bluuebunny/crossref_metadata_2025_split huggingface dataset:
PF278 DECITABINE COMBINED WITH HAAG AS INDUCTION CHEMOTHERAPY FOR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA
Authors: Zhu J. , Cui W. , Zhang Q. , Jin Z. , Sun A. , Zhu X. , Qiu H. , Wu D. , Tang X. 
Published: June 2019

Background:Treatment of newly diagnosed acute myeloid leukemia (AML) remains challenging. Several patients and disease‐related factors contribute to poor outcome in elderly patients or high risk patients with AML, including medical comorbidities, physical frailty, and poor‐risk biologic features. It is confirmed that Decitabine(DAC) has the synergistic reaction with daunomycin or cytarabine. Therefore, we investigated whether DAC combined with HAAG regimen might also be effective for the newly diagnosed of AML patients.Aims:To evaluate the efficacy and toxicity of DAC combined with HAAG regimen as an induction therapy for newly diagnosed AML patients as well as compared with standard IA(IDA 12 mg/m2/d∗3d) regimen.Methods:237 patients with AML who were newly diagnosed in our center between February 2014 and July 2018 were enrolled in this retrospective study. Among them,50 cases received DAC+HAAG regimen(DAC 20 mg/m2/d∗5d combined with low dose of homoharringtonine 1 mg/ m2/ d∗7–14d, cytarabine subcutaneously 10 mg/m2/q12h∗7–14d, aclarubicin 10 mg/d∗4–8d and G‐CSF priming). The other 187 patients received standard IA regimen (idarubicin 12 mg/m2/d∗3d and cytarabine 100 mg/m2/d∗7d).The outcomes of all the patients after one cycle of chemotherapy were evaluated.Results:1.The complete remission(CR) rate of DAC+HAAG group was significantly superior than that of IA group(96.0% vs 75.9%, P = 0.000). And the overall response rate (ORR) of DAC+HAAG group was also superior than that of IA group(100.0% vs 90.7%, P = 0.0.013).2.One‐year OS of DAC+HAAG and IA group were 75.3% and 74.8%.And two‐year OS were 69.0% and 66.1%,respectively. The median OS of the poor‐risk patients receiving DAC+HAAG and IA were 26 months and 32 months, respectively (P = 0.9625). Although the OS of two groups were similar, but the age of patients in DAC+HAAG group were statistically older than the IA group(P = 0.00).Furthermore,there were more patients with PS ECOG>2 in DAC+HAAG group(P = 0.000).3. Treatment related mortality (TRM), duration of neutropenia and thrombopenia were similar in both groups. Patients in DAC+HAAG group had significantly less infection grade 3–4 compared to the patients in IA group(16.0 vs 34.8%,p = 0.011). While the incidence of adverse events including bleeding, cadiotoxicity,liver damage and mucositis were similar(P = 0.424,0.296,0.259,0.060).Summary/Conclusion:DAC+HAAG regimen is a promising induction chemotherapy for newly diagnosed AML patients with mild toxicity, especially for patients who are not suit for standard induction chemotherapy.
PF281 CLI24–001: FIRST IN HUMAN STUDY OF SEL24/MEN1703, AN ORAL DUAL PIM/FLT3 KINASE INHIBITOR, IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Authors: Ravandi F. , Strickland S. , Solomon S. , Nazha A. , Walter R. , Valimberti I. , Tagliavini A. , Fiesoli C. , Binaschi M. , Brzozka K. , Baldini S. , Heeger S. , Pellacani A. 
Published: June 2019

Background:PIM kinases are oncogenic FLT3 targets expressed in acute myeloid leukemia (AML) cells. Increased PIM expression is found in samples of relapsed AML patients exposed to FLT3 inhibitors (FLT3i). There is preclinical evidence that PIM inhibition restores cell sensitivity to FLT3i, and that dual FLT3/PIM inhibition eradicates FLT3‐ITD+ primary AML cells. SEL24/MEN1703, a potent PIM/FLT3 dual inhibitor, showed a significantly broader spectrum of activity in AML cell lines and primary AML blasts, irrespective of FLT3 status compared to FLT3 or PIM inhibitors aloneAims:To determine the recommended phase 2 dose (RP2D), the PK profile and the single agent activity of SEL24/MEN1703 in relapsed/refractory or newly diagnosed AML patients (excluding APL) unsuitable to chemotherapyMethods:First in Human, open label, non‐randomized, multi‐center, dose‐escalation (DE) and cohort expansion (CE) study of oral SEL24/MEN1703. SEL24/MEN1703 is given orally, QD, FOR 14 days in a 21‐day cycle with cycles repeated until disease progression or unacceptable toxicity. Dose escalation follows a 3+3 design to identify the RP2D; CE at RP2D is planned to confirm the safety profile and assess single agent activity. Patients are eligible for the study regardless of mutations and/or prior FLT3i treatment; prior PIM inhibitors are not allowed. White blood count (WBC) of ≤30 x 109/L is required at baseline. Key secondary objectives include PK profile and single agent anti‐leukemic activity; exploratory objectives include assessment of clinical activity in relevant AML subsets of patients (eg FLT3 mutated)Results:As of January 8th, 2019 (data cutoff), n = 17 patients were treated and the study is enrolling. In the RP2D expansion phase, the study (currently running in 5 US sites) will be expanded to approximately 40 sites in the US and EUSummary/Conclusion:SEL24/MEN1703, a first in class, oral dual PIM/FLT3‐ITD inhibitor, is completing the DE part of a two‐part FIH study in patients with relapsed/refractory or unfit newly diagnosed AML unsuitable to chemotherapy. The RP2D expansion phase is planned to involve either US and EU investigational sites. This is the first clinical trial testing a dual PIM/FLT3‐ITD inhibitor, potentially active in AML regardless of FLT3 status and able to overcome FLT3i resistance
PF283 A RETROSPECTIVE STUDY OF MYELOID LEUKAEMIA IN CHILDREN WITH DOWN SYNDROME IN IRELAND
Authors: Dowling G.P. , Piccin A. , O’Marcaigh A. , Gavin K.T. , Malone A. , Betts D. , Cotter M. , Smith O.P. 
Published: June 2019

Background:Children with trisomy 21 have several clinical complications such as a variety of dysmorphic features, congenital malformations and endocrine abnormalities for example. An important complication of Down Syndrome (DS) is that they may also develop leukaemia. Acute myeloid leukaemia (AML) is the type of haematological malignancy most commonly reported in this population. A subtype of AML called M7 leukaemia (as classified by FAB system) has an incidence nearly 200 times greater compared to children without DS. This is a type of leukaemia otherwise very rare in both adults and children. M7 leukaemia is often preceded by a transient neonatal pre‐leukaemic syndrome, called Transient Abnormal Myelopoiesis (TAM). TAM is unique as it has the ability to resolve spontaneously. However, 20–30% of these patients may develop M7 leukaemia over time. This is most likely to occur within the first 4 years of life.Aims:A retrospective national audit of all documented cases of childhood TAM and M7 leukaemia referred from 1990–2018 to the National Paediatric Hematology/Oncology Centre at Our Lady's Children's Hospital Crumlin (OLCHC) Ireland. We also aimed to compare our demographic and outcome findings with the recent medical literature and make recommendations for future research.Methods:All consecutive charts of the children with a diagnosis of M7 leukaemia treated at (OLCHC) between the years 1990 – 2019 were sourced from medical records. The hospital database and charts were reviewed and information including date and age of diagnosis of AML, comorbidities, previous history of TAM, treatment regime and outcome was noted. Cytogenetic information was obtained by accessing a dedicated database. Kaplan‐Meier survival curves were constructed.Results:Twenty‐seven patients with M7 leukaemia were treated in OLCHC. A prior neonatal diagnosis of TAM was described in 10 patients (37%). Patients had a low platelet count (<50 × 109 /L) at presentation. Nineteen patients (70%) are alive and well, in complete remission, at a median follow up of 11.4 years. Overall survival (OS) of this cohort has risen from 54% from those treated between the years 1990 – 2004 (n = 13) to 93% for those treated between the years 2005 – 2019 (n = 14).Summary/Conclusion:Overall an excellent outcome is observed in M7 leukaemia when treated with current poly‐chemotherapy protocols. In general children with DS have a much better response to the cytotoxic‐chemotherapy than constitutionally normal children. Our finding of a low platelet count at diagnosis is in accordance with the current knowledge that M7 leukaemia is a condition affecting platelet precursors. GATA‐1 is mutated universally in M7 leukaemia and therefore appears to be an interesting molecular target.
PF285 ZELLA‐101: PHASE 1 STUDY OF ALVOCIDIB FOLLOWED BY 7+3 INDUCTION IN NEWLY DIAGNOSED AML PATIENTS
Authors: Lee D. , Smith B. , Frattini M. , Anthony S. , Bearss D. , Zeidner J. 
Published: June 2019

Background:Alvocidib, a potent cyclin‐dependent kinase‐9 (CDK‐9) inhibitor, has been studied extensively in newly diagnosed and relapsed/refractory AML in a timed sequential combination with cytarabine and mitoxantrone (ACM) with promising activity. Inhibition of CDK‐9 leads to downregulation of BCL‐2 family member, MCL‐1, which in turn inhibits tumor growth. We hypothesized that alvocidib followed by 7+3 induction therapy would be safe and effective in newly diagnosed non‐favorable risk AML.Aims:To evaluate the safety and clinical activity of alvocidib, in combination with cytarabine and daunorubicin (7+3), in previously untreated AMLMethods:We are conducting a multicenter, open‐label, dose‐escalation, safety and biomarker prediction study (Zella 101) of alvocidib given as timed sequential therapy prior to cytarabine and daunorubicin for adults with previously untreated AML. The key eligibility criteria are: ages 18–65 years; previously untreated AML; ECOG PS 0–2; and no major organ dysfunction. Treatment consisted of increasing dose levels of alvocidib starting at 20 mg/m2as a 30‐minute IV bolus followed by 30 mg/m2over 4 hours on days 1–3, cytarabine 100 mg/m2/day by continuous IV infusion on days 5–11, and daunorubicin 60 mg/m2IV on days 5–7. Dose escalation was assessed by standard 3+3 design. Reinduction therapy with alvocidib (same dose as induction) days 1–3, followed by cytarabine 100 mg/m2/day continuous IV days 5–9 and daunorubicin 45 mg/m2IV days 5–6 was recommended in patients with >10% and >5% cellularity and blasts, respectively.Results:A total of 13 patients have been enrolled to date with the median age of 59 years (Range: 31–65 years) (See Table 1). The maximum dose of alvocidib administered was 30 mg/m2as a 30‐minute IV bolus followed by 60 mg/m2over 4 hours on days 1–3 as previously given in prior studies. Overall, alvocidib was well tolerated. The most common NCI CTCAE ≥Grade 3 treatment emergent nonhematologic AEs noted in ≥3 patients in the safety population were device related infection (30.8%), diarrhea (30.8%) and lung infection (23.1%). Cytogenetics were reported on 7 patients, 5 were intermediate to high risk. Ten patients were evaluable with post baseline response assessments, two patients were too early for disease assessment, and one patient died prior to disease assessment due to septic shock. Nine of the 10 evaluable patients achieved CR (9/10, 90%).Summary/Conclusion:Alvocidib given as timed sequential therapy prior to cytarabine and daunorubicin (7+3) induction in newly diagnosed AML demonstrated an acceptable safety profile with an MTD (30 mg/m2IV bolus followed by 60 mg/m2infusion over 4 hours) similar to previously investigated timed sequential regimens of alvocidib. Future directions include a randomized phase 2 expansion comparing cytarabine and daunorubicin with or without preceding timed sequential alvocidib, and prospective BH3 profiling of AML patients.image
PF324 RITUXIMAB DOSE ASSOCIATED WITH OVERALL SURVIVAL IN DIFFUSE LARGE B CELL LYMPHOMA
Authors: Kong J.H. , Kim H.S. , Lee J.Y. , Hyun S.Y. 
Published: June 2019

Background:The outcome of diffuse large B cell lymphoma (DLBCL) improved significantly, due to the addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. However, significant range of patients showed relapse or refractory to R‐CHOP, and the role of body surface area (BSA) or body mass index (BMI) to overall survival (OS) was not known or still controversial.Aims:We evaluated effects of rituximab dose, BSA or BMI on OS using National Health Information Database.Methods:This study included patients 5,332 patients who were diagnosed with DLBDL and received R‐CHOP as a frontline therapy between 2006 and 2014. The exclusion criteria were as follows;1) age <20 years 2) R‐CHOP was given less than 4 times or over 8 times 3) R‐CHOP 2 months after diagnosis 4) Interval between two consecutive R‐CHOP injection was over 60 days. We extracted age, sex, prescribed medication list, and date of death from NHID. Weight and height of patients who had national general health examination before 1st cycle of R‐CHOP was collected.Results:Median age was 58(20–92) years, and 57%(n = 3021) of them were male. Thirty‐eight % of patients (n = 2019) received R‐CHOP 4–5 times, and 62% (n = 3303), 6–8 times. Median dose of injected rituximab was total 7200(1,600–16,800) mg, and median mean dose of rituximab per each cycle was 600(400–1,000) mg. A total 2,523 patients (47.4%) were treated at medical institution in capital (Seoul) area. About 72% of patients (n = 3813) had national health examination before chemotherapy. Their median weight and height were 63(31–121) kg and 163(131–196) cm, respectively. Median BSA and BMI were 1.69m2 and 23.9 kg/m2.With median 66(24–144) months of follow up, estimated 5‐year and 10‐year overall survival was 37.1% and 25.6% respectively. Log‐rank test for 10‐year OS, age≤60 (vs age>60), female (vs male), 6–8 times of R‐CHOP injection (vs 4–5 times of R‐CHOP), total R dose≥7200 mg (vs <7200), mean R dose≥600 mg, and medical institution in Seoul (vs others) were associated OS, significantly (p < 0.05). However, total R dose did not affect OS in multivariate analysis (p = 0.152).Among 3813 patients who had national health examination before R‐CHOP, patients whose BSA <1.69m2 had worse OS than BSA≥1.69m2. But BMI did not differentiate OS.Summary/Conclusion:With 66 (24–144) months of median follow up, estimated OS at 5‐year and 10‐year of DLBCL patients were 37.1% and 26.5%, respectively. Mean rituximab dose ≥600 mg showed better OS than <600 mg. High BSA showed favorable OS, but BMI did not affected OS significantly.
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PF328 PREDICTORS OF TREATMENT RESPONSE TO IMMUNOSUPPRESSANTS IN ACQUIRED HEMOPHILIA A
Authors: Lau W.N. G. , Leung M.K. G. , Yip P.L. P. , Cheung K.M. C. , Lau S.M. J. , Lee K.K. H. , Mak W.M. V. , Ho S.K. S. , Kwok C.H. K. 
Published: June 2019

Background:Acquired hemophilia A (AHA) is a rare bleeding disorder, caused by inhibitors against factor VIII, which may result in life‐threatening bleeding. Management of AHA is two pronged ‐ to arrest bleeding with hemostatic agent and to eradicate FVIII inhibitors by immunosuppressants. However, immunosuppressants are associated with frequent adverse events, with infection being the leading cause of morbidity and mortality. Identifying predictors of treatment response may help tailor treatment strategies and reduce treatment associated adverse events.Aims:The aims of the study were to evaluate the presenting features, treatment, and outcomes of patients with AHA in our local population, to identify the predictors of normalization of aPTT after immunosuppressive therapy and overall survival; and to investigate the patient characteristics that predict normalization of aPTT by steroid alone within 6 weeks.Methods:This was a retrospective multi‐center study which recruited 108 patients diagnosed with AHA between 1st January 2002 and 31st December 2016. AHA is defined by the presence of a neutralizing FVIII inhibitor ≥ 0.6 Bethesda units (BU)/ml and a FVIII activity <50%. Patients with congenital hemophilia A with inhibitors were excluded.Prognostic factors for normalization of aPTT and overall survival were analyzed using Cox proportional hazards regression analysis.Results:Normalization of aPTT was an independent predictor of overall survival (OR 0.14, 95% CI 0.07–0.27, P < 0.001). Patients with ECOG performance status ≤2 were more likely to attain normal aPTT (HR 2.09, 95% CI 1.28–3.42, P 0.003) while patients with underlying autoimmune diseases were less likely to achieve normal aPTT (HR 0.46, 95% CI 0.23–0.91, P 0.027).Female (OR 3.73, CI 1.15–12.2, P 0.028) and an inhibitor titer ≤20 BU/ml (OR 4.3, CI 1.36–13.63, P 0.013) predicted a higher chance of normalization of aPTT with steroid alone within 6 weeks.Summary/Conclusion:Identification of patients who are more likely to respond to steroid alone within 6 weeks may avoid unnecessary immunosuppressants and thus reduce treatment‐related adverse events. This finding may help individualize treatment strategies.Normalization of aPTT was an independent prognostic factor of survival. This finding echoed other studies and reiterated the importance of achieving remission. To date, the optimal immunosuppressive strategy remains elusive. Further high‐quality evidence is needed to guide the choice and intensity of treatment.
PF331 COST‐EFFECTIVENESS OF EMICIZUMAB VERSUS BY‐PASSING AGENTS IN PATIENTS WITH HAEMOPHILIA A AND FVIII INHIBITORS IN FRANCE
Authors: Polack B. , Trossaert M. , Godard C. , Cousin M. , Baffert S. , Pruvot A. , Pinguet J.‐M. 
Published: June 2019

Background:The development of an anti‐FVIII inhibitor is the most serious complication of haemophilia A. On February 23, 2018, Emicizumab obtained a European Marketing Authorization for the prevention of bleeding episodes in patients with haemophilia A who developed an anti‐FVIII inhibitor. In France, emicizumab is reimbursed by National Insurance since February 7th2019. As part of its inscription on the list of products reimbursed by French National Health Insurance, emicizumab has been evaluated by health authorities (HAS): The Transparency Committee granted a major added medical benefit (ASMR II), and a medico‐economic analysis was evaluated by the Health Economic and Public Health Committee.Aims:The purpose of this analysis is to evaluate the Incremental Cost‐Effectiveness Ratio (ICER) of emicizumab compared to the current management by Bypassing Agents (BPA) taking into account the final price that has just being published.Methods:The analysis is based on a Markov model with two health states (alive, dead) over a 5‐year time horizon. Emicizumab is compared with current BPA management (aPCC and rFVIIa) in prophylaxis or on‐demand, according to their real‐life use in the FranceCoag Network cohort (RFC). The ICER is expressed in euros per QALY (Quality‐Adjusted Life Year). Bleeding rates are derived from the HAVEN 1 clinical trial for emicizumab and BPA on‐demand, and an indirect comparison for BPA prophylaxis. Quality of life data are derived from the HAVEN 1 trial. The costs of treatment acquisition, adverse events and hospitalizations were taken into account. Deterministic and probabilistic sensitivity analyzes were performed to evaluate the uncertainty around the result.Results:Emicizumab prophylaxis is a dominant strategy, in children and adult patients: it is more effective and less costly than the current BPA strategy. Over 5 years, the mean total cost per patient was 2,3 M€ in patients treated with emicizumab, versus 2,7 M€ with BPA, associated to 3,3 and 2,4 QALYs respectively. Thus, emicizumab brings 0,9 additional QALYs per patients for a saving of almost 426 000€. Exploration of uncertainty does not alter these results.Summary/Conclusion:The health economic analysis shows the cost‐effectiveness of emicizumab versus BPA in France. The methodology used was accepted by the CEESP in its Opinion of October 9, 2018. The limitations of this analysis are mainly based on the lack of data to model the consequences of the reduction of bleeding on the long‐term evolution of arthropathy and disability.
PF336 EVALUATION OF THROMBOPOIETIN‐RECEPTOR AGONISTS (TPO‐RAS) «STOP‐THERAPY» IN IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)
Authors: Vinogradova O. , Pankrashkina M. , Tkachenko N. , Chernikov M. , Mukha L. , Perova V. , Kobzev Y. , Shikhbabaeva D. , Ptushkin V. 
Published: June 2019

Background:For a number of years, it has been shown that TPO‐RAs are a highly effective therapy of ITP. Still, there are few published guidelines/recommendations addressing the management of ITP patients (pts) on TPO‐RAs after they achieve continuous remission.Aims:To evaluate the TPO‐RAs «stop‐therapy» in ITP pts with complete response (CR) to TPO‐RAs.Methods:We analyzed data of TPO‐RA «stop‐therapy» in patients with CR. Primary endpoints of the study were the duration and type of response (CR, partial – PR, minor – MR, and loss of response) after TPO‐RAs had been stopped. Secondary endpoints included types of response (CR, PR, MR) after TPO‐RAs had been resumed in those pts who relapsed.Results:194 ITP pts treated at Moscow City Hematology Center (Botkin Hospital) in 2014–2018 were administered TPO‐ARs: (romiplostim (R): n = 123; eltrombopag (E): n = 71). 106 pts (55%) achieved CR (platelets >100х109/l)(R: n = 79 (64%); E: n = 27 (38%).28 pts in continuous CR (≥3 months (mo) had TPO‐RA stopped: (R: n = 19; E: n = 9). Group R (GR) comprised of 4 males and 15 females, with median age (Mе) age at the time of diagnosis of 51 (range 1 ‐ 69) years, and Me follow‐up time from the time of diagnosis was 108 (9 ‐ 483) mo. Group E (GE) included 1 male and 8 females with Me age of 54 (range 12 ‐ 75) years and Me follow‐up time from the time of diagnosis of 74 (27 ‐ 228) mo.Me stop‐therapy length was 69 (range 20 ‐ 276) weeks in GR, and 38 (range 13 ‐ 131) weeks in GE.At the time of analysis, CR was maintained in 5 (26%) GR pts, and in 1 (11%) GE pt. PR was seen in 7 (37%) GR pts and in 2 (23%) GE pts; and MR in 5 (26%) GR pts and in 1 (11%) GE pt. 2 (11%) GR pts and 5 (55%) GE pts did not respond to TPO‐RAs.TPO‐RAs were resumed in 2 GR and 2 GE pts who relapsed (7 pts have relapsed altogether), and 1 PR and 1 MR in each group were achieved.Summary/Conclusion:Our data adds to the growing body of evidence that ITP pts maintain remission after TPO‐RAs are stopped. This may possibly represent a change in therapeutic approach to these patients who usually require continuous maintenance therapy. Longer follow‐up and larger number of pts enrolled in the study are required to fully assess benefits of such approach.