bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS969 HYPOMETHYLATING DRUGS SPECIFICALLY TARGET DNMT3A MUTATION ASSOCIATED CLONAL HEMATOPOIESIS AND ACUTE MYELOID LEUKEMIA
Authors: Scheller‐Wendorff M. , Ludwig A.K. , Rohde C. , Staeble S. , Kraemer S. , Bäumer N. , Arnold C. , Zaugg J. , Lipka D.B. , Müller‐Tidow C. 
Published: June 2019

Background:DNMT3A mutations commonly occur in myeloid malignancies and in clonal hematopoiesis. The codon arginine 882 (R882) is the major hotspot mutation in patients with de novo AML, in secondary AML as well as in individuals with clonal hematopoiesis in the absence of leukemic transformation. Although the majority of patients with DNMT3A‐R882H AML initially respond to conventional chemotherapy, many of them subsequently relapse, suggesting that DNMT3A‐R882H cells persist and drive relapse. No specific therapy exists to date for clonal hematopoiesis or DNMT3A‐R882H mutated AML. Recent studies have shown that DNMT inhibitors (DNMTi) could be particularly beneficial for patients with DNMT3A mutations. However, the extent of this association, the potential to cure patients and the mechanisms remain unresolved.Aims:Our aim is to identify in which context leukemic and pre‐leukemic stem cells with DNMT3A‐R882 mutation can be targeted by DNMT‐inhibitors as mono‐therapy and in combination.Methods:In order to understand the molecular and functional consequences of the DNMT3A‐R882H mutation in leukaemogenesis we generated a novel, inducible knock‐in mouse line of human DNMT3A‐R882H mutations (DNMT3AR882H). DNMT3AR882H knock‐in mice that harbored a floxed stop cassette upstream of the Dnmt3a gene were crossed with mice carrying an interferon‐inducible Cre recombinase allele (Mx1‐Cre). Upon Cre induction the endogenous mouse Dnmt3a gene from exon 2 was efficiently replaced by human DNMT3A cDNA carrying the R882H mutation.Results:Analysis of aged DNMT3AR882H knock‐in mice at pre‐leukemic stage revealed accumulation of myeloid progenitor (GMP) and stem cells (HSC), which showed loss of dormancy, increased cell cycle and exhaustion in serial retransplantation in vivo. Using mouse model of leukemia by mouse‐intercross and retroviral infection, we have confirmed that DNMT3AR882H mutation accelerated leukaemogenesis in the presence of FLT3‐ITD, MLL‐AF9 and Myc‐Bcl2, whereas DNMT3AR882H mutation alone did not induce leukemia in mice up to eighteen months after Cre induction.In search of therapeutic strategies, we identified that DNMTi specifically target DNMT3A‐R882H mutant pre‐leukemic HSC and leukemic blasts. Loss of DNA methylation in DNMT3A‐R882H HSCs associated with enhanced immune signals including increased expression of endogenous retrovirus (ERV) transcripts, increased cytosolic dsRNA, and activation of an IFN‐inducing cellular response. A single therapy cycle of low dose DNMTi (5‐Azacytidine) treatment accelerated loss of DNA methylation in DNMT3A‐R882H HSCs and exhaustion of DNMT3A‐R882H mutant hematopoiesis. 5‐Azacytidine in combination with chemotherapy induced long lasting remissions in DNMT3A‐R882H murine leukemias.Summary/Conclusion:These findings may open the path towards targeted therapy of DNMT3A mutated clonal hematopoiesis and AML.
PS1006 INHIBITORS OF HOXA9 LEUKEMOGENIC TRANSCRIPTION FACTOR ARE EFFICIENT ON HUMAN AML CELL MODELS BUT NOT ON NORMAL HUMAN BONE MARROW CD34+ HEMATOPOIETIC CELLS
Authors: Lambert M. , Depauw S. , Jambon S. , Bellart M. , Lutchmee L. , Louis‐Thérèse L. , Nhili R. , David‐Cordonnier M.‐H. 
Published: June 2019

Background:The HOXA9 protein is a transcription factor associated with normal hematopoiesis and which expression on hematopoietic stem cells and progenitor cells decreases in the course of blood cell differentiation. The expression of HOXA9 is however maintained at high level in several subtypes of acute myeloid leukemia (AML) such as mll‐rearranged leukemias, NPM1‐mutated AMLs and AML presenting MYST3‐CREBP, NUP98‐NSD1 or RUNX/EVI1 translocations. The over‐expression of HOXA9 in these AML subtypes is associated with the maintenance of cell proliferation and the blockade of cell differentiation. It is well known that HOXA9 exerts its leukemic potential through DNA interaction and, therefore, we selected direct inhibitors of HOXA9/DNA interaction to block its activity and evaluate them on a murine leukemia cell model (Depauw et al., 2019).Aims:In order to go further, we aim at evaluating them on human AML cell models expressing or not HOXA9 and on normal human CD34+ hematopoietic cells to address any potential effect of our inhibitors on normal hematopoiesis.Methods:The expression level of HOXA9 was quantified by qRT‐PCR on a series of human AML cell lines. The sensitivity of those cell lines regarding two selected inhibitors was seen addressed using global cell survival analysis using MTS reaction. Methylcellulose clonogenic assays were performed on a series of human AML cell lines and on normal human bone marrow CD34+ hematopoietic cells. Knock‐down of HOXA9 expression was performed as a control using lentiviral delivery of HOXA9‐specific or control shRNAs.Results:A strong correlation between HOXA9 expression and the sensitivity to two of our inhibitors was evidenced in a series of 14 human AML cell lines with linear determination coefficients of R of ∼0.75 and ∼0.8.Clonogenic assays evidenced a decrease in the number and size of the colony forming units of treated related to untreated AML cell models. The relevance of HOXA9 expression in the clonogenicity is addressed by use of lentivirally transduced shHOXA9 in some of the AML cell models. By contrast, no difference were observed on either the number, the size and the differentiation subtypes of the colonies obtained from treated versus untreated normal human CD34+ hematopoietic cells.Summary/Conclusion:In conclusion, we selected inhibitors of HOXA9/DNA interaction that alter cell proliferation and clonogenic activity in a series of HOXA9‐positive AML cell models but that do not affect the progenitor cell number from normal bone marrow CD34+ cells.
PS1044 THE PROGNOSTIC SIGNIFICANCE OF BCR‐1 AND BCR‐3 ISOFORM OF PML‐RARA AND FLT3‐ITD IN PATIENTS WITH ACUTE PROMYELOCYTIC LEUKEMIA
Authors: Rasekh E. , Elsayed G. , Madney Y. , Gammal M. El 
Published: June 2019

Background:Acute promyelocytic leukemia (APL) has a characteristic peculiar morphologic, genetic features and more favorable outcome.Aims:is to study the differential effect of BCR‐1 and BCR‐3 isoforms of PML‐RARA together with FLT3‐ITD mutational status on outcome of APL patients.Methods:All patients referred to the outpatient medical and pediatric oncology clinic, National cancer institute (NCI), Cairo University, Egypt in the period from May 2012 to January 2018. The diagnosis of APL was based on morphologic examination of the bone marrow and peripheral blood smears and was confirmed by the detection of the PML‐RARA transcript by FISH and RT‐PCR.Results:the study included 118 patients with newly diagnosed de novo APL (71 (60%) adults and 47 (39.8%) children). Based on the initial TLC, pediatric APL patients have higher (48.9%) risk than adults (30%) (p = 0.044). The CR rate was 91% (77/84), after excluding early induction related deaths (18) and patients who did not receive treatment at NCI (no beds available) (16). All pediatric patients (both BCR‐1 and BCR‐3) and all adult patients with BCR‐3 achieved CR while 22/28 (78.5%) of patients with BCR‐1 achieved CR (p = 0.04). Adult patients with FLT3 mutation (5/8 = 62.5%) received more high‐risk regimen than patients with wild FLT3‐ITD (10/38 = 26.3%)(p = 0.047). FLT3‐ITD mutation was associated with more hemorrhage and DIC (p = 0.038), and lower 2‐year OS (96% v 44.6%)(p = 0.001) in pediatric patients. Also DIC and Hemorrhage are associated with lower 2‐year OS in pediatric patients (91.4% v 48.6%)(p <  0.001). The 1‐year and 2‐year OS for pediatric patients were better than adults (56.2% v 83% and 80.7 % v 49.8% respectively) with a median of 39.4 month versus 12month respectively (p = 0.005). On multivariate analysis, Age was an independent prognostic variable affecting survival, HR 2.6 (95% CI 1.3–5.3, P = 0.007)(adults had hazards ratio of death 2.6 times higher than pediatrics). DIC & FLT3‐ITD were independent prognostic variables affecting survival in the pediatric APL with HR 12.3 (95% CI 1.46–104.61, P = 0.021) and 5.2 (95% CI 1.01–26.95, P = 0.048) respectively.Summary/Conclusion:BCR‐1 isoform of PML‐RARA is associated with decreased response to ATRA‐based regimens in adult APL patients. DIC & FLT3‐ITD are adverse prognostic factors in pediatric APL patients. Age is an independent prognostic factor in APL patients (whole group). Despite higher high risk groups in pediatric patients, the outcome is better than adult patients.image
PS1062 PEDIATRIC ACUTE MYELOID LEUKEMIA (AML) IN DEVELOPING COUNTRIES, BARRIERS AGAINST BETTER OUTCOME 10 YEARS’ EXPERIENCE AMONG EGYPTIAN PEDIATRIC ACUTE MYELOID LEUKEMIA
Authors: Madney Y. , Ezzelden N. , Elsharkawy N. 
Published: June 2019

Background:Pediatric AML outcome improved significantly with current survival rates of 70% in developed countries. The outcome of childhood AML in developing countries still lacking.Aims:The aim of the study to assess the causes of mortality and survival outcomes among pediatric AML patients in countries with limited resources.Methods:Retrospective analysis of 344 pediatric AML (2007 ‐ 2016) treated at National Cancer Institute, Egypt including 3 phases protocols with different aims and hypothesis.Results:From 2007–2010, Less intensified induction chemotherapy without antimicrobial prophylaxis,103 patients enrolled, Complete remission (CR) post induction 1(55%), Refractory disease (34%) and induction mortality (11%). End of study;Relapse 40 %. Mortality 63 patients (61%):(42%) disease‐related (DRM), (42%) infection related (IRM) and (14%) toxicity related (TRM). 70% had fungal infections. 2 years DFS 27% and OS 30%.From 2011‐ 2013, Hypothesis was Antimicrobial prophylaxis can help for a better outcome,136 patients enrolled used less intensified induction but with levofloxacin and voriconazole prophylaxis. CR rate induction 1 was 75%, refractory disease (17%) and induction mortality was 8%. End of study: Relapse 16%. Mortality in 86(63%) patients: 57 % IRM mostly multidrug resistance (MDR) gram‐negative bacteremia while DRM 33%. 10% had fungal infections but still poor 3y DFS (34%) and OS (37%).From 2014–2016, Hypothesis was intensified induction chemotherapy with antimicrobial prophylaxis can be a better solution; 105 patients enrolled, Post induction1, CR 48%, refractory disease 8% and induction mortality 44%. End of study; Relapse rate 6%, Mortality 88(80%) patients: IRM was 72% with MDR gram‐negative bacteremia was the main cause of deaths (62%), DRM 4% and TRM 4% with poor 2y DFS 34% and OS 24%.Summary/Conclusion:A significant gap in the outcomes of pediatric AML as compared to those reported developed countries. The balance between treatment intensification and toxicity are needed. Infections are the major barrier against better outcome needs more strict guidelines protocols.
PS1073 PRELIMINARY RESULTS OF ASTX660, A NOVEL NON‐PEPTIDOMIMETIC CIAP1/2 AND XIAP ANTAGONIST, IN RELAPSED/REFRACTORY PERIPHERAL T‐CELL LYMPHOMA AND CUTANEOUS T CELL LYMPHOMA
Authors: Mehta A. , Hollebecque A. , Foss F. , Lister J. , Mita M. , Wagner‐Johnston N. , Dyer M.J. , You B. , Prica A. , Hernandez‐Llizaliturri F. , Ferraldeschi R. , Chan D. , Zhang J. , Samaniego F. 
Published: June 2019

Background:ASTX660 is an oral, novel non‐peptidomimetic, small‐molecule antagonist of cellular/X‐linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first‐in‐human phase 1‐2 study in patients (pts) with advanced solid tumors and lymphoma (ClinicalTrials.gov NCT02503423). In the phase 1 part of the study, the recommended phase 2 dose (RP2D) was identified with a favorable safety profile and initial evidence of clinical activity in a pt with mycoses fungoides (Mita et al, presented at the AACR‐NCI‐EORTC Conference 2017, abs #A091).Aims:Herein, we report preliminary efficacy and safety results from the ongoing relapsed/refractory (r/r) peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL) Phase 2 cohorts.Methods:Pts receive treatment with ASXT660 at the RP2D 180 mg/day on Days 1 to 7, and 15 to 22 in a 28‐day cycle. The primary endpoint is response rate as assessed by the investigator according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03.Results:As of 15 January 2019, 16 PTCL pts and 13 CTCL pts have received ASTX660. Pt characteristics: median (range) age: PTCL: 59 (39–81) years and CTCL: 57 (23–75) years; median number of prior therapies: PTCL: 3 (1–7) and CTCL: 3 (1–9). In the PTCL cohort the ORR is 28% (4/14); 2 pts have yet to reach their first assessment. Three responding pts remain on study drug for 7–10 months. Responses have been observed in pts with AITL and PTCL‐NOS. In the CTCL cohort the global response is 25% (3/12); 1 pt has yet to reach their first assessment. Two responding pts remain on study drug for 4–6 months. Responses have been seen in pts with large cell transformation, sezary syndrome and visceral metastases. Among all pts, the most common related AEs of any grade (≥ 15%) were lipase elevation (38%), amylase elevation (34%), ALT elevation (28%), elevation (24%) and rash (24%). Related AEs ≥ Grade 3 occurring in ≥3 pts were rash (n = 5) and lipase elevation (n = 4). Accrual continues; updated efficacy and safety results will be presented at the meeting.Summary/Conclusion:In the ongoing Phase 2 cohorts ASTX660 has shown activity against PTCL and CTCL with manageable safety profile. These early data support continued development of ASXT660 for the treatment of r/r PTCL and CTCL. Correlative studies are aimed at identifying predictors of response.
PS1091 TREATMENT OF ACTIVATED B‐CELL LYMPHOMA WITH RITUXIMAB,DOXORUBICIN,ETOPOSIDE,PREDNISOLONE/IFOSFAMIDE+CISPLATIN PLUS LENALIDOMIDE (R‐ACEP/ICL), CONFERS LONG PROGRESSION FREE AND OVERALL SURVIVAL RATES
Authors: Salamoon M. , Balti M. 
Published: June 2019

Background:gene profiling (GEP) revealed the main two types of DLBCL [the germinal center B‐cell (GCB) and the non‐germinal center or Activated B‐cell lymphoma(ABC)]. Immuno‐histochemistry plays an important role in differentiating between the two types using several algorithms, however, Hans algorithm and the improved Hans are considered the more reliable. Patients with GCB are still doing well in the era of type I and II anti‐CD20, however, ACB patients are experiencing bad prognosis with shorter progression free and overall survival rates, therefore, we have developed a high‐dense high intense protocol to treat those population with ABC.Aims:the study aims at evaluating a new dose intense chemotherapy in patients with ABC lymphoma with end points including progression free and overall survivalMethods:this is a multicenter study Al Bairouni university cancer center in Damascus, Syria between 2013 and 2015 where we recruited 122 patients having ABC DLBCL confirmed by immuno‐histochemistry using the improved Hans algorithm. Patients received a dose dense protocol as follows: (Rituximab 375 mg/m2 with Doxorubicin 75 mg/m2, Cyclophosphamide 1200 mg/m2, Etopdside 300 mg/m2 and Prednisolone 1 mg/kg for 5 days) repeated every 21 days for 6 cycles with 5 days G‐csf support. Then partial and complete responders were given (Ifosfamide 4 gr/m2 day 1–3 + Cisplatine 40 mg/m2 day 1–3) for 4 cycles repeated every 15 days with 4 days G‐csf support. Lenalidomide 10 mg/d was given upfront lasting for 1 year. End‐points were progression free survival and overall survival at 5 years.Results:overall response rate (ORR) was documented in 118 patients (96.7%) (92 complete responders and 26 partial responders). 10 patients progressed at different stages of follow up with a progression free survival (PFS) of 88.6% (95% CI 83–94). However, 113 patients were found to still alive at 5 years with an overall survival (OS) rate of 92.6 (95% CI 86–97). In spite of G‐csf support, neutropenia of different grades was documented in 23 patients (18.8%). Acute and transient renal failure was observed and managed in 15 patients (12.2%) mainly in the first 6 cycles. Other side effects were manageable.Summary/Conclusion:ABC forms a special entity of DLBCL carrying a bad prognosis compared with GCB subtype. Progress was made using the R‐CHOP, however, results were still poor until the addition of Ibrutinib, Lenalidomide or Bortezomib to R‐CHOP in different trials which improved OS to exceed 90%. In this study, we present a dose intense protocol conferring a good PFS and OS rates with acceptable toxicity profile. However, a big randomized trials including both ABC and GCB patients in order to identify factors having bad impact on progression.
PS1100 CONGENITAL FACTOR V DEFICIENCY FROM COMPOUND HETEROZYGOUS MUTATIONS WITH A NOVEL MUTATION C.2426DEL (P.PRO809HISFS∗2) IN THE F5 GENE
Authors: Park C.‐H. , Park M.‐S. , Lee K.‐O. , Kim S.‐H. , Park Y.S. , Kim H.‐J. 
Published: June 2019

Background:Congenital factor V deficiency (FVD) is a rare bleeding disorder characterized by low or undetectable plasma FV levels leading to mild to severe bleeding symptoms. Currently, more than 100 mutations have been reported in F5. The majority of F5 mutations are missense mutations (61.5%), and small deletion and splicing mutations account for 18.5% and 11.9%, respectively.Aims:We herein report a patient with FVD from compound heterozygous mutations including a novel deleterious mutation.Methods:The patient was a 52‐year‐old man with prolonged PT and aPTT corrected by mixing test on preoperative screening. His past medical or family history was not remarkable. Factor assays revealed a markedly reduced FV activity at 7%. Other factors were not decreased. DNA sequencing analysis to detect F5 gene mutations was performed after obtaining written informed consent.Results:Two different heterozygous mutations in F5 were detected: a missense variant (c.286G>C [p.Asp96His]) and a frameshift variant from small deletion (c.2426del [p.Pro809Hisfs∗2]). The Asp96His was previously described missense mutation and Pro809Hisfs∗2 was a novel deleterious mutation.Summary/Conclusion:We herein report an asymptomatic patient with FVD from compound heterozygous mutations of F5 including a novel frameshift mutation. As was the case in our patient, genotype‐phenotype correlations are poor in FVD, and molecular genetic test is necessary to confirm the diagnosis.
PS1109 DENTAL HEALTH STATUS IN PATIENTS WITH HEMOPHILIA. SINGLE CENTER EXPERIENCE IN ROMANIA
Authors: Ursu C.E. , Serban M. , Clevet O. , Traila A. , Boeriu E. , Jinca C. , Boia E. , Arghirescu S. 
Published: June 2019

Background:Shortage of replacement therapy in haemophilia is responsible for the devastating consequences of uncontrolled bleeds, with unfavourable impact on the quality of life, strongly dependent on oro‐dental health.Aims:The objective of our study was to analyse the dental status in persons with haemophilia (PwH) in our treatment conditions, characterised by the introduction of on demand replacement in 1997 and of prophylaxis in 2014‐2015.Methods:This descriptive non‐interventional cross‐sectional study was conducted on 47 PwH (12 children, 35 adults), all with severe form of disease and on a control matched group of 47 persons. For each PwH were recorded laboratory data and history of replacement therapy. Oral health status evaluation was performed according to the criteria suggested by World Health Organization (WHO).Results:We assessed a very bad dental status in PwH with very high values for the majority of the parameters. In haemophilic children comparable to matched control group there were significant differences regarding the D index and PL index (p = 0.04, p = 0.01). Concerning the domain of decayed teeth in children we observed the existence of an age correlation (r = 0.47/0.81), unfortunately with a lowering appeal for dental care in children with haemophilia, the F index (0.2 ± 0.4) being decreased compared to the children from control group (2.2 ± 2.2), with significant difference (p = 0.003). The dental indexes in adult haemophiliacs were found high, significantly higher in the field of D and F than those belonging to the control group. F index was found significantly higher in the control group than in PwH, proving the low addressability for dental care in haemophiliacs. All these results, with the exception of Missing teeth and DMFT index (r = 0.63/r = 0.65), were not correlated with the age. Adult PwH, with mean age of 34.8 ± 9.81 years, had a dismal dental profile, only 7/35 had a complete denture, 7/35 missing 25%, and 3/35 missing more than 50% of their teeth.Summary/Conclusion:Lack of access to treatment or a low consumption, especially in young age, can influence and have a decisive impact on oral health status in PwH. Our results highlight the importance of an accessible dental care for this vulnerable group of patients in the frame of a comprehensive haemophilia care, including preventive dental treatment and an adequate replacement therapy.