bluuebunny/crossref_metadata_2025_split huggingface dataset:
PF292 LOW‐DOSE CYTARABINE WITH OR WITHOUT GLASDEGIB IN NEWLY DIAGNOSED PATIENTS WITH ACUTE MYELOID LEUKEMIA: LONG‐TERM ANALYSIS OF A PHASE 2 RANDOMIZED TRIAL
Authors: Papayannidis C. , Smith B.D. , Heuser M. , Montesinos P. , Sekeres M.A. , Oriol A. , Schiller G. , Candoni A. , Jamieson C. , Hoang C. , Ma W.W. , Zeremski M. , O’Connell A. , Chan G. , Cortes J. 
Published: June 2019

Background:Glasdegib is a potent, selective, oral inhibitor of the Hedgehog signaling pathway, approved in the US – in combination with low‐dose cytarabine (LDAC) – for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients unable to receive intensive chemotherapy due to comorbidities or age (75 years or older).Aims:To evaluate long‐term efficacy and safety of LDAC with or without glasdegib in patients newly diagnosed with AML unable to receive intensive chemotherapy due to comorbidities or age.Methods:In this follow‐up analysis from the phase 2 BRIGHT AML trial (NCT01546038), newly diagnosed patients with AML ineligible for intensive chemotherapy were randomized 2:1 to glasdegib + LDAC or LDAC alone (study design was reported previously: Cortes et al., Leukemia 2018). This long‐term analysis evaluated efficacy and safety after approximately 20 months of additional follow‐up.Results:As of October 11, 2018, 116 patients were assigned to treatment with glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The median follow‐up time for glasdegib + LDAC and LDAC alone was 43.4 and 42.0 months, respectively. The median overall survival was higher with glasdegib + LDAC vs LDAC alone (Table). Improvement in overall survival was consistent across the prespecified subgroups. The main cause of death in both arms was disease progression (both during study and follow‐up). The incidence of adverse events (AEs) and serious AEs on glasdegib was generally lower long term (after 90 days) than short term (during the first 90 days) (83.7% and 51.2% vs 98.7% and 65.3%, respectively).Summary/Conclusion:Addition of glasdegib to LDAC vs LDAC alone continued to demonstrate improved overall survival in patients with AML in this analysis; improvement was consistent across groups stratified by cytogenetic risk. Long‐term follow‐up confirmed that treatment with glasdegib was associated with an acceptable safety profile.image
PF343 CRISPR/CAS9 MEDIATED ELANE KNOCKOUT ENABLES NEUTROPHILIC MATURATION OF HSPCS AND IPSCS OF SEVERE CONGENITAL NEUTROPENIA PATIENTS
Authors: Nasri M. , Ritter M. , Mir P. , Dannenmann B. , Amend D. , Makaryan V. , Xu Y. , Zeidler C. , Dale D.C. , Klimiankou M. , Welte K. , Skokowa J. 
Published: June 2019

Background:Autosomal‐dominant ELANE mutations are the most common cause of severe congenital neutropenia (CN). Although the majority of CN patients respond to daily granulocyte colony stimulating factor (G‐CSF), approximately 15 % do not respond to this cytokine at doses up to 50 μg/kg/day and approximately 15% of G‐CSF treated patients will develop myelodysplasia (MDS) or acute myeloid leukemia (AML).Aims:“Maturation arrest,” the failure of the marrow myeloid progenitors to form mature neutrophils, is a consistent feature of ELANE associated CN. Because mutant neutrophil elastase is the cause of this abnormality, we hypothesized that ELANE associated neutropenia could be treated and “maturation arrest” corrected by CRISPR/Cas9 mediated gene editing.Methods:We applied CRISPR/Cas9‐sgRNA ribonucleoprotein (RNP) mediated ELANE knockout (ELANE KO) in induced pluripotent stem cells (iPSC) and primary hematopoietic stem and progenitor cells (HSPC).Results:We used iPSC from 2 CN patients and HSPC from 4 CN patients harboring ELANE mutations as well as HL60 cells expressing mutant ELANE. We observed that granulocytic differentiation of ELANE KO iPSC and HSPCs was comparable to healthy individuals and phagocytic function of the ELANE KO neutrophils was also normal. Knock down of ELANE in the mutant ELANE expressing HL60 cells also allowed full maturation and formation of abundant neutrophils.Summary/Conclusion:These observations suggest that ex vivo CRISPR/Cas9 RNP based ELANE knockout of patients’ HSPCs followed by autologous transplantation may be an alternative therapy for CN.
PF417 PONATINIB IN CHILDHOOD PHILADELPHIA POSITIVE LEUKEMIAS: THE EXPERIENCE OF THE INTERNATIONAL REGISTRY OF CHILDHOOD CHRONIC MYLELOID LEUKEMIA (I‐CML‐PED‐STUDY)
Authors: Millot F. , Suttorp M. , de Bont E. , Kalwak K. , Nelken B. , Ducassou S. , Bertrand Y. , Baruchel A. 
Published: June 2019

Background:Ponatinib is effective in adults with Philadelphia positive (Ph+) leukemias but only few case reports are available regarding the use of this so far not‐licensed drug in children and adolescents.Aims:To describe the profile of tolerance and efficacy of compassionate use of ponatinib in children and adolescents with Ph+ leukemias.Methods:Data from 11 children with chronic myeloid leukemia (CML) registered to the I‐CML‐Ped‐Study and from 3 children with Ph+ acute lymphoblastic leukemia (Ph+ ALL) treated with ponatinib were retrospectively collected.Results:In 11 girls and 3 boys (median age 14 years, range: 4.5–17) ponatinib was used as a second (n = 2), third (n = 5), fourth (n = 2), fifth (n = 3), sixth (n = 1) or eighth (n = 1) treatment line. Ponatinib was administered as single therapy in 7 patients while the 7 remaining patients (advanced phases CML n = 5, Ph+ ALL n = 2) received additional chemotherapy. The status of the disease when ponatinib was started was: CML advanced phases (accelerated phase, n = 2; blast crisis, n = 6), CML without achievement of major molecular response (MMR, n = 2), T315I mutation (n = 1) and in Ph+ ALL patients molecular relapse (n = 2) or marrow relapse (n = 1). Six patients were previously transplanted. Ponatinib was used as a bridge to transplant in 5 cases. Dose administered ranged between 15–41 mg/m2 (median: 27 mg/m2) and median duration of ponatinib treatment was 2.5 months (range: 0.5–14 months). Treatment responses in the 8 patients in CML‐advanced phases were: no response (n = 2), complete hematologic response (n = 1), MMR (n = 3), MR4.5 (n = 1) or unknown (n = 1). In patients in CML chronic phase, achievement of MMR was obtained in 2 of the patients without prior achievement of MMR while no response was observed in the patient with mutation T315I. Two of the 3 patients with Ph+ ALL achieved MR4.5 and MR5 while the remaining patient did not respond. Grade 1 to 4 side effects were recorded in 5 of 7 patients treated with ponatinib alone; toxicity grade 3–4 was reported in 2 patients (hematologic toxicity). No vascular event related to ponatinib was observed.Summary/Conclusion:With the limitation of the retrospective nature of this study, ponatinib may be a reasonable additional treatment option for children with Ph+ leukemias who failed to several lines of therapy.
PF421 PLANNED PREGNANCY IN FEMALE PATIENTS WITH CHRONIC MYELOID LEUKEMIA RECEIVING TYROSINE KINASE INHIBITOR THERAPY
Authors: Dou X. , Qin Y. , Huang X. , Jiang Q. 
Published: June 2019

Background:Pregnancy has become an important issue in female patients with chronic myeloid leukemia (CML) on tyrosine kinase inhibitor (TKI). Female patients with CML who wish to conceive are currently advised to discontinue TKI before conception due to the recognized teratogenic effects of TKI. However, it is not known what the ideal degree and duration of response a female patient should achieve before stopping TKI‐therapy for pregnancy. Concrete infant outcomes for female patients who discontinued TKI‐therapy immediately once pregnancy was confirmed are also lacking.Aims:To explore disease and fetal outcomes of planned pregnancy in female patients with CML on tyrosine TKI therapy.Methods:Data of female patients with CML proceeding with a planned pregnancy were retrospectively reviewed.Results:A total of 17 female CML patients who achieved at least a major molecular response (MMR) during imatinib (n = 13) or nilotinib (n = 4) therapy prior to a planned pregnancy were enrolled. At the time of TKI interruption, patients had received TKI‐therapy for a median of 49 months (range, 6–102 months), 6 were in MMR, 2 in MR4, and 9 in MR4.5. TKI‐therapy was discontinued at a median of 6 weeks (range, 2–15 weeks) before conception in 4 patients and at a median gestational age of 4 weeks (range, 2–5 weeks) after determination of pregnancy in 13 patients. Apart from one patient who suffered a spontaneous abortion, 16 patients delivered uneventfully at full term. A total of 10 patients lost MMR at a median of 3 months (range, 1–9 months) after stopping TKI; 8 patients lost MR2 at 4 months (range, 2–7 months) and 3 lost complete hematological response (CHR) at 3 months (range, 3–4 months) after TKI cessation. None of the patients progressed to an advanced phase. Log‐rank analyses showed achievement of MR4 (p = 0.030), MR4.5 (p = 0.031), CCyR (p = 0.049) or MMR duration (p = 0.040) ≥3.5 years were significantly associated with longer MMR‐failure free survival. Each of the 10 patients losing MMR during pregnancy regained MMR at a median of 4 months (range, 2–7 months) after resuming TKI‐therapy, and 1 patient who maintained MR4.5 during pregnancy remained off treatment at 6 months after delivery. All 16 babies that were successfully delivered have continued normal growth and development during a median follow‐up of 19 months (range, 7–78 months).Summary/Conclusion:Planned pregnancy might be safe and practicable in female patients with CML on TKI‐therapy. Achieving deep molecular response and importantly MMR duration ≥3.5 years before conception were significantly associated with maintaining MMR during pregnancy.image
PF538 GENETIC EVOLUTION PATTERNS IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA TO SECONDARY ACUTE MYELOID LEUKEMIA: AN ANALYSIS OF 36 PAIRED SAMPLES
Authors: Su Y.‐J. , Kuo M.‐C. , Wang P.‐N. , Wu J.‐H. , Lin T.‐H. , Huang T.‐Y. , Lin T.‐L. , Chang H. , Hung Y.‐S. , Shih L.‐Y. 
Published: June 2019

Background:Chronic myelomonocytic leukemia (CMML) are associated with a tendency to secondary acute myeloid leukemia (sAML) progression.Aims:We sought to examine the patterns of genetic evolution by analyzing a cohort of matched paired samples collected at initial diagnosis and at sAML transformation.Methods:Mutational analyses of 33 genes related to myeloid neoplasms on paired bone marrow samples from 36 patients with CMML at both diagnosis and sAML phase were performed. The samples were analyzed by PCR‐based assays followed by direct sequencing and/or next generation sequencing (NGS). The allele frequency of mutated genes was determined by variant allele frequency with NGS and/or pyrosequencing for validation.Results:Mutational analyses on the 36 paired CMML/sAML samples showed that 92% of patients had at least one mutated gene at initial diagnosis. Gene mutations involving epigenetic regulators (65%), myeloid transcription factors (52%), spliceosome (50 %), and signaling pathway (47%) were frequently detected, followed by BCOR (11%), NPM1 (6%) and SETBP1(6%), mutations of cohesin complex were rare (3%), and none had TP53, WT‐1 or BCORL1 mutations. Co‐existed mutations with different gene classes were present in 78% of CMML patients at diagnosis. The median time from CMML to sAML was 7.2 months (ranged from 1 to 89.6 months). At sAML transformation, 97% of patients had at least one mutated gene, mutation frequencies of epigenetic regulators (62%) and spliceosome (56%) remained mostly unchanged at sAML phase. Acquisition of additional gene mutations was observed in 47% of patients during sAML progression, in which signaling pathway mutations emerged most frequently (RTK/RAS/JAK‐STAT: 5/3/1), followed by transcription factors (3 acquiring RUNX1 mutations and 3 CEBPa). Emergence of new mutant subtypes of the same genes with or without disappearance of pre‐existed mutants was found in 3 RUNX1, and one each for CBL, PTPN11 and TET2 mutated patients during sAML progression. In addition, 8 patients had apparently increase in allele burden (>20%) for 6 genes. Loss of mutations was found in 4 (11%) patients during sAML progression, one each for PTPN11, JAK2V617F, CSF3R and TET2. Eight patients had apparently decrease in allele burden (>20%) for 4 different genes (N‐RAS, PTPN11, CBL and RUNX1).Summary/Conclusion:The present study on a relative large cohort of matched paired CMML/sAML samples showed that genetic evolution from CMML to sAML exhibited different patterns, including stable mutations, acquisition of new mutations, subclone selection or expansion of pre‐existed clones. Loss of mutation might occur but infrequently.
PF571 IDENTIFICATION OF HLA‐E AS A KEY GENE IN MULTIPLE MYELOMA BASED ON BIOINFORMATIC ANALYSIS AND DESIGN HIGH‐AFFINITY PEPTIDES TARGETING HLA‐E BASED ON COMPUTATIONAL TECHNIQUES
Authors: Yang Y. , sun M. , yu Z. , Liu Z. , Wei M. 
Published: June 2019

Background:Multiple myeloma (MM) is a common plasma cell malignancy that is currently incurable. Finding potential drug targets and new drugs are crucial for the treatment of thisdisease. Microarray technology is widely used to investigate differential mRNA expression and identify biomarkers in disease, which provides important clues to identifying new treatment targets and then new drugs could be designed.Aims:To find new treatment target for MM and design targeting affinity peptide.Methods:Two datasets (GSE6691 and GSE39754) were obtained from the Gene Expression Omnibus (GEO) database, and a protein‐protein interaction (PPI) network of differentially expressed genes (DEGs) was constructed to identify hub genes.Key clusters in the PPI network were analyzed by Molecular Complex Detection (MCODE). The gene both in hub genes and key clusters could be considered as potential treatment target and will be verified in clinical patients’ bone marrow samples. As the treatment target identified, crystal structure is obtained from Protein Data Bank and affinity peptide drug designed by Molecular Operating Environment (MOE) software.Results:HLA‐E was identified as hub gene and also located in one of the key clusters which could be a potential therapeutic target for MM.The high expression of HLA‐E in myeloma cells was confirmed by measuring HLA‐E mRNA expression in bone marrow samples from MM patients and healthy volunteers from Shengjing Hospital.The crystal structure of HLA‐E from the Protein Data Bank(PDB ID: 3CDG) was used to find the key active area of HLA‐E. MOE softwarewas used to design high‐affinity targeting peptides using key interaction amino acids as model peptides. A peptide library was constructed and screened to identify peptides with the highest stability and affinity for HLA‐E. Three high‐affinity peptides were selected and verified by peptide‐protein docking. Thus, these peptides could serve as targeting heads to find myeloma cells that express high levels of HLA‐E.Summary/Conclusion:HLA‐E could be recognized as a new treatment target for MM. At the meanwhile, affinity peptide(NALDEYCEDKNR) could be considered as a new targeting drug.image
PF584 C‐MYC‐DRIVEN AND PRMT5‐DEPENDENT REGULATION OF MULTIPLE MYELOMA CELL PROLIFERATION THROUGH SMCHD1 GENE
Authors: Peipei X. , guo D. 
Published: June 2019

Background:The protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetrical bimethylation of arginine residues, which plays an important regulatory role in the life process. Transcription factor c‐Myc is widely proved involved in the alteration and development of tumors, while the regulatory mechanism of c‐Myc‐mediated gene expression has not been fully understood.Aims:In this article we try to investigate the functional role of PRMT5 and c‐Myc in regulating multiple myeloma cell proliferationMethods:The protein and mRNA expression levels of PRMT5 in myeloma cells and normal cells were detected by Western Blot and qPCR. Lentivirally transduced shRNAs targeting PRMT5 (sh‐PRMT5) was constructed using lentivirus mediated RNAi technology, and was packaged to infect MM cells to select positive colonies. The effect of PRMT5 on the proliferation of MM cells was detected by cck‐8 assay. Annexin V/7‐AAD double staining flow cytometry was used to detect cell survival and apoptosis rate. The expression of apoptotic suppressor gene c‐Myc in sh‐PRMT5 cell lines was detected by Western Blot and qPCR. Finally, double‐knockdown of PRMT5 and c‐myc was performed and gene expression differentiation were identified by RNA sequencing (RNA‐seq).Results:PRMT5 expression in MM cell lines (RPMI8226 and U266) was relatively high compared with peripheral blood mononuclear cells (PBMCs), which was correlated with progression‐free survival (PFS) and overall survival (OS) in MM patients. After sh‐PRMT5 infection to MM cell lines, puromycin selection was performed and efficient gene knockdown was evaluated by Western Blot and qPCR. After targeted silencing of PRMT5 expression, the proliferation of MM cells was decreased and apoptosis was significantly increased (P < 0.05). C‐Myc protein and mRNA levels were significantly downregulated after PRMT5 gene silencing. The results showed that PRMT5 promoted the proliferation of MM cells and inhibited the apoptosis of MM cells by regulating the expression of apoptotic suppressor gene c‐Myc. Subsequently, RNA‐seq confirmed SMCHD1 as the common candidate target gene of c‐myc and PRMT5. Therefore, we speculated that PRMT5 and c‐Myc may jointly regulate SMCHD1 gene to promote the proliferation of MM cells.Summary/Conclusion:Altogether, our study not only proposed the mechanism PRMT5 and c‐myc in regulating multiple myeloma related gene expression, but also provided a new strategy and theoretical basis for clinical treatment of multiple myeloma.
PF622 CARFILZOMIB‐LENALIDOMIDE‐DEXAMETHASONE IN THE MANAGEMENT OF LENALIDOMIDE‐REFRACTORY MULTIPLE MYELOMA
Authors: Cerchione C. , Martinelli G. , Nappi D. , Pareto A.E. , Di Perna M. , Ferrara K. , Ferrari A. , Simonetti G. , Pane F. , Catalano L. 
Published: June 2019

Background:Carfilzomib is an epoxyketone proteasome inhibitor of second generation, proved to be effective and safe in relapsed and refractory Multiple Myeloma (rrMM), in combination with dexamethasone or lenalidomide and dexamethasone.Aims:In this retrospective observational trial, it has been evaluated efficacy and safety of carfilzomib, in combination with lenalidomide‐dexamethasone (KRD) as salvage regimen in patients with rrMM, refractory to lenalidomide, whose prognosis is particularly severe.Methods:41 patients (23 M/18 F), with rrMM, median age at diagnosis 63.7 years (r. 43–82), median age at start of treatment 67 years (r. 48–84) previously treated with several lines of treatments (median 3, r. 2–11), underwent to KRD regimen (ASPIRE trial schedule) for a median treatment cycles of 8 (r 2–18). ISS was equally distributed, and all patients had previously been treated with bortezomib and IMIDs, and were refractory to this agents. 61% (19/31) of them had undergone at least to a single ASCT.Results:According to IMWG criteria, after a median follow‐up of 9 months (r. 2–18), ORR was 68,2% (28/41: 9 CR, 12 VGPR, 7 PR) with 5 progressive diseases (PD) and 8 patients in stable disease (SD): this can be considered as an impressive result in this subset of rrMM patients, refractory to lenalidomide. In particular, for 11 patients, KRD was, after having achieved at least a PR, a bridge to second/third autologous SCT. Median time to response was 1.3 months (r.1–4), median OS from diagnosis was 62 months (r. 9–170), median OS from start of Carfilzomib was 11 months (r. 2–18). Carfilzomib was well tolerated, with grade 2 anemia in 39% (16/41) of patients, successfully managed by ESAs, without necessity of blood transfusions; 29% (12/41) grade 3–4 neutropenia (pegfilgrastim in primary prophylaxis was given, no ospedalization was required, no septic shocks were observed); 34% (14/41) grade 2, 21% (9/41) grade 3 and 12% (5/41) grade 4 thrombocytopenia, without hemorrhagic events and transfusion‐dependency. Moreover, it was observed pneumonia in 39% (16/41) of patients, treated by common antibiotic drugs and always solved. A cardiac monitoring was performed for all patients: hypertension (grade 2–3) in 34% (14/41) of patients; fatigue in 39% (16/31) of patients.Summary/Conclusion:Carfilzomib‐Lenalidomide‐Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, also lenalidomide, and it could be considered as a bridge to a second autologous or allogenic SCT.
PF645 EXPOSURE‐RESPONSE ANALYSIS & DISEASE MODELING FOR SELECTION OF OPTIMAL DOSING REGIMEN OF ISATUXIMAB AS SINGLE AGENT IN PATIENTS WITH MULTIPLE MYELOMA
Authors: Thai H.‐T. , Liu L. , Koiwai K. , Brillac C. , Van de Velde H. , Nguyen L. , Veyrat‐Follet C. , Semiond D. 
Published: June 2019

Background:Isatuximab is an anti‐CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement [1].Aims:Exposure‐Response (E‐R) analysis and disease modelling of tumor burden were performed to evaluate the relationship between isatuximab exposure and efficacy outcome and to support dosing regimen selection for isatuximab as a single agent in relapsed/refractory multiple myeloma (RRMM) patients.Methods:The E‐R analyses were conducted in 194 RRMM patients evaluable for pharmacokinetics (PK) from two monotherapy trials, a phase 1/2 trial (NCT01084252)[2] and a phase 1 trial (NCT02514668). Isatuximab was administered intravenously at doses from 1 to 20 mg/kg once a week or every 2 weeks. Several isatuximab exposure parameters were tested and their association with the probability of achieving an objective response (CR, VGPR or PR) was examined by logistic regression modeling. Baseline covariates were also considered in the model to reduce their potential confounding effects. Disease progression was captured in a subset of 122 evaluable patients with the dynamics of the serum M‐protein and accounted for dropout using a joint model. Trial simulations were then performed to evaluate different dosing regimens of interest using both models.Results:The E‐R relationship was best described by Emax model, in which Ctrough at 4 weeks and percent of bone marrow plasma cells were significant predictors of overall response rate (ORR). Patients with bone marrow plasma cells lower than 50% were more likely to respond. For a given bone marrow plasma cell value, higher probability of response to treatment was obtained with higher Ctrough at 4 weeks. Longitudinal data of M‐protein was adequately described by a tumor growth inhibition model [3,4] and provided more insights into the response of patients over time. Therefore, a high loading dose of 20 mg/kg weekly over 4 weeks was chosen for maximizing the tumor response and a maintenance dose of 20 mg/kg every 2 weeks appeared sufficient to sustain efficacy. Clinical trial simulation demonstrated that this dosing regimen presented a probability of success of 76% to reach 30% ORR (5,000 trials with 100 patients) and would allow 52% reduction of serum M‐protein from baseline at 2 months of treatment. In addition, isatuximab appeared to be well tolerated at this dose level.Summary/Conclusion:Model‐based drug development has been successfully applied to support phase II isatuximab monotherapy dosing regimen selection in RRMM patients. This approach increases both the robustness of dose selection decision making and the chances of success for future clinical trials.