bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Severe Bacterial Infection in Febrile Children with Sickle CELL Disease in the Era of Pneumococcal Conjugate Vaccine 13
Authors: Contreras-Yametti Gloria , Haidee Custodio , Imran Hamayun
Published: October 2019

Introduction

The incidence of invasive pneumococcal infections in patients with sickle cell disease (SCD) decreased after introduction of penicillin prophylaxis and pneumococcal conjugate vaccine (PCV). However, the decrease in pneumococcal infections alone may not necessarily mean an overall decrease in severe bacterial infections (SBI). In a previous publication, we reported a 0.4 % prevalence of pneumococcal bacteremia following introduction of PCV 13. In the current study, we aimed to define the prevalence of SBI and hospitalization in febrile patients in the same cohort in the later years.

Methods

We performed a retrospective study of patients with SCD <18 years old presenting with fever to University of South Alabama Children's and Women's Hospital from January 2014 to June 2017. SBI was defined as: bacteremia, pneumonia, pyelonephritis, meningitis, osteomyelitis and abscess (superficial and deep). Univariate analysis and multivariate logistic regression were used to determine factors associated with patient disposition as well as presence of SBI.

Results

There were 258 febrile events in 120 patients resulting in 187 (72%) admissions (figure 1). SBI was seen in 12% of admissions with uncomplicated community acquired pneumonia being the most common. The prevalence of bacteremia was 1.6% with single cases of pneumococcus, E. coli, and H. influenzae bacteremia. Younger age, high fever, and splenectomy were associated with hospitalization (p<0.05). However, only C reactive protein was associated with SBI (p<0.02). Viral infection was diagnosed in 80% of outpatients but 87% were given antibiotics. Among inpatients, all received parenteral antibiotics, and 67% were assessed to have viral illness, although only 23% had a virus identified. Pneumococcal vaccination status was satisfactory in 77% of our sample while compliance rate with penicillin prophylaxis was >85% in both inpatient and outpatient groups.

Conclusion

Although majority of febrile events were due to viral infections, 3 of four febrile episodes in our cohort resulted in hospitalization. A small proportion of patients had SBI and a much smaller proportion had bacteremia. These findings support early virus identification which can have implications on patient discharge disposition and antibiotic use. Further studies looking at risk stratification of febrile patients with SCD are needed to encourage outpatient management without compromising safety.

Figure 1. Figure 1.

Disclosures

Imran: Novo Nordask: Speakers Bureau.
Outpatient Fractionated ICE Protocol in Relapsed/Refractory Lymphomas: Efficacy and Safety
Authors: Dada Reyad , Nawaz Azhar , Abdelghany Ehab Mosaad , Boubakra Tarek
Published: October 2019

Objectives: The diagnosis of cancer significantly affects quality of life (QoL) of patients. Admission on wards and spending several days far from home to receive chemotherapy, especially in young patients with Hodgkin lymphoma (HL), might negatively affect the QoL. Therefore, we are offering our patients with relapsed and refractory lymphomas receiving the so-called outpatient fractionated regimen of ifosfamide, carboplatin and etoposide (ICE) as salvage treatment prior to high dose chemotherapy and autologous stem cell transplantation (ASCT).

Methods: We retrospectively collected the data of patients who received outpatient fractionated ICE between 2011-2017 at a tertiary care center. The ICE protocol consisted of: ifosfamide 1500 mg/m2 infused over 2 h daily on days 1-3, carboplatin (mg dose = 5 · AUC) i.v. on day 1, and etoposide 100 mg/m2 i.v. daily on days 1-3, plus filgrastim 5 ug/kg/day s.c. for 5 days. Rituximab 375 mg/m2 on day 1 was added for patients with CD20 positive B cell Non-Hodgkin lymphoma. The Cycles of outpatient ICE were given every 21 days.

Results: 89 patients (44% female and 56% male) with median age of 34 years (17-72) fulfilled the inclusion criteria. Majority of patients had HL (64%). 88% had stage III and IV with 60% having B symptoms and 38% extranodal disease prior to ICE. 5% had transformed lymphoma. Mean of received ICE was 2.5 cycles. The complete remission and partial remission rates for primary refractory (63%) and non-primary refractory (37%) disease were 7% and 25% versus 19% and 38% respectively. Of patients who achieved a response qualifying for ASCT, stem cells were successfully collected with filgrastim alone and plerixafor plus filgrastim in 77.1% and 22.9% respectively. The median of collected stem cells was 6.13 106/kg with mean apheresis of two days. 75% of eligible patients proceeded to ASCT. The relapse free survival rate was 45 months (95% CI 10-80) and overall survival rate 58 months (95% CI 32-84). Mean follow-up time was 33.1 months (range 8-92).

The rate of hematological toxicities grade 3 were documented in 15% with 10% neutropenia and 9% thrombocytopenia. Febrile neutropenia rate was 5.6%. Non-hematological toxicities included oral mucositis 3%, vomiting and diarrhea each 1%. No grade 4 or serious adverse events were observed.

Conclusions: Our institutional experience is, to our knowledge, the largest of it is kind, which showed the outpatient fractionated ICE as an interesting alternative to the classic ICE regimen with favorable safety profile. However, for patients with primary refractory lymphomas more effective regimens are urgently needed.

Disclosures

No relevant conflicts of interest to declare.
Predicting Treatment Response and Survival of Multiple Myeloma with the Xbp-1 Co-Expression Gene Module
Authors: Lu Xuzhang , Xiaolong Fan , Zhuxia Jia , Jinyuan He , Xiaohui Cai
Published: October 2019

Multiple Myeloma (MM) is a B-cell malignancy characterized by monoclonal expansion and accumulation of abnormal plasma cells in bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems for prognosis have been proposed, but they are not predictive for treatment response. XBP-1 is a critical molecule in coordinating normal plasma cell differentiation and survival because of its role in regulating the unfolded protein response. We identified a module of 100 genes co-expressed with XBP-1 (XBP-1-M) in the dataset GSE2658 by QlucoerOmics Explore 2.2 (Qlucore AB, Lund, Sweden) software. Using unsupervised consensus clustering, we assigned 264 MMs into XBP-1 low or XBP-1 high subtype in the validation dataset GSE9782. Patients in GSE9782 were randomly assigned into bortezomib or high-dose dexamethasone (Dex) treatment arms in the APEX 3 trial (039) (Blood 2007;109:3177-88). We integrated XBP-1-M clustering-based response analysis with the choice of treatment in GSE9782, XBP-1 high MMs had lower response rate (CR+PR) than XBP-1 low group (18.5% vs 59.67%, p<0.01). In the XBP-1 high MMs, significantly different response rate between bortezomib treatment and Dex treatment (36.34% vs 0%, p<0.05) was observed, while in the XBP-1 low MMs, no significantly different response between bortezomib treatment and Dex treatment (55.88% vs 61.18%, p>0.05) was noted. We further integrated XBP-1-M clustering-based survival analysis with the choice of treatment in GSE9782, XBP-1 high MMs showed significantly poorer progression-free survival (PFS) compared with XBP-1 low MMs during the 5-8 years follow-up, using either bortezomib(p=0.0071) or Dex (p=0.0011) regimen. In the patients treated with Dex regimen, XBP-1 high MMs showed significant poorer overall survival (OS) compared with XBP-1 low MMs (p=0.0316), while there were no differences in bortezomib regimen between XBP-1 high MMs and XBP-1 low MMs (p=0.224). Next, we integrated the XBP-1-M clustering-based genetic abnormality in GSE9782, there were higher frequencies of genetic abnormalities in XBP-1 high MMs than those in XBP-1 low MMs (1q gain 49.5% vs 12.6%, p<0.01; 17p del 21.9 % vs 3.2%, p<0.01; 13q del 58.1% vs 28.5%, p<0.05; t(4,14) 22.8% vs 15.8%, p<0.05; t(11,14) 31.4% vs 3.2%, p<0.01). The higher cytogenetic abnormalities may be related to the poorer treatment response and survival in patients with XBP-1 high expression. Therefore, we conclude that XBP-1-M may enable prediction of the treatment response and clinical outcome in multiple myeloma.

Disclosures

No relevant conflicts of interest to declare.
Retrospective Cohort Study Assessing the Prognostic Value of Baseline Necrosis on PET-CT in Hodgkin Lymphoma
Authors: Borges Nuno , Chen Isobel , Winn Luke , Osborne Wendy , Petrides George
Published: October 2019

Background: Identifying prognostic markers at diagnosis is essential to determine optimal tailored therapy for patients. The presence of necrosis has been shown to be associated with worse outcomes in patients with diffuse large B cell lymphoma. We aimed to determine whether necrosis at baseline correlated with clinical outcomes in patients with Hodgkin lymphoma.

Methods: Baseline PET-CT scans of patients diagnosed with Hodgkin lymphoma between January 2015 and December 2016 at a large UK teaching hospital were reviewed for evidence of tumour necrosis by a consultant radionuclide radiologist with a specialist interest in lymphoma. Potential necrosis identified on PET-CT was then confirmed both visually and quantitatively on baseline contrast enhanced CT. The presence or absence of necrosis was correlated with prognostic markers including Total Metabolic Volume (TMV), Total Lesion Glycolysis (TLG) and Hasenclever score as well as metabolic response, current remission status, relapse outcome and mortality.

Results: Fifty one patients' PET-CT scans were reviewed in total. Eight (15.6%) patients were confirmed to demonstrate necrosis both visually and using quantitative criteria. The presence of necrosis was associated with increased mortality (38%) vs no necrosis (9%). At end of treatment, a lower rate of complete metabolic response was achieved in the necrosis cohort (37%) compared with the no necrosis cohort (74%). This was statistically significant using Chi-square test with Yates correction (p=0.049). The presence of necrosis did not correlate with other prognostic markers (TMV, TLG or Hasenclever score).

Conclusion: This study has found that baseline necrosis correlated with both mortality and incomplete metabolic response following initial treatment. Tumour necrosis did not correlate with other prognostic markers and therefore may be able to be used as an independent assessment of prognosis to allow further tailoring of patient treatment. This study has identified a new potential independent prognostic marker in Hodgkin lymphoma. Prospective trials are required to confirm or refute these findings.

Disclosures

Osborne: MSD: Honoraria; Roche: Honoraria; Takeda: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Servier: Honoraria. Petrides:Roche: Honoraria; GE Healthcare: Honoraria.
Treatment with Decitabine Followed By Prednisone for Myelodysplatic Syndrome Concomitant with Sjogren's Syndrome
Authors: Sun Xingfu , Li Jianyong , Lu Hua
Published: October 2019

Myelodysplastic Syndrome (MDS) is rarely concomitant with Sjögren's syndrome (SS) with only 9 previously reported cases in the literature. A case of a previously healthy 31-year-old Chinese female presenting with dysplasia affecting all three lineages without blasts excess showed by bone marrow examination is reported. Autoimmune workup revealed positive antinuclear antibodies and Anti-SSA. Lip biopsy revealed findings consistent with SS. A diagnosis of SS associated with MDS of the refractory cytopenia with multilineage dysplasia (RCMD) subtype was established, and decitabine for five days at 20mg/m2 per day was initiated with only slight increase in platelet counts. Four weeks later, another cycle of decitabine for five days at 20mg/m2 per day was performed. Unfortunately, infection occurred, and the patient suffered from thrombocytopenia and leucopenia. Then the patient received the treatment of Biapenem and Vancomycin Hydrochloride along with granulocyte colony stimulating factor followed by platelet infusion for two weeks. Significant clinical and laboratory response was achieved. In hopes of improving both response rates and durability of response, the third cycle of decitabine for five days at 20mg/m2 per day was performed with again an excellent clinical and laboratory response. However the patient refused further cycle of decitabine due to cost consideration, then prednisone at 10mg per day was used as a basic treatment for SS. It was an amazing feat that the patient was in a state of remission for two years. MDS with SS tends to be incurable. Decitabine alone with prednisone may serve as an effective option to those patients.

Disclosures

No relevant conflicts of interest to declare.
Stratification for Age in Transfusion-Dependent Thalassemia
Authors: Pepe Alessia , Pistoia Laura , Rocca Mario , Palazzi Giovanni , Sorrentino Francesco , Maggio Aurelio , Quarta Antonella , Cosmi Carlo , Argento Crocetta , Armari Sabrina , Peritore Giuseppe , Oliva Matteo , Positano Vincenzo , Meloni Antonella
Published: October 2019

Introduction. Transfusion-dependent β-thalassemia (TDT) is the most severe clinical form of β-thalassemia and requires regular long-term red cell transfusions for survival. 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 TDT patients.

Methods. We considered all TDT patients enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) project at the first MRI examination. Iron concentrations were measured by T2* multiecho technique. All complications were classified according to international guidelines.

Results. Three groups of patients were identified: age<12 years (group 0, N=53), age between 12-17 years (group 1, N=100) and age≥18 years (group 2, N=1857).

The number of transfusional units in the 12 months before the MRI scan resulted significantly lower in group 0 versus both group 1 (20.8±5.3 vs 34.8±10.6; P<0.0001) and group 2 (20.8±5.3 vs 39.2±10.9; P>0.0001) and in group 1 versus group 2 (P=0.021).

The Table shows the comparison of clinical characteristics among the 3 groups.

Serum ferritin levels were significantly higher in both groups 0 and 1 when compared to group 2. Liver aminotransferases were significantly lower in group 1 than in group 2.

The number of patients with MRI LIC (liver iron concentration) >3 mg/g dw was significantly higher in group 1 than in group 2 and the number of patients with global heart T2*<20 ms was significantly lower in group 0 than in group 2.

Among the endocrinopathies, hypogonadism, hypothyroidism and osteoporosis were significantly less frequent in groups 0 and 1 than in group 2 while diabetes was significantly less frequent only in group 1 when compared to group 2.

Frequency of heart failure was comparable among the groups while the frequency of arrhythmias was significantly lower in group 1 than in group 2.

The types of chelation regimens were significantly different among groups (<0.0001) (see Figure).

Conclusions. Younger patients had more hepatic iron, despite the significant lower transfusional burden. Cardiac iron overload occurs early in TDT patients but it is more frequent in older patients. Endocrinopathies (excluding diabetes) and cardiac complications become clinically evident during the second decade and are time-dependent processes. Our data suggest the need for an effective strategy to prevent iron overload since early childhood, in order to reduce its toxic effect and prevent the development of long-term complications.

Figure. Figure.

Disclosures

Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.
Quality of Life in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group
Authors: Nagarajan Rajaram , Alonzo Todd A , Gerbing Robert B , Johnston Donna , Aplenc Richard , Kolb E. Anders , Meshinchi Soheil , Barakat Lamia , Sung Lillian
Published: October 2019

Background: Objectives were to describe guardian proxy-reported quality of life (QoL) during chemotherapy for pediatric acute myeloid leukemia (AML) and to identify treatment and demographic factors associated with worse QoL.

Methods: Children's Oncology Group phase 3 AAML1031 study was a randomized trial for de novo AML patients age 0-30 to receive standard AML therapy with and without bortezomib. Patients with high risk FLT3-internal tandem duplication high allelic ratio (ITD HAR) were allocated to receive sorafenib in addition to the standard chemotherapy. Patients enrolled on the AAML1031 study who were 2-18 years of age at diagnosis with English or Spanish-speaking guardians were eligible to participate in the QoL portion of the study which included the PedsQL 4.0 Generic Core Scales, PedsQL 3.0 Acute Cancer Module and PedsQL Multidimensional Fatigue Scale. QoL assessments were obtained at four timepoints - at diagnosis and following completion of second, third and fourth (final) course of therapy. Guardians provided proxy assessments for all patients, while self-report for patients 5 years of age or older who could understand English was optional. This analysis focused on guardian proxy-reported QoL for patients who did not have FLT3-ITD HAR. In addition to demographic and treatment related factors, the total number of non-hematological grade 3-4 CTCAE (Common Terminology Criteria for Adverse Events) toxicities occurring during the time frame of QoL assessments was examined as a potential predictor of QoL.

Results: There were a total of 4105 QoL submissions and there were 3513 non-hematological grade 3-4 CTCAE toxicities reported: 1339 submissions at diagnosis with 1088 toxicities reported, 1112 submissions following the second course with 721 toxicities, 929 submissions following third course with 911 toxicities, and 725 submissions following the fourth course with 793 toxicities.

In repeated measures linear regression the number of submitted CTCAE toxicities was significantly associated with worse physical health (β±standard error (SE) -3.00±0.69; P<0.001) and general fatigue (β±SE -2.50±0.66; P<0.001). Older age was significantly associated with general fatigue (β±SE -0.58±0.25; P=0.022). In contrast, gender, risk status, bortezomib assignment, duration of neutropenia, private insurance status, white race and Hispanic ethnicity were not associated with physical health, psychosocial health or fatigue.

Conclusions: The number of CTCAE toxicities was an important factor influencing physical QoL and fatigue among children on treatment for AML. Identifying novel approaches for reducing toxicities should be a priority to potentially improve QoL.

Disclosures

No relevant conflicts of interest to declare.
Real-World Efficacy of Anti-Fungal Prophylaxis in Patients Treated for Acute Gastrointestinal Graft-Versus-host Disease (GI-GVHD)
Authors: Yuan Yin , Scott Ashleigh P
Published: October 2019

Aim

Allogeneic progenitor cell transplant (HPCT) recipients who develop acute gastrointestinal graft-versus-host disease (GI-GVHD) are at increased risk of developing invasive fungal infections (IFI). Randomised control trial data supports the use of mould-active fungal prophylaxis in HPCT patients with grade II-IV GVHD (Ullman et al. 2007). We aimed to assess our unit's use of anti-fungal prophylaxis and describe the incidence and species of breakthrough IFI in patients with GI-GVHD.

Method

We conducted a retrospective audit of patients who underwent HPCT at our institution between 2011-2016 and identified those who were treated for acute GI-GVHD using a minimum of prednisone 1mg/kg or equivalent. For those patients the following details were collected: presence of any prior IFIs, anti-fungal prophylaxis before and after initiation of steroids, and the incidence of new IFIs within 6 months of commencing steroids.

Result

Of the 551 HPCT performed during this period, 74 evaluable patients were treated for GI-GVHD. All patients received anti-fungal prophylaxis prior to steroid commencement (66.2% received fluconazole, 10.8% posaconazole, 20.2% voriconazole and 2.7% other). Post steroids 35.1% remained on fluconazole, 21.6% received posaconazole, 35.1% received voriconazole, and 8.1% received other anti-fungals. Of the 26 patients remaining on fluconazole, 9 were transitioned to mould-active prophylaxis at a later time.

Twelve patients (16.2%) experienced a breakthrough IFI (6 definite and 6 probable). In the 42 patients receiving posaconazole or voriconazole, 7 (16.7%) experienced breakthrough IFI, compared with 3 (11.5%) in the fluconazole cohort. Two other cases occurred in patients who received caspofungin. Notably, patients receiving mould-active fungal prophylaxis developed mucormycosis, Fusarium and Scedosporium infections whereas fluconazole lead to invasive aspergillosis.

Conclusion

Despite anti-fungal prophylaxis, real-world GI-GVHD patients remain at particularly increased risk of developing IFI. Anti-mould prophylaxis is associated with lower incidence of invasive aspergillosis but higher incidence of non-Aspergillus mould. Further studies investigating optimal anti-mould strategies are warranted.

Disclosures

No relevant conflicts of interest to declare.
Bortezomib-Based Chemotherapy Reduces Early Mortality and Improves Outcomes in Patients with Ultra-High-Risk Light-Chain Amyloidosis
Authors: Shen Kaini , Zhang Congli , Feng Jun , Zhang Lu , Cao Xinxin , Zhou Daobin , Li Jian
Published: October 2019

【Introduction】Patients with amyloid light-chain (AL) amyloidosis who have advanced cardiac damage are at risk of premature mortality. Currently, bortezomib is the mainstay in the treatment of AL amyloidosis, but the benefits of bortezomib in patients with ultra-high-risk AL amyloidosis have not been proved definitively. In current study, we aimed to establish the effects of bortezomib on early mortality, treatment responses and long-term outcomes in this very high-risk population.

【Methods】We performed a retrospective analysis of patients newly diagnosed with ultra-high-risk (defined by 2004 Mayo Stage IIIb or 2012 Mayo stage IV criteria) AL amyloidosis who received a bortezomib-based regimen or supportive treatment from January 1, 2009 to April 1, 2018 in our hospital. Kaplan-Meier survival curves were plotted. Between-group comparisons of progression-free survival (PFS) and overall survival (OS) were conducted with the log-rank test. To examine the impact of treatment on patients who survived long enough to have potentially benefited from therapy, a 6-month landmark analysis was performed among patients surviving at least 6 months from the start of treatment.

【Results】Patients receiving bortezomib-containing chemotherapy (n = 62) and patients receiving no chemotherapy (n = 24) were included. The overall median age at presentation was 59 years (range 37-81 years), with a male: female ratio of 2.2:1. Organ involvement included the heart (100%), kidney (68.6%) and liver (25.6%). The median number of chemotherapy cycles was four (range 1-12). The overall hematological response rate in the bortezomib group was 59.3%, with 42.6% achieving a complete response, 7.4% having a VGPR. A cardiac response was observed in 36.7% of patients. With an overall median follow-up of 24.3 months, median OS was 30 months in the bortezomib group and 2 months in the control group (p < 0.001) (Figure 1-A), and median PFS was 15.8 months (bortezomib) and 2 months (control; p < 0.001) (Figure 1-B). The early-death rate (within 6 months of diagnosis) was 32.3% (bortezomib) and 66.7% (control; p < 0.001). In a landmark analysis assessing outcomes in patients surviving beyond 6 months, the 2-year OS and PFS in the bortezomib group were 77.3% and 65.8%, respectively.

【Conclusions】Bortezomib-based regimens can help to reduce early mortality and improve long-term survival in patients with ultra-high-risk AL amyloidosis, especially in those who achieve a threshold hematological response. We recommend that both physicians and patients should always consider chemotherapy, regardless of the disease stage, as long as treatment-related complications are controllable.

Figure 1. Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Catabolic Flexibility Enhances Drug Resistance but Induces Selective Vulnerability to New Mitochondrial-Targeted Therapeutic Combinations in IDH Mutant Leukemia
Authors: Sarry Jean-Emmanuel , Recher Christian , Stuani Lucille , Portais Jean-Charles
Published: October 2019

Isocitrate dehydrogenases IDH1/2 mutations and its oncometabolite 2-HG have been of major clinical interest as they have been causally linked to the development of glioma and acute myeloid leukemia (AML). However, global impact of mutations in these two key metabolic enzymes on cellular metabolic networks and chemoresistance is not well defined. We hypothesized that key metabolic fluxes are selectively reprogrammed to maintain biosynthetic homeostasis and chemoresistance in IDH mutant acute myeloid leukemia cells. We show that metabolic reprogramming initiated by IDH1 mutation leads to marked increases in glucose, glutamine and fatty acid catabolism that along with enhancement of wild-type IDH enzyme activity contribute to provision of α-KG required for 2-HG synthesis and to replenish Krebs cycle intermediates for biosynthetic reactions, oxygen consumption and ATP production. Mechanistically, this occurs through both 2-HG-dependent histone methylation-driven CEBPα activation of FAO and reprogramming of systemic metabolic fluxes through other pathways that augment catabolic flexibility. This catabolic flexibility leads to the enhancement of Krebs cycle and OxPHOS activities that are not necessarily rescued by IDH mutant inhibitors. Similarly, generation of 2-HG reflects the catabolic flexibility of IDH1 mutant cells but its reduction does not necessarily reverse the mitochondrial OxPHOS phenotype or reduce cell proliferation and survival in IDH1 mutant cells. This also renders IDH1 mutant cells more resistant to conventional chemotherapy such as cytarabine. While catabolic flexibility is not druggable per se, its metabolic consequence (e.g. enhanced mitochondrial dependency) is a specifically targetable vulnerability in IDH1 mutant AML and mutant cells are more susceptible to mitochondrial inhibition by OxPHOSi (IACS-107839) and BCL2i (ABT-199) compared to WT cells. Treatment with mutant IDH1-specific inhibitors enhances anti-leukemic effects of OxPHOS inhibitors alone and in combination with cytarabine. Our findings also provide a strong scientific rationale for innovative combinatory targeted therapies to treat this subgroup of patients, especially those unresponsive to or relapsing from IDH mutant-specific inhibitors.

Disclosures

No relevant conflicts of interest to declare.
Whole Exome Sequencing Identifies a Novel Variant in the Pklr Gene Which Worsen the Anemia Status in a Congenital Dyserthropoietic Anemia Patient
Authors: Peng Ching-Tien
Published: October 2019

Congenital dyserythropoietic anemia (CDAs) is a group of hereditary disorders characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts in the bone marrow. Diagnosis of CDA is based primarily on the morphology of bone marrow erythroblasts but genetic tests might have more and more important roles recently. Here, we describe a 31-year old female with atypical CDA under regular blood transfusions. The results of blood tests were as followed: RBC: 3080000/µL, Hb: 9.9 g/dL, Hct: 26.8%, MCV: 87.0 fl, MCH:32.2 pg, and MCHC: 36.9 g/L. In this study, analysis of CDA-related genes, including SEC23B, CDAN1, KLF1, and C15orf41, were analyzed by exome sequencing but no pathogenic variant was found. In additional, we analyzed RBC-related genes and a novel variant in the PKLR p.A468G (NP_000289) was found which was also confirmed by Sanger sequence. Variant of PKLR gene has been reported as the cause of pyruvate kinase (PK) deficiency anemia. PK deficiency is the most cause of congenital nonspherocytic hemolytic anemia with GMAF (global minor allele frequency) of 0.0001. The clinical features of PK-deficient patients are highly variable degree of chronic hemolysis with severe neonatal jaundice and fetal anemia at birth. In this case, PKLR p.A468G heterozygous variant was detected in a patient with PK deficiency, as an example of precision diagnosis by exome sequencing.

Disclosures

No relevant conflicts of interest to declare.
A Study about the Relationship between Thrombotic Events and Peripheral Neutrophil-to-Lymphocyte Ratio in Patients with Newly Diagnosed Essential Thrombocythemia
Authors: Cheng Hai , Zhou Dian , Cao Jiang , Chen Wei , Qi Kunming , Xu Kailin , Qiao Jianlin
Published: October 2019

To explore the role of neutrophil-to-lymphocyte ratio (NLR) in patients with newly diagnosed essential thrombocythemia (ET) and the relationship with thrombotic events.150 ET patients with ET from January 2013 to December 2017 were retrospectively enrolled in this study to investigate the risk factors of thrombosis and analyse the role of NLR in thrombotic events. The following parameters were evaluated: age, sex, blood routine examination, JAK2V617F mutation, cardiovascular risk factors, history of previous thrombosis, thrombosis during follow-up, examination and biopsy of bone marrow.Age(P=0.001) and JAK2 V617F mutation(P=0.003) were independent risk factors for thrombotic events at diagnosis after Logistic multivariate analysis. WBC count (P=0.047), NLR (P<0.001), age (P=0.037) and thrombosis at diagnosis (P=0.036) were independent risk factors for future thrombotic events and NLR was better for prediction of future thrombotic events than other risk factors in ROC curve. The thrombosis-free survival of thrombotic events in patients with higher NLR(median survival 22.3 months, 95% CI:17.8-26.8) was significantly shorter than that of patients with lower NLR(median survival 55.5 months, 95% CI:53.4-57.5) in Kaplan-Meier analysis (P<0.001). After 60 months of follow-up, patients with lower NLR had a thrombosis-free survival of 97.4%, while patients with higher NLR had a thrombosis-free survival of 46.7%. NLR at diagnosis was a better predictive parameter for future thrombotic events than other clinical parameters in ET patients, but was not associated with thrombosis at diagnosis.

Disclosures

No relevant conflicts of interest to declare.
MXD1 Regulates the Imatinib Resistance of Chronic Myeloid Leukemiacells By Repressing BCR-ABL1 Expression
Authors: Chen Huan , Lou Jin , Wang Heng , An Na , Pan Yuming , Chen Weihong , Du Xin , Zhang Qiaoxia
Published: October 2019

Tyrosine kinase inhibitors have achieved unprecedented efficacy in the treatment of chronic myeloid leukemia (CML), however, imatinib resistance has emerged as a major problem in the clinic. Because the overexpression of BCR-ABL1 critically contributes to CML pathogenesis and drug resistance, targeting the regulation of BCR-ABL1 gene expression may be a novel therapeutic strategy. In this study, we found that the transcriptional repressor MXD1 showed low expression in CML patients and was negatively correlated with BCR-ABL1. Overexpression of MXD1 markedly inhibited the proliferation of K562 cells and sensitized the imatinib-resistant K562/G01 cell line to imatinib, with decreased BCR-ABL1 mRNA and protein. Further investigations using reporter gene analysis showed that MXD1 significantly inhibited the transcriptional activity of the BCR-ABL1 gene promoter. Taken together, these data show that MXD1 functions as a negative regulator of BCR-ABL1 expression and subsequently inhibits proliferation and sensitizes CML cells to imatinib treatment.

Disclosures

No relevant conflicts of interest to declare.
Factor VIII BAR T-Cell Recognition By Antibodies to Different Domains
Authors: Parvathaneni Kalpana , Pohida Katherine , Scott David W.
Published: October 2019

Up to 30% of patients with hemophilia A develop inhibitory antibodies to therapeutic FVIII and these antibodies block the efficacy of this critical protein. To target the B cells specific for FVIII, we previously generated cytotoxic cells expressing the FVIII C2 or A2 immunodominant domains as chimeric receptors. We termed these antigen-expressing engineered T cells, "BARs", for B-cell Antibody Receptor. These could directly interact and kill with A2 or C2 FVIII-specific B cells as well as FVIII-specific hybridomas in vitro and in vivo. To increase the number of B-cell targets that could be killed, we recently engineered human and murine BAR CD8 T cells to express the FVIII light chain (LC), which includes A3 and C1, as well as C2 domains. In addition, since C2-expressing BAR T cells showed tonic signaling, we hypothesized that LC expressing BARs might not. Our data suggest that LC-expressing BAR T cells do not display tonic signaling but they can be stimulated to proliferate by anti-LC monoclonal antibody (mAb 5G12), for example. Flow cytometry data showed that LC-BAR T cells are stained by anti-C2 mAb (3G6) but this mAb did not stimulate them to proliferate. These data reflect the accessibility of different FVIII domains in BAR T cells, and are important in terms of the utility of FVIII domain expressing BARs to target specific B cells in vivo in the presence of inhibitors. (Supported by NIH grant R01 HL126727)

Disclosures

No relevant conflicts of interest to declare.
Efficacy of a Health Care Transition Program for Patients with Sickle Cell Disease
Authors: Saulsberry Anjelica Christina , Podila Pradeep S. B. , Anderson Shiela , Hodges Jason R , Porter Jerlym , Hankins Jane S.
Published: October 2019

Introduction: Unsuccessful transition from pediatric to adult care among youth with sickle cell disease (SCD) contributes to frequent disease complications and early death. The literature is sparse on longitudinal SCD transition program outcomes. The St. Jude SCD Transition to Adult Care Program started in 2007, is a comprehensive, co-located, and interdisciplinary program embedded in a larger SCD medical home. The objective of this study is to describe transfer rates, time to transfer, and maintenance of adult care over a 9-year period.

Methods: With St. Jude IRB approval, we conducted a retrospective review of the rate of matriculation in adult care, the latency time from leaving pediatric care and initiating adult care, and maintenance of engagement in adult care 12 and 24 months later. Eligibility criteria: 1) SCD diagnosis and 2) Completion of pediatric care between 2007 and 2016.

Results: Three hundred and sixty participants transferred to adult care over the study period. Mean age at transfer was 18 years. Matriculation in adult care within 6 months from leaving pediatric care substantially increased: 71% in 2007 to 93% in 2016. We observed a progressive reduction in the latency time from pediatric to adult care, from 12 months in 2007 to 1.5 months in 2016. Fifty-five percent (n=198) of youth who transitioned to the partner Methodist Comprehensive Sickle Cell Center (MCSCC) post-pediatric care continued to be followed by our program. Of these, 77% and 57% remained with the MCSCC 12 and 24 months after transfer to adult care, respectively.

Conclusions: The St. Jude SCD Transition to Adult Care Program demonstrated a gradual increase in transfer rates and a reduction in length of time-to-adult transfer since its creation. Adult care engagement declined over time and warrants future interventions. Improved health care transition outcomes could potentially translate into improved quality of life and greater longevity.

Disclosures

Hankins: bluebird bio: Consultancy; NCQA: Consultancy; Novartis: Research Funding; Global Blood Therapeutics: Research Funding.
Real-World Data on Frontline (FL) Treatments in Multiple Myeloma (MM) Patients across EU5 Countries
Authors: Anjo Joana , Rider Alex , Bailey Abigail , Gaudig Maren
Published: October 2019

Objective

This analysis was conducted to understand the clinical practice on FL treatment in patients with MM across EU5 countries.

Methods

Real world data were collected through Adelphi's Disease-Specific ProgrammeTM - a point in time survey administered to physicians (n=241) in EU5 countries between Nov 2017 - Feb 2018. Stem Cell Transplant eligibility and treatments, including number of cycles and dosage, were collected from patient record forms (n=1952). Summary statistics were reported and analysed descriptively.

Results

Data on FL treatment was collected for 1952 patients; 988 (51%) were still on FL treatment at the time of data collection.

Bortezomib-based regimens were used in more than 70% of patients - in both transplanted/transplant eligible (TE, n=572) and non-transplanted/transplant ineligible patients (TIE, n= 1380).

In TIE patients, bortezomib, melphalan and dexamethasone (VMP) was the most commonly used regimen, covering almost one third of the patients (31%), followed by bortezomib, either in combination with cyclophosphamide and dexamethasone (VCD, 10%) or thalidomide and dexamethasone (VTD, 10%). The other two FL regimens currently approved in Europe - thalidomide, melphalan and dexamethasone (MPT) and lenalidomide and dexamethasone (Rd) have patient shares of 9% each. When analyzing the TIE patients undergoing FL treatment at time of data collection (n=606), VMP remained the most used regimen (29%) and Rd the second (15%), with VTD and MPT being used in 8% of patients.

In TE patients, VTD was the most commonly used induction regimen, being used in 50% of patients, followed by VCD (21%). The numbers remained the same when analyzing the TE patients in FL treatment at time of data collection (n=382), with 54% and 22% using VTD and VCD, respectively.

Conclusions

Collectively these results indicate that bortezomib-based regimens remain the standard of care in FL treatment of MM in EU5, in both transplant and non-transplant settings.

Disclosures

Anjo: Janssen: Employment. Rider:Adelphi Real World: Employment. Bailey:Adelphi Real World: Employment. Gaudig:Janssen: Employment.
Transcriptional and Functional Description of Stem Cell Heterogeneity in Native and Transplantation Hematopoiesis
Authors: Rodriguez-Fraticelli Alejo E , Weinreb Caleb , Klein Allon Moshe , Camargo Fernando
Published: October 2019

The hematopoietic system follows a hierarchical organization, with multipotent long-term repopulating hematopoietic stem cells (LT-HSCs) occupying the top tier. This paradigm, developed mostly through cell transplantation assays, has recently been contested by a series of studies performed under native conditions, without transplantation. Application of systems-level single cell methods in this setting has revealed a heterogeneity of cell states within progenitors and stem cells, prompting a reevaluation of the theories of hematopoietic lineage fate decisions. We have previously described that hematopoietic stem cell fates are clonally heterogeneous under steady state and uncovered that a fraction of LT-HSCs contributes to a significant proportion of the megakaryocytic cell lineage under steady state, while rarely generating other types of progeny in unperturbed conditions. To elucidate the molecular underpinnings of this functional lineage-output heterogeneity, we developed a technique to barcode hematopoietic cells at the RNA level in order to simultaneously capture the lineage relationships and transcriptional states of HSCs. Using a droplet-based massive single cell RNAseq platform, we analyzed thousands of engrafted hematopoietic stem cells together with a sufficiently significant representation of downstream progenitor cells to measure HSC output. Inspection of the resulting "stem cell state-fate maps" revealed a variety of stem cell behaviors, including single cell quiescence, asymmetric and symmetric divisions, and clonal expansion. We also connected these behaviors with some of the previously observed heterogeneity in stem cell outcomes, including lineage bias, lineage output and clonal competition. Importantly, clustering of expression profiles revealed significant differences in the transcriptional programs related with some of these behaviors, which illuminate the molecular machineries that operate at the stem cell level to define this heterogeneity. Thus, our work has identified potential novel mediators for stem cell heterogeneity, which we are functionally analyzing in further detail to understand their molecular mechanisms.

Disclosures

No relevant conflicts of interest to declare.
Tissue Molecular Genotyping Improves Patient Blood Management in Syrian Injured Patients Treated in Israel
Authors: Akria Luiza , Barhoum Masad , Zisman-Rozen Simona , Suriu Celia , Braester Andrei , Shaoul Ety
Published: October 2019

During the last two decades the importance of molecular biology in transfusion medicine has been growing. Reference centers for immunohematology commonly use molecular methods to clarify problems, discrepancies or unusual results in patient serology. Nowadays there are immunohematology reference laboratories that recommend using molecular genotyping for patient blood management. Our blood bank laboratory is not a reference center, but we routinely use molecular genotyping to solve serologic problems. Due to the proximity to the Syrian border, since the beginning of the Syrian civil war, our medical center has received hundreds of injured patients, some of them with unique features concerning the blood type testing. From our previous experience of such a case in Dec 2015, we realized that due to extreme war conditions and lack of medical amenities, severely injured patients are likely to receive unmatched blood transfusions in Syria, sometimes ABO-incompatible blood transfusions. The patients arriving to our medical center are usually in critical condition and without medical records. Serologic tests show double population (DP) blood type. Molecular genotype of blood samples is not helpful, because it can detect the blood type of the unmatched/incompatible donor. In these cases, we use molecular genotyping from a tissue specimen, usually skin. Until we receive the results, which take about 5 hours in our molecular lab, we give only type O blood and AB plasma. Since Dec 2015, 11 injured patients with DP on serologic typing were admitted to our medical center. Tissue genotyping was performed on 8 of these. We determined that seven of the eleven patients previously received ABO-incompatible blood in Syria. With one exception, all patients were transfused in Israel (detailed data not shown), three with incompatible blood upon admission, based on initial serotype (patients 1,3,4 in the table). Tissue genotyping allowed us to transfuse compatible ABO-matched blood components afterward. All patients survived and were released in good condition. Tissue molecular genotyping helps improve patient blood management in the population of injured causalities from Syria.

Table. Table.

Disclosures

No relevant conflicts of interest to declare.
Early Death in Multiple Myeloma. Analysis of Patients in Real-World Practice
Authors: Lakhwani Lakhwani Sunil , Hernández Miguel T , Lorenzo-Barreto Pablo , Cabrera-Brito Deborah , Fernández-González Marta , Machado-Machado Patricia , Díaz-Gómez Maribel , Raya Sanchez Jose Maria
Published: October 2019

Background. During the last years survival of myeloma patients has improve due mainly to the introduction of new drugs. Despite this, there are patients who die early: before two years from diagnosis. There are few data published of this group of patients with early mortality (EM) and most of them analyzing patients included in clinical trials.

Methods. We reviewed myeloma patients from our center from 1990 to 2017 and identified patients with EM. We recorded many clinical and biological variables, both at diagnosis and in evolution. We compared data of patients with EM with the rest and we analyze which variables confer worse prognosis of this group in a multivariate analysis. We also create a predictive model at diagnosis of patients with EM through a discriminant analysis.

Results. We identified 186 patients with less than two years of survival from diagnosis, 87 women and 99 men. Mean age was 70,3 years old (range 42-99). The most common cause of death was infection (42,33%) followed by progession (39,26%). We could compare data of these patients with those without EM from 1990 to 2009 (n=255) and we found that patients with EM were older (p=0,039), with more comorbidities (p=0,004) and worse ECOG (p<0,001). They had a disease more agressive and more evolved with worse bone disease (p=0,019), lower hemoglobine (p<0,001) and albumin (p<0,001); higher calcium (p=0,007), creatinine (p<0,001), LDH (p<0,001), β2microglobuline (p<0,001), immunoparesis (p=0,007) and percentage of plasma cells in bone marrow (p<0,001) and consequently worse Durie-Salmon (p<0,001) and ISS (p<0,001) prognosis score. We also found a worse response to first line treatment (p<0,001).

In a multivariate analysis, variables that confer a worst prognosis (overall survival) of patients with EM myeloma were β2-microglobuline ≥5,5mg/l (HR: 2,251, p=0,004), >4 points in Cumullative Illness Rating Scale (CIRS) (HR: 1,760, p=0,036) and progressive disease to first line tratment (HR: 2,230, p=0,007).

We create a mathematic predictive model at diagnosis through a discriminant analysis using serum calcium, ISS score and CIRS score to identify patients with EM. With this method we could classify correctly 68,4% of our patients.

Conclusions. In our real-world series patients with EM myeloma die mainly because infection or progression. They have worse basal situation (age, comorbidity, ECOG) an a more agressive and evolved disease as wel as worse response to treatment. We present a model to try to identify these patients at diagnosis, which could involve changing the management like giving antibiotic profilaxis to try to improve survival.

Disclosures

No relevant conflicts of interest to declare.
Evaluating Anti-TNF-Alpha Therapy in Patients with Relapsed and Refractory Langerhans Cell Histiocytosis
Authors: Burke Thomas , Legarreta Alejandra , Lin Howard , Scull Brooks , Eckstein Olive S. , McClain Kenneth L. , Allen Carl E.
Published: October 2019

Purpose: Tumor necrosis factor alpha (TNF-alpha) is produced in Langerhans cell histiocytosis (LCH) lesions and is elevated in active high-risk vs low-risk LCH vs control patient blood, where TNF-alpha has been reported at 12 pg/ml in juvenile rheumatoid arthritis (JRA). Anti-TNF therapeutic etanercept is used in TNF-mediated diseases, such as JRA, and was successfully used in one case of LCH. We therefore conducted phase II study for etanercept therapeutic efficacy for refractory or relapsed LCH patients. Methods: Luminex platform was used to assess patient blood TNF-alpha level. This phase II study was approved by the Baylor College of Medicine IRB with research support from Amgen/Immunex. Eligibility included LCH patients with progressive disease post-initial treatment and ≥1 salvage therapy. Etanercept was injected 0.4mg/kg subcutaneously twice/week for 12 weeks. Therapeutic response were evaluated at 4 and 8 weeks. Results: TNF-alpha is elevated in blood LCH high-risk (average 45pg/ml) vs low-risk (average 13pg/ml) vs control (average 13pg/ml). Five LCH patients (1.6-42 years) with multi-system involvement, 2 with high-risk disease were enrolled. A median of 5 doses of etanercept were administered (range 1-14). One high-risk patient died 18 days after the first dose from disease progression. At week 4 evaluation, one patient had stable disease and 3 progressed and all subjects progressed by week 8. Ultimately 0/5 patients had disease improvement with etanercept. Conclusion: Etanercept therapy, at JRA-effective dose, in this trial did not improve LCH disease. It is possible that this may not be an effective strategy. Alternatively, it is also possible that drug dose or distribution was suboptimal. While anti-TNF therapies, including etanercept, are effective for treatment of RA, etanercept is not effective for granulomatous diseases such as Crohn's, sarcoidosis or Wegner's disease. Additional studies exploring potential efficacy of higher dose or alternative forms of TNF-alpha inhibition in LCH may be warranted.

Disclosures

No relevant conflicts of interest to declare.