bluuebunny/crossref_metadata_2025_split huggingface dataset:
PF694 TREATMENT‐FREE REMISSION AFTER TPO RECEPTOR AGONISTS IN ADULT ITP PATIENTS IN BELGIUM
Authors: Janssens A. , Beguin Y. , Lambert C. , Breems D. , Deeren D. , Efira A. , Fostier K. , Janssen M. , Kentos A. , Maertens V. , Mineur P. , Schauvliege L. , Schuermans C. , Theunissen K. , Vaes M. , Van de Velde A. , Van Eygen K. , Vantilborgh A. , Selleslag D. 
Published: June 2019

Background:Since 2009 treatment of chronic ITP patients with thrombopoietin receptor agonists (TPO‐RA) (romiplostim‐eltrombopag) has been reimbursed in Belgium. Despite the initial assumption that this would be a life‐long therapy, practical experience has shown that a significant number of patients do stop treatment. Reasons of TPO‐RA discontinuation can be no efficacy, adverse events, ITP or non‐ITP related death or spontaneous remission. Spontaneous remission (SR) or treatment free‐remission (TFR) is defined as a treatment‐free period of 3 6 months (mo) with platelets 3 50000/ml and no need of ITP rescue medication.Aims:We performed a survey to know how many patients were treated with TPO‐RA (trial, reimbursed, medical need) and how many of these had stopped this treatment. More details were gathered of patients who discontinued treatment.Methods:The survey was sent by mail to all hematologists who were member of the Belgian Hematological Society.Results:20 Belgian centers participated in our survey and sent data. 42 patients fulfilled the definition of TFR, while 3 of these patients had several episodes of TFR. The baseline characteristics of the patients obtaining TFR were as follows: 26 patients were male and 16 were female; diagnosis of primary ITP was made in 34 patients; the 8 patients with secondary ITP had an underlying lymphoma (n = 5), an Evans syndrome (n = 2) or a previous transplant (n = 1); mean age at ITP diagnosis was 50.5 years (y) (range 1–87y); median platelet count at ITP diagnosis was 5000/ml; median time between ITP diagnosis and the start of TPO‐RA was 5 y (range 1 mo‐24y); at start of TPO‐RA 5 patients fulfilled the definition of acute, 8 of persistent and 28 of chronic ITP; 54% (22/41) were splenectomized; 55% (22/40) needed 3 3 ITP treatments before the start of the TPO‐RA (corticosteroids, intravenous immunoglobulins, rituximab, cyclophosphamide, cyclosporin, fansidar…); median platelet count at start of TPO‐RA was 11000/ml; median time on TPO‐RA was 8 mo (range 0–74 mo); median platelet count was 267000/ml at discontinuation of TPO‐RA and 177000/ml 6 mo later. 178 patients (provided by 15 centers) were treated with TPO‐RA. Of these 100 patients discontinued treatment. 21% of the total cohort discontinued TPO‐RA because of TFR and 37% of the discontinuations was due to TFR.Summary/Conclusion:Our survey confirmed that SR or TFR on TPO‐RA is seen in about 20% of ITP patients treated in daily clinical practice in Belgium. TFR is seen not only in acute or persistent ITP but also in chronic ITP. TFR is seen in patients independent of splenectomy and independent of the number of treatments given before. In the future the incidence of TFR is thought to be even higher when the use of a forced tapering schedule will become common practice.
PF697 LUSUTROMBOPAG IS A SAFE AND EFFICACIOUS TREATMENT OPTION FOR THROMBOCYTOPENIA IN PATIENTS WITH CHRONIC LIVER DISEASE UNDERGOING PLANNED INVASIVE PROCEDURES: INTEGRATED ANALYSIS OF TWO PHASE 3 TRIALS
Authors: Brown R.S. , Imawari M. , Izumi N. , Osaki Y. , Ochiai T. , Kano T. , Bentley R. , Peck‐Radosavljevic M. 
Published: June 2019

Background:Lusutrombopag is an oral, small molecule thrombopoietin receptor agonist approved in Japan and US for improvement of thrombocytopenia, and in EU for severe thrombocytopenia, associated with chronic liver disease in patients undergoing planned invasive procedures.Aims:An integrated analysis was performed to assess the consistency of the efficacy and safety of lusutrombopag clinical trial data across a larger population.Methods:L‐PLUS 1 (Japan; JapicCTI‐132323) and L‐PLUS 2 (global; NCT02389621) were 2 similar Phase 3 multicenter, randomized, double‐blind, placebo‐controlled studies. Adults with thrombocytopenia associated with chronic liver disease and platelet counts (x109/L) <50 at baseline received lusutrombopag 3 mg or placebo for up to 7 days prior to an invasive procedure scheduled 9–14 days after randomization. Platelet transfusion was mandated if the platelet count remained <50 no more than 2 days prior to procedure. The efficacy endpoint for the integrated analysis was the proportion of patients who required no platelet transfusion prior to the invasive procedure and no rescue therapy for bleeding from randomization through 7 days after the invasive procedure. Another key efficacy endpoint was duration of the increase in platelet count (≥50).Results:A total of 312 patients were randomized in the 2 studies. In the intent‐to‐treat and per‐protocol populations, 68.2% and 73.7% of patients randomized to lusutrombopag avoided the need for platelet transfusion vs 23.9% and 17.3% of patients randomized to placebo for a difference of proportion of 44.4% and 55.8% (P < 0.0001), respectively (Figure). Platelet counts remained ≥50 for a median of 20.9 days in the lusutrombopag group for patients not requiring a platelet transfusion, compared to 0.3 days for patients requiring a platelet transfusion in the placebo group. Three patients experienced treatment‐related thrombotic or thromboembolic adverse events; 2 with lusutrombopag (portal vein thrombosis and cardiac ventricular thrombosis; maximum platelet counts were 79 and 119, respectively) and 1 with placebo (portal vein thrombosis; maximum platelet count = 167). The proportion of patients experiencing ≥1 adverse event were similar in the lusutrombopag (61.9%) and placebo groups (64.5%); of these, 6.5% and 9.0% events, respectively, were deemed treatment‐related.Summary/Conclusion:Lusutrombopag demonstrated efficacy and safety in the pooled analysis. Lusutrombopag was superior to placebo as treatment for thrombocytopenia associated with chronic liver disease in patients undergoing planned invasive procedures; statistically significantly more patients avoided platelet transfusion with lusutrombopag treatment. Patients maintained platelet counts ≥50 for almost 3 weeks. Lusutrombopag had a similar safety profile to placebo.image
PF703 LONG‐TERM FOSTAMATINIB TREATMENT OF ADULTS WITH IMMUNE THROMBOCYTOPENIA (ITP) DURING THE PHASE 3 CLINICAL TRIAL PROGRAM
Authors: Bussel J. , Arnold D. , Boccia R. , Boxer M. , Cooper N. , Hill Q. , Liles D. , Scholzberg M. , Numerof R. , Zayed H. , Tong S. , Duliege A.‐M. 
Published: June 2019

Background:Fostamatinib (Tavalisse®), an oral SYK inhibitor was approved in 2018 for the treatment of adults with chronic ITP who had an insufficient response to a prior treatment. In two randomized, double‐blind studies, 102 patients received fostamatinib and 48 received placebo; in the open‐label extension study, 123 received fostamatinib, including 44 from the placebo group.Aims:This abstract provides an update on 146 patients who have had up to 3 years of fostamatinib treatment.Methods:Adults with persistent/chronic ITP who had failed ≥1 prior therapy and had ≥3 platelet counts <30,000/μL at screening, were treated with fostamatinib at 100 mg BID, which increased to 150 mg BID based on tolerability, if platelets were <50,000/μL after 1 month. An overall response (post‐hoc analysis) was defined as achieving ≥1 platelet count of ≥50,000/μL within the first 12 weeks of treatment. Analyses excluded counts within 4 weeks of rescue therapy.Results:At the time of analysis, 42 (29%) of the 146 patients who received fostamatinib were continuing treatment. Reasons for treatment discontinuation included lack of response (41%), adverse events (AEs) (18%) and other (12%).An overall response occurred in 64/146 (44%) patients. Responders had reduced need for rescue medications and fewer bleeding episodes. The median platelet count in overall responders remained above 50,000/μL for more than 36 months.The most common AEs were diarrhea, hypertension and nausea, which were manageable with targeted treatment, dose modifications, or treatment withdrawal. Serious adverse events (SAE) were reported in 27% of patients and were possibly related to fostamatinib in 6%. SAEs led to treatment discontinuation in 3% of patients.Summary/Conclusion:44% of patients had an overall response to fostamatinib. Fostamatinib was well tolerated for an extended period of time. No new safety signals and no cumulative toxicity was detected during long‐term treatment with fostamatinib (up to 41 months).image
PF780 STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA: THE ROLE OF THE CONDITIONING REGIMEN
Authors: Giammarco S. , Van Lint M.T. , ONETO R. , Di Grazia C. , Raiola A.M. , Bregante S. , Lamparelli T. , Gualandi F. , Varaldo R. , Sica S. , Angelucci E. , Bacigalupo A. 
Published: June 2019

Background:Hemopoietic stem cell transplantation (HSCT) remains the standard of care for eligible patients with acquired aplastic anemia (AA). Conditioning rfegimens have changed over the yearsAims:To asses the role of different conditioning regimens over the years in HSCT in patients with acquired AAMethods:We have analyzed the outcome of 179 patients with acquired aplastic anemia (AA) undergoing an HSCT in 3 consecutive eras: before year 2000, between 2001 and 2010 and beyond year 2010. The median age of the patients was 20,28,31 years in the three periods, and there has been an increased use of donors other than HLA identical siblings (6%, 45%, 62% respectively). The major change in the 3 periods, has been in the use of conditioning regimens: cyclophosphamide (CY) 200 mg/kg was used in 92%, 32% and 20% of patients respectively in the 3 periods; the combination of fludarabine (FLU), CY low dose (1200 mg/m^2) and total body irradiation 2 Gy (FLU‐LDCY‐TBI) was used in 5%, 58% and 20% of patients in the 3 periods; finally the combination of FLU CY 120 mg/kg and TBI 2 Gy (FLU‐CY‐TBI) was given to 0%, 9%, 58% of patients respectively. GvHD prophylaxis remained unchanged during the three transplant periods: cyclosporin methotrexate and ATG for all patients, with the addition of rituximab 200 mg on day+5, as of year 2002.Results:The 5 year survival has improved in three consecutive transplant eras, from 58% before year 2000, to 73% in the years 2001–2010, and 92% in the years 2011–2018.We then compared the outcome of transplants prepared with FLU‐LDCY‐TBI (n = 38) or with FLU‐CY‐TBI (n = 21): the 2 groups were comparable for patients age (31 years for FLU‐LDCY‐TBI, range 17–60, versus 39 years for FLU‐CY‐TBI, range 18–62, p = 0.2) and donor type (p = 0.2), with 44% and 55% of donors being unrelated. The 5 year survival was 62% for FLU‐LDCY‐TBI vs 95% for FLU‐CY‐TBI (p = 0.02). In the FLU‐LDCY‐TBI, 4 patients died of graft failure (11%), 7 died of infections (18%) and 3 (8%) of toxicity. In the FLU‐CY‐TBI, 1 patient died of rejection (4%) and 1 of GvHD (4%). No patient experience EBV‐driven post transplant lymphoproliferative disorders (PTLD)Summary/Conclusion:In conclusion CY200 mg/kg remains standard of care for young patients grafted from identical siblings. The combination of FLU‐CY 120 mg/kg and TBI2 Gy appears to allow a better engraftment as compared to FLU‐LDCY‐TBI, and may be preferred for older patients and patients grafted from unrelated donors. We recommend low dose rituximab on day+5, which will effectively prevent PTLD.
S825 EVALUATION OF AMG 420, AN ANTI‐BCMA BISPECIFIC T‐CELL ENGAGER (BITE®) IMMUNOTHERAPY, IN R/R MULTIPLE MYELOMA (MM) PATIENTS: UPDATED RESULTS OF A FIRST‐IN‐HUMAN (FIH) PHASE 1 DOSE ESCALATION STUDY
Authors: Topp M. , Duell J. , Zugmaier G. , Attal M. , Moreau P. , Langer C. , Kroenke J. , Facon T. , Salnikov A. , Lesley R. , Beutner K. , Kalabus J. , Rasmussen E. , Riemann K. , Minella A. , Munzert G. , Einsele H. 
Published: June 2019

Background:BCMA, a member of the TNFR family, is expressed on MM and plasma cells (PC).Aims:Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B‐Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM.Methods:In this FIH study (NCT02514239), 6‐week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo‐SCT. MRD was defined as <1 tumor cell / 104 bone marrow cells per flow cytometry.Results:As of Dec 10, 2018, 42 patients received AMG 420 (0.2–800 μg/d). Patients D/C for PD (n = 24), adverse events (AE, n = 7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles.There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n = 21, 50%), 18 required hospitalization. SAEs occurring in >1 patient were infections (n = 12) and polyneuropathy (PN, n = 2). Treatment‐related SAEs included 2 grade 3 PNs and 1 edema. Grade 2–3 CRS was seen in 3 patients. No anti‐AMG 420 Ab were detected. In this study, 800 μg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved.At 400 μg/d, there were 5 minimal residual disease (MRD)‐negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6–10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted >1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month, with 9 of 13 patients responding in the first cycle.Summary/Conclusion:In this FIH study of AMG 420, a BiTE® vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 μg/d, a recommended dose for further investigation.image
PS1067 AXICABTAGENE CILOLEUCEL (AXI‐CEL) IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B CELL LYMPHOMA: PRELIMINARY RESULTS OF EARLIER STEROID USE
Authors: Topp M.S. , van Meerten T. , Wermke M. , Lugtenburg P.J. , Minnema M.C. , Song K.W. , Thieblemont C. , Jiang Y. , Plaks V. , Kerber A. , Kersten M.J. 
Published: June 2019

Background:Axicabtagene ciloleucel (axi‐cel) is an autologous anti‐CD19 chimeric antigen receptor (CAR) T cell therapy approved in the European Union and United States for patients with relapsed/refractory large B cell lymphoma with ≥ 2 prior systemic therapies. In the 2‐year follow‐up of ZUMA‐1, the objective response rate was 83% with a complete response rate of 58%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of patients, respectively; 26% of patients received steroids, and 43% received tocilizumab (Locke et al. Lancet Oncol. 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs).Aims:To assess the impact of early steroid use on outcomes in patients treated with axi‐cel.Methods:Eligible patients with relapsed/refractory large B cell lymphoma were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 106 anti‐CD19 CAR T cells/kg. Patients in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE.Results:As of September 14, 2018, 21 of 40 planned patients received axi‐cel with a minimum follow‐up of 1 month (median, 2.6 months). The median age was 63 years (range, 36 – 73), 67% were male, 81% had disease stage III‐IV, 76% were relapsed/refractory to ≥ second‐line therapy, and 10% had relapsed post‐autologous stem cell transplantation. Seventy‐six percent of patients received steroids and 81% received tocilizumab. Most patients (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of patients; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of patients, respectively. No patient had Grade ≥ 3 CRS; 33% of patients had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 patient died due to disease progression. The objective response rate per investigator assessment was 76% with 48% of patients achieving a complete response. Pharmacokinetic data will be presented.Summary/Conclusion:Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in patients treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit:risk profile of CAR T cell therapy.
PS1125 LINKING MICROENVIRONMENTAL SIGNALS TO METABOLIC SWITCHES AND IBRUTINIB RESPONSE IN CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Chen Z. , Burg H. ter , Andrejeva G. , Rathmell J.C. , Forconi F. , Kater A.P. , van der Windt G.J. , Eldering E. 
Published: June 2019

Background:Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous B cell malignancy, with accumulation of clonal CD5+ B cells in blood, lymph nodes (LN) and bone marrow. CLL has become a paradigm for a cancer that depends on signals from the microenvironment. This is evidenced by the clinical success of the Btk inhibitor ibrutinib, which drives CLL cells out of the LN to eventually die by neglect. In peripheral blood, CLL cells are quiescent, non‐cycling, with low metabolic activity. In contrast, in LN CLL cells receive various signals from surrounding cells, crucial for proliferation, and protection from chemotherapeutic drugs. These acquired advantages are possibly linked with altered metabolism, but it is unclear if and how CLL cells change their metabolism in the LN environment.Aims:We aimed to investigate the altered metabolism of CLL cells in the tumor microenvironment, and what signals determine these changes.Methods:Glucose uptake, glycolysis, mitochondrial mass, oxidative phosphorylation and lipid uptake were measured by flow cytometer or Seahorse XF96 analyzer, and 90 metabolites were analyzed by LC mass‐spectrometry.Results:We first established that the metabolic activity profile of circulating recent LN emigrants (CXCR4high/CD5dim PB lymphocytes) resembled that of actual LN residents (obtained by a core biopsy), which showed both higher mitochondrial mass and glucose uptake than paired peripheral blood CLL cells. In vitro stimulation of isolated blood‐derived CLL samples demonstrated that CD40 but not BCR signaling recapitulate these metabolic changes. Next, 10 patient samples were stimulated with/without CD40L for 48 hours and analyzed by mass‐spec for metabolic intermediates. To draw a further parallel with the situation in LN, metabolomics was performed on 13 patients sampled before and after 3 months of ibrutinib treatment. Combined, the data shows that various metabolic pathways are activated in the tumor microenvironment, particularly TCA cycle, pyruvate metabolism, glycolysis, and fatty acid metabolism. Apart from these overall changes, the highest ranking shifts in metabolites point to involvement of amino acids to fuel the TCA cycle. Moreover, aberrant patterns in metabolic changes after ibrutinib were noted in some patients, possibly linked with clinical response.Summary/Conclusion:CD40 signaling leads to increased oxidative phosphorylation and glycolysis in the CLL microenvironment. Opposite changes were observed in ibrutinib treated samples, together providing indirect insight into the metabolism in the CLL LN.
PS1157 EFFECT OF DOSE MODIFICATIONS ON RESPONSE TO DUVELISIB IN PATIENTS WITH RELAPSED/REFRACTORY CLL/SLL IN THE DUO TRIAL
Authors: Ghia P. , Flinn I. , Lamanna N. , Montillo M. , Illés Á. , Etienne G. , Delgado J. , Kuss B. , Tam C. , Offner F. , Bosch F. , Davids M. , Jäger U. , Cymbalista F. , Weaver D. , Lustgarten S. , Youssoufian H. , Stilgenbauer S. 
Published: June 2019

Background:Duvelisib (DUV), a first‐in‐class oral dual PI3K‐δ,γ inhibitor, is approved for treatment of relapsed/refractory (R/R) CLL/SLL after ≥ 2 prior therapies. In the phase 3 DUO trial, DUV 25 mg BID significantly improved efficacy vs ofatumumab (OFA; mPFS, 13.3 vs 9.9 mo; HR, 0.52 [P < .0001]; ORR, 74% vs 45% [P < .0001]) in pts with R/R CLL/SLL (Flinn et al. Blood 2018). Treatment‐emergent AEs (TEAEs) of special interest (AESIs) such as infections, diarrhea, colitis, neutropenia, rash, ALT/AST elevation, and pneumonitis, were moderate and manageable with early intervention and dose modification.Aims:To examine dose‐modification patterns and their impact on response to DUV in the DUO trial.Methods:TEAEs were assessed according to the NCI CTCAE v4.03. Dose interruptions (DI) or reductions (DR) to 15, 10, or 5 mg BID were permitted per study protocol to manage TEAEs. Responses were assessed by an independent review committee before and after dose modifications and were analyzed using descriptive statistics.Results:Among 158 DUV‐treated pts, median duration of DUV exposure was 11.6 mo (vs 5.3 mo, OFA). DI and DR occurred in 80% (126/158) and 27% (43/158) of pts, respectively. The most common cause of DI was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n = 118), median time to first response on DUV was 1.9 mo and estimated median duration of response was 11.1 mo. Median time to first DI was 3.9 mo and median duration of DI was 15 d (range, 1–133 d). Response to DUV was improved or maintained in most pts evaluated for response who had ≥ 1 DI for > 1 wk (84% [42/50]) or > 2 wk (82% [31/38]) followed by ≥ 3 wk on DUV. In a landmark analysis, median PFS was similar in pts with DI and those without DI for > 1 wk (17.8 vs 16.3 mo) or > 2 wk (17.8 vs 16.3 mo) within the first 3 mo. The median time to DR after CR/PR was 5.6 mo (n = 25) and median duration was 3.4 mo. Median time to onset across AESIs after starting DUV ranged from 2.2 to 4.3 mo; median time to resolution was within 4 wk across AESIs. Proportions of pts experiencing AESIs were stable or decreased over time after 3–6 mo: 0–3 mo, 64% (101/158); > 3–6 mo, 63% (86/137); > 6–9 mo, 47% (54/114); > 9–12 mo, 52% (52/100), and seldom led to discontinuation of DUV (≤ 10%).Summary/Conclusion:DI/DR can contribute to the effective management of TEAEs with DUV. These findings suggest that DI of > 1–2 weeks or more do not appear to significantly impact response to DUV or PFS.