bluuebunny/crossref_metadata_2025 huggingface dataset:
Stratification for Age in Non-Transfusion-Dependent Thalassemia: Data from a National Italian Networking
Authors: Pepe Alessia , Pistoia Laura , Romano Nicola , Colaci Giuseppe , Maggio Aurelio , Carollo Antonella , Campisi Saveria , Putti Maria Caterina , Fotzi Ilaria , D'Ascola Domenico , Grassedonio Emanuele , Positano Vincenzo , Meloni Antonella
Published: October 2019

Background: Non-transfusion-dependent thalassemia (NTDT) is a term used to indicate patients who do not require lifelong regular transfusions for survival. Morbidity in NTDT patients is more common and serious than previously recognized. This study aimed to examine the association of age with the presence of iron overload assessed by Magnetic Resonance Imaging (MRI) and cardiovascular and endocrine complications in NTDT patients.

Methods: We considered 170 patients with thalassemia intermedia never transfused o who received occasional transfusions consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project. Iron overload was quantified by the T2* Magnetic Resonance Imaging (MRI) technique. All complications were classified according to international guidelines.

Results: Six groups of patients were identified: age<18 years (N=7), age 18-30 years (N=36), age 30-40 years (N=48), age 40-50 (N=45), age 50-60 years (N=26), and age≥60 years (N=8). The Table shows the comparison among the groups.

The youngest patient showing hepatic iron (MRI liver iron concentration-LIC>3 mg/g dw) had 9 years of age and the frequency of hepatic iron did not significantly increase with age.

Only one patient showed cardiac iron (global heart T2*<20 ms).

Diabetes appeared only in patients with more than 50 years and showed a trend toward increasing with increasing age. Hypothyroidism and osteoporosis were not present in pediatric patients and were not associated to age. Hypogonadism was not present in patients with less than 30 years and its frequency was comparable among the age groups. No patient showed hypoparathyroidism.

Only patients older than 30 years showed a cardiac complication (heart failure or arrhythmias), but the rate did not significantly increase with increasing age.

Conclusions: Our data in NTDT are indicative of high rate of liver iron overload at early age and extremely rare cardiac iron overload. Endocrine or cardiac complications were not present in pediatric patients but in adult patients the frequency did not increase with advancing age.

Table. Table.

Disclosures

Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.
Variables Correlating to Transition of Care for the Bleeding Disorder Population at the University of California San Francisco
Authors: Burdekin Emma D , Suzuki Sachiko , Riddel James , Lesh Mary B. , Tobase Patricia , Lin Tiffany
Published: October 2019

Background An effective and coordinated process of transitioning adolescents with bleeding disorders from pediatric to adult medical care is essential for maintaining continuity of care and establishing a lifelong medical support system. Barriers to transition among people with a bleeding disorder (PWBD) at the University of California San Francisco (UCSF) are currently unknown.

Objective The purpose of this study is to collect and evaluate data on potential demographic, clinical and socioeconomic determinants of the length of time to transition among PWBD at UCSF.

Methods A retrospective chart review of 60 patients with bleeding disorders born between 1982 and 1996 was conducted to collect baseline demographic, clinical and socioeconomic data. The data was analyzed using a two-tailed t-test to determine factors associated with length of time to transition.

Results Of the 60 total patients included in this analysis, 15 were lost to follow-up. The average length of time to transition for the 45 patients who completed transition into adult care was 1.31 years, and the average age at transition was 22 years old. We analyzed various determinants of length of time to transition that fell into five categories: demographics, socioeconomic status, disease severity, level of independence and adherence to recommended care. Females trended toward a longer average time to transition of 1.93 years compared to 1.13 years for males (p=0.08). One variable had a statistically significant correlation to length of time to transition. Patients prescribed a factor product had a significantly shorter time to transition of 0.85 years compared to 2.13 years for patients not prescribed a factor product (p=0.0009). Of the 45 patients who completed transition into adult care, 62% were prescribed a factor product.

Conclusions Our study demonstrated that prescription of a factor product, which is likely an indicator of a greater disease severity, is correlated with time to transition. Our univariate analysis did not indicate that demographics, socioeconomic status, level of independence or adherence to recommended care related to length of time to transition. The results of this study are preliminary and further analysis is required to better understand the barriers to transition that exist among PWBD at UCSF.

Disclosures

Lesh: Bayer: Membership on an entity's Board of Directors or advisory committees, Other: International Nursing Advisory Board 2017. Tobase:Partners: Consultancy, Honoraria.
Does Mixed Chimerism after Allogeneic Hematopoietic Cell Transplantation in Patients with Fanconi Anemia Impact on Outcome?
Authors: Ayas Mouhab , Siddiqui Khawar , Amao Antonette , Aljefri Abdullah , Ahmari Ali Abdallah , Ghemlas Ibrahim A. , Alsaedi Hawazen S. , Alanazi Awatif , Al-Seraihy Amal
Published: October 2019

Fanconi anemia (FA) cells are characterized by genomic instability which places FA patients (pts) at risk for malignancies; leukemia and oropharyngeal/urogenital cancers. The risk of development of leukemia is theoretically eliminated after hematopoietic cell transplantation (HCT).

Simultaneous presence of both host- and donor-derived cells in the recipient often referred to as mixed chimerism (MC) is observed in a large proportion of patients after HCT with non-malignant disorders. In FA patients however, MC might have a unique implication and the persistent existence of FA cells represents a management dilemma as the lingering FA cells may theoretically evolve into a malignant clone. We have studied a large population of FA patients who underwent allogeneic HCT at our institution and report here the outcome of those with MC.

From January 1995 until December 2017, 163 FA pts underwent allogeneic HCT at our center; chimerism data at last contact were available on 100 pts who are the subject of this analysis. Females (51) had a mean age at HCT of 8.7 (SD:3.0, Min-Max: 2.0-14.1) years whereas in males (49) it was 8.1 (SD:3.4; Min-Max: 1.4-17.4) years (P-Value: 0.415). Donor was HLA matched family member in 78 pts, Haplo-identical family member in 17 (92 of them were bone marrow and 3 peripheral stem cells); 3 had unrelated cord blood. Total body irradiation was used in 24 pts.

Median time to ANC and platelets recovery was 14 and 22 days respectively. Cumulative incidence of overall aGVHD Grade III or above was 4%. Median follow up time was 67.2±14.6 months (95% CI: 38.7-95.7) from HCT date (Min: 7.3, Max:188.1). Chimerism analysis at last follow up showed full chimerism (100%; Myeloid/lymphoid) in 46 pts; 54 had MC defined as the presence of any residual recipient cells. No statistically significant association was noted between full and MC pts in the incidence of aGvHD (P-Value: 0.331). The 10-year cumulative probability of Overall Survival (OS) was 0.904±0.042. No significant difference was observed in OS between full and MC pts (0.954±0.032 vs. 0.883±0.059, P-value: 0.943) with 4 deaths in each group. New malignancy occurred in 4 pts; 2 in each group. In full Chimerism pts: Acute Mixed Lineage Leukemia and carcinoma and in MC pts: acute myeloid leukemia and acute lymphocytic leukemia, (P-Value=1.00). Graft failure occurred in 2 pts in the mixed chimerism group vs none in the full chimerism group (P-Value=1.0).

We conclude that mixed chimerism in FA pts does not appear to have an adverse effect on outcome in our follow-up period; longer follow-up time however is needed to confirm the validity of this statement.

Disclosures

No relevant conflicts of interest to declare.
18f-FDG PET/CT and the Revised International Staging System Are More Discriminating of Survival Outcomes in Newly Diagnosed Multiple Myeloma
Authors: Jung Sung-Hoon , Kwon Seong Young , Min Jung-Joon , Bom Hee Seung , Ahn Seo-Yeon , Jung Seung-Yeon , Lee Seung-Shin , Park Moo-Rim , Yang Deok-Hwan , Ahn Jae-Sook , Kim Hyeoung-Joon , Lee Je-Jung
Published: October 2019

Purpose : This study evaluated the prognostic role of 18F-FDG PET/CT at baseline in patients with newly diagnosed multiple myeloa (MM) and evaluated the prognostic relevance of 18F-FDG PET/CT for each stage according to the Revised International Staging System (R-ISS).

Method: We retrospectively analyzed the records of 167 patients with newly diagnosed MM. 18F-FDG PET/CT was performed prior to induction therapy in patients with newly diagnosed MM. A Focal lesions (FL) at diagnosis was defined as focally increased FDG uptake greater than the physiologic bone marrow or liver uptake, with or without any underlying lesion. Extramedullary disease (EMD) was defined as FDG-avid soft tissue that was not contiguous to bone.

Results: A total of 102 patients (61.1%) had at least one FL at diagnosis, and 44.9% had more than three FLs. EMD was present in 13.2% of all patients. In the total cohort, the presence of more than three hypermetabolic FLs or EMD on baseline PET/CT was associated with significantly inferior progression free survival (PFS) and overall survival (OS) than other patients. Because most patients (91%) with EMD had more than three FLs, PET/CT positivity was defined as the presence of more than three FLs or the presence of EMD. The C-reactive protein level was higher (0.550 vs. 0.245 mg/L, P = 0.004) and the serum albumin level was lower in the PET/CT-positive group (3.5 vs. 3.6 g/dL, P = 0.040). Patients who were PET/CT-positive had a significantly lower complete response rate after first-line therapy compared with those who were PET/CT-negative (15.6% vs. 34.4%, P = 0.007). In multivariate analyses, PET/CT positivity was an independent predictor of PFS and OS in all patients. Fifty-five patients (46.1%) with R-ISS II were PET/CT-positive at baseline and had significantly shorter PFS and OS. PET/CT positivity was also correlated with poor PFS and OS in patients with R-ISS III.

Conclusion : 18F-FDG PET/CT was an independent predictor of survival outcomes in patients with newly diagnosed MM. In addition, performing 18F- FDG PET/CT at diagnosis may be useful for determining the survival outcomes of MM patients with R-ISS II and III.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
The Three E Proteins Define a Heterogeneity of the AML1-ETO-Containing Transcription Factor Complex (AETFC) and Differentially Regulate t(8;21) Leukemogenesis
Authors: Liu Na , Song Junhong , Xie Yangyang , Wang Xiao-Lin , Rong Bowen , Man Na , Zhang Meng-Meng , Zhang Qunling , Gao Fei-Fei , Du Mei-Rong , Zhang Ying , Shen Jian , Xu Chun-Hui , Hu Cheng-Long , Wu Ji-Chuan , Liu Ping , Zhang Yuan-Liang , Xie Yin-Yin , Liu Ping , Huang Jinyan , Huang Qiu-Hua , Lan Fei , Shen Shuhong , Nimer Stephen D. , Chen Zhu , Chen Sai-Juan , Roeder Robert G. , Wang Lan , Sun Xiao-Jian
Published: October 2019

The leukemogenic AML1-ETO fusion protein is produced by the t(8;21) translocation, which is one of the most common chromosomal abnormalities in acute myeloid leukemia (AML). In leukemic cells, AML1-ETO resides in and functions through a stable protein complex, AETFC, that contains multiple transcription factors and cofactors. Among these AETFC components, E2A (also known as TCF3) and HEB (also known as TCF12), two members of the ubiquitously expressed E proteins, directly interact with AML1-ETO, confer new DNA (E-box) binding capacity to AETFC, and are functionally essential for leukemogenesis. However, we find that the third E protein, E2-2 (also known as TCF4), is specifically silenced in AML1-ETO-expressing leukemic cells, suggesting E2-2 as a negative factor of leukemogenesis. Indeed, ectopic expression of E2-2 selectively inhibits the growth of AML1-ETO-expressing leukemic cells, and this inhibition requires the basic helix-loop-helix (bHLH) DNA-binding domain of E2-2. Gene expression profiling and ChIP-seq analysis reveal that, despite some overlap, the three E proteins differentially regulate many target genes. In particular, consistent with the fact that E2-2 is a critical transcription factor in dendritic cell (DC) development, our studies show that E2-2 both redistributes AETFC to, and activates, some genes associated with DC differentiation, and that restoration of E2-2 triggers a partial differentiation of the AML1-ETO-expressing leukemic cells into the DC lineage. Meanwhile, E2-2, but not E2A or HEB, represses MYC target genes, which may also contribute to leukemic cell differentiation and apoptosis. In AML patients, the expression of E2-2 is relatively lower in the t(8;21) subtype, and an E2-2 target gene, THPO, is identified as a potential predictor of relapse. In a mouse model of human t(8;21) leukemia, E2-2 suppression accelerates the development of leukemia. Taken together, these results reveal that, in contrast to HEB and E2A, which facilitate AML1-ETO-mediated leukemogenesis, E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. The three E proteins thus define a molecular heterogeneity of AETFC, which merits further study in different t(8;21) AML patients, as well as in its potential regulation of cellular heterogeneity of AML. These studies should improve our understanding of the precise mechanism of leukemogenesis and assist development of diagnostic and therapeutic strategies.

Disclosures

No relevant conflicts of interest to declare.
Adrenomedullin Receptor Calcrl Drives Drug Resistance of Leukemic Stem Cells in Acute Myeloid Leukemia
Authors: Sarry Jean-Emmanuel , Recher Christian , Larrue Clément
Published: October 2019

After intensive chemotherapy, the emergence of cells with drug resistant and/or stem cell features might explain frequent relapses and the poor outcome of patients with acute myeloid leukemia (AML). Herein, we first uncovered that the adrenomedullin receptor CALCRL is overexpressed in AML patients compared to normal cells and preferentially in the immature CD34+CD38- compartment. Then, we demonstrated its role in the maintenance of leukemic stem cell function in vivo (Figure A). Moreover, CALCRL depletion strongly affected leukemic growth in xenograft models and sensitized to chemotherapeutic agent cytarabine in vivo. Accordingly, we showed that ADM-CALCRL axis drove BCL2 pathway, cell cycle and DNA integrity in E2F1-dependent manner, and high OxPHOS status that we previously described as a feature of minimal residual disease after chemotherapy (Farge et al., 2017). Moreover, CALCRL expression predicted the response to chemotherapy in vivo in mice (n=10 Patient Derived Xenografts; Figure B) and in patients. Further, using the combination of limiting dilution assays, single cell RNA-seq analysis of primary AML samples at diagnosis and relapse and before and after transplantation in NSG mice, we revealed the pre-existence of a chemoresistant leukemic stem cell sub-population harboring a CALCRL gene signature (Figure C-D). All of these data highlight the critical role of CALCRL in stem cell function and metabolism. They also identify this receptor as a new druggable marker of chemoresistant leukemic stem cell population and a promising therapeutic target to specifically eradicate them and overcome relapse in AML.

Disclosures

No relevant conflicts of interest to declare.
Hematopoeitic Cell Transplant - Comorbidity Index (HCT-CI) Score Is a Useful Tool for Predicting Induction Mortality and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia Patients
Authors: Saini Neeraj Y , Cerny Jan , Furtado Vanessa , Puthawala Imran , Desmond Angela , Ramanathan Muthalagu , Nath Rajneesh
Published: October 2019

Intro:

Assessment of induction mortality risk in acute myeloid leukemia (AML) patients is challenging. Hematopoietic cell transplant comorbidity index (HCT-CI) score was designed for risk assessment of patients undergoing an allogeneic transplant. However, it is often used in clinical practice to assess induction mortality risk in AML patients. We analyzed the predictive power of the score to assess induction mortality risk as well as overall survival in AML patients at our institution.

Methods:

Between Jan 2009 and March 2013, 101 consecutive newly diagnosed AML patients treated at our institution were included for analysis. All patients received bolus HiDAC (3gm/m2) on day 1-5 and high dose mitoxantrone (80mg/m2) on day 2. The median age was 65 years (range18-90). The total number of patients in the age group <60, 60-69 and ≥70 were 30(29.7%), 35(34.6%) and 36(35.6%) respectively. HCT-CI scores were calculated before induction chemotherapy. Kaplan Meir curve was used to calculate OS and PFS. 4-week induction mortality was calculated from the date of the induction chemotherapy. The patient cohort was divided into those with HCT-CI scores of > or ≤3.

Results:

The number of patients with the HCT-CI score of 0,1,2 and 3 were 8,13,17 and 13 respectively. 50% of our patients (51 patients) had a score of 4 or more on the HCT-CI index. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%) respectively. 4-week induction mortality in <60, 60-69 and ≥70 years of age groups were 0/30(0%), 1/35(2.8%) and 2/36(5.5%) respectively. Similarly, in above age groups, 8-week induction mortality were 0/29(0%), 2/34(5.8%) and 5/36(13.8%) respectively. The median OS in patients with an HCT-CI score ≤3 was 87 months versus 11.5 months in those with a score >3 (log-rank, p=0.0046, Fig1). 2-yr NRM rate for patients with HCT-CI score ≤3 and >3 was 47% and 71%, respectively (p=0.01, Fig2). Hazard ratio for overall mortality in patients with HCT-CI score >3 is 1.793 with p=0.023, 95% CI = (1.083 - 2.971). HR for 8-week mortality in patients with an HCT-CI score >3 is 2.035 (p=0.412), although not statistically significant due to a low number of events. However, by Cox multivariable regression analysis HCT-CI retained a significant impact on 8-week mortality (HR=1.24, p= 0.03) and overall survival (HR=1.144, p= 0.006).

Conclusion:

An HCT-CI score is a valuable tool in the assessment of the induction mortality in newly diagnosed AML patients and can be used for risk assessment of overall mortality.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Open-Label, Expanded Access Study of Taliglucerase Alfa in Patients with Gaucher Disease Requiring Enzyme Replacement Therapy
Authors: Kuter David J. , Wajnrajch Michael , Hernandez Betina , Wang Rong , Chertkoff Raul , Zimran Ari
Published: October 2019

Taliglucerase alfa, an enzyme replacement therapy (ERT) approved in several countries for the treatment of adult and pediatric patients with Type 1 Gaucher disease, is the first FDA-approved plant cell-expressed recombinant therapeutic protein for humans. PB-06-004 (NCT00962260) was a multicenter, open-label, expanded access study designed to follow the safety of taliglucerase alfa in patients with Gaucher disease who required ERT and who were previously treated with imiglucerase but had a dose reduction or discontinued due to a shortage of imiglucerase. Eligible patients (aged ≥18 years) with Type 1 Gaucher disease received taliglucerase alfa every 2 weeks for ³9 months at a dose equivalent to their previous imiglucerase dose, before it was reduced or discontinued (Part A), and had the option of continuing treatment for up to 33 months (Part B); a later amendment allowed treatment-naïve patients. Fifty-eight patients received treatment (55.2% male, mean age 46.1 years, mean bi-weekly dose 35.2 U/kg, mean duration 17.8 months); 51 patients previously received ERT, 7 were treatment-naïve. Thirty-six patients completed the study. Hemoglobin concentration and platelet counts were also explored. Most adverse events (AEs) were mild or moderate in severity and not related to taliglucerase alfa; treatment-related AEs were mild and transient in nature. In previously treated patients, mean (SE) hemoglobin concentration was 13.0 (0.3) g/dL at baseline, 13.4 (0.2) g/dL at 9 months, and 13.4 (0.2) g/dL at last follow-up; mean (SE) platelet count was 179,242 (15,344)/mm3 at baseline, 209,727 (17,157)/mm3 at 9 months, and 215,242 (17,867)/mm3 at last follow-up. In treatment-naïve patients, mean hemoglobin concentration and platelet counts increased. In conclusion, taliglucerase alfa was well tolerated for up to 33 months of treatment and demonstrated a durable therapeutic effect, as evidenced by stable or improved hemoglobin concentration and platelet counts in this expanded access study.

Disclosures

Kuter: BMS: Research Funding; Bioverativ: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Protalex: Research Funding; Novartis: Consultancy; Principia: Research Funding; Amgen Inc.: Consultancy; Argenx: Consultancy; ONO: Consultancy; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wajnrajch:Pfizer Inc: Employment. Hernandez:Pfizer Inc: Employment. Wang:Pfizer Inc: Employment. Chertkoff:Protalix Biotherapeutics: Employment. Zimran:Pfizer Inc: Honoraria; Shire: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.
A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations
Authors: Sirdesai Shreerang , Weekes Kerryn , Alam Asif , Tran Huyen A , Barnes Christopher , Kaplan Zane
Published: October 2019

Aim:

Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients.

Methods:

Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1.

Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor.

Results:

318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1)

In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA.

20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations.

Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical care

Conclusion:

This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally.

Disclosures

No relevant conflicts of interest to declare.
Incidence, Prevalence, Mortality, and Causes of Death in Waldenström Macroglobulinemia in South Korea: A Nationwide, Population-Based Study
Authors: Jeong Seri , Kong Seom Gim , Kim Dajung , Lee Ho Sup
Published: October 2019

Backgroud: Studies investigating the epidemiology of Waldenström macroglobulinemia (WM) in Asia are scarce. The aim of this study was to provide the epidemiological and clinical features of WM in South Korea at a national level, including incidence, prevalence, mortality, survival with competing risks, and causes of death.

Methods: We used a national, population-based database maintained by the Health Insurance Review and Assessment Service, which includes information on all WM patients, diagnosed based on uniform criteria from 2003 to 2016.

Results: The total number of patients newly diagnosed with WM was 429 during study period with a female to-male ratio of 3.2. The incidence from 2003 to 2016 increased from 0.03 to 0.11 per 105, and the prevalence in 2016 was 0.42 per 105. A total of 217 WM patients died during the study period (standardized mortality ratio =22.07) and the overall survival (OS) of WM patients was 47.5%. In the multivariate analysis, a significant factor associated with a worse OS was older age, whereas stem cell transplantation showed a better outcome (hazard ratio = 0.163; P = 0.0109). WM was the most common cause of death (n = 173; 79.7%), followed by other malignant neoplasms (n= 21; 9.7%).

Conclusions: The national incidence of WM in Korea, a racially homogeneous country of Asia, was lower than that in previous reports from other countries, reflecting ethnic disparities. However, the incidence increased and mortality was the highest ever reported. The main cause of death was WM itself and stem cell transplantation was considerably effective. This study reflects the need for greater awareness of WM, particularly in Asian countries.

Disclosures

No relevant conflicts of interest to declare.
Albumin Improves Stratification in the Low IPI Risk Patients with Diffuse Large B-Cell Lymphoma
Authors: Wei Xiaolei , Wei Yongqiang , Huang Weimin , Song Jialin , Zeng Hong , Zheng Jingxia , Wei Qi , Feng Ru
Published: October 2019

Our previous study showed albumin at diagnosis can be used to predict survival in diffuse large B-cell lymphoma (DLBCL) patients, but whether albumin could improve the international prognostic index (IPI) risk stratification in DLBCL remains unknown. Herein, we retrospectively analyzed 440 de novo DLBCL patients treated with R-CHOP in this study. The cutoff value of albumin for survival analysis was 34.4 g/L with an area under the curve value of 0.642±0.0037 (p<0.001) by receiver operating characteristic curve. Patients with low serum albumin showed worse overall survival (OS) and event-free survival (EFS) (p<0.001 and p=0.002, respectively). Multivariate analysis revealed that low serum albumin, independent of IPI, indicated different survival in both OS(relative ratio [RR] .0481; 95% confidence interval [CI], 0.294 - 0.789, p=0.004) and EFS (RR, 0.617; 95% CI, 0.419 - 907, p=0.014) in DLBCL patients.According to IPI, there were 170 patients (40.2%) in low risk group, 101patients (23%) in low-intermediate risk group, 97(22.0%) patients in high-intermediate risk group and 65 patients (14.8%) in high-risk group. Low IPI risk patients showed favorable survival (p<0.05). However, there were no significant survival difference in low-intermediate, high-intermediate and high-risk group (p>0.05). Especially low albumin could identify a subgroup of patients with poorer overall survival in low/ low-intermediate IPI risk patients (p = 0.003). In conclusion, our study suggests that albumin at diagnosis is a simple and effective prognostic factor in DLBCL patients,allowing the identification of an inferior outcome subgroup in low/ low-intermediate DLBCL patients, which may help to guide treatment.

Disclosures

No relevant conflicts of interest to declare.
Incidence of Thromboembolic Disease in Hereditary Hemorrhagic Telangiectasia (Osler Weber Rendu Syndrome)
Authors: Serra Marcelo Martin , Elizondo Cristina Maria , Alonso Marina , Peuchot Veronica , Vazquez Fernando Javier
Published: October 2019

The Hereditary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia that affects 1-5000 individuals worldwide. Is characterized by fragile mucocutaneous telangiectasia and vascular malformations in organs such as brain, lungs, liver and the gastrointestinal tract. Nose and gastrointestinal bleeding are remarkable, leading to frequent iron deficiency anemia (IDA) or life threatening bleeding episodes. Venous thromboembolic events (VTE) in HHT are probably more frequent than general population due to high plasmatic levels of FVIII specially in clinical conditions like long time immobilization due to brain abscesses or severe anemia. Additionally, in those patients with pulmonary fistula, the thromboembolic events can produce paradoxal strokes. On the other hand, almost all HHT medical treatments usually used to treat HHT related bleeding could produce thromboembolic disease. Anticoagulation (ACO) in this bleeding condition is a challenge, nevertheless, almost 50% can tolerate it well.

Objective: To report the incidence of VTE in the HHT population.

Methods: Ambispective cohort of adult based on the Institutional Registry of HHT. VTE was defined as the first episode of pulmonary embolism (PE), deep venous thrombosis (VTE) or thrombosis in the fistula sac or the progression of a prior event after its first 48 hs despite anticoagulation.

Result: Over 524 patients 394 adults with HHT confirmed by Curazao criteria or positive genetic test and complete data were included. There were 18 VTE events 4.6% (CI95% 2.7-6.8%), 9 DVT (2.3% IC95% 1.2-4.4%) and 3 PE (0.7% IC95% 0.13-2%). The female gender represents 72%. The median age at the event was 67 years (IIQ 25-75% 56-73).

Five patients (27%) were on ACO prior to the event, mainly for atrial fibrillation, and 3(18%) suffered a previous VTE.

The most frequent risk factors were recent hospitalization (44%) and iron deficiency anemia (44%), immobility (33%), recent surgery (18%), as well as cancer (5%) and recent travel (5%) patient each.Fifteen (83%) patients received ACO, 10(55%) received LMH followed by acenocumarol, 3(30%) of which had to be stopped due to nose or gastrointestinal bleeding.In 5 (27%) a cava vein filter were inserted, of which 3 are under anticoagulation therapy.

Conclusion: VTE incidence in our study was significantly higher than reported in general population at similar age. However, the inclusion of more symptomatic and serious HHT patients could be selection bias. The low number of patients, may influence the results. IDA and hospitalization were the most important associated conditions. Most patients tolerated well the anticoagulation therapy.

Disclosures

No relevant conflicts of interest to declare.
Elevated FANCA Expression Marks a Worse Prognosis in Chronic Lymphocytic Leukemia. Evidence of a New Role of FANCA in the Stability of p53 By a Neddylation-Related Mechanism
Authors: Pipaon Carlos , Bravo Navas Sara , Romon Iñigo , Conde Eulogio , Yanez San Segundo Lucrecia
Published: October 2019

Background: Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in western countries. It is characterized by a failure in the mechanisms of apoptosis that leads to an accumulation of mature B cells in peripheral blood, bone marrow and lymphoid organs. With exceptions, CLL is considered incurable and some patients show a worse prognosis related to the expression of certain cytogenetic or molecular markers such as p53 dysfunction (17p13 deletion or TP53 inactivation), 11q23 deletion, unmutated IgVH and the presence of a complex karyotype. FANC proteins have been related to chromosomal instability and alterations in the mechanisms of p53 activation, control of cell cycle and apoptosis. Germline mutations in any of the 20 FANC genes known so far generates Fanconi Anemia, a syndrome characterized by a extraordinary proneness to cell apoptosis leading to a progressive bone marrow aplasia and pancytopenia. Some FANCA proteins aggregate in response to DNA damage forming the FANCcore complex that mediates the monoubiquitination of FANCD2 and FANCI, thus activating the mechanism to repair stalled replication forks. In addition, individual FANC proteins have been involved in functions out of the FANCcore. This is the case of FANCA, that has recently been involved in the neddylation of CXCR5 and beta-2-microglobulin, processes reported to be altered in CLL.

Hypothesis: Given the fragmentary information connecting FANC proteins with cellular processes altered in CLL, like apoptosis, cell cycle or neddylation, we hypothesize a role of these proteins in the diagnosis or prognosis of CLL.

Methods: We analyzed the expression of 5 FANC genes in a cohort of 160 patients of CLL by quantitative RT-PCR. Statistical analysis were carried out to establish relations between FANC genes deregulation and clinical manifestations. We also investigated the role of the FANCA gene in primary circulating B-lymphocytes from CLL patients by either gain- or loss-of-function approaches.

Results: Our data identified a group of CLL patients with high expression of FANCA in peripheral B-CLL cells, and we stablished its relationship with the deletion of 11q23 and a worse prognosis. When we investigated the molecular mechanisms of this bad prognosis, we observed a reduction in the mRNA expression of two p53 target genes, p21 and ∆Np73, in CLL primary cells transfected with FANCA. Luciferase studies demonstrated an impairment of p53 function by FANCA. Moreover, we obtained evidence of a cooperation between FANCA and the NEDD8-interacting protein NUB1L in the destabilization of p53.

Conclusion: These results point to FANCA as a bad prognosis marker in CLL and unveils a new role of this protein aside from its role in the FA-BRCA DNA repair pathway.

Disclosures

No relevant conflicts of interest to declare.
CAR-T Cells Targeting gp350 Recognize Immortalized Cells Latently Infected with EBV
Authors: Danisch Simon , Slabik Constanze , Zeidler Reinhard , Ganser Arnold , Stripecke Renata
Published: October 2019

Objectives: Epstein-Barr virus (EBV) is associated with lymphoproliferative disease in immunocompromised hosts and with human B-cell lymphomas and carcinomas. Adoptive transfer of virus-specific T cells is not practical when memory T cells from HLA-matched donors are not available. Hence, we designed T cells expressing EBV-specific chimeric antigen receptors (CARs) to bypass the need of matched memory T cells. The surface-bound glycoprotein 350 (gp350) was used as target, because it is abundantly expressed during lytic EBV replication and it can also be detected in EBV-immortalized cells.

Methods: gp350-CARs were constructed by fusion of single-chain variable fragments of two high affinity gp530-specific human mABs (7A1 and 6G4) to CAR-backbones containing the CD28/CD3ζ domains. Transduction of human T cells from PBMC and cord blood with γ-retroviral vectors showed higher expression levels of 7A1-gp350-CAR than 6G4-gp350-CAR.

Results: We used 293T cells expressing gp350 and B95-8 immortalized cells from a tamarin monkey (6-10% gp350+) and human B cells immortalized with the EBV laboratory strain M81 (30% gp350+) in order to compare the potency of gp350-CAR T cells in vitro. Both 7A1-gp350-CAR and 6G4-gp350-CAR were activated and proliferated in the presence of gp350+ cells, inducing cytotoxicity of the target cells. Pilot experiments in a preclinical humanized mouse model consisting of Nod.Rag mice transplanted with human cord-blood (CB) stem cells and infected with an EBV/fLUC strain, we could confirm persistence of CB-matched 7A1-gp350-CAR T cells in spleen, bone marrow and lung for up to 6 weeks. In some animals, this was correlated with lower EBV dissemination measured by optical imaging and PCR.

Conclusions: We showed that EBV-specific CARs can reprogram naïve or memory T cells from PBMC or CB to react against EBV infected cells in an HLA-independent manner. This approach can be translated in the future for the generation of anti-EBV-CAR T cells for patients in Need.

Disclosures

Ganser: Novartis: Membership on an entity's Board of Directors or advisory committees.
Prediction of Response to Fostamatinib Based on the Presence of Plasma Platelet Autoantibodies in Adult Patients with Immune Thrombocytopenia (ITP) — Exploratory Analyses from Phase 3 Studies
Authors: Markovtsov Vadim V. , Yi Sothy , Young Chi , Duliege Anne-Marie , Masuda Esteban
Published: October 2019

Background: Initial results of an analysis of anti-platelet autoantibodies in patients with ITP from two phase 3 studies showed that patients were more likely to respond to treatment with the SYK inhibitor fostamatinib if they were positive for anti-platelet autoantibodies. Stable platelet responses to fostamatinib were reported in 36% of 28 patients who tested positive for anti-platelet autoantibodies and in 9% of 32 patients who tested negative (p<0.02). This analysis has been expanded to include 85 patients and to evaluate various platelet antigens.

Methods: Plasma samples from 85 patients in the phase 3 studies were collected with informed consent at 2 weeks after the first dose of fostamatinib. Samples were analyzed for anti-platelet autoantibodies via Luminex beads-based PakLx assayand FACS-based indirect platelet immunofluorescence test (iPIFT) using platelets from healthy volunteers.

Results: Of 85 patient samples, 38 (45%) were positive for one or more anti-platelet autoantibodies and 19 (22%) were from patients with a stable platelet response to fostamatinib. Of 38 patients positive for autoantibodies, 13 (34%) had stable platelet responses. Of 47 patients negative for autoantibodies, 6 (13%) had stable platelet responses.

Conclusions: The presence of anti-platelet autoantibodies appeared to be associated with a stable platelet response to fostamatinib. This exploratory analysis provides support for the hypothesis that fostamatinib prevents platelet loss through inhibition of autoantibody-directed platelet destruction in ITP. Further studies are ongoing.

Disclosures

Markovtsov: Rigel: Employment, Equity Ownership. Yi:Rigel: Employment, Equity Ownership. Young:Rigel: Employment, Equity Ownership. Duliege:Rigel: Employment, Equity Ownership. Masuda:Rigel Pharmaceuticals: Employment, Equity Ownership.
Targeted Next Generation Sequencing for Myeloid Neoplasm in Pakistani Patients
Authors: Shahid Saba , Ahmed Shariq , Siddiqui Saima , Sohail Misha , Shamsi Tahir S.
Published: October 2019

Introduction:

Myeloid malignancies are heterogenous diseases caused by excessive accumulation of apparently myeloid clone of cells. Genomic studies on myeloid malignancies in recent years have identified new genetic alterations with biological and clinical significance. In addition to cytogenetics and morphological examination these genetic mutation play an important role in diagnosis, prognosis and treatment of the patient. We assessed the frequency and clinicopathologic significance of 54 genes in myeloid neoplasm patients by using targeted next-generation sequencing.

Methods:

About 50 samples were collected from OPD at National Institute of Blood Diseases (NIBD), that consisting of 17 MDS, 18 AML and other myeloid neoplasms. They comprises of 33 males and 17 females with median age of 33 years (range: 5-69 years). The myeloid sequencing panel of 54 genes (complete coding exons of 15 genes and exonic hotspots of 39 genes) was sequenced. The panel total coverage was 141 kb in genomic sequence. TruSight myeloid sequencing (Illumina, CA) libraries were prepared and runs were performed on a MiSeq (Illumina) genome sequencer. The generated data were analyzed by on-instrument software or TruSeq Amplicon® and BaseSpace Apps®.

Results:

Overall 3092 variants were identified, after excluding intronic and synonymous variants, 380 missense variants were found in 50 patients. Around 38 mutations in 22 genes were identified in 23 out of 50 samples (46 %). The recurrent mutations found in RUNX1, ASXL1, GATA2 and CEPBA genes in our cohort.

Conclusion:

Most of the myeloid neoplasms are not easily manageable with limited treatment options. Therefore, targeted gene panel by next generation sequencing was an appropriate method for precise identification of mutations in myeloid neoplasms at our institution. Based on the obtained findings we will be able to design patient management plan with respect to individualize genetic mutations in the clinical setting.

Disclosures

No relevant conflicts of interest to declare.
MiR155 Sensitized B-Lymphoma Cells to PD-L1 Blockade Via PD-1/PD-L1-Mediated Lymphoma Cell Interaction with CD8+T Cells
Authors: Zheng Zhong
Published: October 2019

Diffuse large B-cell lymphoma (DLBCL) represents the most common neoplastic disorder of B-lymphocytes. Besides genetic aberration of lymphoma cells themselves, dysfunction in immune cells can lead to lymphoma cell resistance to immunochemotherapy. Immune checkpoint inhibitors have emerged as successful treatment strategies for DLBCL. However, the underlying mechanisms that lymphoma cells escape from anti-tumor immune responses need to be further investigated.

MiR155 was assessed by quantitative RT-PCR in a large cohort of patients with newly diagnosed DLBCL. Serum miR155 was significantly elevated, correlated with tumor miR155, and indicated poor prognosis. In peripheral blood, miR155 overexpression was associated with decreased CD8+T cells, reduced IFN-γ level and inhibition of T-cell receptor signaling. RNA sequencing was performed on blood samples of 82 DLBCL patients, which indicated that 73 genes closely related with lymphoma were differentially expressed between high miR155 group and low miR155 group. Above genes were plotted by heatmap. Dysregulation of multiple signaling pathway enriched by KEGG pathway analysis. Gene set enrichment analysis (GSEA) analysis manifested that miR155 is closely related with T cell receptor signaling pathway, cell cycle pathway and cytokine-cytokine receptor interaction pathway.

In co-culture systems of B-lymphoma cells with immune cells, miR155 modulated Fas-mediated apoptosis of CD8+T cells, which was targeted by PD-1 and PD-L1 antibodies. As mechanism of action, miR155 enhanced lymphoma cell PD-L1 expression, recruited CD8+T cells via PD-1/PD-L1 interaction, and inhibited AKT/ERK phosphorylation of CD8+T cells. Moreover, EBV-positive patients showed higher serum miR155 than EBV-negative patients. In vivo in a murine xenograft model established with subcutaneous injection of A20 cells, PD-L1 blockade particularly retarded the growth of miR155-overexpressing tumors, consistent with AKT/ERK phosphorylation and CD8+T cell persistence.

Taken together, as a serum oncogenic biomarker of DLBCL, miR155 indicated the sensitivity of B-lymphoma cells to PD-L1 antibody via PD-1/PD-L1-mediated interaction with CD8+T cells. Persistence of CD8+T cells could be an alternative target of action of PD-L1 antibody in treating B-lymphoid malignancies.

Disclosures

No relevant conflicts of interest to declare.
Comparable Outcomes of Myeloablative Conditioning Regimen without ATG in CBT for Pediatric Patients with Hematological Malignancies with a Weight of More Than 30 Kilograms Vs. Less Than 30 Kilograms
Authors: Luo Chenhui , Sun Zimin , Xia Lijun
Published: October 2019

Purpose

Cord blood transplantation (CBT) is an effective option for the treatment of pediatric patients with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS), but children with heavier weight (weighing more than 30kg) always have inferior outcomes than children with lighter weight. This article aims to identify the outcomes of myeloablative conditioning regimen (MAC) without antithymocyte globulin (ATG) in CBT for pediatric patients with different weight.

Methods

We conducted a retrospective analysis including 142 pediatric patients weighing less than 30kg and 130 pediatric patients weighing more than 30kg from May 2008 to September 2017 in our center. All the children were given a combination of cyclosporine (CsA) and mycophenolate mofetil (MMF) without ATG for graft-vs.-host disease (GVHD) prophylaxis. Most of the lighter children and two third of the heavier children were given busulfan(Bu) based MAC while another one third of the heavier children were given total body irradiation (TBI) based MAC.

Results

Children with different weight had no difference in gender, disease status, disease risk, and blood type. However, heavier children were older and had more loci of human leukocyte antigen(HLA) mismatch (P=0.000 and P=0.016). More children weighing more than 30kg suffered ALL than children weighing less than 30kg (P<0.05). The cumulative neutrophil engraftment rate by 42 days and the platelet engraftment rate by 120 days were almost the same in heavier children group and lighter children group (97.7% vs. 94.4% and 86.2% vs. 86.6%, p=0.284 and p=0.313, respectively). Non-relapse mortality (NRM) and relapse rate were also similar in these two groups (16.3% vs. 12.3% and 22.0% vs. 21.9%, p=0.345 and p=0.923, respectively). While the incidence of chronic GVHD (cGVHD) was higher in heavier children group (17.9% vs. 9.4%, P<0.05), but not grade II to IV acute GVHD (aGVHD) nor grade III to IV aGVHD. Three years of overall survival (OS), disease-free survival (DFS) and GVHD-free/relapse-free survival (GRFS) showed no significant difference in these two groups.

Conclusions

This study is the first to demonstrate the similar curative effect of myeloablative conditioning regimen without antithymocyte globulin in CBT for pediatric patients with different weight. A large-scale prospective study is needed.

Disclosures

No relevant conflicts of interest to declare.
Hepatitis E Virus Infection after Haploidentical Hematopoietic Stem Cell Transplantation:Incidence and Clinical Course
Authors: Tang Fei-Fei , Mo Xiao-Dong , Wang Yu , Yan Chen-Hua , Chen Yu-Hong , Chen Huan , Han Wei , Chang Ying-Jun , Zhang Hai-Ying , Xie Yan-Di , Ma Hui , Wei Lai , Xu Lan-Ping , Huang Xiao-Jun , Zhang Xiaohui
Published: October 2019

Introduction: Hepatitis E virus (HEV) is increasingly found to cause hepatitis in allogeneic hematopoietic stem cell transplantation (HSCT) patients. However, little is known about HEV infection in patients treated with haploidentical HSCT (haplo-HSCT). Here, we retrospectively evaluate the incidence and clinical course of HEV infection in haplo-HSCT patients.

Methods: From January 2014 to July 2017, 177 patients with unexplained elevated transaminases after receiving haplo-HSCT at Peking University Institute of Haematology were screened for HEV infection using HEV serology. HEV RNA were performed when HEV-IgG and/or IgM antibodies were positive.

Results: Acute HEV infection was identified in seven of these patients (3.9%), none of whom had developed a chronic HEV infection. The median time from haplo-HSCT to HEV infection was 17.5 (range, 6-55) months. Median peak alanine transaminase during HEV infection was 716 (range, 164-1763) U/L. In 7 cases, HEV infection was confirmed by the presentation of anti-HEV IgM + anti-HEV IgG (rising) (n=5) or HEV-RNA + anti-HEV IgM + anti-HEV IgG (n=2). None patients died of HEV infection directly. Two patients with HEV infection died showing signs of ongoing hepatitis and the median duration of HEV infection was 2.7 months. Five patients cleared HEV and the median duration of HEV infection was 1.5 (range, 1.0-5.7) months.

Conclusions: In conclusion, HEV infection is a rare but serious complication after haplo-HSCT. We recommend screening of HEV infection in haplo-HSCT.

Disclosures

No relevant conflicts of interest to declare.