bluuebunny/crossref_metadata_2025 huggingface dataset:
PF619 LENALIDOMIDE IN COMBINATION WITH DEXAMETHASONE AS FIRST‐LINE THERAPY IN TRANSPLANT‐INELIGIBLE PATIENTS WITH MULTIPLE MYELOMA: INTERIM RESULTS OF THE OBSERVATIONAL STUDY FIRST‐NIS
Authors: Nückel H. , Hurtz H.‐J. , Schulz H. , Schulze M. , Koenigsmann M. , Dechow T. , Merling M. , Houet L. , Vannier C. , Potthoff K.
Published: June 2019

Background:

The lenalidomide‐dexamethasone (Rd) combination is a non‐alkylator‐based oral first‐line treatment option in transplant‐ineligible patients (pts) with multiple myeloma (MM). Approval of this regimen was based on the results of the pivotal phase III FIRST trial comparing Rd to the melphalan‐prednisone‐thalidomide (MPT) combination. Median OS was 10 months longer with Rd continuous versus MPT (Facon T et al., Blood 2018). Real‐world effectiveness and safety data of this commonly used first‐line treatment approach in the elderly population are still scarce.

Aims:

The focus of the first interim analysis is to evaluate baseline characteristics and early evidence for safety and effectiveness of first‐line Rd therapy documented in a real‐world patient population.

Methods:

The prospective, multicenter, non‐interventional, observational FIRST‐NIS study was designed to collect data on 167 pts with multiple myeloma receiving Rd as first‐line therapy from about 50 sites across Germany. Primary objective was to evaluate effectiveness of Rd assessed by 24‐month progression‐free survival (PFS) rate. Secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), duration of response (DOR), quality of life (QoL) and safety. Descriptive statistics were used to analyze the data. The prespecified interim analysis was performed 24 months after the enrollment of the 50th patient.

Results:

At the cut‐off date of the interim analysis (July 3rd, 2018), 167 pts had been enrolled. Thereof, 155 pts qualified for effectiveness analysis and 159 pts for safety analysis. Baseline characteristics of all pts and of pts stratified by age (≤ 75 years, > 75 years) are presented (Table 1). The ORR was 53.5% in all pts, 60.9% in pts ≤ 75 years and 50.5% in pts > 75 years. 52.8% of pts developed grade 3/4 adverse events (AEs). Grade 3/4 AEs that occurred in at least 5% of pts were anemia (n = 9, 5.7%) and pneumonia (n = 8, 5.0%).

Summary/Conclusion:

The preliminary data of this interim analysis demonstrate a favorable risk‐benefit profile of Rd in the real‐world setting. Rd seems to be a reasonable first‐line treatment option that can also be provided to elderly pts > 75 years. The ORR results at this early analysis, however, are inferior compared to the outcomes of the pivotal phase III FIRST trial. One reason might be the high proportion of pts aged > 75 years in the FIRST‐NIS, i.e. 70% versus 35% in the FIRST trial. Results need to be confirmed in the final analysis.

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PF621 REAL WORLD EXPERIENCE IN THE MANAGEMENT OF WALDENSTRÖM'S MACROGLOBULINAEMIA FROM ANALYSIS OF THE RORY MORRISON REGISTRY
Authors: Bomsztyk J. , D'Sa S. , McCarthy H. , El‐Sharkawi D. , Scorer H. , Kothari J. , Pratt G. , Cuthill K. , Kyriakou C.
Published: June 2019

Background:

Waldenström's Macroglobulinaemia (WM) is characterised by the presence of an IgM paraprotein and bone marrow infiltration by lymphoplasmacytic lymphoma (Owen et al. 2003); patients present in a variable manner (Castillo et al 2016). A variety of treatments are used at front line and relapse. Current guidelines advocate chemoimmunotherapy in both settings (Owen et al. 2014). Novel agents are also effective spurred on by biological discoveries, including the somatic mutations in MYD88 and CXCR4 genes, but their precise role remains to be determined. Ibrutinib became available in the UK in 2017 via the Cancer Drugs Fund (CDF) for WM in the relapsed setting (NICE TA491).

Aims:

To describe the natural history of WM, monitor usage and impact of treatments including emerging therapies on outcomes in the UK

Methods:

The Rory Morrison Registry (RMR) collects data from existing and new patients with WM & related conditions from (so far) 14 centres across the UK using entry on to a web‐based platform. 701 patients are registered including 560 with a confirmed WM diagnosis. We describe treatment trends from across the UK at front line and first relapse. To facilitate analysis, we grouped the regimens.

Results:

383 patients have received front line therapy with at least 29 different regimens since 1984, and 215 second line therapy with at least 32 different regimens.

The most common categories were DRC (90 patients; 23%), Alkylator based (75, 20%), R‐Bendamustine (50; 13%) and CHOP‐based (42; 11%), Other (37, 10%), Purine analogue (PA)‐based therapy (35; 9%), Rituximab monotherapy (R‐mono) (34, 9%), Bortezomib‐based (17; 4%) and BTK inhibitors (3, 1%).

The use of each treatment has noticeably changed over time (See graph). The peak treatment choices in the early 2000 s were Alkylator‐ or CHOP‐based therapies. This has been superseded by DRC (since 2007) and R‐Bendamustine (since 2011). There has been a stable role for R‐mono and PA‐based therapy.

Regimens used at first relapse have been highly variable till 2017 when Ibrutinib became available. Treatments from 209 patients at first relapse since 1984 show that the most common category was ‘Other’ (52; 25%), followed by BTK Inhibitors (41; 21%), R‐mono (including maintenance rituximab) (22; 11%), Alkylator‐based (21; 10%), PA‐based (19; 9%), DRC (19, 9%), Bendamustine‐based (17, 8%), CHOP‐based (13; 6%) and Bortezomib‐based (5; 2%). Notably, since 2017, of the 58 patients having 2ndline therapy 34 (58%) received BTK inhibitors.

Summary/Conclusion:

Observations from the Rory Morrison Registry demonstrate the evolving trends in WM treatment in the UK, including the emergence of DRC and R‐Bendamustine as standard frontline therapy and a preference for BTK inhibition as 2ndline therapy, since their availability. Further analysis is planned to assess the ‘real world’ impact of the emerging treatments.

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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.

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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).

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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 years

Aims:

To asses the role of different conditioning regimens over the years in HSCT in patients with acquired AA

Methods:

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.

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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.
PS1173 PROTEIN CASEIN KINASE 2 IS INVOLVED IN CHRONIC MYELOID LEUKEMIA RESISTANCE TO IMATINIB AND ALSO TO DASATINIB
Authors: Mitrovský O. , Myslivcová D. , Macháčková T. Lopotová , Klamová H. , Žáčková M.
Published: June 2019

Background:

Protein casein kinase 2 (CK2) is a Ser/Thr kinase, which is ubiquitously expressed in eukaryotic cells. It phosphorylates a broad number of proteins, regulates a number of key signaling pathways and promotes cell proliferation and survival. Although CK2 does not belong to the “oncogenic kinases”, it is overexpressed in many solid tumours and also in hematological malignancies. Previous results by Donella‐Deana et al. indicated CK2 association with resistance to imatinib in CML cell lines. In our study, we explored the role of CK2 in cell resistance to imatinib as well as to dasatinib, both in CML cell lines and in patient samples.

Aims:

We aimed 1) to verify the involvement of CK2 kinase in the resistance to imatinib, in cell line model and in patient samples and 2) to investigate possible role of CK2 in the resistance to dasatinib.

Methods:

Sublines resistant to either 2 nM dasatinib or 2 μM imatinib were derived from established CML cell lines JURL‐MK1, MOLM‐7, and K562. Sensitive and resistant cells were then treated with the CK2 inhibitor CX‐4945, imatinib, or dasatinib, individually or in selected combinations. Alternatively, siRNAs against CK2 subunits were used. Cell viability was determined using Alamar test. Protein levels and phosphorylation were measured using western blots. CK2 activity was assessed through phosphorylation of its substrates [(pS/pT)DXE] and of its natural target, Cdc37. To evaluate the extent of apoptosis, PARP and caspase 3 cleavage was analysed.

Results:

We have successfully established JURL‐MK1, MOLM‐7 and K562 sublines resistant to either 2 nM dasatinib or 2 μM imatinib. We found increased protein levels of CK2 kinase and increased phosphorylation levels of CK2 substrates in all resistant cells as compared to sensitive cells. All cells were treated with imatinib, dasatinib and CK2 inhibitor CX‐4945 and their combinations. Despite the loss of response to TKIs, the resistant cells remained sensitive to CK2 inhibition. CX‐4945 reduced CK2 substrates phosphorylation and also cell proliferation in both type of resistant cells. It also increased apoptotic indicators (cleaved PARP, caspase 3) and the dead cell fraction. Preliminary results showed a decrease of cell viability and/or apoptosis induction also in primary cells from four patients resistant to imatinib or dasatinib. Leukocytes from healthy donors were not affected by any of the inhibitors tested.

Summary/Conclusion:

Altogether, our results suggest that CK2 kinase is involved in CML resistance to both imatinib and dasatinib. Further research is necessary to fully understand the role of CK2 in CML and its potential to become a new target of therapy.
PS1206 TRANSCRIPTION FACTOR BOB1 IS ESSENTIAL FOR GERMINAL CENTER‐DERIVED B CELL MALIGNANCIES OFFERING AN ATTRACTIVE TARGET FOR TCR‐BASED THERAPY
Authors: Reijmers R. , Meeuwsen M. , Kweekel C. , Kop M. , Meringa A. , Jahn L. , Falkenburg F. , Heemskerk M.
Published: June 2019

Background:

Antigen‐loss tumor escape variants are a major concern when targeting cancer, while tumor‐specific targeting is crucial to prevent unwanted toxicity. Thus, targeting essential cancer‐ or lineage‐specific genes might represent attractive targets for antineoplastic therapies since antigen‐loss is less likely to occur, and toxicity is limited. Here, we describe B cell lineage‐specific transcriptional coactivator BOB1 to meet these important criteria. Interestingly, in our lab we have successfully identified several distinct T cell receptors (TCRs) that are BOB1‐specific with demonstrable preclinical efficacy.

Aims:

With this study we aimed to demonstrate that the transcriptional coactivator BOB1 is essential for survival of B cell malignancies with a germinal center origin, and that these neoplasms are recognized by our recently and newly identified BOB1‐specific TCRs in the context of HLA‐B∗07:02 and HLA‐B∗35:01, respectively.

Methods:

Using a CRISPR/Cas9 puromycin plasmid containing a sgRNA or by applying a doxycycline‐inducible system, we set out to target BOB1 in different B cell malignancies. Upon targeting, we selected puromycin resistant single‐cell clones or tracked cell growth upon induction, and used sanger‐sequencing to identify possible indel mutations. Besides single‐cell analysis, Tracking of Indels by DEcomposition (TIDE) was used to accurately quantify the editing efficacy and most prominent types of indel mutation in different pools of B cell tumors. Finally, we performed in vitro co‐cultures with BOB1‐specific TCR transduced CD8 T cells and a plethora of B cell malignancies, including myeloma and lymphoma, and assessed preclinical efficacy targeting myeloma in vivo.

Results:

Remarkably, for each type of B cell tumor used, we were unable to generate BOB1‐deficient clones, unveiling the importance for cell survival. In line, using the TIDE algorithm for easy detection of predominant types of indel mutations in targeted pools of distinct types of B cell malignancies, we found unmutated BOB1 sequences only (>90%), while generally a mere 5% is expected to be unaltered for any irrelevant gene. Finally, we further established the essentiality of BOB1 in a broad panel of B cell malignancies containing inducible CRISPR/Cas9, which uniformly resulted in rapid cell death upon induction. Interestingly and importantly, using our recently and newly identified TCRs recognizing peptides derived from BOB1 in the context of HLA‐B∗07:02 and HLA‐B∗35:01, we observed highly specific and efficient targeting of a vast majority of B cell malignancies in vitro and in vivo.

Summary/Conclusion:

Altogether, we postulate BOB1 as an essential B cell lineage‐specific target, fortifying gene transfer of our unique TCRs into CD8+ cytotoxic T cells as an efficient therapeutic treatment option for a large variety of B cell neoplasms.
PS1284 GLOBAL GUIDELINE FOR THE DIAGNOSIS AND MANAGEMENT OF MUCORMYCOSIS: AN INITIATIVE OF THE ECMM IN COOPERATION WITH THE MSG ERC
Authors: Cornely O. , Chakrabarti A.
Published: June 2019

Please indicate where the abstract has been published before: The Lancet Infectious Diseases

Background:

Mucormycosis is a rare disease that may progress rapidly. Although urgent surgical and medical intervention is lifesaving, diagnosis is often delayed and mortality rates are high. Guidance on the complex multidisciplinary management has the potential to improve prognosis. Management pathways depend on recognising disease patterns and availability of diagnostic and therapeutic options.

Aims:

To address differences between the regions of the world, authors from 33 countries analysed published evidence on mucormycosis management and provide recommendations as part of the “One World One Guideline” initiative.

Methods:

Consensus process involving experts from all UN regions, comprising physicians and scientists involved in various aspects of mucormycosis management, representing the fields of microbiology, pathology, radiology, infectious diseases, surgery, paediatrics, haematology, intensive care, dermatology, and pharmacology.

Results:

This guidance document provides practical help in clinical decision making and identifies areas of uncertainty and future research direction.

Summary/Conclusion:

Mucormycosis requires different tailored approaches in different regions of the world‐ This guidance document is the first in a series from One World One Guideline initiative.
PS1288 SAFETY AND UTILIZATION OF MIDLINE CATHETERS VERSUS TUNNELED CENTRAL VENOUS CATHETERS IN THE MANAGEMENT OF ACUTE MYELOID LEUKEMIA PATIENTS: A SINGLE CENTER EXPERIENCE
Authors: Gardeney H. , Gallego P. , Diaz J.M. Torregrosa , Cayssials E. , Maillard N. , Rammaert B.
Published: June 2019

Background:

Tunneled central venous catheters (TCVCs) are used in cancer patients for irritant or vesicant infusions such as chemotherapy or antibiotics. However, they can be associated with significant complications. Midline catheters (MCs) are peripheral intravenous access devices that ends in a large peripheral vein. They are easier to install and which may reduce the need for CVCs.

Aims:

Therefore, the aim of this study is to assess the rate of adverse events with both kind of catheter, in hospitalized patients for the treatment of acute myeloid leukemia.

Methods:

We retrospectively compared the use and complications of TCVCs and MCs at our institution between December 2017 and July 2018. Data were collected using electronic medical records. Both devices were used indistinctly among our hospitalized patients for chemotherapy, antibiotics and parenteral nutrition. The following complications were recorded: catheter‐related bloodstream infection (defined as documented bacteriemia and differential time to positivity pointing to TCVC as main source), local signs of infection (such as erythema or inflammation) at insertion site, thrombosis which requires an anticoagulant treatment, extravasation and local bleeding at insertion site.

Results:

Through this period, 59 chemotherapy episodes were recorded among 36 different patients: 39 of them were performed through TCVC and 20 through MC. As expected duration of the device was shorter for MCs (mean 31days) as they were ablated on discharge, compared to Hickman (51 days) or Port‐à‐cath (48days). Main complications were related to infections, with 17 (43.6%) among TCVCs and 6 (30%) in MCs (p = 0.4). Local signs of infection were also present on 5 (12.8%) of TCVCs. Median aplasia duration (defined as polymorphonuclear neutrophils count in peripheral blood <500/mm3) was 19.0 days [0 to 55 days], with no differences among the groups (18.3 days in MCs vs 19.7 days in TCVCs). No extravasation was found in any group. As expected local bleeding was not observed among MC and only in 3 (7.7%) TCVCs. There is a trend towards more frequent complications (infection, thrombosis and bleeding) were more frequent among TCVCs (n = 32) than among MCs (n = 6; p = 0.08) even when reported to the length of the catheter (0.63 complications/day in TCVCs and 0.19 complications/day in MCs).

Summary/Conclusion:

MCs insertion ‐quick and easy‐ makes them user‐friendly for hematologists and can be safely used among acute leukemia patients.
PS1293 OSTEOGENESIS IMPERFECTA: A NEW UNRECOGNIZED ETIOLOGY FOR FUNCTIONAL IRON DEFICIENCY
Authors: Elsayed S. , Ragab I. , Yacoup A. , Sallam M.
Published: June 2019

Background:

Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue primarily affecting bone with a wide spectrum of clinical expression that varies from death in the perinatal period to normal life expectancy. Although data is scarce, we observed a high frequency of anemia in patients with OI and hypothesized that functional iron deficiency (FID) may occur secondary to the inflammation resulting from frequent fractures and multiple surgical procedures.

Aims:

The aim of this work was to study the frequency of anemia in children with OI and try to classify them according to iron status by conventional tests to analyze the possibility of presence of FID and the possible association of hepcidin level with such etiology.

Methods:

A cross‐sectional study included 56 patients diagnosed with osteogenesis imperfecta regularly following at the genetics clinic, Children'sHospital, Ain‐Shams university. All patients were subjected to detailed clinical scoring with complete blood count, serum iron, serum ferritin, and total iron binding capacity, C‐reactive protein (CRP) and serum hepcidin by ELISA, Dexa scan and lateral and AP spine x‐ray. Patients were classified into five groups, Group‐1 including 7 OI patients fulfilling criteria of FID; serum ferritin > 100ng/ml, TS < 20% and CRP> 1 mg/dl, Group‐2 including 27 OI patients fulfilling criteria of combined ACD&IDA; serum ferritin level was ≤ 100ng /ml, TS < 20% and CRP> 1 mg/dl, Group‐3 including 16 OI patients without anemia according to WHO classification, other anemia group including 6 OI patients with anemia that could not be classified according to the classification adopted in this study, IDA anemia including zero OI patients as there were no patients fulfilling criteria of pure IDA; ferritin < 12ng/ml in children aged <5 years, or ferritin <15ng/ml in children aged > 5 years, when the corresponding CRP was <1 mg/dl and TS < 20%.

Results:

The frequency of anemia among the studied patients with osteogenesis imperfecta was 71.4%. Combined IDA and FID formed 48.2%, 12.5%, 28.6% and 10.7% hadFID, no anemia and other anemia groups respectively. functional iron deficiency was found in 60.7%.

Median hepcidin level was significantly increased in pure FID patients 120 (100 – 510 ng/mL) as compared to those in no anemia patients 80 (65 – 100 ng/mL) and other anemias 60 (50 – 70 ng/mL). The serum hepcidin concentration was mildly reduced in ACD patients with ID with a median of 100 (60 – 150 ng/mL).

Patients with severity score levels less than 70% had significant higher number of WBCS, platelets and serum hepcidin levels and significant lower serum iron compared to patients with severity score levels more than 70% and less than 90%.

Summary/Conclusion:

Anemia is an unrecognized complication in patients with OI. Functional iron deficiency constitutes a significant etiology adding to dietetic problems. New therapeutic approach for FID is suggested to improve the quality of fracture healing in such group.
PS1297 EFFICACY AND SAFETY OF INTRAVENOUS IRON THERAPY IN CHILDREN: A KOREAN SINGLE CENTER STUDY
Authors: Jung N. , Shim Y.J. , Kim H.S.
Published: June 2019

Background:

Although Intravenous (IV) iron is widely and safely administrated to adults for various indications including severe anemia, chronic blood loss and postoperative anemia, Administration of IV iron is rarely used in children due to lack of pediatric data.

Aims:

The aim of this study was to determine the indications for IV iron and to evaluate the efficacy and safety of IV iron infusions to children who were visited a single Korean center.

Methods:

This retrospective study collected data from ≤18 year‐old children who were received IV iron at the Keimyung University Dongsan Medical Center between July 2003 to December 2018. Exclusion criteria included: (1) receiving a packed red blood cell transfusion or erythropoietin, (2) surgery or massive bleeding before obtaining the laboratory results of post IV iron infusion. We compared laboratory results including hemoglobin (Hb) concentrate, mean corpuscular volume (MCV), serum ferritin level between pre and post‐IV iron infusion. Also, the medical records were reviewed for adverse effects. All statistical analyses were performed using IBM SPSS software (version 23.0; IBM Corp., Armonk, NY), and P‐values of <0.05 were considered statistically significant.

Results:

Total 31 children (male:female = 18:13; median age 4.5 years, range 0.3–17.9) received total 80 infusions of IV iron therapy. The most common etiology of anemia was gastrointestinal cause. Oral iron intolerance (32%) and refractoriness (26%) were common indications for IV iron infusion. Seventeen patients received a total 43 infusions of iron sucrose (median dose, 3.9 mg/kg, range 1.0 to 20.4), fifteen patients received a total 37 infusions of ferric carboxymaltose (median dose, 5 mg/kg, range 3.3 to 18.8). All Patients had follow up laboratory test at 1–120 days (median 15 days) after their infusions. Except 2 patients, all patients showed good hematologic response. The median pre‐infusion Hb, MCV and ferritin values were 9.0 g/dL (range 6.1–13.6), 75.9 fL (55.9–94.3) and 12.2 ng/mL (1.7–284.9), respectively. The median post‐infusion Hb, MCV and ferritin values were 10.7 g/dL (6.3–14.7), 79.6 fL (64.9–103.5) and 54.0 ng/mL (3.9–842.8), respectively. There were statistically significant improvements in these values (p‐value <0.001). No patients experienced severe adverse effects such as anaphylaxis.

Summary/Conclusion:

The most common indication for IV iron among Korean children was oral iron intolerance. The use of IV iron is effective and safe treatment in children.

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PS1446 THE ROLE OF THE THROMBOPOIETIN RECEPTOR (MPL) IN JAK2V617F‐POSITIVE MYELOPLROLIFERATIVE NEOPLASMS
Authors: Behrens K. , Viney E.M. , Willson T.A. , Babon J.J. , Nicola N.A. , Alexander W.S.
Published: June 2019

Background:

Constitutive activation of the Jak/Stat signalling pathway is a hallmark of Myeloproliferative Neoplasms (MPN), with 60–90% of patients carrying the activating JAK2 mutation, JAK2V617F. Several studies suggest expression of a type I cytokine receptor is essential for JAK2V617F‐mediated transformation, but the precise contribution of such receptors is unresolved.

Aims:

Here we investigate the functional role of Mpl in JAK2V617F‐driven MPN.

Methods:

Mpl mutants lacking various functional domains were screened for their capacity to support JAK2V617F‐mediated factor independence in BaF/3 cells. Using CRISPR/CAS9 genome editing Mpl‐mutant mice were generated to extend these findings to an in vivo model of JAK2V617F MPN.

Results:

In vitro studies confirmed that Mpl expression was required for JAK2V617F‐induced transformation, but identified a Mpl truncation mutant retaining the JAK2‐interaction domain, but lacking the C‐terminus (Mpl‐IC36), typically associated with Stat5 binding, to be sufficient to support JAK2V617F‐induced transformation. Interestingly, Stat5‐phosphorylation was maintained. In contrast, deletion of the entire cytoplasmic receptor domain abrogated Stat5 phosphorylation and factor‐independent proliferation. In vivo Mpl‐wt;JAK2V617F mice exhibited the thrombocytosis and erythrocytosis typical of MPN, while Mpl deficiency abrogated thrombocytosis but sustained high red blood cell counts. Although the Mpl‐IC36 receptor was sufficient for JAK2V617F‐induced factor independence in BaF/3 cells, Mpl‐IC36;JAK2V617F mice did not develop thrombocytosis, indeed platelet counts were similar to those in Mpl null mice. This underlines differences that may emerge from in vitro and in vivo systems and highlights the important role of the Mpl cytoplasmic region for JAK2V617F‐mediated signalling.

Summary/Conclusion:

JAK2V617F requires Mpl to induce transformation. While a Mpl truncation mutant retaining the JAK2‐interaction domain, but lacking the C‐terminus (Mpl‐IC36) was sufficient to induce JAK2V617F‐mediated cytokine independence in BaF/3 cells in vitro, this receptor was insufficient for development of thrombocytosis in JAK2V617F mouse model. These results suggest that the role of Mpl in JAK2V617F‐induced MPN extends beyond a simple scaffold for active JAK2 and that signalling from the Mpl C‐terminal domain is required in vivo.
PS1474 NON‐HODGKIN LYMPHOMA IN PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS
Authors: Yoshinaga K. , Shiseki M. , Ryuzaki M. , Iizuka Y. , Watanabe A. , Tanaka N. , Ishiyama M. , Shinohara A. , Kazama H. , Hagiwara S. , Mori N. , Tanaka J.
Published: June 2019

Background:

Development of aggressive B‐cell lymphomas during JAK1/2 inhibitor therapy in patients with myeloproliferative neoplasms (MPN) were reported in 2018 European Haematology Association Meeting in Stockholm. It's important to evaluate the incidence of lymphomas in patients with ruxolitinib.

Aims:

We conducted a retrospective study to evaluate the incidence and clinical characteristics of lymphomas in patients with MPN.

Methods:

We reviewed laboratory data and clinical record of the patients with MPN diagnosed until Dec 2017 in Tokyo Women's Medical University Hospital.

Results:

Among 207 patients with MPN, including 129 essential thrombocytosis (ET), 68 polycythemia vera (PV), and 10 primary myelofibrosis (PMF), three patients (1.4%) developed an aggressive non‐Hodgkin Lymphoma (NHL) (Table). Among 207 patients with MPN 15 patients (7.2%) received ruxolitinib. Two of three patients developing NHL had a history of ruxolitinib treatment. There was significant difference in the incidence of NHL occurrence between MPN patients with ruxolitinib treatment (2/15, 13.3%) and those without ruxolitinib treatment (1/192, 0.5%) (Fisher's exact test, P = 0.014). Initial symptoms of lymphoma were extra‐nodal mass (cutaneous or colon mass) in two patients with ruxolitinib treatment. Times from starting ruxolitinib treatment to the diagnosis of lymphoma in these two patients were 2 and 16 months, respectively. They did not achieve complete response by anti‐lymphoma chemotherapy, and died from AML. In contrast, the DLBCL patient without ruxolitinib achieved complete response and is still alive.

Summary/Conclusion:

The occurrence of lymphoma was more common in patients with ruxolitinib than in the non‐administered group. Porpaczy et al reported that pre‐existing B‐cell clones in myelofibrosis developed to B‐cell lymphoma after ruxolitinib treatment. In the present cases, lymphoma occurred within relatively short period after starting ruxolitinib treatment, suggesting that there were pre‐existing lymphoma clones before ruxolitinib treatment. Extra‐nodal site involvements were seen in present cases similar to the previous reports, suggesting biological difference of lymphoma complicated with MPN patients. Unlike previous report, one T‐cell lymphoma case was included in the present study. It remains unclear whether there is difference in clinical features and mechanisms between B‐cell lymphoma and T‐cell lymphoma development in MPN patients with ruxolintinib treatment. It may be underestimated to the occurrence of lymphoma if biopsy may not perform depending on the condition of patient. We need to careful watch and actively examine the tumor in MPN.

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