bluuebunny/crossref_metadata_2025 huggingface dataset:
PS1149 SECOND CANCER INCIDENCE IN CLL PATIENTS RECEIVING BTK INHIBITORS
Authors: Bond D. , Huang Y. , Fisher J. , Ruppert A. , Owen D. , Bertino E. , Rogers K. , Bhat S. , Jaglowski S. , Grever M. , Byrd J. , Maddocks K. , Woyach J.
Published: June 2019

Background:

Patients (pts) with chronic lymphocytic leukemia (CLL) suffer morbidity and mortality from CLL and increased risk for second primary neoplasia (SPN). BTK inhibitors (BTKi) are highly effective for the treatment of CLL and are associated with partial restoration of immune function with ongoing treatment. The impact of BTKi on the risk for and patterns of SPN is yet to be characterized.

Aims:

We aimed to determine the incidence of SPN including NMSC in a cohort of CLL pts treated with either ibrutinib or acalabrutinib at a single center, assess for association between baseline clinical characteristics and SPN incidence, and compare the observed with the expected incidence for sex and age matched controls within the Surveillance, Epidemiology, and End Results Program (SEER) database.

Methods:

CLL pts treated with ibrutinib or acalabrutinib at our center were identified retrospectively. Baseline and outcome data were collected including incidence of Richter's transformation (RT), non‐melanoma skin cancer (NMSC), and SPN.

Standard incidence ratio (SIR) with 95% confidence intervals (CI) were calculated using expected incidence rates from the SEER, assuming a Poisson distribution for the observed incidence. Cumulative incidence rate (CIR) of SPN (excluding RT and NMSC) was calculated from BTKi start date to the diagnosis of SPN; death was a competing risk and pts without event were censored at last follow‐up. SPN was correlated with baseline data using the Fine‐Gray model.

Results:

691 pts were included; the median age was 64 years, median prior lines of treatment was 2 (20% treatment‐naïve, 66% with prior chemo‐immunotherapy), and 56% were never smokers. At a median follow‐up of 44 months, 68 pts (10%) were diagnosed with SPN (SIR 2.4, CI 1.9–3.0) including 13 lung (SIR 3.2, CI 1.7–5.5), 9 melanoma (SIR 6.9, CI 3.1–13), 9 prostate (SIR 1.4, CI 0.6–2.6), 7 bladder (SIR 5.2, CI 2.1–10.6), 4 breast (SIR 1.7, CI 0.5–4.5), and 3 kidney cancers (SIR 2.9, CI 0.6–8.5). CIR of SPN at 3 year was 7.6% (Table). Smoking (hazard ratio (HR) 2.9, CI 1.7–5.0, p < .01) and low baseline CD8 count (HR 0.9 for 2‐fold increase, CI 0.8–0.9, p < .01) were associated with higher incidence of SPN. RT was diagnosed in 58 pts (8%) and NMSC in 138 pts (20%). 179 pts had died with 3 year overall survival of 79% (CI 76–82); the most common causes of death were CLL/RT (57%) and SPN (13%).

CIR of Second Cancers

Summary/Conclusion:

The incidence of SPN in pts treated with BTKi for CLL is increased relative to the general population. With a 5 year CIR of NMSC and SPN of 23% and 12% respectively, these data support consideration of intensive cancer screening for CLL pts receiving BTKi.

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PS1151 PHASE 2 STUDY OF ACALABRUTINIB IN IBRUTINIB‐INTOLERANT PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: Rogers K. , Thompson P.A. , Allan J.N. , Coleman M. , Sharman J.P. , Cheson B.D. , Izumi R. , Frigualt M.M. , Quah C. , Raman R.K. , Wang M.H. , Kipps T.J.
Published: June 2019

Background:

In patients with chronic lymphocytic leukemia (CLL) treated with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, intolerance was the most common reason for discontinuation (50% to 63%; Mato AR, et al. Haematologica. 2018).

Aims:

This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in ibrutinib‐intolerant patients with relapsed/refractory CLL.

Methods:

Patients with relapsed/refractory CLL (≥1 prior therapy) who discontinued ibrutinib due to Grade 3/4 adverse events or persistent/recurrent Grade 2 adverse events and had progressive disease after ibrutinib discontinuation were eligible. Acalabrutinib was given orally at 100 mg twice daily in 28‐day cycles until progressive disease or unacceptable toxicity. The primary endpoint was overall response rate (ORR).

Results:

Sixty patients were treated. The median age was 70 years (range, 43 to 88). Patient characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%), and unmutated IGHV (79%). Fifty‐two of 55 patients (95%) with available baseline samples were wild type for BTK and PLCG2. The median number of prior therapies was 2 (range, 1 to 10). The median duration of prior ibrutinib therapy was 6 months (range, <1 to 55); common adverse events that led to ibrutinib discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). At a median follow‐up of 19 months (range, 1 to 31), 67% of patients remain on acalabrutinib; discontinuations were mostly due to progressive disease (13%) and adverse events (10%; pneumonia [n = 2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n = 1]). Efficacy outcomes are in the Table. Common adverse events (any grade) were diarrhea (48%), headache (40%), contusion (35%), and dizziness (32%). Serious adverse events (≥2 patients) were pneumonia (10%), anemia (3%), and syncope (3%). Atrial fibrillation occurred in 3 patients (5%; all Grade 1/2) and major hemorrhage in 2 (3%; Grade 3 hematuria and Grade 2 subdural hematoma). Grade 5 adverse events were pneumonia (n = 2), bronchopulmonary aspergillosis (n = 1), and ventricular fibrillation (n = 1); all were considered not related to treatment.

Summary/Conclusion:

Acalabrutinib is tolerable and effective in ibrutinib‐intolerant patients, providing a viable strategy for continuing BTK inhibitor therapy.

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PS1199 SCREENING FOR HEREDITARY SPHEROCYTOSIS IN DAILY PRACTICE: WHICH IS THE BEST ALGORITHM USING ERYTHROCYTE AND RETICULOCYTE PARAMETERS?
Authors: Adam A.‐S. , Gulbis B. , Cotton F.
Published: June 2019

Background:

Hereditary spherocytosis (HS) is the most common inherited chronic haemolytic anemia in Northern Europe. Its prevalence is estimated to 1 in every 2000 births. The actual guidelines for the screening and diagnosis of HS are based on clinical and family histories, physical examination and laboratory findings. Additional parameters based on complete blood count (CBC) and reticulocyte parameters have been developed on haematology analyzers leading to many publications about their effectiveness as HS screening tool.

Aims:

We evaluated and compared the effectiveness of four published algorithms for the screening of HS using two haematology analyzers i.e. the UniCel DxH800 (DxH; Beckman‐Coulter, Miami, FL) and the XN‐9000 (XN; Sysmex, Kobe, Japan) and determined which algorithm could be the most suitable in our daily clinical practice.

Methods:

A total of 96 EDTA samples obtained for HS screening were analyzed prospectively on both haematology analyzers and a CBC with extended reticulocyte parameters were collected. These included 12 confirmed HS patients and 84 non‐HS patients. The diagnosis of HS was based on clinical and family histories, cryohaemolysis test, eosin‐5’‐maleimide (EMA) dye binding test, ektacytometry and identification of the defective protein. The specific reticulocyte parameters used on the DxH800 were mean reticulocyte volume (MRV), immature reticulocyte fraction (IRF) and mean sphered cell volume (MSCV), and on the XN‐9000 were hypohaemoglobinized erythrocytes (Hypo‐He), microcytic erythrocytes (MicroR) and IRF. For each algorithm, we established sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV).

Results:

The results are reported in Table 1. The only algorithm that provided a sensitivity of 100% was the algorithm published by Lazarova et al. in 2014 using the DxH800. The three algorithms published based on the Sysmex parameters showed much lower performances than the one based on the DxH800 parameters i.e. out of the 96 patients with HS, between 2 to 6 patients were screened as negative for HS. Three of the published algorithms were evaluated on a previous XE model i.e. XE‐5000, mode of HS diagnosis is not always comparable as well as the amount of patients involved in the different studies.

Table 1: Performance characteristics of the different algorithms (original stated performance characteristics) tested prospectively on 12 HS and 84 non‐HS patients.

Summary/Conclusion:

To screen for HS in the daily practice, the extended reticulocyte parameters provided by the Sysmex analyzers seem promising but the clinical cut‐offs on the XN‐9000 should be reevaluated on a larger number of patients.

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PS1210 DEVELOPMENT OF A NEXT GENERATION ALLOGENEIC CAR‐T CELL PLATFORM WITHOUT GENE EDITING
Authors: Sotiropoulou P.A. , Michaux A. , Raitano S. , Bornschein S. , Bolsée J. , Lenger S.R. , Machado H.B. , Moore J.D. , Gilham D.E.
Published: June 2019

Background:

Autologous CAR‐T cell therapy is now a proven breakthrough technology in the treatment of B cell malignancies and holds promise in the therapy of all types of cancer. However, autologous CAR‐T cell therapy does have significant challenges relating to logistics and product consistency. Allogeneic CAR‐T therapeutic products could allow treatment of multiple patients with cells from the same healthy donor, increasing product consistency, likely reducing manufacturing costs and avoiding the time delay required to generate an autologous T cell product.

Aims:

Allogeneic CAR‐T cell therapy is dependent upon eliminating the activity of the endogenous T Cell Receptor (TCR) within the engineered T cell, thereby preventing the induction of a graft versus host response and resultant potentially life‐threatening toxicity. We have explored RNA interference to modulate the TCR and to assess the potential of short hairpin RNA (shRNA) as a platform technology for Allogeneic CAR T cell therapy.

Methods:

shRNAs targeting the CD3ε and CD3ζ chains of the TCR complex were expressed in primary T cells where the efficacy of the individual shRNAs to downregulate the CD3 component and subsequent impact upon TCR expression assessed. The optimal shRNAs were tested in a head to head fashion against the state‐of‐the‐art gene editing technology, CRISPR‐Cas9, in vitro for response against mitogenic stimulation and in animal models for control of xenoGvHD.

Results:

shRNAs specific for CD3ε and CD3ζ reduced the transcriptional expression of their relevant targets, as well as the cell surface expression of the TCR. Downregulation of TCR expression and inhibition of the in vitro mitogenic response when challenged with anti‐CD3 antibodies was similar between shRNAs and CRISP‐Cas9 targeting CD3ζ. Importantly, in vivo experiments with T cells adoptively transferred to NSG mice showed that shRNAs targeting CD3ζ protected animals from GvHD, while T cell persistence was significantly higher compared to T cells genetically engineered with CRISP‐Cas9 targeting CD3ζ.

Summary/Conclusion:

This work demonstrates that the expression of shRNA in a standard retroviral vector provides a one‐step solution to produce cells suitable for Allogeneic CAR T cell therapy. Our testing continues, involving the examination of the anti‐tumor potency of such shRNA‐Allo CAR‐T cells. Importantly, this approach provides a one vector solution that offers an alternative to strategies such as gene editing to eliminate the TCR, while also requiring no major alteration to current CAR‐T cell manufacturing, that should enable the rapid adoption of the approach into clinical testing.
PS1249 EXTRANODAL AND SPLEEN DISEASE DETECTED BY FDG‐PET/CT IS ASSOCIATED WITH EARLY CLINICAL FAILURE IN UNTREATED FOLLICULAR LYMPHOMA
Authors: St‐Pierre F. , Broski S. , Laplant B. , Ristow K. , Maurer M. , Macon W. , Habermann T. , Ansell S. , Thompson C. , Micallef I. , Nowakowski G. , Witzig T.
Published: June 2019

Background:

Predicting early clinical failure in patients with untreated follicular lymphoma (FL) is important but difficult. Lymphoma involvement of extranodal (EN) sites is better detected by FDG‐PET/CT than CT alone, but PET parameters are not part of the usual predictive indices.

Aims:

We aimed to determine the incidence and patterns of EN and spleen disease, and learn if they were useful in predicting early clinical failure.

Methods:

PET/CT images from 613 cases of newly diagnosed FL between 2003 – 2016 were retrospectively reviewed for EN and spleen involvement. The location, number, and pattern of EN sites, as well as splenic involvement, were recorded. Associations with outcomes were assessed using event‐free survival (EFS), overall survival (OS), and early clinical failure at 24 months (EFS24).

Results:

49% (301/613) of patients had PET/CT‐detected EN involvement, and 28% (171/613) had spleen involvement. Presence of ≥2 EN sites, spleen, bone or soft tissue involvement all predicted failure to achieve EFS24. These factors, as well as pattern of bone involvement by imaging, were predictors of EFS on univariate analysis; presence of ≥2 EN sites and bone involvement pattern were also predictive of OS. In a multivariate analysis with FLIPI‐2 factors, spleen involvement, pattern of bone involvement, and soft tissue involvement independently predicted a lower EFS (Table 1). When the multivariate analysis was performed using PRIMA‐PI factors (marrow and B2 M), the presence of ≥2 EN sites was an adverse independent prognostic factor for OS (HR 2.28; 95% CI 1.01–5.18; p = 0.05).

Table 1: Extranodal and spleen involvement by PET/CT as predictors of event‐free survival

Summary/Conclusion:

Baseline PET/CT identifies EN and spleen sites of disease that can predict early clinical failure in FL. These results, when combined with other factors, may better identify high‐risk patients and guide appropriate therapy.

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PS1271 PREDICTORS, RATES AND COSTS ASSOCIATED WITH READMISSION FOR CLOSTRIDIUM DIFFICILE INFECTION WITHIN 90 DAYS OF HEMATOPOIETIC STEM CELL TRANSPLANTATION: INSIGHT FROM THE NATIONWIDE READMISSION DATABASE
Authors: Elsabbagh E.M. , Hageman J.
Published: June 2019

Background:

Clostridium difficile infection (CDI) is a common and serious disease attributable to substantial morbidity, and mortality following the bone marrow transplant in pediatric population. Rates of readmission, during the first 3‐month follow‐up are poorly characterized.

Aims:

We aimed to identify rates, predictors and hospitalization cost of CDI readmission after Hematopoietic Stem Cell Transplant (HSCT) using the Nationwide Readmission Database (HCUP‐NRD)

Methods:

Using administrative claim codes for CDI in the 2014 Nationwide Readmission Database, pediatric patients admitted after HSCT with at least 3 months of follow‐up were included for analysis. Patients were stratified according to HSCT type, either Umbilical Cord Blood Transplant (UCBT) or Bone Marrow Transplant (BMT) which was further stratified into autologous and allogenic transplantation, then evaluated for CDI readmission through day 90.

Results:

A total of 2057 pediatric patients met the inclusion criteria, including 2.2 % that received UCBT, 97.8% that received BMT. All‐causes readmission rate was 65% (1338/2057) and CDI readmission rate was 4.7% (63/1338). The mean age was 4 years, 71.4% were male, mean length of stay was 12.9 days and the median time lapsed after transplant discharge and CDI readmission was 52 days. Medicaid was the most common payer at 54.7%. The median cost per CDI admission was $67999 with net total cost $12.2 million. The respective rates of CDI 90‐day readmission according to transplant type were 11.5% for UCBT and 88.5% for BMT (p < 0.001). The most frequent diagnosis associated with CDI readmission in the first 90 days was neuroblastoma (19.5%; p < .001)

Summary/Conclusion:

Conclusion(s): (1) Among pediatric patients treated with HSCT, CDI 90‐day readmission rate is significant and associated with significant high cost. (2) The most common diagnosis associated with high burden of CDI 90day readmission was neuroblastoma. (3) Additional study is warranted to evaluate factors that may lead to decreased rate of CDI readmissions following HSCT
PS1280 FUNGAL INFECTIONS IN ACUTE MYELOID LEUKEMIA IN THE POSACONAZOLE ERA
Authors: Marini C. , Baldaia A. , Chorão P. , Bergantim R. , Aguiar E. , Cancela J. , Trigo F. , Guimarães J.E.
Published: June 2019

Background:

Posaconazole prophylaxis in patients with acute myeloid leukaemia (AML) changed the paradigm of fungal infections (FI).

Aims:

Description of FI and analysis of factors that might predispose to this type of infection in non‐allotransplant AML patients in the posaconazole era.

Methods:

Retrospective analysis of 144 consecutive non‐M3 AML patients diagnosed between January 2012 and June 2018 in a tertiary center and treated with intensive chemotherapy regimens with posaconazole prophylaxis, including autologous transplantation when performed in these patients. Multivariate regression analysis was performed to identify characteristics related to FI.

Results:

Median age at diagnosis was 52 years [19;71], 52% were females and 90% had an age‐adjusted Charlson score ≤3. Genetic risk group according to the European Leukemia Net 2017 classification was favourable in 28%, intermediate in 41% and adverse in 22%. Fourteen percent of patients (n = 20) had secondary AML. Patients were included since diagnosis and if completed remission‐induction intensive therapy up to transplant referral, the latter which occurred in 52% of patients (n = 75), with a median follow‐up of 7 months [1;81]. Only 7 patients had 1 episode of prophylaxis interruption, 3 due to mucositis and 4 out of our protocol. Median time of neutropenia per cycle was 26 days [5;180] and 10% of patients had >2 episodes of prolonged neutropenia (defined as ≥28 consecutive days of <500 neutrophils/microliter).

Fungal infections were identified in 25 patients (17.4%) and classified according to EORTC criteria, with 5 proven, 13 probable and 7 possible infections. In 32% of patients FI occurred during remission‐induction (n = 8) of which 3 were diagnosed in the first week of neutropenia, 20% during consolidation treatment in first remission and 48% during relapse treatment. Of the confirmed infections, 3 were aspergillosis and 2 candidemia. Probable infections had pulmonary origin with no microbiology isolate or serologic positivity but identified by typical radiologic evidence; of these, broncho‐alveolar lavage and/or pulmonary biopsy was performed in 4 patients (31%) with negative results. For possible infections, antifungal therapy was initiated in a pre‐emptive manner for high risk patients with persistent fever despite large spectrum antibiotics.

In a multivariate analysis, patients with FI had a higher odds of having relapsed AML and >2 episodes of prolonged neutropenia during treatment (p = 0.049 and p = 0.011, respectively). There was no mortality related to FI in this cohort of patients.

Summary/Conclusion:

Despite posaconazole prophylaxis, FI is still prevalent in AML patients. Infection during salvage treatment for relapsed disease and >2 previous periods of neutropenia exceeding 4 weeks should raise awareness for an increased risk of FI.
PS1295 IRON IN THE HUMAN HEARTS: DISTRIBUTION AND ASSOCIATION WITH R2∗ VALUES BY CMR
Authors: Meloni A. , Maggio A. , Positano V. , Angelini A. , Putti M.C. , Maresi E. , Pucci A. , Basso C. , Leto F. , Perazzolo M. , Pistoia L. , Pepe A.
Published: June 2019

Background:

T2∗ (or R2∗ = 1000/T2∗) cardiac magnetic resonance (CMR) allows the non‐invasive and reproducible measurement of myocardial iron and has been established as fundamental to the best practice management of iron loaded patients to improve morbidity and mortality.

Aims:

In the present study we calibrated cardiac R2∗ values against myocardial tissue ‐measured iron concentration by using a segmental approach and we assessed the distribution and regional variations in iron distribution.

Methods:

Five hearts of patients with thalassemia were donated after death (N = 4) or cardiac transplantation (N = 1) to the CoreLab of the MIOT (Myocardial Iron Overload in Thalassemia) Network. A multislice multiecho T2∗ approach was adopted. After CMR, used as guidance, the heart was cut in three short‐axis slice and each slice was cut into different equiangular segments accordingly with AHA segmentation and differentiated into endocardial and epicardial layer, the same ones in which the T2∗ was assessed. Tissue iron concentration in the segments was measured with an atomic absorption spectrometer.

Results:

55 samples were used since it was possible to analyze all the 16 samples only from two hearts due to medical‐forensic reasons. The mean iron concentration in all samples was 4.71 ± 4.67 mg/g dw. Segmental iron levels ranged from 0.24 to 13.78 mg/g dw. Mean iron concentration was significantly higher in the epicardial than in the endocardial layer (5.99 ± 6.01 mg/g dw vs 4.84 ± 4.87 mg/g dw; P = 0.042).

The coefficient of variability (CoV) of iron for myocardial segments ranged from 8.08% to 24.54%, with a mean value for all patients of 13.49 ± 6.93%. Four different main circumferential regions (anterior, septal, inferior and lateral) were defined. A circumferential heterogeneity was noted, with more iron observed in the anterior region, followed by the inferior region. The heterogeneity in circumferential iron concentration expressed as percentage deviation of the regions from the global value is shown in the Figure 1A.

A strong linear correlation (R‐square = 0.956) was found by plotting ln(R2∗‐ROI) and ln[Fe] with a slope s = 0.654 (95% confidence intervals‐CI = 0.616–0.693) and intercept i = 4.216 (95% CI = 4.150–4.281) (Figure 1B). The linear relation was converted to the calibration curve: [Fe] = 0.001591 X (R2∗)1.529.

Summary/Conclusion:

Our data suggests an heterogeneous pattern of cardiac iron distribution with higher epicardial layer involvement. Heart R2∗ provided a robust calibration against chemically assayed cardiac iron, further validating the current clinical practice of monitoring cardiac iron in vivo by CMR.

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PS1298 TISSUE IRON DISTRIBUTION IN PATIENTS WITH LOW‐RISK MDS
Authors: Grosse R. , Asemissen A.M. , Ganster C.G. , Starekova J. , Schafhausen P. , Schoennagel B. , Nielsen P. , Yamamura J. , Haase D. , Fischer R.
Published: June 2019

Background:

Iron accumulation occurs in MDS patients by upregulated iron absorption due to ineffective erythropoiesis with decreased hepcidin levels (Santini et al, 2011) and by chronic blood transfusion therapy. Elevated liver iron concentration (LIC) is regularly found in transfusion dependent patients. Abnormal cardiac iron (50–1) was observed in few studies and severe cardiac iron overload was almost not present although cardiac death appeared in 8% of deceased patients (Nachtkamp et al, 2016). Little is known about corresponding pancreatic iron and iron accumulation in the bone marrow. The release of NTBI in the bone marrow may directly affect hematopoiesis by oxidative stress (Porter et al, 2016).

Aims:

To compare the relationship of iron concentration and fat content in different organs in low ‐ risk MDS patients.

Methods:

We studied the iron accumulation in bone marrow, liver, spleen, pancreas and septal heart muscle in 14 mainly low‐risk MDS patients (age 39–87 y), partly transfused and chelated. Tissue iron concentration and fat content were assessed by magnetic resonance imaging (MRI ‐ R2∗) with 3D data acquisition at 3 Tesla using chemical shift relaxometry (Pfeifer et al, 2015).

Results:

About 50% of patients showed iron overload in the spleen, pancreas and vertebral bone marrow (VBM). Mean LIC (±SD) was found as 1.709 ± 0.914 mg/gliver (10.3 ± 5.5 mg/gdry weight). Patients with iron overload in the pancreas showed as well abnormal pancreatic fat contents (11–32%) and fasting glucose values (101–186 mg/dL). As expected, septal cardiac iron was normal for all patients. Bone marrow (VBM) iron was elevated in 8/14 patients (R2∗ = 149–330 s−1) with the highest R2∗ in a non‐chelated patient.

Summary/Conclusion:

The feasibility of multi‐organ iron and fat measurements by MRI in heart, liver, spleen, pancreas and bone marrow was shown in a small group of elderly MDS patients within a reasonable scan time (30 min).

The iron concentration and fat content in different organs will contribute further information about disease process in low ‐ risk MDS patients, as well as success of iron chelation therapy.
PS1322 ASTX660, A NON‐PEPTIDOMIMETIC ANTAGONIST OF CIAP1/2 AND XIAP, INDUCES APOPTOSIS IN T CELL LYMPHOMA BY ENHANCING IMMUNE MEDIATED AND DEATH RECEPTOR DEPENDENT KILLING
Authors: Sims M. , Ward G. , Munck J. , Jueliger S. , Davis M. , Gewinner C. , Ferraldeschi R. , Lyons J.
Published: June 2019

Background:

ASTX660 is a potent, non‐peptidomimetic antagonist of the cellular and X‐linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I‐II study in patients with advanced solid tumors and lymphomas (NCT02503423). IAP antagonists enhance tumor necrosis factor (TNF) receptor superfamily mediated apoptosis and are potent anti‐tumor immune enhancers.

Aims:

Herein, we describe the profile of ASTX660 in a range of T cell lymphoma (TCL) cell lines and evaluate ASTX660's ability to enhance immune mediated killing of tumor cells.

Methods:

A panel of human and mouse T‐cell lymphoma cell lines were tested in proliferation (Alamar blue or CellTiterGlo) or apoptosis assays (activated caspase‐3 substrate assays by IncuCyte or FACS) for sensitivity to ASTX660 alone or in combination with recombinant Death Receptor ligands (TNFα, FASL or TRAIL). Additionally, we used a novel co‐culture system of tumor cell lines with anti‐CD3 activated human peripheral blood mononuclear cells (PBMC) to assess ASTX660 effects on immune mediated cell killing. Target engagement and induction of apoptosis markers were analysed by Western blotting.

Results:

ASTX660 antagonises IAPs in TCL cell lines, as indicated by a decrease in cIAP1 protein levels. This ASTX660‐dependent decrease in cIAP was associated with an increase in TNFα‐dependent apoptosis in the EL4 and L5178 TCL cell lines. Several T‐cell lymphoma models, including HuT‐78, HH and My‐La expressed low levels of TNFR1 and therefore did not respond to ASTX660 in the presence of TNFα. However, in these cell lines, ASTX660 conferred a significant increase in FASL or TRAIL‐dependent apoptosis, indicating that ASTX660 sensitises TCL cells to various death receptor ligands and response correlates with receptor expression levels. In addition to this direct effect on TCL cell lines, ASTX660 also enhances anti‐CD3 stimulated PBMC‐dependent killing of multiple tumour cell lines, including TCL lines, via induction of caspase activity. Additional preclinical experiments (both in vitro and in vivo) are underway to further characterise the mode of action of ASTX660 in TCL.

Summary/Conclusion:

The combination of both direct and indirect effects of ASTX660 on TCL lines, described here, supports the ongoing clinical testing of ASTX660 in TCL (NCT02503423). Preliminary clinical efficacy and safety data of ASTX660 in relapsed/refractory (r/r) peripheral T cell lymphoma and cutaneous T cell lymphoma is the subject of a separate abstract.
PS1330 VARIABILITY IN THE EXTENT OF DEL(5Q) AND ITS CLINICAL IMPLICATION IN MYELODYSPLASTIC SYNDROMES (MDS)
Authors: Zemanova Z. , Brezinova J. , Michalova K. , Svobodova K. , Lhotska H. , Vesela D. , Izakova S. , Sarova I. , Lizcova L. , Ransdorfova S. , Pavlistova L. , Belickova M. , Vesela J. , Siskova M. , Neuwirtova R. , Cermak J. , Stopka T. , Jonasova A.
Published: June 2019

Background:

The interstitial deletion of the long arm of chromosome 5—del(5q)—is the most common cytogenetic abnormality in MDS occurring either as a sole aberration or as a part of complex karyotypes (CK). MDS with isolated del(5q) are associated with a favorable outcome while MDS with CK relate to poor prognosis. Extent of deleted segment is highly variable. However, it remains unclear whether its size matters for the different MDS phenotypes.

Aims:

The aim was to compare the extent of deletion in 264 MDS patients [116 with isolated del(5q) and 148 with del(5q) involved in CK] and to assess the relationship of del(5q) extent and TP53 gene mutation.

Methods:

Extent of del(5q) was analyzed using I‐FISH (Abbott, MetaSystems), mBAND (MetaSystems) and array CGH/SNP (CytoChip Cancer SNP 180K, Illumina or SurePrint G3 Cancer CGH+SNP 4x180K, Agilent). CK were analyzed with mFISH (MetaSystems). Sequence analysis of TP53 gene was performed in 84 cases using amplicon deep sequencing (exons 4–11) on a 454 GS Junior system (Roche) or with TruSight Myeloid Panel Kit on MiSeq sequencing instruments (Illumina).

Results:

In the group with isolated del(5q), the most frequently deleted segment ranged between the bands 5q14 and 5q33.3, with the smallest deletion encompassing the 5q31.1–5q31.3 region (18.527 Mb). The TP53 mutation was proved in 19.4% cases. The size of the deletion did not significantly differ in patients with and without TP53 mutation. In the group with CK, the deletion often involved entire long arm including the telomeric region. In some cases, a part of short arm was also deleted, but we never observed the loss of the entire chromosome 5. The commonly conserved region (CCR) was localized in bands 5p12 to 5p14.1. In this group, the mutation of TP53 and/or LOH17p was detected in 49% of patients. The commonly deleted regions (CDR) were in the band 5q31.1 (5.522 Mb) in cases with isolated del(5q) and between the bands 5q31.1 and 5q31.3 (18.527 Mb) in patients with CK.

Summary/Conclusion:

Patients with isolated del(5q) had a smaller size of the deleted segment. More extensive 5q deletion was associated with higher karyotype complexity, increased frequency of TP53 aberrations and worse prognosis. Accurate analysis of breakpoints and range of del(5q) points out to the correlation of deletion size with increasing genomic instability in MDS and contributes to a better understanding of the MDS pathogenesis.

Supported by RVO‐VFN64165, GACR P302/12/G157, ProgresQ28/LF1, MHCR 00023736.
PS1338 TEMPORAL TRENDS IN TRANSFUSION BURDEN AMONG NEWLY DIAGNOSED PATIENTS WITH MYELODYSPLASTIC SYNDROMES: A U.S. CLAIMS DATABASE STUDY
Authors: Slabaugh S.L. , Mearns E.S. , Copher R. , Johnson J. , Buzinec P. , Mukherjee S.
Published: June 2019

Background:

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematologic stem cell disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenias. Anemia is the most prevalent of all cytopenias and is often treated with red blood cell transfusion (RBCT). There is a paucity of data on how the transfusion requirements of MDS patients change early in their clinical course. Understanding the temporal changes in transfusion needs in patients with MDS can provide data on the clinical need of MDS‐specific therapies based on the pace and burden of transfusion dependency.

Aims:

This retrospective study assessed the status and temporal trends in RBCTs among newly diagnosed patients with MDS in the United States, using a large administrative claims data set, Optum Research Database.

Methods:

All patients aged ≥ 18 years with newly diagnosed MDS (≥ 2 medical claims with an International Classification of Diseases, 9th or 10th Revision [ICD‐9 or ICD‐10] diagnosis codes ≥ 30 days apart) and in continuous health plan enrollment for ≥ 6 months pre‐ and 3 months post‐index date between January 2012 and May 2018 were included. Index was defined as date of first diagnosis. Transfusion status was evaluated during the 6‐month pre‐, and at 3‐month, 6‐month, and 9‐month post‐index periods for patients managed with observation alone, or with RBCT with or without erythropoiesis‐stimulating agents (ESAs). Transfusion independence (TI) was defined as patients receiving no transfusions; transfusion users (TU) was defined as 1 transfusion episode; and transfusion dependence (TD) was defined as patients receiving ≥ 2 transfusions during the observation periods.

Results:

Among the 3,803 patients identified, 56.3% were male, 85.4% were ≥ 65 years old (median age was 76), 78.0% were enrolled in a Medicare Advantage with Part D plan, and mean Quan‐Charlson Comorbidity Index was 1.98. Most patients (61.7%) were diagnosed with MDS, unspecified (ICD‐9‐CM 238.75, ICD‐10‐CM D46.9) on index date. Anemia was the presenting cytopenia in 78.8% of patients and 24.4% needed ≥ 1 RBCT (11.5% were TD and 12.9% were TU) preceding the MDS diagnosis. Common comorbidities observed in the pre‐index period were: hypertension (69.6%), cardiac diseases (58.1%), and dyslipidemia (54.8%). ESAs were administered to 40.7% of patients during the post‐index period. During the 9 months following diagnosis, a steady increase in TD was observed (Table).

Summary/Conclusion:

Disease burden in patients with MDS remains considerable. Considering that RBCT needs increased steadily despite ESA use with up to 37% still reliant on RBCT at 9 months post diagnosis indicates a critical unmet need for newer therapies for MDS patients who have TD anemia and for whom limited therapies exist beyond ESAs and RBCT.

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PS1347 PHF19 INDUCES EZH2 PHOSPHORYLATION AND PROMOTES DRUG RESISTANCE IN MULTIPLE MYELOMA
Authors: Du C.‐X. , Yu T.‐T. , Liu L.‐T. , Xu J. , Li Z.‐Q. , Yu Z. , Zhan F.‐H. , Ma X.‐K. , Qiu L.‐G. , Hao M.
Published: June 2019

Background:

Multiple myeloma (MM) is a plasma cell malignancy characterized by consecutive progression and increased invasion. It is becoming increasingly evident that tumor development and the acquisition of drug resistance involves the alteration of epigenetic regulation. PcG (polycomb group) proteins are key to epigenetic repression through two main complexes, PRC1 (Polycomb repressive complex 1) and PRC2. PHF19, also known as PCL3, combines with histone methyltransferase EZH2 (Enhancer of Zeste 2) and participates in the formation of PRC2 complex. Our study is the first report that depicts the role of PHF19 in the drug resistance of MM, providing new therapeutic choices for these patients.

Aims:

To disclose the role of PHF19 in promoting drug resistance of multiple myeloma and explore the therapeutic strategy based on the mechanism research.

Methods:

RNA‐seq data from 351 newly‐diagnosed patients, 44 MGUS, 12 SMM and 22 healthy plasma cells reported the role of PHF19 as an independent risk predictor for survival. We then studied the functional role of PHF19 by overexpression or shRNA knockdown in ARP1 and OCI‐My5 MM cell lines, conducting cell proliferation counting, Annexin V/7AAD assay for apoptosis, and mouse xenograft experiments. Gene expression profile was performed in ARP1 MM cell line. Western blot was used to investigate the expression of the potential targets of PHF19. Dual luciferase assay was used to reveal the relation between miR‐15a and PHF19 mRNA.

Results:

PHF19 was associated to high‐risk and dismal outcome of MM patients. It promoted cell growth and resistance to bortezomib both in vitro and in vivo. PHF19 activated the bypass of canonical PRC2 function by recruiting AKT to phosphorylate EZH2, which released the expression of HIF‐1α, Bcl‐xL and Mcl‐1. PI3K inhibitor LY294002 reversed the upregulation of the mentioned pro‐survival proteins. miR‐15a bound to 3’UTR of PHF19 mRNA to negatively regulate its expression.

Summary/Conclusion:

PHF19 is correlated to disease progression and drug resistance of MM. In vitro and in vivo experiments reveal PHF19 significantly promotes cell survival and inhibites apoptotic activity. PI3K/AKT signaling pathway is highly involved in the function of PHF19, indicating inhibition of PI3K/AKT may be an effective strategy to treat those patients with high level of PHF19.
PS1368 IGH AND IGK REARRANGEMENT AND IGH SOMATIC HYPERMUTATION ANALYSIS USING NEXT‐GENERATION SEQUENCING FOR THE DETECTION OF CLONALITY IN HIGH‐RISK KOREAN MULTIPLE MYELOMA PATIENTS
Authors: Lee J. , Lee Y.K. , Kim M. , Kim H.J.
Published: June 2019

Background:

Clonality assessment in patients with multiple myeloma (MM) is important both for initial diagnosis and detecting minimal residual disease. Next‐generation sequencing (NGS)‐based immunoglobulin gene rearrangement assays may be useful for assessing clonality, although their applicability has not been convincingly demonstrated.

Aims:

We intended to evaluate the primer set most widely used with the only commercially available NGS‐based clonality assay in high‐risk MM patients for the first time.

Methods:

Thirty bone marrow aspirate samples were included in the study. The samples were evaluated for IGH rearrangements and IGH somatic hypermutation using the LymphoTrack®
IGH‐FR1 assay (InVivoScribe, San Diego, CA) on a MiSeqDx instrument (Illumina, San Diego, CA). When kappa‐type cases showed negative IGH rearrangement (and somatic hypermutation), LymphoTrack®
IGK assay (InVivoScribe) was performed.

Results:

IGH‐FR1 and/or IGK assay detected clonality (demonstrated by rearrangements) in 22 out of 26 MM cases (84.6%) who were not lambda‐type light chain disease. Detailed analysis on IGH clonality/somatic hypermutations and IGK clonality is presented in Table 1. IGH clonality were observed in 20 of the 26 samples (76.5%), and among them 17 cases (85.0%) showed IGH somatic hypermutations. By testing IGK clonality on 5 kappa‐type samples which did not show any IGH clonality including 1 kappa‐type light chain disease, 2 samples (40.0%) showed IGK clonality. One out of 2 kappa‐type light chain disease cases and 1 out of 3 lambda‐type light chain disease cases showed IGH clonality, suggesting that the heavy chain clonality could have been missed in immunofixation electrophoresis assay. The IGH or IGK clonality was not statistically associated with heavy chain type or light chain type, even though all the 10 IgA‐type cases showed either IGH or IGK clonality. Neither the existence of IGH clonality nor its quantity (expressed as a percentage) was associated with the percentage of plasma cells in the specimens.

Table 1. IGH clonality, IGH somatic hypermutation and IGK clonality according to the heavy chain and light chain types in 30 high‐risk Korean multiple myeloma samples.

Summary/Conclusion:

By combining the IGH‐FR1 assay and/or IGK assay, we detected clonality in approximately 85% of high‐risk Korean MM patients. Somatic hypermutations of IGH gene was observed in 85% cases with IGH clonality. Different sets of primers of immunoglobulin genes might increase the clonality detection rate in MM.

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PS1430 INTEGRATION OF FOUR COLOUR FLOW TO PREDICT RELAPSE/PROGRESSION AND TIME TO NEXT TREATMENT IN MULTIPLE MYELOMA AFTER UPFRONT AUTOLOGOUS STEM CELL TRANSPLANT
Authors: Chorão P. , Maia T. , Bergantim R. , Aguiar E. , Pires J. Cancela , Trigo F. , Guimarães J.E.
Published: June 2019

Background:

Four colour multiparameter flow cytometry (4MFC) is widely available and easier to apply than conventional minimal residual disease methods, although less sensitive.

Aims:

Our objective was to integrate 4MFC results in a clinical model to predict relapse/progression free survival (R/PFS) and time to next treatment (TNT) after upfront autologous stem cell transplant (ASCT) in a resource limited setting.

Methods:

Single center retrospective review of 146 consecutive MM patients with 4MFC bone marrow (BM) evaluation at day 100 after upfront ASCT with melphalan conditioning between 2008 and 2016. The 4MFC panel included CD38, CD138, CD45, CD19 and CD56. CD38+, CD138+ plasmocytes (PC) with (CD45 ± )CD19‐CD56+ or CD45‐CD19‐(CD56 ± ) were considered abnormal. Baseline PC 4MFC was only available in 50% of patients and was not considered for this analysis. Multivariate Cox regression analysis was performed to elect statistically significant variables to integrate R/PFS (either biochemical or clinic) and TNT clinical models at 3 years (y) after ASCT.

Results:

Median follow‐up after ASCT was 43 months (interval 2–126). At diagnosis, median age was 58y (interval 36–70), 56% were male, 23% had hypercalcemia, 15% renal insufficiency, 41% anemia, 67% lytic lesions and 33% plasmacytomas. Induction regimens included a proteasome inhibitor (PI) in 62%, immunomodulator (IMiD) in 6%, IP and IMiD in 24% and neither in 8%. At day 100 after ASCT, 57% had a complete remission, 32% a very good partial remission (VGPR) and 11% had <VGPR. BM evaluation at day 100 detected a median of 0.3% PC, with 17% of patients having abnormal PC. For all follow‐up, relapse/progression was documented in 75%, 69% was biochemical and 31% clinic.

In multivariate analysis, kidney insufficiency at diagnosis, >0.25% BM PC at day 100 and detection of abnormal BM PC at day 100 impacted on R/PFS at 3y. Different risk groups for relapse/progression were defined according to the presence of 0, 1 or >1 of these characteristics (median R/PFS not reached versus (vs) 24 vs 14 months, respectively; p < 0.001; Figure 1A). In multivariate analysis, the three characteristics above and also age >58y impacted on TNT at 3 years. Three groups with distinct timings for second line treatment were defined according to the presence of 0–1, 2 or >2 of these risk factors (median TNT not reached vs 24 vs 16 months, respectively; p < 0.001; Figure 1B).

Summary/Conclusion:

The addition of BM 4MFC PC analysis at day 100 after upfront ASCT to clinical characteristics identifies subgroups of MM patients with increased risk for relapse/progression and need for second line treatment, which may require different post‐ASCT observation. Further efforts are needed in order to validate and integrate affordable end of treatment disease burden evaluation in resource limited settings.

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PS1432 3‐WEEKLY DARATUMUMAB‐IMID‐DEXAMETHASONE IS HIGHLY EFFICACIOUS, HENCE FINANCIALLY AFFORDABLE WITH ENORMOUS ECONOMIC IMPACT FOR RELAPSED/REFRACTORY MULTIPLE MYELOMA IN LESS AFFLUENT COUNTRIES
Authors: Chim C.S. , Wong V.K. C. , Au Y.L. E. , Kwong Y.L.
Published: June 2019

Background:

Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) is highly effective in relapsed multiple myeloma (MM). The recommended schedule of dara is weekly for 8 doses, followed by 2‐weekly for 8 doses, and then every 4‐weekly thereafter. Given the high cost and the long half‐life as an antibody, a 3‐weekly dosing of dara was used together with IMiD/dexamethasone.

Aims:

Dara at 16 mg/kg was used every 3‐weekly with lenalidomide or pomalidomide. Patient achieving best response received single agent IMiD maintenance until disease progression.

Methods:

Fourteen relapsed MM patients were enrolled. One had received weekly dara from a private oncologist, hence was excluded from analysis. Thirteen patients at a median age of 63 years (range: 50–84 years) were studied. The median number of previous therapies was 2 (range: 1–5), with nine patients (69.2%) having undergone autologous stem cell transplantation. Three patients (23.1%) were refractory to bortezomib, seven patients (53.8%) to lenalidomide, and eight patients (61.5%) to last treatment. At relapse, two (15.4%) had high LDH, eight (61.5%) impaired renal function, and three (23.1%) extramedullary disease. Treatment was dara‐lenalidomide‐dex in six (46.2%), and dara‐pomalidomide‐dex in seven (53.8%).

Results:

Responses after four cycles included CR in 5 patients (38.5%), VGPR in five patients (38.5%), and PR in three patients (23.1%). After a median of four dara infusions (range: 3–10), the best responses included CR in seven patients (53.8%), nCR in two patients (15.4%), VGPR in two patients (15.4%), and PR in two patients (15.4%). Median time to VGPR was one month. At 10 months, the OS was 90%, and PFS 54.7%. Three patients progressed, one of whom died of ruptured hepatic plasmacytoma. The most frequent toxicity was haematological especially neutropenia (all grades: 92.3%, Grade 3/4: 76.9%), infusion reaction (38.5%, all grade 1/2), neuropathy (38.5%, all grade 1/2), gastrointestinal (all grades: 38.5%, grade 3/4 : 7.7%), and sepsis (all grades: 30.8%; grade 3/4: 23.1%). Neutropenia was effectively prevented with prophylactic G‐CSF.

Summary/Conclusion:

In conclusion, a 3‐weekly dara‐IMiD‐dex regimen is highly efficacious, inducing deep and rapid responses, hence cost‐effective for less affluent countries. In view of prevalent grade3/4 neutropenia despite less frequent dara, 3‐weekly dara might be more suitable for Asian patients.

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PS1433 RESULTS OF AUTOLOGOUS STEM CELL TRANSPLANTATION IN MULTIPLE MYELOMA PATIENTS WITH RENAL FAILURE
Authors: Tuğlular A. Tülin , Elibol T. , Uzunoğlu C. , Aldağ B. , Dedeoğlu Ö. , Ercan T. , İpek Y. , Arıkan F. , Yılmaz A.F. , Atagündüz I. Kaygusuz , Toptaş T.
Published: June 2019

Background:

Multiple Myeloma (MM) is a hematological malignancy in which renal involvement is common. Almost half of MM patients have increased creatinine levels at the time of diagnosis. In 20% of these patients, creatinine level is above 2 mg/dl. Kidney damage can be reversible in 50% of these patients.

Aims:

In this retrospective study, we evaluated the outcomes of autologous stem cell transplantation (ASCT) which was done in our center in multiple myeloma patients with renal failure. We compared the outcomes of these patients with patients with normal renal functions and who underwent ASCT. In patients with renal failure, melphalan 140 mg/m2 was used as conditioning regimen.

Methods:

We retrospectively analyzed the files of 574 patients with multiple myeloma in our center. We identified 106 patients who had ASCT between 2007–2018. We calculated creatinine clearances (CrCl) with Modification of Diet in Renal Disease (MDRD) formula at diagnosis. Patients were divided into 2 categories according to their CrCl results: patients with CrCl above 60 ml/min (n = 41), patients with CrCl below 60 ml/min (n = 28).

Demographic data, laboratory results, pre‐transplant treatment and response to treatments were presented in Table 1.

Results:

Median follow‐up of the patients was 54 months. Median progression‐free survival (PFS) in patients with CrCl<60 ml/min and ≥60 ml/min was 56 months and 62 months, respectively. Three‐year PFS in these patients was 56.4% and 58%, respectively (p = 0.859). Median overall survival in patiens CrCl<60 ml/min was 69 months; median OS was not reached in patients with CrCl≥60 ml/min (p = 0.001). Median OS of all patients was 90 months. Four‐year OS of patients with CrCl<60 ml/min and≥ 60 ml/min was 69.9% vs. 97%, respectively (p = 0.001).

We found that patients who had an improvement after ASCT in their renal functions had a better OS than compared to patients who had no improvement after ASCT (49 vs 73 months, respectively, p = 0.095). Four of the 7 patients with dialysis‐dependent renal failure at the time of diagnosis became dialysis independent. Median creatinine clearences of patients with CrCl <60 ml/min before and after ASCT was 25.45 ml/min and 54.39 ml/min respectively. CrCl increased above 60 ml/min in 11 patients. CrCl increased %50 above baseline in 18 patients.

Summary/Conclusion:

In conclusion treatment response rates and progression‐free survival rates were not affected by renal failure. Treatment of patients with renal insufficiency should not be different than those of patients who do not have renal failure. Standard myeloma treatment and ASCT should be used in these patients; melphalan dose can be reduced to 140 mg/m2 in patients with CrCl <60 ml/min.

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