this resistance can be countered by combination treatment for additional inhibition of the compensatory anti-apoptotic proteins. Venetoclax is still effective on cells resistant to it, by inducing DNA damage and sensitising these cells against inhibitors of the members of DNA repair pathway. The transcriptional upregulation of PARP1 and the increase in its auto-catalytic activity suggests the DNA damage-inducing effects of the triple combination treatment [Ven + Aza + Tal].
  • Shimoni, Avichai; Labopin, Myriam; Savani, Bipin; Byrne, Michael; Volin, Liisa; Finke, Jurgen; Niederwieser, Dietger; Ehninger, Gerhard; Blaise, Didier; Beelen, Dietrich; Tabrizi, Reza; Sengeloev, Henrik; Ganser, Arnold; Cornelissen, Jan J.; Mohty, Mohamad; Nagler, Arnon (2019)
    Allogeneic stem cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated donors (MUDS) in recent years. However, there are limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older patients with AML. We analyzed these outcomes in a large cohort of patients with AML (n = 1134), age >= 50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n = 848) or MUDs (n = 286), with a median follow-up of 8.9 years. The median age was 56 and 58 years after SCT from siblings and MUDs, respectively (P=.005). In the sibling group, 77%, 12%, and 11% were in first complete remission (CR1), second complete remission (CR2), and active leukemia at SCT compared with 50%, 25%, and 25% in the MUD group, respectively (P
  • Hajkarim, Morteza Chalabi; Karjalainen, Ella; Osipovitch, Mikhail; Dimopoulos, Konstantinos; Gordon, Sandra L.; Ambri, Francesca; Rasmussen, Kasper Dindler; Gronbaek, Kirsten; Helin, Kristian; Wennerberg, Krister; Won, Kyoung-Jae (2022)
    Large-scale multiparameter screening has become increasingly feasible and straightforward to perform thanks to developments in technologies such as high-content microscopy and high-throughput flow cytometry. The automated toolkits for analyzing similarities and differences between large numbers of tested conditions have not kept pace with these technological developments. Thus, effective analysis of multiparameter screening datasets becomes a bottleneck and a limiting factor in unbiased interpretation of results. Here we introduce compaRe, a toolkit for large-scale multiparameter data analysis, which integrates quality control, data bias correction, and data visualization methods with a mass-aware gridding algorithm-based similarity analysis providing a much faster and more robust analyses than existing methods. Using mass and flow cytometry data from acute myeloid leukemia and myelodysplastic syndrome patients, we show that compaRe can reveal interpatient heterogeneity and recognizable phenotypic profiles. By applying compaRe to high-throughput flow cytometry drug response data in AML models, we robustly identified multiple types of both deep and subtle phenotypic response patterns, highlighting how this analysis could be used for therapeutic discoveries. In conclusion, compaRe is a toolkit that uniquely allows for automated, rapid, and precise comparisons of large-scale multiparameter datasets, including high-throughput screens.
  • European Soc Blood Marrow Transpla; HOVON-SAKK (2018)
    Background. Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). Aims. The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. Materials and Methods. We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. Results. In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P <0.001), patient age (P = 0.012), time interval from CR1 to transplant (P <0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P <0.001), presence of FLT3-ITD mutation (P <0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P <0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). Discussion and Conclusion. Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.
  • Lin, Wei Yu; Fordham, Sarah E.; Hungate, Eric; Sunter, Nicola J.; Elstob, Claire; Xu, Yaobo; Park, Catherine; Quante, Anne; Strauch, Konstantin; Gieger, Christian; Skol, Andrew; Rahman, Thahira; Sucheston-Campbell, Lara; Wang, Junke; Hahn, Theresa; Clay-Gilmour, Alyssa I.; Jones, Gail L.; Marr, Helen J.; Jackson, Graham H.; Menne, Tobias; Collin, Mathew; Ivey, Adam; Hills, Robert K.; Burnett, Alan K.; Russell, Nigel H.; Fitzgibbon, Jude; Larson, Richard A.; Le Beau, Michelle M.; Stock, Wendy; Heidenreich, Olaf; Alharbi, Abrar; Allsup, David J.; Houlston, Richard S.; Norden, Jean; Dickinson, Anne M.; Douglas, Elisabeth; Lendrem, Clare; Daly, Ann K.; Palm, Louise; Piechocki, Kim; Jeffries, Sally; Bornhäuser, Martin; Röllig, Christoph; Altmann, Heidi; Ruhnke, Leo; Kunadt, Desiree; Wagenführ, Lisa; Cordell, Heather J.; Darlay, Rebecca; Andersen, Mette K.; Fontana, Maria C.; Martinelli, Giovanni; Marconi, Giovani; Sanz, Miguel A.; Cervera, José; Gómez-Seguí, Inés; Cluzeau, Thomas; Moreilhon, Chimène; Raynaud, Sophie; Sill, Heinz; Voso, Maria Teresa; Lo-Coco, Francesco; Dombret, Hervé; Cheok, Meyling; Preudhomme, Claude; Gale, Rosemary E.; Linch, David; Gaal-Wesinger, Julia; Masszi, Andras; Nowak, Daniel; Hofmann, Wolf Karsten; Gilkes, Amanda; Porkka, Kimmo; Milosevic Feenstra, Jelena D.; Kralovics, Robert; Grimwade, David; Meggendorfer, Manja; Haferlach, Torsten; Krizsán, Szilvia; Bödör, Csaba; Stölzel, Friedrich; Onel, Kenan; Allan, James M. (2021)
    Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 x 10(-8); KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 x 10(-10); HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA). Genome wide association studies in cancer are used to understand the heritable genetic contribution to disease risk. Here, the authors perform a genome wide association study in European patients with acute myeloid leukemia and identify loci associated with risk of developing the disease.
  • Silventoinen, Kristiina (Helsingin yliopisto, 2019)
    Tiivistelmä Referat – Abstract Akuutti myelooinen leukemia (AML) on geneettisesti heterogeeninen hematologinen tauti, jossa epäkypsät solut, blastit, valtaavat tilaa luuytimessä. WHO:n määritelmän mukaan leukemiassa blasteja on luuytimessä tai perifeerisessä veressä > 20%. Blastien lisääntyminen luuytimessä johtaa punasolujen, verihiutaleiden ja valkosolujen tuotannon vähenemiseen ja altistaa vuodoille, anemialle, kivuille sekä infektioille ja johtaa lopulta potilaan menehtymiseen. Hematologisiin kantasoluihin kerääntyy mutaatiota, jotka altistavat leukemian synnylle. Aikaisempien tutkimusten perusteella tiedetään, että inflammaatiolla on merkitystä mutaatioiden kehittymisessä ja syövän synnyssä, ja tämä on osoitettu niin kiinteiden kasvainten kuin hematologisten syöpien osalta. Tutkimme vuosina 2010-2017 Helsingin ja Uudenmaan sairaalan (HUS) hematologisella klinikalla AML-diagnoosin saaneiden potilaiden eksomit, ja etsimme niistä patologisia variantteja inflammaatiota säätelevissä geeneissä. Eksomit analysoitiin Suomen molekyylilääketieteen instituutissa (FIMM) ja analyysin käytettiin laskennallisia arvoja, (predicition score), jotka ennustavat geenien yhden emäksen muutosten eli snippien (SNV) sekä insertioiden että deleetioiden patogeenisuutta. Keskityimme alle 1 %:lla suomalaisessa väestössä esiintyviin variantteihin. Tarkastelun alla olevat geenit vaikuttavat usealla eri mekanismilla inflammaation syntyyn ja kävimme läpi 40 geeniä. 24 %:lla kohortin potilaista löytyi yhteensä 22 eri geenistä 32 erilaista patogeenistä varianttia. Lisäksi löysimme kuusi mahdollisesti uutta patologista varianttia. Tulos on merkittävä ja viittaa siihen että inflammaatiolla voi olla merkitystä AML:n kehittymisessä Jatkotutkimukset suuremmalla aineistolla sekä geenipaneelilla ovat aiheellisia tulosten varmistamiseksi.
  • Koenecke, Christian; Goehring, Gudrun; de Wreede, Liesbeth C.; van Biezen, Anja; Scheid, Christof; Volin, Liisa; Maertens, Johan; Finke, Juergen; Schaap, Nicolaas; Robin, Marie; Passweg, Jakob; Cornelissen, Jan; Beelen, Dietrich; Heuser, Michael; de Witte, Theo; Kroeger, Nicolaus; MDS Subcomm Chronic Malignancies (2015)
    The aim of this study was to determine the impact of the revised 5-group International Prognostic Scoring System cytogenetic classification on outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia who were reported to the European Society for Blood and Marrow Transplantation database. A total of 903 patients had sufficient cytogenetic information available at stem cell transplantation to be classified according to the 5-group classification. Poor and very poor risk according to this classification was an independent predictor of shorter relapse-free survival (hazard ratio 1.40 and 2.14), overall survival (hazard ratio 1.38 and 2.14), and significantly higher cumulative incidence of relapse (hazard ratio 1.64 and 2.76), compared to patients with very good, good or intermediate risk. When comparing the predictive performance of a series of Cox models both for relapse-free survival and for overall survival, a model with simplified 5-group cytogenetics (merging very good, good and intermediate cytogenetics) performed best. Furthermore, monosomal karyotype is an additional negative predictor for outcome within patients of the poor, but not the very poor risk group of the 5-group classification. The revised International Prognostic Scoring System cytogenetic classification allows patients with myelodysplastic syndromes to be separated into three groups with clearly different outcomes after stem cell transplantation. Poor and very poor risk cytogenetics were strong predictors of poor patient outcome. The new cytogenetic classification added value to prediction of patient outcome compared to prediction models using only traditional risk factors or the 3-group International Prognostic Scoring System cytogenetic classification.
  • Schmaelter, Ann-Kristin; Labopin, Myriam; Socie, Gerard; Itälä-Remes, Maija; Blaise, Didier; Yakoub-Agha, Ibrahim; Forcade, Edouard; Cornelissen, Jan; Ganser, Arnold; Beelen, Dietrich; Labussiere-Wallet, Helene; Passweg, Jakob; Savani, Bipin N.; Schmid, Christoph; Nagler, Arnon; Mohty, Mohamad (2020)
    Following chemotherapy, secondary acute myeloid leukemia (sAML), occurring after antecedent hematologic diseases, previous chemotherapy or radiation, has an inferior prognosis compared with de novo AML. To define the outcome of sAML in the context of allogeneic stem cell transplantation (alloSCT), a retrospective, registry-based comparison was performed, including 11,439 patients with de novo and 1325 with sAML. Among transplants in first complete remission (CR1) (n = 8,600), the 3-year cumulative incidence of relapse (RI) and non-relapse mortality (NRM) was 28.5% and 16.4% for de novo, and 35% and 23.4% for sAML. Three-year overall survival (OS), leukemia-free survival (LFS) and Graft-versus-Host Disease/relapse-free survival (GRFS) was 60.8%, 55.1%, and 38.6% for de novo, and 46.7%, 41.6%, and 28.4% for sAML, respectively. In multivariate analysis, sAML was associated with a lower OS (HR = 1.33 [95% CI = 1.21-1.48]; p <10(-5)), LFS (HR = 1.32 [95% CI = 1.19-1.45]; p <10(-5)) and GRFS (HR = 1.2 [95% CI = 1.1-1.31]; p <10(-4)) and higher NRM (HR = 1.37 [95% CI = 1.17-1.59]; p <10(-4)) and RI (HR = 1.27 [95% CI = 1.12-1.44]; p <10(-3)). Results of the Cox model were confirmed in a matched-pair analysis. In contrast, results did not differ between de novo and sAML after alloSCT in induction failure or relapse. Hence, this analysis identified sAML as an independent risk factor for outcome after alloSCT in CR1.
  • Canaani, Jonathan; Labopin, Myriam; Socie, Gerard; Nihtinen, Anne; Huynh, Anne; Cornelissen, Jan; Deconinck, Eric; Gedde-Dahl, Tobias; Forcade, Edouard; Chevallier, Patrice; Bourhis, Jean H.; Blaise, Didier; Mohty, Mohamad; Nagler, Arnon (2017)
    Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3-ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the European Society of Blood and Marrow Transplantation. A cohort of 357 patients with hyperleukocytosis (159 patients with white blood count [WBC] 50 K-100 K, 198 patients with WBC >= 100 K) was compared to 918 patients without hyperleukocytosis. Patients with hyperleukocytosis were younger, had an increased rate of favorable risk cytogenetics, and more likely to be FLT3 and NPM1 mutated. In multivariate analysis, hyperleukocytosis was independently associated with increased relapse incidence (hazard ratio [HR] of 1.55, 95% confidence interval [CI], 1.14-2.12; P = .004), decreased leukemia-free survival (HR of 1.38, 95% CI, 1.07-1.78; P = .013), and inferior overall survival (HR of 1.4, 95% CI, 1.07-1.84; P = .013). Hyperleukocytosis retains a significant prognostic role for AML patients undergoing HSCT.
  • Shimoni, Avichai; Labopin, Myriam; Savani, Bipin; Volin, Liisa; Ehninger, Gerhard; Kuball, Jurgen; Bunjes, Donald; Schaap, Nicolaas; Vigouroux, Stephane; Bacigalupo, Andrea; Veelken, Hendrik; Sierra, Jorge; Eder, Matthias; Niederwieser, Dietger; Mohty, Mohamad; Nagler, Arnon (2016)
    Background: Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods: We analyzed long-term outcomes in a cohort of 1423 AML patients, age >= 50 years, after SCT from HLA-matched siblings, during the years 1997-2005, median follow-up 8.3 years (0.1-17). Results: The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27-35) and 32 % (28-35) after MAC and RIC, respectively (P = 0.57). The 10-year GVHD/relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18-25) and 21 % (18-24), respectively (P = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65-76) and 73 % (67-78) after MAC and RIC, respectively (P = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions: Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.
  • Al Hamed, Rama; Labopin, Myriam; Daguindau, Etienne; Niittyvuopio, Riitta; Huynh, Anne; Socie, Gerard; Srour, Micha; Bourhis, Jean Henri; Kroeger, Nicolaus; Tholouli, Eleni; Choi, Goda; Poire, Xavier; Martin, Hans; Rubio, Marie-Therese; Jindra, Pavel; Blaise, Didier; Beelen, Dietrich; Labussiere-Wallet, Helene; Nagler, Arnon; Bazarbachi, Ali; Mohty, Mohamad (2022)
    Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age >= 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10(-5) and HR 1.71, p < 10(-5), respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score >= 90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10(-5)), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score >= 90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.
  • Schmid, Christoph; de Wreede, Liesbeth C.; van Biezen, Anja; Finke, Juergen; Ehninger, Gerhard; Ganser, Arnold; Volin, Liisa; Niederwieser, Dietger; Beelen, Dietrich; Alessandrino, Paolo; Kanz, Lothar; Schleuning, Michael; Passweg, Jakob; Veelken, Hendrik; Maertens, Johan; Cornelissen, Jan J.; Blaise, Didier; Gramatzki, Martin; Milpied, Noel; Yakoub-Agha, Ibrahim; Mufti, Ghulam; Rovira, Montserrat; Arnold, Renate; de Witte, Theo; Robin, Marie; Kroeger, Nikolaus (2018)
    No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation (P
  • Canaani, Jonathan; Labopin, Myriam; Itälä-Remes, Maija; Blaise, Didier; Socie, Gerard; Forcade, Edouard; Maertens, Johan; Wu, Depei; Malladi, Ram; Cornelissen, Jan J.; Huynh, Anne; Bourhis, Jean Henri; Esteve, Jordi; Mohty, Mohamad; Nagler, Arnon (2019)
    Baseline cytogenetic studies at diagnosis remain the single most important determinant of outcome in patients with acute myeloid leukemia (AML). However, the prognostic role of the complete gamut of cytogenetic aberrations in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently undefined. In addition, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Using the ALWP/EBMT registry we conducted a retrospective analysis to determine the clinical outcomes of AML patients undergoing allo-HSCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-HSCT from either a matched sibling or a matched unrelated donor. Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Trisomy 14, del(9q), and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Our analysis supports the added prognostic significance of FLT3-ITD to baseline cytogenetics in patients undergoing allo-HSCT.
  • Awad, Shady Adnan; Dufva, Olli; Ianevski, Aleksandr; Ghimire, Bishwa; Koski, Jan; Maliniemi, Pilvi; Thomson, Daniel; Schreiber, Andreas; Heckman, Caroline A.; Koskenvesa, Perttu; Korhonen, Matti; Porkka, Kimmo; Branford, Susan; Aittokallio, Tero; Kankainen, Matti; Mustjoki, Satu (2021)
    Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations,RUNX1mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate thatPHF6andBCORL1mutations,IKZF1deletions, and AID/RAG-mediated rearrangements are enriched inRUNX1(mut)BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primaryRUNX1(mut)CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity ofRUNX1(mut)blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells fromRUNX1(mut)patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygousRUNX1(-/-)and heterozygousRUNX1(-/mut)BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role ofRUNX1mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treatingRUNX1(mut)BP-CML patients.
  • Poire, Xavier; Labopin, Myriam; Polge, Emmanuelle; Volin, Liisa; Finke, Juergen; Ganser, Arnold; Blaise, Didier; Yakoub-Agha, Ibrahim; Beelen, Dietrich; Forcade, Edouard; Lioure, Bruno; Socie, Gerard; Niederwieser, Dietger; Labussiere-Wallet, Helene; Maertens, Johan; Cornelissen, Jan; Craddock, Charles; Mohty, Mohamad; Esteve, Jordi; Nagler, Arnon (2020)
    Monosomy 7 or deletion 7q (-7/7q-) is the most frequent adverse cytogenetic features reported in acute myeloid leukemia (AML), and is a common indication for allogeneic stem cell transplantation (SCT). Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion of chromosome 3 (inv(3)), the presence of which may influence the outcomes after SCT. A total of 1109 patients were allocated to this study. Two-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. Two-year probability of non-relapse mortality (NRM) was 20%. We defined five different cytogenetic subgroups: the "-7/7q- +/- CK group- designated group1," the "MK group-designated group 2," the "-5/5q- group- designated group 3," the "abn(17p) group- designated group 4" and the "inv(3) group- designated group 5." The 2-year probability of LFS in first remission was 48% for group 1, 36.4% for group 2, 28.4% for group 3, 19.1% for group 4 and 17.3% for group 5, respectively (P <.001). Multivariate analysis confirmed those significant differences across groups. Note, SCT in -7/7q- AML provides durable responses in one third of the patients. The presence of -7/7q- with or without CK in the absence of MK, abn(17p) or inv (3) is associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of patients with poor prognosis even after SCT.
  • Heikura, Henri Hannu Juhani (Helsingin yliopisto, 2021)
    Tämä tutkielma käsittelee rahanpesun ehkäisemistä ja etenkin raportointivelvollisten yritysten ja yksityissektorin roolia siinä. Tutkielma käsittelee rahanpesua yleistasolla, moderneja rahanpesun muotoja, ja vaikutuksia yhteiskunnalle. Tämän lisäksi tutkielma esittelee EU-lainsäädäntöä aiheeseen liittyen erityisesti EU:n neljättä, viidettä ja kuudetta rahanpesudirektiiviä, ja niiden asettamia vaatimuksia. Tutkielma esittelee ja arvioi yritysten AML-compliance prosesseja kuten asiakkaan tunnistamista, riskiarvion tekemistä, tilitapahtumien seurantaa sekä epäilyttävien tapahtumien raportointia. Tämän lisäksi, tutkielma arvioi rahanpesun ehkäisemistä corporate governance – näkökulmasta, sekä arvioi compliance-prosessista syntyviä kuluja sekä riskejä yrityksille, sekä näiden perusteella rahanpesun ehkäisemisen tehokkuutta. Johtavatko nämä varsin tiukat vaatimukset ja korkeat compliance-kulut tehokkaaseen lopputulokseen? This master’s thesis discusses and analyzes the topic of anti-money laundering, and especially the role of obliged entities and private sector. The thesis will introduce the general topic of money laundering, its modern methods, impact to the society and why preventing money laundering is of utmost importance. The thesis will present the relevant EU legislation, from which the obligations for obliged entities spring from, mainly, the fourth, fifth and sixth anti-money laundering directives. In addition to presenting the phases of companies’ compliance processes such as know your customer, risk assessment, transaction monitoring and suspicious activity reporting, the thesis will analyze the issue from a point of view of corporate governance and evaluate the costs and risks for obliged entities, and on the basis of these, the efficiency of the framework and process for prevention of money laundering. Do strict requirements towards obliged entities and their high compliance costs lead to an efficient result in preventing money laundering.
  • Lohmann, Ditte J. A.; Asdahl, Peter H.; Abrahamsson, Jonas; Ha, Shau-Yin; Jonsson, Olafur G.; Kaspers, Gertjan J. L.; Koskenvuo, Minna; Lausen, Birgitte; De Moerloose, Barbara; Palle, Josefine; Zeller, Bernward; Hasle, Henrik (2019)
    Background Supportive-care use of granulocyte colony-stimulating factor (G-CSF) in pediatric acute myeloid leukemia (AML) remains controversial due to a theoretical increased risk of relapse and limited impact on neutropenic complications. We describe the use of G-CSF in patients treated according to NOPHO-AML 2004 and DB AML-01 and investigated associations with relapse. Procedure Patients diagnosed with de novo AML completing the first week of therapy and not treated with hematopoietic stem cell transplantation in the first complete remission were included (n = 367). Information on G-CSF treatment after each course (yes/no) was registered prospectively in the study database and detailed information was gathered retrospectively from each center. Descriptive statistics were used to describe G-CSF use and Cox regression to assess the association between G-CSF and risk of relapse. Results G-CSF as supportive care was given to 128 (35%) patients after 268 (39%) courses, with a large variation between centers (0-93%). The use decreased with time-the country-adjusted odds ratio was 0.8/diagnostic year (95% confidence interval [CI] 0.7-0.9). The median daily dose was 5 mu g/kg (range 3-12 mu g/kg) and the median cumulative dose was 75 mu g/kg (range 7-1460 mu g/kg). Filgrastim was used in 82% of G-CSF administrations and infection was the indication in 44% of G-CSF administrations. G-CSF was associated with increased risk of relapse-the adjusted hazard ratio was 1.5 (95% CI 1.1-2.2). Conclusions G-CSF as supportive care was used in a third of patients, and use decreased with time. Our results indicate that the use of G-CSF may be associated with an increased risk of relapse.