bluuebunny/crossref_metadata_2025 huggingface dataset:
PF537 THE STAT SIGNALING BIOSIGNATURE OF CD4+ T CELL SUBSETS REFLECT THE IMMUNOGENICITY OF HIGH‐RISK MDS AND PREDICT AZACYTIDINE TREATMENT OUTCOME
Authors: Lamprianidou E. , Kordella C. , Zoulia E. , Papoutselis M. , Bezirgiannidou Z. , Vrachiolias G. , Spanoudakis E. , Vassilakopoulos T. , Galanopoulos A. , Papageorgiou S. , Pappa V. , Vakalopoulou S. , Garipidou V. , Papaioannou M. , Hatjiharissi E. , Diamantopoulos P. , Viniou N.‐A. , Kotsianidis I.
Published: June 2019

Background:

Azacytidine (AZA) is the mainstream treatment in high‐risk Myelodysplastic Syndromes (MDS), but the exact mechanism of action and resistance is largely unknown. AZA potentially acts, at least partially, by upregulating the antitumor immune response, but literature reports are still contradictory. Similarly, CD4+ T cells appear to play a critical role in the antitumor immune response in MDS, even though the exact mechanism remains unclear.

Aims:

As STAT proteins are key regulators of both physiological and pathological polarization and differentiation of CD4+cells, we investigated the STAT signaling profile of high‐risk MDS patients during AZA treatment and its correlations with clinical and biological parameters.

Methods:

Peripheral blood mononuclear cells were isolated before the initiation of AZA from 67 high‐risk MDS patients and 13 age‐matched healthy donors. We applied phosphospecific flow cytometry to measure both basal and potentiated levels of pSTAT1, pSTAT3 and pSTAT5. A signaling profile (SP) was constracted for T conventional (Tconv) and T regulatory cells (Tregs) and their functional subsets: PD1+ cells, central memory (TCM), naïve (TN), effector memory (TEM) and terminal effector memory (TEMRA) cells. We further characterized the functional and polarization state of T cells by staining with Perforin, IFNg, IL4, IL17 and Helios.

Results:

pSTAT signaling profile of Tconv cells revealed three signaling clusters (SC). SC#2 was characterized by higher potentiated responses of pSTAT3 after IL‐6 stimulation (IL‐6/pSTAT3) and was enriched in patients with longer median‐overall survival (mOS, p = 0.047, figure 1A). The SP of both PD1+ Tconv and TEM revealed three SCs. In both cases patients with shorter median event free survival (mEFS) segregated in SCs with downregulated potentiated responses (p = 0.055 and p = 0.04 respectively). The pretreatment SP of Tregs was also associated with mEFS though without reaching significance (p = 0.068), whereas the SP of PD1+ Tregs separated patients with intermediate potentiated responses which showed longer OS (p = 0.023).

Summary/Conclusion:

Collectively, are results reveal for the first time the clinically significant heterogeneity of CD4+ T cell subsets and their diverse role in the antitumor immunity in MDS. Moreover, the beneficial effect of the activation of IL‐6/pSTAT3 pathway in CD4conv cells comes in line with current data in CAR‐T cells and further suggests that the STAT signaling biosignature on CD4+ cells may represent a response biomarker to AZA and a therapeutic target for high‐risk MDS.

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PF547 FACTORS ASSOCIATED WITH THE NEED FOR TRANSFUSIONS IN PATIENTS WITH LOWER RISK MYELODYSPLASTIC SYNDROME (MDS). DATA FROM THE REGULAR CARE MDS‐REGISTRY IN GERMANY
Authors: Steinmetz H.T. , Toczek‐Thiel J. , Hellmich M. , Lipke J. , Liersch R. , Sauer A. , Tesch H. , Hessling J. , Schmitz S.
Published: June 2019

Background:

In 2009 we started a registry to evaluate the course of MDS in routine care in Germany.

Aims:

The aim of the current evaluation was to analyze factors associated with the need for red blood cell transfusions in patients (pts) with IPSS low and intermediate‐1 (int‐1) risk at diagnosis and in the course of the disease.

Methods:

2,447 patients (pts) with MDS were included in the regular care MDS‐registry from July 2009 till December 2016, provided that the diagnosis was confirmed by bone marrow biopsy and the pts had given their written informed consent. Baseline parameters at diagnosis and the clinical course were quarterly documented in an online database (IoStudy by Iomedico) by 90 centers all over Germany.

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Results:

At the data‐cut in April 2017 1,240 of 2,428 evaluable pts (50.7%) had a low‐ (612 pts/49,4%) or an int‐1 ‐risk MDS (628 pts. /50.6%). The median age of the lower risk pts was 74 years (range 26–94), 484 (39%) were women and the median time of observation was 25 months (mo, range 0–97, mean 30,62mo). At diagnosis 114 (18.6%) low‐ and 169 (26.9%) int‐1‐ risk pts were transfusion‐dependent (TD). The median time to become TD was significantly different (log rank (Mantel‐Cox) p = <0.01) between low‐ (28mo, SD 4.030, 95% CI 20.1 – 35.9) and int‐1‐ risk pts (9mo, SD 1.380, 95% CI 6.295 – 11.705). Survival (OS) was estimated by Kaplan‐Meier curves for pts without TD mean 82,661mo (SD 1,813mo, 95%>CI 79,108 ‐ 86,214) and pts with TD mean 51,261mo (SD 1,453mo, 95%>CI 48,413 ‐ 54,109)(fig. 1A). Furthermore, OS after becoming TD was estimated by a time‐to‐TD stratified Kaplan‐Meyer curve (fig. 1B), that shows a significant difference (0.00 Log Rank, Mantel‐Cox). In an univariate analysis the following baseline parameters were significantly associated with a shorter duration to become TD: age ≥80years, hemoglobin (hb), count of reticulocytes, LDH, endogenous erythropoietin level (epo), ferritin, and fibrosis in bone marrow histology. The following parameters were not associated: sex, thrombocyte‐, leucocyte‐ and granulocyte‐count, folic‐acid‐, vitamin B12 level, and CRP. Del‐5q and trisomy 8 were the only cytogenetic abnormalities significantly associated with a shorter duration to become TD. In a cox regression analysis (table 1) hb and epo were significant only.

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Summary/Conclusion:

The sooner pts becomes TD in the course of MDS, the poorer is the prognosis. It should be tested if a therapy that respites TD can prolong OS.

Supported by an unrestricted grand from Celgene, Munich, Germany
PF568 INVESTIGATING MECHANISMS OF ELOTUZUMAB AND LENALIDOMIDE THERAPY IN MULTIPLE MYELOMA
Authors: Richardson K.J. , Robbins M. , Bezman N.A. , Quach H. , Harrison S.J. , Prince M.H. , Ritchie D.S. , Jenkins M.R. , Beavis P.A. , Darcy P.K. , Neeson P.J.
Published: June 2019

Background:

Multiple myeloma (MM) is currently incurable. To investigate new treatment options, patients with refractory relapsed (RR) MM were treated with combination of Elotuzumab (Elo, anti‐SLAMF7 antibody) and Lenalidomide (Len, IMiD) and had a 84% objective response rate. We hypothesized this Elo+Len clinical efficacy was due to repair of NK dysfunction in MM patient NK cells.

Aims:

To explore the mechanisms whereby Elo+Len rescued MM patient NK cell function.

Methods:

We co‐cultured MM patient PBMCs with myeloma cells and drug combinations in vitro, and compared changes in NK cell activation, cytotoxicity, cytokine/chemokine levels, and adhesion molecule expression between healthy donor (HD) and MM patient cohorts. We also used a humanized MM model to explore the in vivo efficacy of the Elo+Len combination.

Results:

We showed that Elo engaged NK cell FcγRIIIa, initiated anti‐myeloma cell cytotoxicity and NK cell secretion of pro‐inflammatory cytokines (IFNγ, TNFα) and chemokines (CCL3, CCL4, CCL5), suggesting recruitment of other immune effector cells to the tumour. Elo+Len treatment significantly enhanced in‐vitro Elo‐induced cytotoxicity of healthy donor (HD) and newly diagnosed MM (NDMM) patient PBMCs. In contrast, RRMM patient NK cells had divergent responses to Elo+Len treatment, including impaired cytotoxicity (7/11 patients), and normal cytotoxicity (4/11 patients) (Fig 1A). Len significantly increased the chemokine secretion of HD PBMCs and to a lesser extent, NDMM and RRMM patient PBMCs, with the exception of CCL5 which was upregulated similarly between all groups. Interestingly, both MM‐derived NK cells and OPM2 myeloma cells upregulated CD54 following Elo and Len therapy, strongly correlated with myeloma cell killing (P = 0.002, R2 = 0.76). This was most evident on the 4 responding RRMM patient PBMCS and their OPM2 targets (Fig 1A‐B, data points highlighted in red). Surprisingly, NK cell CD107a was upregulated equally on all groups in response to Elo, regardless of killing activity. This suggests MM patient dysfunctional NK cells are sufficiently activated to degranulate, but are unable to kill myeloma cells due to inefficient adhesion and synapse formation. We also found that Elo induced in‐vivo therapeutic efficacy of human NK cells against RPMI8226.huSLAMF7 (RPMI8226 cells engineered to express human SLAMF7) multiple myeloma tumors, this was further enhanced with Len co‐treatment (Fig 1C).

Summary/Conclusion:

Our data suggests that Len improved Elo‐induced tumor control via increased cytotoxicity, chemotactic recruitment of effector cells and enhanced NK‐target synaptic adhesion. These data also suggest that monitoring an increase in CD54 expression on MM patient myeloma cells and NK cells may be a useful biomarker that tracks with Elo+Len efficacy.

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PF603 FASTER & SUSTAINED IMPROVEMENT IN HEALTH‐RELATED QUALITY OF LIFE IN TRANSPLANT‐INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA PTS TREATED WITH DARATUMUMAB, LENALIDOMIDE & DEXAMETHASONE (D‐RD) VS RD: MAIA
Authors: Perrot A. , Facon T. , Plesner T. , Usmani S.Z. , Kumar S. , Orlowski R.Z. , Bahlis N.J. , Nahi H. , Mollee P. , Ramasamy K. , Roussel M. , Chaleteix C. , Araujo C. , Jaccard A. , Delforge M. , Karlin L. , Arnulf B. , Chari A. , Wang J. , Kobos R. , McKay C. , Gries K.S. , Trudeau J. , Hulin C. , Weisel K.
Published: June 2019

Background:

MAIA, an ongoing phase 3 trial of transplant‐ineligible patients with NDMM, demonstrated significant improvement in progression‐free survival with D‐Rd vs Rd alone. Assessment of patient‐reported outcomes (PRO) alongside efficacy endpoints provides patient perspective on their quality of survival and overall value of health‐related quality of life (HRQoL) while on treatments.

Aims:

To utilize PRO assessments as a tool in capturing the patient perspective on quality of survival and HRQoL changes in MAIA.

Methods:

The EORTC QLQ‐C30 and EQ‐5D‐5L questionnaires were completed by patients using an electronic device at baseline and every 3 months during treatment; interim results are presented for first 12 months. Treatment effects were assessed using repeated measures, mixed effects models and thresholds for clinically meaningful benefit were based on established criterion from the literature.

Results:

Compliance rates in completing the assessment tools were high and comparable at baseline (>90%) and through month 12 (>80%) for both groups (D‐Rd [n = 368]; Rd [n = 369]). Improvement in Global Health Status (GHS) occurred in both groups; however, for D‐Rd, significantly greater improvement was observed at cycle 3 (LS mean change; D‐Rd: 4.5 [95% CI: 2.4, 6.6], Rd: 1.5 [95% CI: −0.7, 3.7]; [p = 0.0454]) and increasing improvement occurred across all time points. Significant improvement and clinically meaningful benefit in HRQoL for D‐Rd was also observed in EQ‐5D‐5L Visual Analog Scale (VAS) scores (LS mean change; D‐Rd: 10.1 [95% CI: 8.1, 12.1], Rd: 4.9 [95% CI: 2.8, 7.0]; [p = 0.0002]). The VAS median time to worsening was 10 mo longer for D‐Rd. Of note, meaningful differences were observed between the treatment groups in two subscale scores, pain symptoms and cognitive functioning. Statistically significant less pain was reported early with D‐Rd (LS mean change at cycle 3; D‐Rd: −17.9 [95% CI: −20.7, −15.0], Rd: −11.0 [95% CI: −14.0, −8.1]; [p = 0.0007]); clinically meaningful reduction in pain symptoms was sustained with D‐Rd. There was a decline in cognitive functioning through Cycle 12 in both treatment arms with the peak difference occurring at Cycle 9, but mean differences between groups were not statistically significant.

Summary/Conclusion:

Faster and sustained improvement in patients treated with D‐Rd was observed using HRQoL assessments compared with Rd, with similar findings reflected across the pain subscale.
PF604 THE AUSTRALASIAN LEUKAEMIA AND LYMPHOMA (ALLG) GROUP MM17 TRIAL: RESPONSE ADAPTIVE SALVAGE WITH CARFILZOMIB‐THALIDOMIDE‐DEXAMETHASONE FOR MULTIPLE MYELOMA PATIENTS FAILING FRONT‐LINE BORTEZOMIB
Authors: Spencer A. , Quach H. , Horvath N. , Kerridge I. , Yuen F. , Lee E. , Morris E. , Kalff A. , Bergin K. , Sirdesai S. , Gorniak M. , Mithraprabhu S. , Khong T. , Reynolds J.
Published: June 2019

Background:

Over 90% of transplant eligible newly diagnosed multiple myeloma (TE‐NDMM) patients (pts) in Australia are induced with bortezomib (V)‐ cyclophosphamide‐dexamethasone. Of these, 15% demonstrate either a sub‐optimal response (<partial response [PR]) (SOR) or primary refractoriness (1REF). These pts experience short progression free (PFS) and overall survival (OS), thus representing an area of ongoing unmet medical need.

Aims:

The ALLG MM17 trial was designed to evaluate an early response adaptive switch to carfilzomib‐thalidomide‐dexamethasone (KTd) and to define the mutational spectrum of disease in TE‐ NDMM patients failing V‐induction.

Methods:

Pts were either SOR (defined as 2on D1, 2, 8, 9, 15 and 16 of each 28‐day cycle (27 mg/m2D1 and 2 of cycle 1); T 100 mg D1–28; and, d 40 mg on D1, 8, 15, and 22 of each cycle. Pts were planned to receive KTd x 4 cycles then undergo re‐staging. Those achieving a stringent complete response (sCR) (morphologically normal bone marrow [BM], IF negativity, normalisation of the involved light chain isotype) proceeded to a MEL200 ASCT. Those with

Results:

Fifty pts were recruited between 9/2016 and 4/2018. Data cut‐off date was November 7, 2018 with the reverse‐Kaplan‐Meier estimate of the median potential follow‐up for survival being 14.8 months (95% CI: 9.7 – 17.8 months). Median age was 50 years (36–71) with 72% males. Median time from initial therapy to study entry was 4 months with disease status at entry of SOR in 26 (66%) (<MR n = 13, <PR n = 13) and 1REF in 13 (33%). EMC92 stratification demonstrated high‐risk disease in 48%. The tumour suppressor CDC27 (Anaphase‐promoting complex E3 ubiquitin ligase) was the most commonly mutated gene at study entry with a high proportion of patients also manifesting potentially targetable lesions – ATR, ATM, PIK3CA, FGFR3 and KRAS. The median number of pre‐ASCT KTd cycles was 6 (range 1 to 6). ORR was 78% (95% CI: 64–87%)∗‐ sCR 12%, CR 6%, VGPR 38% and PR 22%. On an intention‐to‐treat basis 32% of pts were MRD neg pre‐ASCT, 40% at day 100 post‐ASCT and 51% post KTd consolidation. Ten pts have progressed, 7 with highly aggressive extra‐medullary disease. No patient that achieved MRD negativity has progressed. Neither median PFS nor OS have been reached.

Summary/Conclusion:

KTd produces high response rates and MRD negativity in TE‐NDMM patients failing V‐based induction. TAS revealed a novel mutational spectrum consistent with treatment selection of V‐resistant sub‐clones likely present at diagnosis.
PF612 ONCE‐WEEKLY (70 MG/M2) VERSUS TWICE‐WEEKLY (56 MG/M2) DOSING OF CARFILZOMIB FOR PATIENTS WITH RELAPSED AND/OR REFRACTORY MULTIPLE MYELOMA
Authors: Moreau P. , Stewart A.K. , Dimopoulos M.‐A. , Siegel D. , Facon T. , Berenson J. , Raje N. , Berdeja J.G. , Orlowski R.Z. , Yang H. , Ma H. , Klippel Z. , Zahlten‐Kumeli A. , Mezzi K. , Iskander K. , Mateos M.‐V.
Published: June 2019

Background:

Carfilzomib (CFZ) combined with dexamethasone is approved to treat patients (pts) with relapsed and/or refractory multiple myeloma (RRMM), with CFZ given once‐weekly at 70 mg/m2 (Kd70 QW) or twice‐weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW.

Aims:

We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION‐1 trials.

Methods:

Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION‐1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION‐1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW.

Results:

Among BTZ non‐refractory pts with 2–3 lines of prior therapy, median progression‐free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well‐tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69).

Summary/Conclusion:

This post hoc analysis suggests that once‐weekly Kd70 has a comparable benefit‐risk profile to twice‐weekly Kd56.

© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.
PF613 CLINICAL UTILITY OF [18F]FLORBETABEN PET/CT SCAN FOR IMAGING AMYLOIDOSIS IN MULTIPLE MYELOMA PATIENTS
Authors: Jo J.‐C. , Seo M. , Choi Y.S. , Lee Y.J. , Park S.H. , Cha H.J. , Park S.H.
Published: June 2019

Background:

[18F]Florbetaben is a positron emission tomography (PET) tracer that specifically binds to amyloid beta‐pleated structure. Diagnosis of immunoglobulin light‐chain amyloidosis in patients with multiple myeloma (MM) is clinically important to manage symptoms and signs associated with amlyoidosis.

Aims:

We aimed to evaluate the feasibility of [18F]Florbetaben PET for detecting amyloid deposits in MM patients and to explore the most optimal method for PET analysis.

Methods:

Fourteen patients with multiple myeloma were prospectively enrolled (6 patients with amyloidosis and 8 controls) between Aug 2018 and Nov 2018. After injection of 300 MBq of [18F]Florbetaben, dynamic imaging of the kidneys was acquired for 20 minutes. Time‐activity curve was generated by using a region of interest placed over the kidney and retention index (RI) was obtained. At 90 minutes post‐injection, PET image was acquired, with a scan field from the vertex to mid‐thigh. All images were assessed both qualitatively and quantitatively. Comparison between amyloidosis and non‐amyloidosis groups was performed, regarding SUVmax, SUVmean, and SUV ratio (SUVR = tissue of interest/reference region), which were obtained from both sphere and manually drawn volumes of interest (VOI). Amyloid deposition was confirmed according to international consensus guidelines.

Results:

All patients in the control group did not show any abnormal amyloid uptake on 18F‐Florbetaben PET/CT (0/8), while those in the amyloid group had amyloid positive findings in more than one organ (6/6, 100%). Among 15 organs confirmed to have amyloidosis involvement prior to PET/CT, 9 were positive on 18F‐Florbetaben PET/CT. The detection rates of amyloidosis involvement in the heart, stomach, and tongue were excellent (100%), whereas those of the liver, esophagus, and colon were poor. 18F‐Florbetaben PET/CT found 12 unexpected abnormal amyloid uptakes in the tongue, thyroid, heart, lung, stomach, and spleen. Three of these 12 unexpected uptakes were later clinically determined to be amyloidosis (1 tongue, 1 heart, and 1 lung).

Summary/Conclusion:

[18F]Florbetaben PET can be one of the tool to detect systemic amyloid deposits in MM patients, especially in the heart, stomach, and tongue.
PF618 PROGNOSTIC IMPACT OF 18F‐FDG PET/CT IN PATIENTS WITH MULTIPLE MYELOMA PRESENTING WITH RENAL IMPAIRMENT
Authors: Jung S.‐H. , Ahn S.‐Y. , Song G.‐Y. , Heo M.H. , Yang D.‐H. , Ahn J.‐S. , Kim H.‐J. , Lee J.‐J.
Published: June 2019

Background:

18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography/computed tomography (PET/CT) has become a standard imaging technique for predicting prognosis in multiple myeloma (MM), but have potential inaccuracies in patients with renal impairment (RI).

Aims:

In this study, we investigated the prognostic role of 18F‐FDG PET/CT in patients with MM presenting with RI.

Methods:

Retrospective data for 74 patients with MM and RI between March 2012 and March 2017 were analyzed. Renal function was assessed using the estimated glomerular filtration rate (eGFR), which was calculated by the simplified Modification of Diet in Renal Disease (MDRD) formula. RI was defined as an eGFR of <60 mL/min/1.73 m2 at initial diagnosis. Severe RI was defined as eGFR <30 mL/min/1.73 m2. 18F‐FDG PET/CT was performed prior to induction therapy and PET/CT positivity was defined as the presence of more than three focal lesion (FL) or the presence of extramedullary disease (EMD).

Results:

A total of 29 patients (39.2%) had more than three FLs and 12 (16.2%) had EMD on baseline 18F‐FDG PET/CT. Thirty patients (40.5%) demonstrated PET/CT positivity. The median eGFR was 37.9 mL/min (range 3.0–59.8) and 24 (32.4%) had severe RI at initial diagnosis. Over the median follow‐up duration of 37.5 months, 54 patients (73.0%) had progressed and 22 (29.7%) had died by the time of the last follow‐up visit. The median progression free survival (PFS) was 24.2 months (95% CI, 17.4–31.1) and the median overall survival (OS) was 68.3 months (95% CI, 44.1–92.5). Patients with PET/CT positivity had significantly inferior survival outcomes than those with PET/CT negativity (PFS, 12.7 months vs. 34.0 months, P < 0.001; OS, 42.5 months vs. not reached, P = 0.012). In patients with severe RI, PET/CT positivity was significantly associated with poorer PFS and OS (PFS, 12.7 months vs 34.4 months, P = 0.011; OS, 42.4 vs not reached, P = 0.081). By multivariate analyses, PET/CT positivity was independently prognostic factor for PFS and OS in total patients.

Summary/Conclusion:

18F‐FDG PET/CT may be useful imaging technique for predicting survival outcomes in patients with MM presenting with RI.

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PF665 SERUM FERRITIN LEVELS ARE INCREASED IN IDIOPATHIC ERYTHROCYTOSIS BUT REDUCED IN POLYCYTHEMIA VERA
Authors: Biagetti G. , Bertozzi I. , Cosi E. , Fabris F. , Randi M.L.
Published: June 2019

Background:

Absolute erythrocytosis is characterized by persistently raised Haemoglobin (Hb) and hematocrit (Ht) levels. The most studied form is Polycythemia Vera (PV), a clonal disease in which the proliferation of red cells is driven by mutations in JAK2. Secondary erythrocytosis are represented by rare congenital diseases, acquired forms, or idiopathic erythrocytosis (IE), a poorer studied disease in which the erythrocytosis has not a definite cause. Over‐production of red blood cells should drive a depletion of iron, and thus low serum ferritin levels. However, we often observe increased levels of ferritin at diagnosis in IE and we recently found that mutations or polymorphisms of HFE gene are commonly found in these patients.

Aims:

Could serum ferritin be an early help to hypothesize the cause of erythrocytosis in a patient? To answer this question, we retrospectively analysed levels of ferritin at diagnosis in PV and IE patients.

Methods:

We studied 72 patients with PV and 67 patients with IE, followed in our department. In each patient we recorded ferritin at diagnosis out of phlebotomy treatment. Other causes of hypo‐ and hyper‐ ferritinemia were excluded. Ferritin normal levels were considered 20–300 μg/L in men and 15–200 μg/L in women. All patients with a diagnosis of PV carried JAK2V617F or JAK 2 exon 12 mutation, while none of the patients with IE carried JAK2 or EPOR, VHL, PHD2, HIF‐1 alpha genes mutations. Presence and absence of HFE mutations in IE patients, if known, were registered. Statistical analysis was performed using the Mann‐Whitney test, Fisher's exact test and the t Student test.

Results:

Results are shown in the Table I.

In addition, HFE mutations had been searched in 26 (39%) IE patients, and 13 (50%) of them had at least a mutated allele.

Summary/Conclusion:

Our results show a dramatic difference between levels of ferritin at diagnosis in PV and IE: in fact, 22% of PV patients had reduced ferritin at diagnosis out of phlebotomies, while on the contrary 28% of IE patients had increased levels of ferritin. Then, serum ferritin at diagnosis could address the physician to the origin of erythrocytosis. In addition, nearly half of IE patients have been already studied for presence of HFE mutations, and half of them carry at least one HFE mutated allele. We believe that a large part of IE patients carries a genetic impairment of the iron metabolism that could drive an enhancement of iron production: this could explain why in the presence of erythrocytosis iron is more consumed in PV patients than in IE ones. Further studies are needed about the presence of iron metabolism impairments in IE patients and, on the other hand, possible overlays of JAK2 and HFE mutations in PV patients.

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PF699 LUSUTROMBOPAG IS A SAFE TREATMENT OPTION FOR THROMBOCYTOPENIA IN PATIENTS WITH CHRONIC LIVER DISEASE UNDERGOING A SCHEDULED INVASIVE PROCEDURE: POOLED SAFETY ANALYSIS FROM 3 STUDIES
Authors: Brown R.S. , Izumi N. , Kano T. , Ochiai T. , Kurosaki M. , Violi F. , Shrestha P.
Published: June 2019

Background:

Lusutrombopag is a 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. In an integrated analysis of 2 Phase 3 studies, lusutrombopag reduced the need for platelet transfusions compared to placebo.

Aims:

Treatment with thrombopoietin receptor agonists has been associated with an increased risk of thrombotic events in patients with chronic liver disease. Thus, a thorough safety assessment of new agents is critical. A pooled retrospective analysis of 3 clinical studies was performed to assess safety of lusutrombopag.

Methods:

Safety data from 3 double‐blind, randomized, placebo‐controlled studies in patients with chronic liver disease and thrombocytopenia undergoing a scheduled invasive procedure (Phase 2b: M0626 [Japan; JapicCTI‐121944], Phase 3: L‐PLUS 1 [Japan; JapicCTI‐132323] and L‐PLUS 2 [global; NCT02389621]) were pooled. Adults with platelet counts <50x109/L at baseline received lusutrombopag 3 mg or placebo for up to 7 days before a procedure scheduled 9–14 days after randomization. Platelet transfusion was given if the platelet count remained <50x109/L no more than 2 days prior to procedure. Adverse event data were collected from signing of informed consent until the end of the post‐treatment period or early termination.

Results:

The pooled safety population included 341 patients (n = 171, lusutrombopag; n = 170 placebo). Approximately 65% of patients in the lusutrombopag and placebo groups experienced an adverse event (Table). Thrombotic and thromboembolic adverse events occurred in 1.8% (3/171) of lusutrombopag patients (cardiac ventricular thrombosis, n = 1 [patient had prior history of cardiac ventricular thrombosis]; portal vein thrombosis, n = 2) and 2.4% (4/170) of placebo patients (mesenteric vein thrombosis, n = 2; portal vein thrombosis, n = 2). Overall, bleeding‐related adverse events occurred in less lusutrombopag vs placebo patients (15 [8.8%] vs 27 [15.9%]), respectively. The 3 adverse events leading to death were not considered treatment‐related but due to the progression of underlying disease.

Summary/Conclusion:

In this pooled safety analysis, lusutrombopag was safe and well‐tolerated in patients with thrombocytopenia and chronic liver disease undergoing invasive procedures. Approximately 50% fewer bleeding‐related adverse events and no increased risk of thrombotic and thromboembolic adverse events were observed in patients treated with lusutrombopag vs placebo.

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PF706 OCCULT BLEEDING IN CHILDREN WITH IMMUNE THROMBOCYTOPENIA: RELATION TO LABORATORY PARAMETERS &ITP HEALTH QUALITY OF LIFE
Authors: Tantawy A. , Elsherif N. , Aboulfotouh K. , Kenny M.
Published: June 2019

Background:

Occult hemorrhage can occur in any internal organ in ITP patients. Four sites of occult hemorrhage deserve special attention including microscopic hematuria, fecal occult blood, retinal hemorrhage, and silent intracranial hemorrhage.

Aims:

The aim of this study was to investigate for the frequency of subclinical bleeding in Egyptian children with ITP and its relation to different clinical and laboratory parameters of the disease including bleeding score and health quality of life.

Methods:

This cross sectional study included 40 ITP patients recruited from the Pediatric Hematology&Oncology unit, Children Hospital, Ain Shams University. Occult blood in stools and urine analysis, fundus examination, and non‐contrast brain MRI, for brain microbleed, were done

Results:

The total number of patients with occult bleeds was eleven. Two patients had occult blood in stool, five had microscopic hematuria, one had retinal bleeds and three patients had brain microbleeds. Their mean age was 10.23 ± 4.18 and their mean initial bleeding score was 2.55 ± 0.82. Nine patients with occult bleeding were chronic, one persistent and one acute ITP patients. There was no significant differences between patients with occult bleeding and those without as regards the initial bleeding score, the platelet counts & hemoglobin level, as well as the mean platelet counts & mean hemoglobin level over the disease duration. Although the scoring of the effect on the parent's life, Child and parents quality of life was low in 3 out of 11 patients with occult bleeding, we did not find a significant difference between patients with occult bleeding and those without as regards the ITP health quality of life items

Summary/Conclusion:

Our results suggest that subclinical bleeding is a potential risk in children with ITP, more commonly chronic ITP patients. We could not demonstrate a significant relation of occult bleeding to the laboratory findings, bleeding score, and the ITP health quality of life; nevertheless, the significance of the routine assessment of occult bleeding in ITP and the identification of high‐risk patients require additional studies.
PF739 SICKLE CELL DISEASE IN GERMANY IS HETEROGENEOUS AND RESULTS IN SEVERE MORBIDITY: ANALYSES FROM A NATIONAL REGISTRY
Authors: Kunz J. , Lobitz S. , Andrea J. , Regine G. , Cario H. , Oevermann L. , Hakimeh D. , Le Cornet L. , Beck D. , Karapanagiotou‐Schenkel I. , Tagliaferri L. , Kulozik A.
Published: June 2019

Background:

Sickle Cell Disease (SCD) in Germany exclusively affects immigrants and their descendants. Its increasing prevalence results in challenges for medical care for these patients.

Aims:

The registry aims at describing the epidemiology, clinical course and treatment of patients with SCD in Germany.

Methods:

To date, 367 patients have been included in the registry by 36 mainly pediatric institutions. At initial registration, basic data including date of birth, date and circumstances of diagnosis, genotype, country of origin, blood type and complications in the patient's history are reported. Annual follow‐ups document details on complications, laboratory parameters and treatment. Data of 327 patients were analyzed for this abstract.

Results:

Genotypes of registry patients were homozygous SCD in 75% of patients, HbSC disease in 12%, HbS/β0thal in 6% and HbS/β+thal in 7%. The main regions of origin were sub‐Saharan Africa (in total 69% of patients, including Ghana 19%, Nigeria 19%, Togo 9%) and the Middle East (in total 21%, including Lebanon 6%, Turkey 5%, Syria 4%). Although pilot projects for newborn screening for SCD were in place in some of the centers, only 35% of patients were diagnosed during their first year of life, 85% before the age of six. SCD was diagnosed on the occasion of presenting symptoms in 60% of patients. The mean age at registration was 12 years (median 10), with 10% of patients being older than 21 years at registration. The most frequent complications in the patients’ prior history were pain crises with hospitalization (67% of patients), acute chest syndrome (32%), splenic sequestration (15%), aplastic crisis (10%), stroke (4%) and sepsis (4%).

During the first year of observation, 47% of the registry patients were hospitalized, 11% required treatment on an intensive care unit. Red blood cell transfusions were given to 27% of patients. 96% of patients with homozygous SCD or with HbS/β0thal at an age of 2 years or older were prescribed hydroxycarbamide, 76% of these patients under the age of 18 were annually examined by transcranial Doppler ultrasound (TCD).

Summary/Conclusion:

Patients with SCD in Germany are genetically and ethnically highly heterogeneous and suffer from severe morbidity. The diagnosis is frequently made too late because of the lack of a routine newborn screening for SCD. While the high rate of hydroxycarbamide prescription indicates good care at the institutions that contribute to the registry, the insufficient proportion of patients receiving routine TCD checks indicates an incomplete availability of the diagnostic infrastructure required for the optimal care of this challenging group of patients.
PF779 VIABILITY OF HEMATOPOETIC STEM CELLS FOLLOWING STORAGE AT −80OC WITH 5% DIMETHYLSULFOXIDE AND HEMATOLOGIC RECOVERY IN TRANSPLANTED MYELOMA PATIENTS
Authors: Tonev I. , Simeonov S. , Mitkov I. , Ilieva M. , Petrov Y. , Ganeva P. , Arnaudov G. , Spassov B. , Mincheff M.
Published: June 2019

Background:

Dimethylsulfoxide (DMSO) is a major intracellular cryoprotectant, used for cryopreservation of stem cells. It is toxic to both cells and patients at temperatures above 0oC. Reduction of this effect is achieved by either washing of cells after thawing or by reduction of DMSO during freezing and storage. The latter requires addition of extracellular cryoprotectants to the freezing media.

Aims:

We assessed the effect of low DMSO concentration and different hematocrits of the frozen cells on cell viability and hematologic recovery in patients, transplanted for multiple myeloma.

Methods:

Cells were non‐programmed frozen and stored at −80oC in a cryoprotectant solution achieving final concentrations of 5% DMSO, 3.6% of hydroxyethyl starch (HES, Weight average molecular weight 450 000 Da) and 3% of human serum albumin. The cell concentration in the frozen product for the first 77 patients (84 transplantations) varied between 100x106 and 250x106 cells/ml. In an attempt to reduce the amount of DMSO infused, for the rest of the patients (n = 172; 192 transplantations) we further decreased the volume of the freezing suspension by removal of the entire plasma.

The average age of the transplanted patients was 55 (35 ‐ 71). The cells were bedside thawed at 37oC water bath. The average cell dose was 2,95x106/kg (1,3 – 9,2x106/kg).

Results:

Viability of the stem cells following thawing assessed by trypan blue exclusion was 95,34% (70–99). The hematocrit of the frozen cells had no effect on cell viability (94,80%(low) vs 95,52%(high)). The major complaints, if any, during stem cell infusion were coughing and an increase in nausea and vomiting induced by the prior conditioning.

The average time for hematological recovery was 11,66 days (between 9 and 19) for the neutrophils, and 12,17 (between 9 and 20) days for the platelets. There was no significant difference in viability and hematologic recovery (11,86 and 12,60 vs 11,59 and 12,02) between patients receiving cells frozen with low or high hematocrit.

Summary/Conclusion:

Dimethylsulfoxide, despite its cryoprotective properties, is toxic for stem cells at temperatures above zero C and induces many side effects (cardiac, neurologic, respiratory, etc.) in the patients. To reduce those side effects we use lower DMSO concentration, high hematocrit resulting in lower volume of the frozen cell suspension, thus reducing the final quantity of DMSO to be infused to the patients. This does not affect the cell viability or the hematologic recovery of patients after transplantation. Our easily performed method for unprogrammed freezing of stem cells with final DMSO concentration 5% at −80oC is safe, well tolerated, and provides cryopreservation, which allows high viability and stable cell engraftment, while reducing the undesired side effects of DMSO.
PF789 8‐YEARS’ OVERALL AND EVENT FREE SURVIVAL IS SUBOPTIMAL IN A LARGE GROUP OF TRANSFUSION‐DEPENDENT THALASSEMIC PATIENTS
Authors: Kattamis A. , Mikelatou A. , Koumasi K. , Nitsa E. , Rigatou E. , Kyriakopoulou D.
Published: June 2019

Background:

Current therapeutic modalities with proper transfusion regimen and chelation therapy have dramatically increased life expectancy and decreased anemia and iron overload related complications in transfusion dependent thalassemic (TDT) patients. In many countries where thalassemia prevention programs were introduced, the majority of TDT population is of middle age. Data on morbidity and new complications on this ageing thalassemics are sparse.

Aims:

To determine the 8‐years’ overall survival (OS) and event‐free survival (EFS) and to examine factors affecting survival in a large group of TDT patients.

Methods:

This is a retrospective analysis of mortality and morbidity in a large group of homogenously –treated TDT patients in a single institution. Patients with TDT, regularly transfused in our unit on 31/12/2010, were followed for 8 years till 31/12/2018. ‘New event’ was defined as a new complication significant enough to require therapeutic intervention. The effect of different factors (like age, splenectomy, history of hepatitis C, burden of transfusions, iron overload, etc) on mortality and morbidity was evaluated. Burden of transfusion was evaluated as continuous (cc of transfused red blood cells/kg/year) and dichotomous variable (up to, and, more than 10 units/12 weeks). The majority of adult TDT patients (76.4%) received >10 units/12 weeks.

Results:

435 patients (mean 33.3 ± 7.9 years, max 52.3 years) were longitudinally followed. During an observation period of 8 years, 30 deaths occurred, corresponding to an 8‐years OS of 93.1%. Deaths significantly increased after the age of 40 years (figure). Splenectomy and history of hepatitis C were risk factors for death (O.R. 7.0 and 4.5, respectively, both p < 0.05). Improvement of iron overload was noted between 2010 and 2018 (ferritin levels: 2108.6 ± 2098 vs. 1550.8 ± 1883.5 μg/l, respectively, p < 0.05). During the observation period, percentages of patients experiencing new events were as follows: hypothyroidism 20.7%, cardiac complications 8.6%, glucose homeostasis disturbances 7.3%, hypogonadism 21.6%, significant osteoporosis 6.4%, renal failure 1%, neurological complications 5.5% and cancer 6.1%. 8 years’ EFS was 55%. Apart from age, no other factors were related to the occurrence of new events.

Summary/Conclusion:

Despite adequate transfusion regimen and improvement on iron overload, OS and EFS of TDT patients remain suboptimal, with mortality increasing significantly after the 4th decade of life. Contributing factors to death, like splenectomy and history of hepatitis C, may be related to the initial treatment period. Effect of transfusion burden needs further evaluation. Ageing TDT population is likely to develop more complications with advanced age with the occurrence of malignancies being a major concern.

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PF795 EXPLORING THE REAL‐LIFE CLINICAL VALUE OF LOW DOSE DIRECT ANTICOAGULANTS FOR SECONDARY PREVENTION OF THROMBOEMBOLISM
Authors: Saul S. , McIlroy G. , Smith N. , Perrin D. , Fair S. , Kartsios C.
Published: June 2019

Background:

Anticoagulation is the mainstay of acute venous thromboembolism (VTE) therapy. Until recently Vitamin‐K antagonists (VKAs) were the standard of care for extended treatment of VTE. In the last decade, direct oral anticoagulants (DOACs) have been studied and approved for use in treatment and secondary prevention of VTE. The apixaban AMPLIFY‐EXTEND clinical trial and the rivaroxaban EINSTEIN CHOICE study, have offered evidence that low dose anticoagulation up to 12 months following completion of standard VTE treatment, can be equally effective to standard dose apixaban/rivaroxaban for secondary prevention of thromboembolism. To date there is no real‐life study recording the outcomes of patients on low dose DOACs in this setting.

Aims:

In this audit, we sought to identify patients on long term low dose apixaban/rivaroxaban for secondary prevention of VTE and record their outcomes.

Methods:

Between January 2015 and September 2018, 4,625 patients were initiated to DOACs in our clinics. Amongst them 394 patients were put on either apixaban 2.5 mg bd (N = 352) or rivaroxaban 10 mg od (N = 42). Their median age was 65(16–98) years. The index event to offer long term anticoagulation was unprovoked VTE in 271 patients while 123 had suffered a provoked VTE with permanent risk factors. Cancer‐associated thrombosis was recorded in 42 patients, 69 individuals had documented thrombophilia and/or family history of thrombosis. Recurrent VTE was recorded in 41 patients. The median time from thrombosis to low‐dose anticoagulation switch was 7.26(3–280) months. The median follow‐up time on low dose anticoagulation was 15(3–45) months.

Results:

Major bleeding occurred in 3/394 patients (0.76%), all 3 patients were on low dose apixaban. Major plus clinically relevant non‐major bleeding was recorded in 30 patients (7.6%). Recurrent VTE occurred in 13/352 patients (3.69%) in the apixaban group and 1/42 patients (2.3%) in the rivaroxaban group (p = NS). No statistical differences in bleeding rate and VTE recurrence were identified between the total patient population, the cancer related thrombosis and the thrombophilia/family history of VTE subgroup respectively (table).

Summary/Conclusion:

Our study although small, is the first to record the clinical experience of using long term low dose DOACs to prevent VTE recurrence in real life. Our results confirm that low dose DOACs are very safe with major bleeding rate oof <1% in 15 months. We did however find a higher incidence of recurrent VTE (3.55%) compared to the AMPLIFY‐EXTEND (1.7%) and the EINSTEIN CHOICE (1.2%) trials.

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PF804 SEC22B‐DEPENDENT TRAFFICKING IS ESSENTIAL FOR VWF MULTIMERIZATION AND FORMATION OF ELONGATED WPBS
Authors: Karampini E. , Jennifer O. , Geerts D. , Voorberg J. , Bierings R.
Published: June 2019

Background:

Von Willebrand factor (VWF) is a key hemostatic glycoprotein that is predominantly synthesized in endothelial cells. Upon synthesis, the pro‐VWF precursor dimerizes in the ER and is subsequently transported to the Golgi where it undergoes proteolytical processing, multimerization and finally is stored in newly emerging secretory organelles, known as Weibel‐Palade bodies (WPBs). Assembly of VWF into high molecular weight (HMW) multimers, packaging in elongated WPBs and regulated release to the extracellular environment as ultra‐long VWF strings is crucial for its ability to recruit platelets to sites of vascular injury. The adhesive properties of VWF are strongly tied to the length of the secretory organelles in which it's contained in, however, how endothelial cells control the dimensions of their WPBs is still unclear.

Aims:

In this study, we investigated the crucial role of SNARE‐mediated ER/Golgi trafficking in VWF maturation and WPB biogenesis.

Methods:

In a shRNA screen of longin‐containing SNAREs in primary endothelial cells, we identified the proteinsinvolved in ER/Golgi trafficking. Protein expression was assessed by Western Blot and the morphology of intracellular compartment was studied using confocal microscopy.

Results:

We found that silencing of Sec22b resulted in the loss of the typically elongated morphology of WPBs. VWF was partially retained in the ER, resulting in a significantly higher ratio of proVWF:VWF. Decreased VWF influx to the Golgi affected the morphology of both WPBs, that were short and “stubby”, as well as the trans‐Golgi network (TGN). In addition, downmodulation of Sec22b expression resulted in the absence of HMW VWF multimers. Overexpression of a dominant‐negative Sec22b variant lacking its SNARE domain confirmed these phenotypes, revealing that correct localization and/or function of Sec22B is important for VWF trafficking and WPB formation.

Summary/Conclusion:

Our data suggest that Sec22b is a novel regulator of VWF trafficking and WPB biogenesis that modulates VWF multimerization and the elongated shape of WPBs by controlling ER/Golgi VWF influx.
PF809 ARE NATIONAL GUIDELINES AND MANDATORY TRAINING ENOUGH TO ENSURE SAFE TRANSFUSION PRACTICE?
Authors: Lovato S. , Morganti E. , Gourgui‐Naguib H. , Sasidharan D. , Patel C. , Patel R.
Published: June 2019

Background:

Errors in administering blood product represent a risk for patient safety. The British Society of Haematology (BSH) published guidelines to promote safe transfusion practice (1). These guidelines states that should be recorded: the unique component donation number and the date, start time and the identification of the person administering the component.The guideline also sets the standard for monitoring the patient during the transfusion with pulse, temperature, respiratory rate and blood pressure at the start of the transfusion, after 15 minutes of the start and within one hour from the end.

Transfusion training is mandatory for all health professionals involved in transfusion practice.

Aims:

The aim of this study was to establish if the guidelines established by BSH are applied in clinical practice across different departments.

Methods:

We performed a retrospective audit on transfusion documentation and patient monitoring and in a district general hospital. We included transfusion of red packed cells, platelets and fresh frozen plasma.

Results:

We identified 160 unit transfused (132 RPC, 16 PLTS and 12 FFP). Documentation of donation number and the date, start time and the identification of the person administering the component were complete in 88% of the cases, in 8% of the cases there was no documentation at all (Figure 1A); of the remaining in 80% of the cases was missing the signature of the administering person.

Regarding the monitoring of the patient only 25% of the unit transfusions were monitored according to the guidelines, in 33% of the cases there was no documentation of the patient monitoring. The least monitored parameter was respiratory rate; the most frequent missed monitoring point was the one at the end of the transfusion (Figure 1B).

Summary/Conclusion:

Despite clear guidelines and compulsory training transfusion practice is still poor with more than a tenth of the transfusion being not fully documented in the notes and the number of transfusion episodes lacking adequate patient monitoring information outnumbering the transfusion monitored according to the guidelines (33% vs 25%).

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Performing an audit across the entire hospital allowed us to identify the departments where transfusion procedures were not applied systematically with the plan to offer target training and re‐audit to improve transfusion practice.