bluuebunny/crossref_metadata_2025 huggingface dataset:
Co-Transplantation of Mesenchymal Stem Cells Further Improves the Prognosis of Allo-HSCT in the Treatment of High Risk and Refractory/Relapse Hematologic Malignancies: A Single-Center Retrospective Study of 175 Patients
Authors: Ren Jinhua , Luo Xiaofeng , Chen Minmin , Xiao Min , Li Qian , Lin Kangni , Zheng Zhihong , Chen Zhizhe , Hu Jianda , Yang Ting
Published: November 2019

BACKGROUD:

Mesenchymal stem cells (MSCs) are known to have immunomodulatory, anti-inflammatory and pro-angiogenic properties and thus have the potential to improve the likelihood of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of hematologic malignancies.

OBJECTIVE:

To explore the efficacy and safety of allo-HSCT by co-transplantation with MSCs in hematologic malignancies patients.

METHODS:

We conducted a single-center retrospective study to comparing the incidence and severity of acute GVHD, recurrence rate and overall survival (OS) of high risk and refractory/relapse hematologic malignancies patients undergoing allo-HSCT with or without co-injection of MSCs. A total of 175 patients (113males/62 females) at Fujian Medical University Union Hospital from January 2016 to June 2019 were analyzed. The median age of the patients is 22 (range 1-65 years). Patients received salvaged conditioning regimens FA5-BuCy as previous reported for high risk and refractory/relapse hematologic malignancies, registered on http://ClinicalTrials.gov (NCT02328950), among whom 31(17.7%)were MSD-HSCT, 21(12%) MUD-HSCT and 123(70.3%)haplo-HSCT. All patients received ATG, cyclosporine A with short course methotrexate for prevention of GVHD. 85 patients transplanted with donor HSCs only, and 90 patients transplanted with HSCs and MSCs .MSCs infusion dose was 1-2×106/kg, at -1~+1 days following HSCs infusion.

RESULTS:

The two groups were well matched demographically. All patients achieved successful engraftment within one month post-HSCT. There was no difference in time to leukocyte and platelet engraftment in the two groups. The incidence of aGVHD (36.5 % versus 26.7 %, P =0.163) was similar in the HSC versus MSC groups. With a median follow-up time of 373 days (range:29-1265days), the 2-yr OS was much better in MSC co-injection groups (77.6% versus 48.4%, P =0.005). Moreover, there was no significant difference in the 2-yr cumulative recurrence rate between the two groups (25.1% vs 16.2%, P = 0.4).

CONCLUSION:

FA5-BUCY as an intensive conditioning regimen facilitates the outcome of advanced diseases with allo-HSCT, and co-transplantation with MSCs could further improve the survival of hematologic malignancies patients who did not reach remission.

Disclosures

No relevant conflicts of interest to declare.
A Phase 1, Open-Label, Multi-Center Study of Alteminostat (CKD-581) in Combination with Lenalidomide and Dexamethasone in Patients with Previously Treated Multiple Myeloma (MM)
Authors: Min Chang Ki , Kim Kihyun , Kim Seok Jin , Yoon Dok Hyun , Park Sung-Soo , Han Seunghoon
Published: November 2019

Background

Alteminostat (CKD-581), a novel hydroxamate-based pan-HDAC inhibitor, increases acetylation of histones and other proteins involved in multiple oncogenic pathways. It modulates gene expression involved in cell-cycle regulation, differentiation, and apoptosis. Altemonstat in combination with lenalidomide and dexamethasone demonstrated promising anti-cancer efficacy both in vitro and in vivo studies, including xenograft models of multiple myeloma (MM). In addition, it was well tolerated in patients with lymphoma and MM refractory to standard therapy. On the basis of this background, we conducted a phase I dose-finding study of alteminostat in combination with lenalidomide and dexamethasone in relapsed MM patients.

Methods

Subjects with MM who had relapsed after at least one prior treatment were infused alteminostat iv (90, 120, or 160 mg/m2, level 1-3, respectively once weekly for 3 weeks out of a 4-week cycle in a standard 3+3 dose-escalation, phase 1 design, combined with lenalidomide 25 mg on day 1-21 and dexamethasone 40 mg on day 1, 8, 15, 22 in a 28-day cycle

Results

As of July 11th, 2019 the study has enrolled 10 patients with relapsed MM to Level 3. The median age was 56 (range 46-64), and the median number of previous regimens received was 2.5 (range 1~8). Based on the data cut off day, no dose-limiting toxicities were identified. 2 patients were in progress on the maximum planned dose of 160 mg/m2. The most common (>20% of subjects) drug-related adverse events (AEs) were thromobcytopenia (80%), neutropenia (60%), anemia (50%), muscle spasms (50%), fatigue (30%), upper abdominal pain (30%), and constipation (30%). Serious adverse drug reaction was not reported. AEs related with cardiac disorder have not been observed. The most common ≥Grade 3 hematologic AEs were neutropenia (70%), thromobcytopenia (60%), and anemia (60%). The most common ≥Grade 3 non-hematologic AEs are pneumonia (40%). One patient at dose level 2 died from pulmonary embolism after pneumonia. Two of ten patients had exposed to lenalidomide before participating in this clinical trial. The median cycle was 3 in level 1, 4 in level 2 and 2 in level 3, while level 3 is still in progress. The overall response rate, defined as achieving more than partial response (PR), for all patients was 70%, including 10% stringent complete response (sCR), 10% CR, 20% very good PR and 30% PR. The median duration of response was 236 days and median progression-free survival was 232 days.

Conclusions

Alteminostat, a novel hydroxamate-based pan-HDAC inhibitor, can be combined safely with lenalidomide and dexamethasone, demonstrating significant clinical activity in subjects with MM. Enrollment is ongoing and full phase 1 will be updated and presented.

Disclosures

No relevant conflicts of interest to declare.
The Appropriateness of Fresh Frozen Plasma (FFP) Administration in Three Community Teaching Hospitals
Authors: Shikdar Sufana , Agrawal Kavita , Ghionni Nicholas , Hommadov Kakageldi , Abdollahi Shahrzad , Micaily Ida , Green Eric
Published: November 2019

Objective: Although Fresh Frozen Plasma (FFP) is indicated in critically ill patients, there are growing concerns about it's cost effectiveness and adverse effects in instances that do not conform to evidence-based indications. Despite a range of adverse reaction with the inappropriate usage of FFP, its usage has significantly increased over the last decade. We previously evaluated the overuse of FFP in our community teaching hospital in 2010-2011 and 2016-2017. The interventions to reduce the inappropriate FFP transfusion were implemented after the results from 2016-2017. The present multicenter study is a post-interventional study that describes practices regarding administration of FFP in three community teaching hospitals between 2017-2018.

Methods: A retrospective chart review of patients who received FFP transfusion in three community teaching hospitals between 2017-2018 were included in our study. Criteria were established to evaluate the appropriateness of FFP. Descriptive statistics were utilized to compare the appropriateness of FFP transfusion among the participating hospitals.

Results: Overall, 306 participants were evaluated where 25% of the participants (77 out of 306) received inappropriate FFP transfusions. The most common rationale for inappropriate FFP transfusions were bleeding with INR less than 1.5 followed by INR over 1.5 (without any evidence of active bleeding).Based on our study criteria, the proportion of inappropriate FFP transfused out of the total FFP transfused decreased from 49% in the study period 2016-2017 to 25% in the study period 2017-2018. 15% of the study population received inappropriate FFP transfusion for bleeding in 2017-2018 compared to 42% in 2016-2017.

Conclusion: Our study showed a reduction in inappropriate FFP transfusions in 2017-2018 compared to 2016-2017. This can be attributed to the interventions implemented after obtaining study results from 2016-2017. The interventions included creating fliers educating about lack of effectiveness of FFP to reduce INR below 1.6 and arranging educational talks from transfusion committee about the evidence-based usage of FFP transfusion. Such interventions are essential to reduce healthcare expenditure and transfusion related adverse events.

Disclosures

No relevant conflicts of interest to declare.
An Electronic Health Record Facilitates a Safer and More Efficient Rural Outreach Haematology/Oncology Service
Authors: Cashman Helen , Hamad Nada , Moore John , Milliken Sam , Lavee Orly , Withers Barbara , Mayson Eleni , Kliman David , Kesby Janet , Bell Jenny , Vachalec Sue
Published: November 2019

Background: Rural Australian oncology patients are known to have inferior mortality rates compared to metropolitan patients, possibly related to access to appropriate healthcare services and treatments. Replacement of paper-based chemotherapy charting with electronic systems improves the safety of chemotherapy administration through reduced prescribing and administrative errors.

Aims: To integrate the electronic healthcare delivery systems at a metropolitan hospital and a rural outreach haematology clinic to facilitate streamlined and safe rural outpatient care.

Method: The MOSAIQ v2.64 [Elekta] system utilized at St Vincent's Hospital, Sydney, was introduced at a linked rural outreach haematology clinic in Griffith, a city in the Riverina region of New South Wales. MOSAIQ is a comprehensive practice management system incorporating all relevant patient results and notes along with administrative capabilities. The two systems were consolidated into one with patient information accessible from both sites.

Results: The electronic systems were successfully linked between the two sites in October 2017. As of November 2018 there were 497 patients registered with the service with the breakdown of diagnoses shown in Figure 1, with lymphoma found to be the most common haematological diagnosis. Tracking of service activity over time including clinic appointments and patient numbers is now possible, with increases in both seen since implementation. Nine chemotherapy regimen types encompassing 2174 overall treatments were delivered at the service over the fifteen months since implementation, the most common being R-CHOP [Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone] followed by azacitidine. The linked system has improved streamlined care during patient transitions between the two hospitals with enhanced continuity of documentation and management. Chemotherapy prescribing has transitioned to electronic at the Griffith site and is guided by inbuilt, pharmacist-reviewed protocols allowing for safer and flexible prescribing remotely which has standardized management of haematology patients across both hospitals.

Conclusion: Our study provides a novel example of the successful implementation of a centralised electronic healthcare record and chemotherapy prescribing system in a haematology setting shared between a metropolitan service and a rural outreach hospital clinic. This has positive implications for the safety and efficiency of healthcare delivery at the rural site applicable to all linked rural clinics, as well as allowing data collection to assist future planning of the service.

Disclosures

No relevant conflicts of interest to declare.
Managing Multiple Myeloma with Second and Later Lines of Therapy: A Challenge in Developing Countries
Authors: Pydi Venkateswar Rao , Bala Stalin Chowdary , Gundeti Sadashivudu
Published: November 2019

Introduction:

Multiple myeloma is characterised by abnormal plasma cell proliferation leading to anaemia, hypercalcemia, skeletal lytic lesions and renal failure. Though myeloma is incurable, novel agents have improved the outcomes. Despite the availability of multiple new agents which lead to improvement in survival, majority of patients are still unable to receive second and further lines of therapy. The present study was designed to analyse the outcomes of patients who received 2nd line and later lines of therapy.

Materials and methods:

Data of all patients diagnosed with multiple myeloma from 2013-2018 was retrieved. Clinical, haematological, other significant lab parameters, treatment details were noted. For patients who progressed on 1st line therapy and those who had responses of less than PR, 2nd line therapy was started. PFS 2 was calculated from start of 2nd line therapy till progression. Survival probabilities were estimated by Kaplan-Meier method and compared by log rank test. SPSS 25 software was used for statistical analysis.

Results:

A total of 258 patients were diagnosed between 2013 and 2018. The median age at presentation was 56 years (range, 28-84 years). Male to female ratio was 2.03:1. Of these 258 patients, 191(74%) patients took planned therapy and 172(66%) patients had at least one response evaluation. Of these, only 81(47%) patients were able to receive 2nd line therapy. Five patients died during therapy, 16 patients did not complete planned therapy and 58(33%) patients had response evaluation. Seventy five percent of patients received triplet chemotherapy. MPT and VRD were the most commonly used regimens. Median number of cycles before response evaluation was 4 cycles. Of these 81 patients, 14(17.2%) patients underwent autologous stem cell transplantation. The baseline characteristics and outcomes were shown in Table 1. Twenty (34%) patients received 3rd line and further lines of therapy. Of these 20 patients, best response was VGPR, seen in 50% percent of patients. The median progression free survival (PFS2) was 15 months (range1-59 months). At a median follow up of 18 months, 2-year PFS was 61.6%. The 2-year OS of all patients and those who receive 2nd and later lines were 76% and 84% respectively.

Conclusion:

Only 30% of patients received second line and one tenth of all patients were able to receive third and later lines of therapy. Majority of the patients who received second and later lines of therapy had ≥ VGPR. Overall survival was higher in patients who received further therapy at progression. Outcomes in multiple myeloma can be improved by optimal sequencing of available drugs. Treatment discontinuity is major caveat in management of myeloma in real-world scenario and overcoming this challenge might improve survivals.

Disclosures

No relevant conflicts of interest to declare.
Cerebral Thrombosis As an Initial Presentation of Pediatric Acute Promyelocytic Leukemia
Authors: Aytac Selin , Coskun Cagrı , Aksu Tekin , Kuskonmaz Baris
Published: November 2019

Disseminated intravascular coagulopathy and bleeding are common manifestations of acute promyelocytic leukemia(APL) which are both associated with significant mortality and morbidity. However APL related thrombosis is very rare and majority of the reported cases are adults in the literature. In the past 14 years, 14 cases with APL were found in our hospital database.There were 6 female and 8 male children with a mean age of 10.7±4.6 years (2-17y). Here, we report two pediatric APL case who presented with cerebral thrombosis at the initial presentation. 8/14(57%) had disseminated intravascular coagulation at the initial presentation and one patient had intracardiac and cerebral sinovenous thrombosis during the induction period.

Case 1:A 13-year-old boy was admitted to our hospital with a complaint of headache for two days. His physical examination revealed a papilledema and cranial MRI did show sinovenous thrombosis. At the time of the evaluation his WBC count was found to be low and there were myeloid blasts on his peripheral smear,bone marrow aspiration was done and diagnosed as translocation t(15;17)positive APL. He remain in remission more than 4 years without any event however deceased after relapse.

Case 2: A 8-year-old boy was admitted to our hospital with a complaint of right hemiparesis, there was a thrombotic occlusion of the left middle cerebral artery associated cerebral infarct on his MRI.His WBC was 5.9x109/l with 76% blasts and bone marrow aspiration and flow-cytometry were both compatible with APL. Patient died after 2 weeks of admission because of thrombosis and bleeding.

The incidence of APL related thrombosis was 4.5 and 5.6% in two large adult cohorts. Both arterial and venous thrombosis may ocur in patients with APL. To the best of our knowledge there were limited number of pediatric APL case reports in the literature who presented with thrombosis. In our small group of pediatric APL patients 14% presented with thrombosis and the total number of thrombotic events were found to be 28% during the follow up.

Disclosures

No relevant conflicts of interest to declare.
Rebound Thrombocytosis after Induction Chemotherapy Is a Strong Biomarker for Favorable Outcome in AML Patients
Authors: Pabst Thomas , Schnell Bianca R , Bacher Ulrike , Jeker Barbara , Banz Yara , Novak Urban , Seipel Katja -
Published: November 2019

Background: Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic suppression and recovery following induction chemotherapy remain enigmatic. In addition, thrombocytopenia at diagnosis is related to deregulated cytokine expression in specific leukemia subtypes rather than on the degree of bone marrow infiltration per se. Similarly, recovery of platelets after the first induction cycle among individual patients can vary from incomplete to excess recovery even if morphologic remission is achieved. In particular, excess platelet rebound (EPR) with values exceeding 500 G/L can be observed in some patients. However, this clinical observation of EPR is poorly understood so far, and its prognostic relevance is unknown.

Methods: We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients receiving at least one cycle of intensive "3+7" based induction treatment. We defined excess platelet rebound (EPR) as a platelet increase above 500 G/L during hematologic recovery after the first induction cycle.

Results: We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 versus 41 months; P=0.04), as was disease-free survival (Figure 1). By multivariate analysis, achievement of EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p<0.0001), while GATA-1, GATA-2 and MPL mRNA expression did not differ between EPR+ and EPR- patients. Finally, transcription factors blocking early megakaryopoiesis were upregulated in EPR- patients, while NFE2 involved in late megakaryocyte differentiation was increased in EPR+ patients.

Conclusion: This study suggests that excess platelet rebound (EPR+) defined as platelets exceeding 500 G/L is a common event identified in AML patients after the first induction cycle. EPR+ was predominantly observed in ELN favorable risk AML, and it was associated with significantly better overall and disease-free survival as compared to EPR- patients. In addition, achievement of EPR+ represented an independent prognostic parameter for improved survival in a multivariate analysis, and may contribute to prognostic assessment in AML patients undergoing intensive treatment with intention to cure.

Disclosures

No relevant conflicts of interest to declare.
Serum microRNA Prognostic Model and Underlying Immune Alterations in Diffuse Large B Cell Lymphoma
Authors: Rui Sun , Zhao Weili
Published: November 2019

Serum microRNA prognostic model and underlying immune alterations in diffuse large B cell lymphoma

Abstract

Background: MicroRNAs (miRs) have been investigated as prognostic biomarkers and therapeutic targets in diffuse large B-cell lymphoma (DLBCL). Translating these findings into clinical approaches should be validated by independent patient cohorts and a better understanding of underlying biology mechanism remains great interests.

Methods: MiRNA microarray was performed on serum samples of 20 DLBCL patients at diagnosis, remission and at relapse. Subsequent real-time PCR validation of 504 newly diagnosed DLBCL patients was used to generate a serum prognostic model in predicting clinical outcomes. The mechanism of action of miR signature on tumor progression was further analyzed by whole exome sequencing and RNA sequencing.

Results: Four serum miRs (miR-21, miR-155, miR-130b and miR-28) were identified to predict relapse in a training cohort of 225 DLBCL patients and validated in a validation cohort of 279 DLBCL patients. Multivariate Cox regression models indicated that when the International Prognostic Index was controlled, this serum miR prognostic model was an independent prognostic factor in DLBCL. Moreover, mutations of transcription factors (TFs) were significantly correlated with these four miRs. Twenty lymphoma-associated TFs regulated at least one miR by transmiR v2.0 database and different genetic mutation burden was present between low-index and high-index of the model. Furthermore, RNA sequencing data manifested that the four-miR signature correlated with immune status of the DLBCL patients.

Conclusions: An easy-to-use miR prognostic model was utilized to predict disease relapse and prognosis of DLBCL patients. The tumor-specific mutation burden and immune dysregulation potentially contribute to tumor progression in DLBCL.

Key words: MicroRNAs, Diffuse Large B-cell Lymphoma, Prognosis, Signaling pathways.

Disclosures

No relevant conflicts of interest to declare.
Pharmacokinetics of Extended Half-Life Factor VIII Products By myPKFiTR Is Useful for Personalized Treatment in Children with Severe Hemophilia a
Authors: Matsumura Risa , Tomioka Keita , Nishimura Shiho , Mizoguchi Yoko , Kawaguchi Hiroshi , Kobayashi Masao
Published: November 2019

Prophylactic administration of factor VIII products is necessary to prevent bleeding and preserve normal musculoskeletal function in children with severe hemophilia A (HA). Recently, extended half-life recombinant factor VIII (EHL-rFVIII) products have been utilized in HA patients. Therefore, the pharmacokinetics (PK) of EHL-rFVIII in individuals is needed to determine the appropriate administration for personalized prophylaxis according to the age, bleeding phenotype, the presence of arthropathy, and physical activity. The myPKFiTR ver 3.0 has been developed as the device to estimate the personalized dosing with a 2 sample PK based on the population PK (Bayesian) tool. In this study we report our single-center experience to study PK profiles and to individualize dose and dosing interval based on myPKFiTR. Eight patients with severe HA aged from 10 to 20 years were enrolled in this study for personalized prophylaxis. The half-life of EHL-rFVIII was approximately 15 to 18 hours in all patients studied. The clearance of FVIII was inversely correlated with the half-life of EHL-rFVIII. The EHL-rFVIII products have been basically administered twice a week. The trough levels of FVIII were more than 3% in all patients. The prophylactic regimen in adolescents was individually determined according to the personal simulation of PK study and to patients' life style and physical activities. Adolescent patients actively participated in sports, such as track and field, basketball, and football after school. The FVIII level after school was easily estimated by the use of myPKFiTR according to the dose and duration of replacement. The doses of EHL-rFVIII products were individually determined to have more than 10 to 30% of FVIII level at the time of sports activity. During personalized prophylaxis (6 to 18 months), all of patients studied have been no bleeds during sports as well as no spontaneous bleeds. Additionally, myPKFiTR has the capability of presenting the real-time FVIII level on the screen of smartphone after the replacement of EHL-rFVIII based on the individual PK. Some patients have referred their own FVIII level before the beginning of sports through their smartphone and then have decided the necessity of the replacement. These experiences suggest the enhancement of treatment concordance in the supportive relationship between patients and medical staff. Thus, the use of myPKFiTR may be essential for the optimization of prophylactic administration of EHL-rFVIII and for the medical adherence and concordance in each individual.

Disclosures

No relevant conflicts of interest to declare.
GATA2 Zinc Finger Mutations Influence Erythroid Differentiation and Chemotherapy Response
Authors: Leubolt Georg , Redondo Monte Enric , Wilding Anja , Kerbs Paul , Cusan Monica , Bagnoli Johannes , Enard Wolfgang , Hiddemann Wolfgang , Wichmann Christian , Schotta Gunnar , Greif Philipp A.
Published: November 2019

The transcription factor GATA2 plays an important role in cell lineage decisions during hematopoiesis. GATA2 Zinc-Finger (ZF) mutations are associated with distinct entities of myeloid malignancies. Alterations of the N-terminal ZF1 were identified in AML patients with biallelic CEBPA mutations, whereas the C-terminal ZF2 is typically affected by germline mutations predisposing to MDS and AML, or by somatic lesions in CML blast crisis. Nevertheless, the context-dependent mechanisms underlying GATA2 ZF mutations remain mostly unclear. Here, we set out to study the functional consequences of GATA2 ZF mutations.

To test the effect on differentiation, we expressed GATA2 wild-type (WT) or GATA2 ZF mutants in human CD34+ hematopoietic stem and progenitor cells, stimulated with appropriate cytokines. Differentiation was evaluated by FACS-measurements of surface marker expression (erythroid markers: CD71, CD235a; granulocytic/monocytic markers: CD15, CD14). GATA2 WT caused a block of erythroid differentiation that is overcome by the ZF1 mutants (A318T and G320D), whereas the ZF2 mutant L359V may aggravate this block. For granulocytic/monocytic differentiation an overall block was observed for GATA2 WT and all the ZF mutants tested (Figure 1 A, B).

Recently, we and others observed GATA2 mutation gain in AML relapse (Greif et al., 2018 Clin Cancer Res; Christopher et al., 2018, NEJM), pointing towards a potential role in therapy resistance. Therefore, we treated K562 cells stably expressing GATA2 WT or mutants with Daunorubicin (one of the two drugs commonly used in AML chemotherapy). Expression of GATA2 A318T in K562 cells correlated with higher sensitivity to Daunorubicin and lower expression levels of IDH2. (Figure 1 C, D). Interestingly, this particular ZF1 mutation was the only one that got lost at relapse in the study by Christopher and colleagues, consistent with therapy sensitivity, whereas most of the GATA2 mutations gained at relapse were localized in the ZF2 domain.

In summary, GATA2 ZF mutations influence hematopoietic differentiation and chemotherapy response in a position-dependent manner. In the present study, we report distinct roles for individual GATA2 mutations depending on the affected ZF domain and altered amino acid positions. Understanding the oncogenic collaboration of GATA2 mutations with other driver genes in distinct patient subgroups is a challenge ahead.

Figure.1

Disclosures

Hiddemann: Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding.
Blocking MAPK Activation and Immune Checkpoints Reverse Immune Dysfunction and Reduce Disease in a Mouse Model of LCH
Authors: Sengal Amel , Hahne Meryl , Velasquez Jessica , Abhyankar Harshal , Burke Thomas , Olea Walter , Reyes Robert , Scull Brooks , Bigenwald Camille , Bollard Catherine M. , Yu Wendong , Merad Miriam , McClain Kenneth L. , Allen Carl E. , Chakraborty Rikhia
Published: November 2019

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with persistent mitogen-activated protein kinase (MAPK) pathway activation. Standard of care chemotherapy strategies are inadequate or overly toxic for the majority of patients with multisystem disease. The mechanisms underlying development of inflammation in LCH lesions are poorly understood, and potential for immunotherapy has not been determined. Analysis of the LCH lesion identified the most prominent immune cells as T lymphocytes, second only to pathologic CD207+/CD1a+ DCs (LCH DC). Both CD8+ and CD4+ T cells exhibited 'exhausted' phenotypes with high expression of the immune checkpoint inhibitor receptors. LCH DC cells also showed robust expression of ligands to checkpoint inhibitor receptors. Lesion CD8+ T cells exhibited blunted expression of Th1 cytokines with impaired effector function. In contrast, regulatory T cells (Tregs) isolated from LCH lesions demonstrated intact suppressive activity. Treatment of BRAFV600ECD11c LCH mice with anti-PD-1, anti-TIM-3 and MEKi decreased the lesion size: MEKi treatment resulted in reduction of the myeloid compartment; anti-PD-1 and anti-TIM-3 were associated with reduction in the lymphoid compartment. However, combined treatment with MEKi and either anti-PD-1 or anti-TIM-3 significantly decreased both CD8+ T cell and myeloid LCH cells in a synergistic fashion. These results thus indicate MAPK hyperactivation in myeloid LCH cells drives recruitment and activation of functionally exhausted T cells within the LCH microenvironment. While the results from this study did not demonstrate a significant impact of checkpoint inhibition alone on tumor burden in experimental mice, combined MAPK and checkpoint inhibition may be a potentially effective therapeutic strategy for patients with LCH.

Disclosures

Bollard: self: Patents & Royalties: patent on HIV T cells; NexImmune: Equity Ownership; Torque: Equity Ownership; Cellectis: Membership on an entity's Board of Directors or advisory committees; Caballetta: Equity Ownership; Mana Therapeutics: Equity Ownership.
Melatonin Increases the Chemosensitivity of Diffuse Large B Cell Lymphoma Cells to Epirubicin By Inhibiting P-Glycoprotein Expression Via the NF-Κb Pathway
Authors: Sun Xiuhua , Qin Hong
Published: November 2019

Epirubicin (EPI) is a first-line chemotherapeutic drug for the clinical treatment of diffuse large B cell lymphoma (DLBCL), but the overexpression of multidrug resistance (MDR) transporter proteins, such as P-glycoprotein (P-gp), renders EPI ineffective. On the basis of some studies, melatonin (MLT) is considered to possess the potential for chemotherapeutic synergy that can be leveraged to overcome MDR. In this study, we investigated the effect of MLT on the sensitivity of DLBCL cells to EPI. The human DLBCL cells SUDHL-6 and SUDHL-10 were incubated with MLT and/or EPI for 48 h. We found that MLT significantly enhanced the EPI-induced suppression of cell proliferation and EPI-induced apoptosis and reduced the IC50 value of the EPI-treated cells. We also found that MLT synergized with EPI to promote the activation of the mitochondria-mediated apoptosis pathway. Further mechanistic studies demonstrated that the sensitivity of DLBCL cells to EPI may be affected by the MLT influence on the expression and function of P-gp. Immunohistochemical staining studies in DLBCL cells from tumor tissues revealed that the expression of P-gp was positively correlated with NF-κB P65 expression. EPI was subsequently discovered to upregulate the expression of P-gp by activating the NF-κB pathway in the DLBCL cells. Further, we found that MLT reduced the amount of NF-κB P65 protein in the nucleus and abrogated the ability of P65 to bind to the ABCB1 promoter, decisively suppressing P-gp expression. In conclusion, our results demonstrated that MLT inactivates the NF-κB pathway and downregulates the expression of P-gp, ultimately sensitizing DLBCL cells to the EPI that suppresses their growth.

Disclosures

Qin: InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership.
Assessment of Cardiac Abnormalities in Sickle Cell Disease Patients Using Echocardiography
Authors: Mukarram Osama , Lima Gian , Crooks Samuel , Kim Min Jung , Kim Agnes S
Published: November 2019

Background: Sickle Cell Disease (SCD) is characterized by chronic anemia and recurrent ischemia-reperfusion episodes that contribute to high output heart failure. The effects of SCD on the heart are significantly underrecognized.

Methods: SCD patients who underwent echocardiography between March 2016 and March 2018 were retrospectively analyzed. Patients with reduced Left Ventricular Ejection Fraction (LVEF) and valvular heart disease were excluded. Cardiac chamber size, systolic and diastolic function parameters, and LV and RV strain were compared between hemoglobin SS (most severe form of SCD) and SC (less severe form) subtypes and against healthy controls. Wilcoxon signed rank test was used for statistical analysis.

Results: SS patients (n = 48, mean age 31.9) had lower mean hemoglobin 8.9 g/dl vs 11.3 g/dl (p < 0.001) and hematocrit 25.8% vs 31.4% (p = 0.008) and higher LDH 437 IU/L vs 258 IU/L (p < 0.001) compared to SC patients (n = 11, mean age 34.4). Both SS and SC patients had worse diastolic function compared to healthy controls: higher E velocity 98.9 cm/s (SS), 86.4 cm/s (SC), 76.4 cm/s (control) (SS vs control, p < 0.01; SC vs control, p < 0.05) and higher E/A ratio 1.76 (SS), 1.59 (SC), 1.15 (control) (SS vs control, p < 0.001; SC vs control, p < 0.01). SS patients had larger indexed left atrial volume compared to SC patients (39.3 ml/m2 vs 28.4 ml/m2, p = 0.007). There was no significant difference in LVEF, left ventricular global longitudinal strain, or right ventricular strain between SS and SC subtypes compared to healthy controls. Furthermore, SS patients with a serum LDH > 500 IU/L had higher E/e' ratio (11.3 vs 7.2, p=0.001) and larger indexed Left Ventricular End Diastolic Volume (LVEDVi) (80.8 ml/m2 vs 53.4 ml/m2, p=0.002) compared to SS patients with LDH < 500 IU/L.

Conclusion: SCD genotype adversely determines the degree of cardiac dysfunction in patients with SCD. LVEDVi, left atrial size, E velocity, E/A ratio, and E/e' ratio may serve as useful echocardiographic parameters to follow in this patient population. Serum LDH has been associated with poor clinical outcomes in patients with SCD, and as demonstrated by our study, it also portends worsening cardiac function in this population at high risk for heart failure.

Figure

Disclosures

No relevant conflicts of interest to declare.
Impact of Primary Ambulatory Thromboprophylaxis (PATP) with Low-Molecular Weight Heparins (LMWHs) on Survival in Patients with Locally Advanced or Metastatic Lung Cancer (LC) Receiving Chemotherapy
Authors: Thein Kyaw Zin , Tijani Lukman , Oo Thein H.
Published: November 2019

Introduction: LC is the leading cause of cancer mortality in USA. PATP was provided in experimental trials to decrease the venous thromboembolism (VTE) rates and to provide anti-tumor effect with ultimate aim to improve survival in patients with solid cancers as VTE is the second leading cause of death in cancer patients. We undertook a systematic review and meta- analysis of randomized controlled trials (RCTs) to determine the impact of PATP with LMWHs on overall survival (OS) in patients with locally advanced or metastatic LC.

Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through July 26, 2019. The references of all potential studies were also reviewed for any additional relevant studies. RCTs utilizing PATP with LMWHs in patients with locally advanced or metastatic lung cancer were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression or metastasis free survival and OS with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied.

Results: A total of 3,452 patients with lung cancer from six RCTs were included in our meta-analysis. The prophylactic doses of bemiparin, dalteparin, tinzaparin, nadroparin and intermediate dose of enoxaparin were used in the studies. The duration of LMWH ranged from 3 to 6 months. The randomization ratio was 1 to 1 in all studies. The I2statistic for heterogeneity was 64, suggesting moderate heterogeneity among RCTs. The pooled HR for OS was not statistically significant at 1.02 (95% CI: 0.83-1.26; P = 0.83). In a subset of small cell lung cancer (SCLC) patients, the pooled HR for OS was 1.03 (95% CI: 0.72-1.48; P = 0.85). The HR for OS was noted at 1.70 (95% CI: 0.70-4.15; P = 0.24) in patients with limited stage SCLC. In a subset of non-small cell lung cancer, the pooled HR of OS was 1.00 (95% CI: 0.79-1.26; P = 0.98). The pooled HR for progression or metastasis free survivalwas 1.03 (95% CI: 0.86-1.24; P = 0.74) according to an analysis of 5 RCTs.

Conclusions: Our meta- analysis demonstrated that no survival advantage was noted with the addition of PATP with LMWHs to routine standard chemotherapy in patients with locally advanced or metastatic LC, regardless of histology types as well as stages of SCLC.

Disclosures

Oo: Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: Research: site co-investigator .
Updated Meta-Analysis of Randomized Controlled Trials on Primary Ambulatory Thromboprophylaxis (PATP) in Patients with Advanced Pancreatic Cancer (APC) Receiving Chemotherapy
Authors: Thein Kyaw Zin , Quick Donald P. , Oo Thein H.
Published: November 2019

Introduction: Thrombosis is the second leading cause of death in cancer patients and patients with APC are categorized as high-risk of developing venous thromboembolism (VTE). Many trials had failed to demonstrate improvement in survival with PATP. Despite decreasing VTE events, PATP in solid cancer patients is not routinely recommended. We conducted an updated meta- analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWH) and direct oral anticoagulants (DOAC) in patients with APC receiving chemotherapy.

Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. The primary meta- analytic approach was a random effects model using the Mantel-Haenszel (MH) method. It was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic.

Results: A total of 1,013 patients with APC from two RCTs and a subgroup of another three RCTs were included in our meta-analysis. The prophylactic, intermediate and therapeutic doses of LMWH and prophylactic dose of DOAC (rivaroxaban) were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2statistic for heterogeneity was 60, suggesting some heterogeneity among RCTs. The VTE incidence was 28 (5.43%) in PATP group and 60 (12.07%) in control group with a RR of 0.44 (95% CI: 0.20 to 0.99, P = 0.05) and RD of -0.06 (95% CI: -0.11 to -0.01, P = 0.01). In fixed effects model, the pooled RR was 0.45 (95% CI: 0.29 to 0.70, P = 0.0003) and the absolute RD in VTE was -0.07 (95% CI: -0.10 to -0.03, P = 0.0002) with an estimate of the number needed to treat (NNT) of 15 to prevent one VTE event. MB events were reported in 9 (4.11%) patients in PATP group compared to 7 (3.27%) in control group according to an analysis of 2 RCTs. The pooled relative risk for MB was statistically non-significant at 1.25 (95% CI: 0.47 to 3.31, P = 0.65).

Conclusions: In our study, PATP in APC may statistically significantly decrease VTE events, approximately with relative risk reduction of 55% and a NNT of 15, without increasing MB events. Proper selection of patients who are high risk for VTE in outpatient setting is important. More RCTs are required to further define high risk subsets of APC patients receiving chemotherapy who may benefit from PATP.

Disclosures

Oo: Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: Research: site co-investigator .
BALB/c-hCD3E Transgenic Mice: An Ideal Animal Model for In Vivo Efficacy Study of CD3-Bispecific Antibodies
Authors: Ju Cunxiang , Zhang Mingkun , Jia Dongjing , Tang Jing , Li Shuai , Zhao Jing , Wang Demin , Gao Xiang
Published: November 2019

T cell-mediated immunotherapy is an important strategy for treatment of a variety of tumors.T-cell bispecific antibody (TCB), which binds to a tumor associated antigen (TAA) and human CD3ε (hCD3ε) and directs specific killing of tumor cells carrying the TAA. However, there is still an unmet need for suitable animal models to evaluate the therapeutic efficacy of TCB candidates. Although immune-deficient mice transfused with human PBMCs can be used to evaluate the TCBs, these mice are not fully immune competent and have limitation in studying immune system activation by TCBs. Herewe developed a human CD3ε-transgenic mouse model with BALB/c background (BALB/c-hCD3E) to overcome the limitation.

CD3ε plays a critical role in formation and function of the TCR-CD3 complex. However, hCD3ε shares only 47% homology with mouse CD3ε (mCD3ε) in the extracellular domain, indicating that hCD3ε and mCD3ε are not functionally interchangeable. Thus, we established BALB/c-hCD3E mice that carry the human CD3E gene and its entire regulatory sequence and co-express hCD3ε and mCD3ε in over 90% of T cells. BALB/c-hCD3E mice were phenotypically normal and had normal T-, B- and NK-cell populations compared to wild-type BALB/c mice. In addition, splenic T cells from BALB/c-hCD3E mice could be activated by either anti-hCD3 or anti-mCD3 antibodies to produce IFNg, IL2 and TNFa in vitro. Moreover, we knocked out mCD3e in BALB/c-hCD3E mice to generate BALB/c-hCD3E/mCd3e-KO mice that displayed a marked reduction in the number of splenic T cells. BALB/c-hCD3E/mCd3e-KO mice also had reduced percentages and numbers of CD4+ and CD8+T cells. Importantly, anti-mCTLA4 antibodies strongly inhibited the growth of subcutaneously inoculated CT26 tumor cells in BALB/c-hCD3E but not BALB/c-hCD3E/mCd3e-KO mice.

Taken together, these findings demonstrate that mCD3ε is indispensable for T-cell development and function in BALB/c-hCD3E transgenic mice and these mice are a novel and valuable model to assessing the therapeutic efficacy of TCBs.

Disclosures

Ju: GemPharmatech Co., Ltd: Employment. Zhang:GemPharmatech Co., Ltd: Employment. Jia:GemPharmatech Co., Ltd: Employment. Tang:GemPharmatech Co., Ltd: Employment. Li:GemPharmatech Co., Ltd: Employment. Zhao:GemPharmatech Co., Ltd: Employment. Wang:GemPharmatech Co., Ltd: Employment. Gao:GemPharmatech Co., Ltd: Employment.
Delayed Time to Emergency Hip Surgery in Patients Taking Oral Anticoagulants
Authors: Cafaro Teresa , Tagalakis Vicky , Koolian Maral , Camille Simard
Published: November 2019

Abstract

Introduction

Surgical intervention within 48 hours of admission in patients with acute hip fractures has been associated to lower morbidity and mortality. Patients anticoagulated with Vitamin K Antagonists (VKAs) have longer time to corrective surgery than those not anticoagulated. Sparse data exists on time to surgery (TTS) in patients taking direct oral anticoagulants (DOACs). The aim of this study is to establish TTS among non-anticoagulated and anticoagulated patients taking either VKA or DOAC.

Materials and Methods

We conducted a retrospective cohort study of consecutive patients admitted with acute hip fracture between July 1, 2016 and December 31, 2017. Patient-, anticoagulant- and surgery-related characteristics were collected. The primary outcome was TTS calculated from time of admission. Median TTS with interquartile range (IQR) was compared among 3 groups of patients: DOAC, VKA and No OAC.

Results

A total of 472 patients were included: 12.5% (59/472) were anticoagulated (28/472 on VKAs and 31/472 on DOACs). Median TTS was longer in the VKA group [64 hours (IQR: 50-84)] and in the DOAC group [(61 hours; IQR: 42 to 77)] versus the No OAC group [44 hours (IQR: 28-63), p =0.0006 and p=0.003 respectively]. There was no significant difference in median TTS in the VKA group versus the DOAC group (p =0.6396).

Conclusion

Patients taking either VKA or DOAC have significant delays to emergency hip fracture surgery compared to those not anticoagulated. An action plan aimed at early identification and cessation of anticoagulation is warranted in this vulnerable group of patients.

Keywords: Direct Oral anticoagulants, Vitamin K antagonists, Anticoagulation, Acute hip fracture, Emergency surgery

Disclosures

Tagalakis: BMS-Pfizer: Other: participated on ad boards; Sanofi Aventis: Other: investigator initiated grant;participated on ad boards; Pfizer: Other: participated on ad boards; Bayer: Other: participated on ad boards; Servier: Other: participated on ad boards.
Probing Aberrant Splicing in a Novel Model of SF3B1-Mutant Myelodysplastic Syndromes
Authors: Clough Courtnee , Busch Stephanie , Pangallo Joey , Bradley Robert K. , Doulatov Sergei
Published: November 2019

Splicing is a fundamental process by which introns are removed from primary RNA transcripts. Alternative splicing is widely appreciated to be a major mechanism of gene regulation by which eukaryotic cells expand their transcriptional repertoire. By contrast, aberrant splicing generates novel transcripts not found in normal cells. Heterozygous mutations in a core U2 spliceosome factor SF3B1 are strongly associated with MDS with ring sideroblasts (MDS-RS). MDS-RS is characterized by iron retention in mitochondria and ineffective erythropoiesis. How aberrant splicing induced by mutant SF3B1 causes ring sideroblasts and erythroid defects remains poorly understood.

There are no genetically accurate models of MDS-RS that recapitulate ring sideroblast formation. Our lab has established an iPSC reprogramming approach to generate an in vitro model of MDS-RS. This method captures genetically distinct MDS subclones as well as normal cells in individual patients enabling internal normalization to the patient's isogenic normal clone. By differentiating iPSCs we generated inducibly immortalized MDS-RS CD34+ progenitor cell lines with robust expansion and erythroid differentiation potential enabling extensive analysis of SF3B1-mutant aberrant splicing throughout erythroid differentiation. We show that SF3B1-mutant lines form abundant ring sideroblasts compared to normal isogenic controls. We next performed RNA-sequencing and splicing analysis at different stages of erythroid differentiation. We show that global splicing patterns are maintained in SF3B1-mutant cells, while revealing distinct subsets of aberrantly spliced transcripts in CD34+ progenitors and erythroblast populations. This suggests that different aberrant splicing events contribute to erythroid progenitor expansion and inefficient erythropoiesis and iron dysregulation in MDS-RS.

Taken together, this novel iPSC model of MDS-RS is a robust tool for studying the role of aberrant splicing in SF3B1-mutant erythroid progenitor expansion, inefficient erythropoiesis and ring sideroblast formation.

Disclosures

No relevant conflicts of interest to declare.