bluuebunny/crossref_metadata_2025 huggingface dataset:
Marrow Blast Percentage Impact on High-Grade Myelodysplastic Syndrome By the Revised International Prognostic Scoring System
Authors: Alkharabsheh Omar , Patnaik Mrinal M. , Gangat Naseema , Begna Kebede H. , Alkhateeb Hassan B. , Shah Mithun Vinod , Hogan William J. , He Rong , Greipp Patricia , Nguyen Phuong L. , Litzow Mark R. , Al-Kali Aref
Published: October 2019

Introduction:

The revised international prognostic scoring system (IPSS-R) for myelodysplastic syndrome (MDS) is widely accepted and has been validated in multiple studies. Patients with adverse cytogenetics do poorly and that is reflected in this scoring system by having the highest score for cytogenetics; 2 for intermediate, 3 for poor and 4 for very poor. Little is known about the effect of marrow blasts in adverse cytogenetic in the high-grade MDS defined by IPSS-R intermediate (>3), high (>4.5) and very high (>5). The goal is to examine the effect of marrow blast percentage on outcome in patients with adverse cytogenetics that is present in the high-grade MDS.

Methods:

We performed data collection from the Mayo clinic records for patients with confirmed MDS after obtaining appropriate IRB approval. Patients were divided based on their total IPSS-R score and we extracted high-grade MDS cases with intermediate, high and very-high IPSS-R only. Cytogenetics and baseline CBC were available for analysis. We calculated the survival difference in patients with blasts <5% and patient with blasts of 5% to 19% for every group. Survival estimates were calculated by Kaplan-Meier method and compared by log-rank testing using JMP v.13.

Results:

Our database had 1300 patients with confirmed MDS, 41% (N=536) are high-grade MDS. From those, the median age was 70 and 70% were males. Median bone marrow blast was 6% (0-19). Baseline hemoglobin is 9.2 g/dL, WBC 2.7, ANC 1.05, and platelets 69. Their cytogenetics were 1% very good, 31% good, 23% intermediate, 16% poor and 29% very poor. The total IPSS-R groups were 39%,31%, and 30% for the intermediate, high, and very-high groups respectively. The overall survival (OS) for the high-grade MDS with marrow blast <5% was 12.3 months and for patients with marrow blasts ≥5% 11.4 months (P=.4). At each high-grade MDS; intermediate, high and very high, there were no statistically significant differences for patients with marrow blasts below or above 5%. In term of risk of progression to AML, patients with blasts ≥5% were at higher risk of progression compared with <5% (25% vs 10% , P<.001), with no statistically significant difference in term of time-to-AML progression.

Conclusion:

The percentages of bone marrow blasts had no impact on overall survival among patients with high grade MDS. However, patients with ≥5% marrow blasts are at a higher risk for progression to AML.

Disclosures

Al-Kali: Novartis: Research Funding.
The Analysis of HIV-Associated Lymphoma in Japan
Authors: Hagiwara Shotaro , Yoshinaga Kentaro , Shiseki Masayuki , Tanaka Junji , Okada Seiji
Published: October 2019

Background.

The recent advance of antiretroviral therapy decreased the morbidity of opportunistic infections. However, the incidence of HIV-associated lymphoma remains high. Also, the outcome of the HIV-associated lymphoma is unclear in the era of rituximab. In order to address these clinical questions, we performed a nation-wide epidemiological study.

Methods.

Patients with HIV-associated lymphoma were extracted from the database of Japanese society of hematology blood disease registry from January 2012 to December 2015. We analyzed the patient's age, sex, subtypes of lymphoma, the international prognostic index (IPI) for diffuse large B cell lymphoma, and overall survival.

Results. Eighty-one patients were extracted from the database. Eighty patients were available for the survival analysis. Seventy-six (93.8%) patients of them were male. The median age was 52.5(25-88) year-old. However, there were two peaks of age; the first peak was 38-40-year-old and the second was 59-62-year-old. Sub-types of lymphomas were diffuse large B cell lymphoma (DLBCL)(48.1%), Burkitt lymphoma(19.8%), primary CNS lymphoma(8.6%), plasmablastic lymphoma(7.4%), peripheral T cell lymphoma(3.7%), Hodgkin's lymphoma(3.7%), primary effusion lymphoma(2.5%), MALT lymphoma(1.2%), Follicular lymphoma(1.2%) and Adult T cell lymphoma/leukemia(1.2%). Extra-nodal involvement at the diagnosis was observed in 61.7%. The involved sites were the brain, stomach, small bowel, colon, thyroid and the others. In DLBCL, the patients with IPI high and high-intermediate risk was 51.3%. The median observation period was 26 months. Estimated 3 years overall survival (OS) in all cases was 68.8+/-0.63%. Although there was no statistical significance, however, the 3 years, OS of Burkitt lymphoma tended to be better than that of DLBCL (84.6%+/-10.0 versus 67.7+/-8.8%). Log-rank analysis showed the OS in DLBCL patients with IPI high-intermediate and high risk was significantly worse than the patients with low, and low-intermediate risk (p<0.001). Estimated 3 years OS was 90+/-9.5% vs. 38.0+/-13.0%, respectively. The outcome of patients with primary CNS lymphoma remains poor, estimated 3 years OS was 45.7+/-22.4%.

Conclusion.

Our study showed diversity in the pathological subtype of HIV lymphoma. In the era of rituximab, the outcome seemed to be improved in patients with DLBCL and Burkitt lymphoma. However, the survival remains short in patients with poor prognostic factors and primary CNS lymphoma.

Figure. Figure.

Disclosures

Hagiwara: Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Shiseki:NOVARTIS Pharma: Honoraria, Research Funding; Bristol-Myers Sqibb: Honoraria; Otsuka: Speakers Bureau. Tanaka:Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Otsuka: Honoraria; Pfizer: Honoraria.
The Expression of BTK/p-BTK Is Different between CD5+ and CD5- B Lymphocyte from Autoimmune Hemolytic Anemia/Evans Syndromes
Authors: Xing Limin , Qu Yingying , Duan Ningning , Shao Zonghong
Published: October 2019

Objective To investigate the expression level of Bruton's tyrosine kinase (Btk) on CD19+B lymphocytes in peripheral blood (PB) of autoimmune hemolytic anemia (AIHA)/Evans patients.

Methods The expression of Btk and Phosphorylated Btk(p-Btk) on CD5+CD19+B and CD5-CD19+B lymphocytes were detected using flow cytometry in AIHA/ Evans patients with different disease states, healthy controls (HC) and chronic lymphocytic leukemia (CLL) patients and analyzed its correlation with clinical parameters.

Results

36 AIHA/ES patients (16 hemolytic, 20 remission), 11 CLL patients and 15 healthy controls (HC) were enrolled in this study. The expression of Btk and p-Btk on CD5+B lymphocytes in AIHA/Evans patients were higher than those in HCs and CLL patients, the latter two groups had no significant difference, and were positively correlated with the quantity of IgE. The ratio of p-Btk to Btk on CD5+B lymphocytes of hemolytic group and remission group was obviously higher than that on CD5-B lymphocytes [(74.62±6.42)%, (29.63±10.19)%, P=0.001], [(77.95±9.57)%, (26.29±6.86)%, P=0.006]. The ratio of p-BTK to BTK on CD5+B lymphocytes [(54.89±9.56)%] and CD5-B lymphocytes [(30.86±12.47)%, P=0.109)] showed no significant difference in HCs. There was no significant difference of Btk on CD5+B and CD5- B lymphocytes in AIHA/Evans patients, but the expression of p-Btk on CD5+B lymphocytes significantly higher than that on CD5-B lymphocytes in AIHA/Evans patients.

Conclusion The expression levels of p-BTK in different B cell subsets of AIHA/Evans patients were significantly different, the expression levels of p-BTK in CD5+B cells were obviously higher than that in CD5-B cells, and higher than that in CD5+ B cells in CLL patients, and positively correlated with the number of serum IgE.

Key words: anemia hemolytic autoimmune; Bruton's tyrosine kinase, Phosphorylated Bruton's tyrosine kinase; B cell subsets

Disclosures

No relevant conflicts of interest to declare.
High PARP-1 expression Predicts Poor Survival in Acute Myeloid Leukemia and PARP-1 Inhibitor and SAHA-Bendamustine Hybrid Inhibitor Combination Treatment Synergistically Enhances Anti-Tumor Effects
Authors: Li Xia , Li Chenying , Jin Jingrui , Wang Jinghan , Jin Jie
Published: October 2019

PARP-1 plays a critical role in DNA damage repair and contributes to progression of cancer. To address the role of PARP-1 in AML, we analyzed the expression of PARP-1 in acute myeloid leukemia (AML) using RT-PCR. We found high expressers had higher levels of blast cells in bone marrow (P=0.003) and WBC in peripheral blood (P=0.008) and were associated with a more frequent FLT3-ITD mutation (28.2% vs 17.3%, P= 0.031). The overall survival (OS) and event free survival (EFS) of the high expression group were significantly shorter than those of the low expression group (P=0.005 and P=0.004, respectively). High PARP-1 expression predicts poor survival in AML patients. Then, we investigated the efficacy and mechanism of PARP inhibitor BMN673 (Talazoparib) combined with, NL101, a novel SAHA-bendamustine hybrid in vitro and in vivo. The combination significantly enhanced apoptosis of AML cells and induced G2/M cell cycle arrest. Mechanistically, BMN673 and NL101 combinatorial treatment promoted DNA damage. In vivo, the combination effectively delayed the development of AML and prolonged survival.The synergistic effects of PARP inhibitor BMN673 in combination with SAHA-bendamustine hybrid, NL101, provide a new therapeutic strategy against AML.

Disclosures

Jin: College of Medicine, Zhejiang University: Employment; The National Natural Science Foundation of China: Research Funding.
The Demographic, Clinical and Survival Rate of Classical Hogkings Lymphoma Patients in Oman, Retrospective Study
Authors: Al Hashmi Khalid Nasser , Alwahaibi Kamla , Al-Khabori Murtadha K.
Published: October 2019

Background and Objectives

Hodgkin's lymphoma (HL) is a B cell lymphoma characterized by the presence of Reed-Sternberg cells. HL comprises 1% of all cancer cases and 14% of all lymphoma cases. The clinical presentation and survival rate of these patients have not been described in Oman. We, therefore, aimed to describe the clinical characteristics and survival rate of patients with classical Hodgkin's lymphoma.

Methods

This is a retrospective study that was conducted in a tertiary care centers in the Sultanate of Oman. All Omani adults with histopathological confirmed diagnosis of classical Hodgkin's lymphoma from 2000 to 2016 were included in this study. The demographic, clinical, and survival rate were recorded and analyzed.

Results

A total of 273 patients (45 % females and 55% males, mean age 32) fulfilled the inclusion criteria with histopathological confirmed diagnosis of classical Hodgkin's lymphoma. The commonest presenting feature was lymph node enlargement (83%); followed by fever (48%). The most common classical HL histological subtype was nodular sclerosing HL (NSHL) (71%). The most common stage was II 34%. The most common chemotherapy regimen used as the first line was doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) (89%). Five and 10-year survival rates were 93.8 % and 99.2%, respectively.

Conclusions

This is the first study that demonstrates the demographic, clinical and survival rate of HL patients in Oman, and provides a general picture of the HL patients in our country.

Disclosures

No relevant conflicts of interest to declare.
Tandem Autologous Hematopoietic Stem Cell Transplantation Treatment for Adult T-Cell Lymphoblastic Lymphoma: A Multiple Center Prospective Study in Southwestern China
Authors: Liu Yao , Rao Jun , Li Jiali , Wen Qin , Lou Shifeng , Su Yi , Yang Tonghua , Wang Sanbin , Lei Gao , Zhang Cheng , Peiyan Kong , Gao Li , Mai-Hong Wang , Zhu Lidan , Xiang Xixi , Zhou Sha , Peng Xiangui , Zhong Jiangfan , Zeng Defu , Zhang Xi
Published: October 2019

Backgroud

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive lymphoma with very poor clinical outcomes which has not standard treatment. This study evaluated the efficacy and safety of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) treatment for adult T-LBL and assessed the factors that affect survival.

Methods

160 newly diagnosed adult T-LBL patients were divided into three groups: chemotherapy group (68 patients), single auto-HSCT group (46 patients), and tandem auto-HSCT group (46 patients). The primary outcome measure was failure-free survival. The intermediate primary outcomes were progression/relapse rate and overall survival. Factors influencing toxicity related to tandem auto-HSCT treatment and prognosis for the patients were analyzed as well.

Results

The 3-year progression/relapse rate of the tandem auto-HSCT group was significantly lower than that of the single auto-HSCT group and chemotherapy group (19.6% vs 45.7% and 70.6%, p < 0.05). The 3-year PFS rate and OS rate of the tandem auto-HSCT group (68.3% and 72.5%, respectively) were significantly higher than those of the single auto-HSCT group (41.5% and 55.4%, respectively, p < 0.05) and the chemotherapy group (23.3% and 43.3%, respectively, p < 0.05). In the tandem auto-HSCT group, age and disease status after the first transplant had an influence on the OS and PFS. Multivariate analysis identified disease status after the first transplant as the only independent prognostic factor for outcome in T-LBL.

Conclusions

Tandem auto-HSCT improves long-term survival of adult T-LBL patients. Disease status after the first transplant was an independent prognostic indicator for those patients.

Disclosures

No relevant conflicts of interest to declare.
Thalidomide Combined with Interferons for the Treatment of Recurrent or Refractory Non-Hodgkin's Lymphoma
Authors: Yuan Fangfang , Ai Hao , Yin Qingsong , Chen Lin , Mi Ruihua , Wei Xudong , Song Yongping , Liu Delong
Published: October 2019

This study examined the clinical efficacy and safety of thalidomide combined with interferons for the treatment of recurrent/refractory non-Hodgkin's lymphoma. We retrospectively analysed the clinical data of 42 patients with recurrent or refractory non-Hodgkin's lymphoma (NHL) who were treated with a regimen of thalidomide combined and interferon α-1b (IFNα-1b) at Henan Tumour Hospital from July 2007 to January 2017. Specifically, the patients initially received 100 mg thalidomide in tablet form once daily at bedtime. If the patient tolerated the drug, the dose was increased to 200 mg. Recombinant human interferon α-1b was subcutaneously injected at a dosage of 60 μg every other day over a period of four weeks. The efficacy was monitored throughout each treatment cycle, adverse reactions were evaluated, and the progress of the disease was assessed during follow-up visits. Relevant indicators, such as the overall response rate (ORR), the overall survival (OS), the progression-free survival (PFS) for all patients, and the safety of the regimen, were analysed. Forty-two patients were treated with a regimen of thalidomide combined with interferons for at least 1 period. The efficacy of the treatment was evaluated for each patient. The objective response rate (CR + PR) was 73.8%. The median overall survival time was 28 months and the median progression-free survival (PFS) time was 21 months. According to the standards of lymphoid malignancies classified by the WHO in 2001, 36 patients were diagnosed with B-cell lymphoma, 24 of whom suffered from recurrent or refractory mantle cell lymphoma (MCL). The combination of thalidomide and interferons improved the conditions of 16 MCL patients, 8 of whom experienced CR and 8 of whom experienced PR. The median OS was 28 months, and the median PFS was 19 months for the patients with MCL. The primary adverse effects of the regimen were drug-induced fever and joint pain caused by the IFN and neurotoxicity and constipation caused by the thalidomide. The adverse reactions ranged in severity from degree I~II and could be alleviated by symptomatic treatment. Serious adverse reactions, such as anaphylactic shock, deep vein thrombosis and bradycardia, did not occur.

Disclosures

No relevant conflicts of interest to declare.
EARLY Post-Transplant Events , Cost of Admission and Mortality, in Patients Undergoing Allogeneic Transplants from Identical Siblings, Unrelated Donors or Haploidentical Donors
Authors: SORA Federica , Chiusolo Patrizia , Laurenti Luca , Giammarco Sabrina , Autore Francesco , Innocenti Idanna , Sica Simona , Elisabetta Metafuni , Bacigalupo Andrea
Published: October 2019

Background. The outcome of allogeneic hemopoietic stem cell transplantation (HSCT) is measured in terms of graft versus host disease (GvHD), non-relapse mortality (NRM) and survival. Days of Hospital stay and number of re-admissions, are important surrogates of outcome, quality of life, and also of costs, but are usually not reported.

Aim of the study . Assess the number of days alive and outside the Hospital (DAOH) , together with the frequency of a new re-admission, in the first 100 days after transplant. Patients. We analyzed 212 patients who received an allogeneic HSCT from matched sibling (SIB) (n=64), unrelated donors (UD) (n=74) and family haploidentical donors (HAPLO) (n=74). Median age was 49 years (19-71), disease phase was in remission in 53%; diagnoses was acute leukemia (66%) , MDS (14%) chronic disorders 20%.

DAOH. The median DAOH for SIB, HAPLO and UD grafts was 78, 72 and 66 days (p=0.0001). The median DAOH for SIB patients was significantly longer than for UD patients (p=0.00002) and for HAPLO grafts (p=0.0008); the median DAOH for UD and HAPLO patients were comparable (p=0.4). Donor type was the strongest predictor of DAOH , followed by a Sorror score >2 (p=0.04).

Re-admission. Fifty four patients, of 185 discharged, required a re-admission for complications. the first cause for readmission was fever of unknown origin (54%), followed by GvHD (18,5% ) ,cystitis (8%) , relapse (7%) and respiratory problems (7%). The only factor predicting re-admission was advanced disease (p=0.01). Patients who were re-admitted to hospital within 100 days had a significantly higher risk of non relapse mortality (NRM) (25%) as compared to patient non re-admitted (5%) irrespective of the cause for re-admission (p=0.0001). In a multivariate analysis re-admission was the strongest predictor of NRM, with a risk ratio of 10.9 (p=0.0002).

Days of admission and cost. The average number of days in hospital within 100 days from transplant, was 37,6 for UD, 35,0 for HAPLO and 25,0 for SIBS (p=0.0002). The average cost of admission within 100 days from HSCT, was €69522 for UD, €64715 for HAPLO and €46225 euros for SIBS.

Conclusion. HAPLO transplants with PT-CY and UD transplants , have lower numbers of DAOH, as compared to SIB grafts, which implies longer stay in hospital and greater cost. Re-admission to Hospital within 100 days is predicted by disease phase and has a very strong impact on non relapse mortality.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Rituximab Maintenance Treatment for a Maximum of 5 Years in Follicular Lymphoma: Final Results of the Randomized Phase III Trial SAKK 35/03
Authors: Taverna Christian , Martinelli Giovanni , Hitz Felicitas , Mingrone Walter , Pabst Thomas , Cevreska Lidija , del Giglio Auro , Vanazzi Anna , Laszlo Daniele , Raats Johann , Rauch Daniel , Vorobiof Daniel , Lohri Andreas , Zucca Emanuele , Rueegsegger Celine , Rondeau Stephanie - , Rusterholz Corinne , Ghielmini Michele
Published: October 2019

Background: Follicular lymphoma is usually a disase with a prolonged course and a chemotherapy-free regimen might be a favourable treatment strategy. SAKK 35/03 investigated two different durations of rituximab maintenance (5 years vs. 6 months) in patients with follicular lymphoma after induction with 4 weekly doses of rituximab monotherapy. With a median follow-up of 6.4 years we were not able to show a benefit with long-term rituximab maintenance up to five years in event-free survival (EFS) or overall survival (OS ). Here we report the final results with a median follow-up of 10 years.

Methods: 270 patients (median age 57 years: range 25-82) with untreated, relapsed, stable or chemotherapy resistant follicular lymphoma were treated with 4 doses of rituximab monotherapy in weekly intervals (375 mg/m²). Patients achieving at least a partial response were randomly assigned to receive maintenance therapy with one infusion of rituximab every 2 months, either on a short-term schedule (four administrations) or a long-term schedule (maximum of five years or until disease progression or unacceptable toxicity). The primary endpoint was EFS . Progression-free survival (PFS), OS, and toxicity were secondary endpoints. Comparisons between the two treatment arms were performed using the log-rank test for survival endpoints.

Results: 165 patients were randomly assigned to short-term (n=82) or long-term (n=83) maintenance. At a median follow-up period of 10 years, the median EFS is 3.4 years (95% CI 2.1-5.5) in the short-term arm and 5.3 years (95% CI 3.5-7.5) in the long-term arm. Using the pre-specified log-rank test this difference is statistically not significant (p=0.39 ). There is no significant difference in PFS and OS. Median OS in the short-term arm is 11.0 years (95% CI 11.0, NA ) and not reached in the long-term arm (p=0.80). The incidence of subsequent cancers increased in both arms over time, nine patients developed a subsequent cancer in the short-term maintenance arm and 10 in the long-term maintenance arm. There was no major additional toxicity with longer follow-up.

Conclusions : Even with a long follow-up of 10 years we were not able to show a significant benefit of long-term compared to short-term rituximab maintenance in EFS, PFS and OS. Treatment strategies and study designs need to take these results into consideration in order to guarantee optimal medical and scientific results.

Disclosures

Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.
Impact of Immune Thrombocytopenia in Patients Admitted with Coronary Artery Disease: Results from National Inpatient Sample 2009-2011
Authors: Aryal Madan , Basnet Sijan , Dhital Rashmi , Gosain Rohit , Donato Anthony
Published: October 2019

Background

Patients with immune thrombocytopenia (ITP) may be at increased risk of thromboembolism related to different causes, including the use of thrombopoietin receptor agonists and splenectomy. Patients with ITP who develop coronary artery disease (CAD) can be a further challenge given their risk of both thromboembolism and bleeding, which may significantly increase the risk of mortality and length of stay (LOS) compared to patients who do not have ITP. We aimed to study the impact of ITP in hospital outcomes of patients with CAD.

Methods

We utilized the National Inpatient Sample database from years 2009 - 2011. We selected non-pregnant inpatients over the age of 18 with history of CAD. We selected patients with CAD and ITP based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). We used STATA version 13.0 (College Station, TX) for database analysis.

Results

A total of 4,777 cases of ITP with CAD were identified compared to 2,614,008 without ITP (Table 1). Logistic multivariable analyses found that patients with ITP had higher in-hospital mortality (95% CI: 1.21 to 1.55, p=0.0001) and LOS (95% CI: 1.32 to 1.72, p<0.0001) after adjustment for age, sex, race, smoking, obesity, dyslipidemia, diabetes, hypertension, chronic kidney disease, peripheral vascular disease, smoking, obesity, stroke, and Charlson comorbidity index (Table 2).

Conclusion: Our study shows that in patients with coronary artery disease-associated ITP, adjusted LOS and mortality was significantly higher compared to patients without ITP.

Disclosures

No relevant conflicts of interest to declare.
Long Term Survival Analysis of Multiple Myeloma Patients Receiving Induction Therapy+ Autologous STEM CELL Trasplantation, Comparing Velcade-Dexametasone to Alkylating Polichemotherapy As Induction Therapy
Authors: Caceres Sara , Cardesa Rocio , Cabrera Carmen , Bañas M. Helena , Ibañez Fatima , Prieto Julio , Groiss Jorge , Toran Damian , Hernandez Carmen , Sergio Ortegon , Elena Duvos , Casado Maria Soledad , Cerezo Esperanza , Siguenza Raul , Suarez-Varela Sara , Carnicero Fernando , Martin Mateos Maria Luisa , Arcos Maria J. , Rodriguez Angel , Moriano Baldomero , Casas Ignacio , Perez Leal Francisco , Vazquez Godoy Teresa , Bagace Jose M. , Sanz Miguel A. , Bergua Burgues Juan Miguel Miguel
Published: October 2019

Introduction: Multiple Myeloma (MM) is an incurable disease. In young patients, autologous bone marrow transplantation (ABMT) remains a cornerstone treatment after induction therapy. Induction therapy has varied during time, from alkylating polychemotherapy (VBAD,VCMP) or VAD chemotherapy (AVAD) to Velcade-Dexametasone based regimens (VD). We present results of follow-up of a large cohort of patients treated with ABMT. We described overall survival (OS; from transplant to death by any cause) and progression free survival (PFS; from transplant to death by any case or progressive disease defined by reappearance by inmunofixation, or duplication of monoclonal peak after ABMT) , and the impact of induction therapy regiments.

Patients: 183 patients transplanted from 2002 to 2017. The median age of the patients was 59 years (33-72). Before 2008 all the patients were treated in alkylating based chemotherapy (42 patients). After 2008 patients were treated with VD based regimens (141patients). Only 12 patients received maintenance therapy based in PETHEMA trials 2005 and 2012. No one patient received a planed second transplant; only 32 patients received a second transplant after relapse as consolidation therapy.

Results: Median follow-up of patients still alive is 3.65 years (0.15-14.77). Median OS of all patients was 9.12 years (95% confidence interval (CI): 6.28-NR); Median PFS was 3.02 years(95% CI: 2.46-3.76). At 13 years only 2% of patients remains progression free (CI: 0.00-17%). There were significant differences between patients treated before and after VD regimens. The median OS of patients treated with APVAD was significantly shorter compared to VD (6.22 years, CI[3.39-12] vs. NR, CI[6.28-NR], p=0.025) (HR=0.49, p=0.01).

Conclusions: VD schemes of induction before ABMT have improved remarkably OS inpatients with Myeloma; nonetheless, plateau is not observed in EFS. Further analysis must address if EFS could represent a strong indicator of OS, mainly due to novel effective salvage therapies after relapse/refractoriness could be a confounding factor.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Development of a Clinical Prediction Rule for the Risk of Venous Thromboembolism in Patients with Acute Leukemia
Authors: Al-Ani Fatimah , Wang Yimin Pearl , Lazo-Langner Alejandro
Published: October 2019

Background: The impact of venous thromboembolism (VTE) on morbidity and mortality is significant in hematological cancer patients, including acute leukemia (AL). However, VTE in AL receives little attention in comparison to other more frequently occurring complications. Identifying risk factors for the development of VTE among patients with AL will enable clinicians to stratify their patients according to their VTE risk and consider them accordingly for tailored surveillance or prophylaxis strategies.

Methods: We aimed to derive a prediction rule for assessing VTE risk in AL patients. We conducted a retrospective cohort study of consecutive adult patients diagnosed with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) diagnosed between June 2006 and June 2017 at the London Health Sciences Centre, a tertiary care center in London, Ontario, Canada. Included participants were followed from diagnosis until last follow up, the occurrence of VTE, or death. Potential predictors were compared between groups using χ2 or Fisher's exact tests for categorical variables and T tests for continuous variables. Potentially significant predictors were evaluated using logistic regression and Cox regression analysis. A risk score was derived based on weighed variables included in the final model and compared using Kaplan-Meier survival analysis.

Results: A total of 396 patients with AL (335 AML and 61 ALL) were included in the preliminary analysis. Population characteristics are shown in the Table. VTE occurred in 68 (17%) patients. Median time to VTE was 3 months (Interquartile range 1-5). In univariate analysis a diagnosis of ALL, prior history of VTE, platelet count at presentation and the number of attempts for line insertion were potential predictors. However, in multivariate analysis only ALL diagnosis and prior history of VTE remained significant. A score was derived based on these predictors (ALL 1 point; Prior VTE 2 points). Kaplan-Meier analysis showed good discrimination between categories (Figure; Log-rank p<0.001).

Conclusion: We derived a score predictive of VTE in acute leukemia patients. Further confirmatory and validation studies are ongoing.

Disclaimer. FA-A is a fellow of the CanVECTOR Network; ALL-L is an investigator of the CanVECTOR Network. This study was funded by the CanVECTOR Network which receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654).

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Inhibition of Autophagy with 3-Methyladenine Potentiates Bortezomib-Induced Apoptosis of Myeloma Cell Via up Regulation of Mitochondrial Reactive Oxygen Species
Authors: Mun Yeung-Chul , Ahn Jee Young , Yoo Eun Sun , Lee Kyoung Eun , Nam Eunmi , Lee Soon Nam , Woo Hyun Ae , Rhee Sue Goo , Seong Chu Myong
Published: October 2019

Backgrounds : Autophagy plays an important role in the pathogenesis of multiple myeloma. Autophagy usually acts on a pro-survival mechanism, and cooperates with the ubiquitin proteasome system in the homeostasis of myeloma cells by degrading excessive and misfolded proteins for energy recycling. Therefore, the inhibition of autophagy could effectively induce death and could synergize with proteasome inhibitors in myeloma cells. In this study, we investigated the synergistic mechanism of apoptosis with bortezomib (BTZ) and autophagy inhibitors in the MM cells.

Methods : We evaluated the change of autophagy, apoptosis, mitochondrial ROS and cellular level of redox enzymes, including peroxiredoxin (Prx), thioredoxin (Trx), thioredoxin reductase (Trx-R) using human myeloma cell lines, MM.1S and MM.1R during BTZ treatment. To study the status of oxidation for redox enzyme, sulfinic acid (SO2) or multimeric form of Prx, Trx and Trx-R by western blot were measured using non-reducing or reducing gel.

Results : Mitochondrial over cytosolic ROS of MM cells was increased significantly after 24 hour of BTZ (2.5 nM) treatment. Apoptosis of MM cell after BTZ treatment was increased in concordance with mitochondrial ROS increment of MM cells. N-acetylcystein (NAC) reversed BTZ-induced mitochondrial ROS elevation and apoptosis of MM cells as well. Increased expressions of cleaved caspase-9 and cleaved caspase-3 were also observed during BTZ-induced MM cell apoptosis. LC3-II expression was elevated along with increment of mitochondrial ROS and apoptosis of MM cells after BTZ treatment. Oxidation of PRX4 and TRX2 was observed during BTZ-induced apoptosis of MM cells. After treatment of NAC, LC3-II and PRX4/TRX2 expression was reversed. Inhibition of autophagy with 3-Methyladenine (3-MA) not only resulted in a further increase in BTZ-induced apoptosis but also induced mitochondrial ROS in MM cells.

Conclusions : Autophagy is induced during BTZ treatment in MM cells. Our experiment showed crosstalk between autophagy and mitochondrial ROS and its redox enzymes during BTZ-induced MM cell apoptosis. Inhibition of autophagy with 3-MA potentiates BTZ-induced apoptosis of MM cells via up regulation of mitochondrial ROS. Our results provide new perspective on the cellular mechanism of action of BTZ and support the synergism of BTZ with autophagy inhibitor for an improved therapy of the multiple myeloma.

Disclosures

No relevant conflicts of interest to declare.
Reduction of Graft Rejection By Fludarabine Combined Busulfan, Cyclophosphamide and Antithymocyte Globulin Conditioning in Cord Blood Transplantation for Children with Wiskott-Aldrich Syndrome
Authors: Xiao Peifang , Lu Jun , Li Jie , Zheng Defei , Gao Li , Guo Ailian , Liu Hu , Liu Suxiang , He Hailong , Hu Shaoyan
Published: October 2019

Background and Objectives: Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency with microthrombocytopenia. Hematopoietic stem cell transplantation is a curative treatment for WAS. Unrelated cord blood transplantation (UCBT) become a more successive alternative donor transplantation for WAS with the improvement of high resolution HLA-typing method. However, graft rejection is the primary cause for mortality of WAS after UCBT. We hypothesized that the addition of fludarabine to a myeloablative conditioning regimen with antithymocyte globulin (ATG) would support engraftment for these children.

Methods: Seventeen Children with WAS underwent UBCT matched 6-10/10 at higher resolution (HLA-A, -B, -C, -DRB1and DQB1) in our center between 2013 and 2018. The conditioning regimen consisted of fludarabine 160 mg/m2 , busulfan (BU)12.8 mg/kg, cyclophosphamide (CY)120 mg/kg, ATG 7.5 mg/kg, and cyclosporine and mycophenolate for GVHD prophylaxis. Median follow-up time is 2.5 years (range, 0.2 to 3.5 years).

Results: All children had sustained donor cell engraftment and are stable engraftment. Twelve (71%) patients had cytomegalovirus (CMV) antigenemia and no one developed into CMV disease. Six (35%) children underwent acute Graft-versus-host disease (GVHD) (grade II-IV) and four (24%) children developed into chronic GVHD (cGVHD). Among these cases, only one child with HLA matched 6/10 died of kidney failure because of cGVHD. He experienced aGVHD with skin bullosa. Sixteen (94%) children are survival.

Conclusion: Conditioning regimen consisted of Fludarabine combined BUCY and ATG was able to reduce graft rejection in the WAS children after UCBT without increasing infection related mortality. Future efforts will focus on further reducing rates of acute GVHD and extensive cGVHD.

Disclosures

No relevant conflicts of interest to declare.
Silencing HDAC3 Enhances Apoptosis of Acute B Lymphoblastic Leukemia Cells smurf2 Inducing By Inhibiting JAK/STAT3 Signal Pathway
Authors: Guo Yongling , Ma Dan , He Zhengchang , Xiong Jie , Kuang Xingyi , Wang Weili , Yu Kunling , Zhang Zhaoyuan , Wang Jishi
Published: October 2019

Purpose Smad ubiquitin regulatory factor 2(Smurf2) as a member of ubiquitinated E3 ligase was certificated to regulate the ubiquitination level of target gene. In this study, smurf2 as tumor suppressor was studied in acute B lymphoblastic leukemia, Histone deacetylases 3(HDAC3) which was connected with smurf2 was related with poor prognosis. It is further proved that smurf2 and HDAC3 were expected to be therapeutic targets for B-ALL cells and improve the prognosis of patients with B-ALL.

Methods Realtime-PCR and westernblot were used to detect the expression of smurf2 and HDAC3 in healthy donors and B-ALL patients by us. Sup-B15 and CCRF-SB were treated with MG-132, small interfering RNA of smurf2 or HDAC3. Up-regulating smurf2 plasmid was also transfected to B-ALL cells by lipo3000. Flow cytometry and westernblot were used to validate the difference of apoptosis and cell cycle.

Results Smurf2 mRNA in B-ALL patients was significantly lower than that in healthy donors. HDAC3 was higher in B-ALL patients than that in healthy donors. Protein level of smurf2 and HDAC3 was consistent with mRNA level. Up-regulating smurf2 by plasmid or MG-132 and silencing smurf2 could influence HDAC3, which further depressed JAK/STAT3 signal pathway inducing apoptosis of B-ALL cells. Sup-B15 and CCRF-SB were treated with siHDAC3 and MG-132 for 24h, we discovered that silencing HDAC3 enhanced the apoptosis level of B-ALL cells MG-132 inducing by depressing JAK/STAT3 pathway. It was expected to become a therapeutic target for improving the clinical prognosis of B-ALL patients. On the other hand, we found that MG-132 caused G2/M phase arrest in B-ALL cells and successfully inhibited the JAK/STAT3 pathway leading to apoptosis.

Conclusions Silencing HDAC3 inhibited the JAK/STAT3 pathway and further enhanced apoptosis in B-ALL cells MG-132 inducing. HDAC3 and smurf2 were expected to become therapeutic targets for clinical treatment of acute B lymphocytic leukemia and improve survival rate of leukemia patients.

Key words Smurf2; HDAC3; Apoptosis; Prognosis;

Disclosures

No relevant conflicts of interest to declare.
Preclinical Evaluation of an Engineered AAV Capsid in Non-Human Primates for the Treatment of Haemophilia B
Authors: Dane Allison , McIntosh Jenny , Lee Doyoung , Sheridan Rose , Maginn Mark , Corbau Romuald , Davidoff Andrew M. , Nathwani Amit C
Published: October 2019

Introduction

Over recent years, proof-of-concept academic and early phase commercial trials have demonstrated long-term therapeutic benefit of liver directed AAV-mediated gene transfer of human FIX (hFIX). Extending this success to a greater number of haemophilia B patients is hampered by the need for large vector doses required for efficient gene transfer and associated liver toxicity. To improve potency, we focused on developing a novel synthetic capsid, AAVS3, to increase human hepatocyte transduction.

Here we present the preclinical in vitro and in vivo evaluation of AAVS3 pseudotyped vectors. In addition to showing strong liver tropism we demonstrate clinically relevant expression levels of hFIX expression in non human primates.

Methods

Primary human hepatocyte cultures were used to compare transduction efficiency of our novel capsid with AAV5 and AAV8, variants currently in the clinic. To extend this data in vivo, a humanised mouse liver model was utilised. Subsequently, fourteen Rhesus macaques were dosed with AAVS3 pseudotyped FIX vectors, via saphenous vein injection. Levels of hFIX were determined using an ELISA assay that is able to distinguish hFIX protein from the native Rhesus macaque FIX protein. At harvest biodistribution of vector was detected by quantitative PCR.

Results

We demonstrate that gene transfer efficiency with AAVS3 was up to 10-fold higher in primary human hepatocytes, when compared to vectors pseudotyped with AAV serotype 5 or 8 capsids. In addition, studies in a chimeric human-murine liver model revealed AAVS3 was 6-fold more efficient at transducing human hepatocytes compared with an AAV8 vector. Using two distinct optimised FIX expression cassettes, we demonstrate highly efficient gene transfer in Rhesus macaques. Indeed, AAVS3 FIX vectors injected at clinically relevant doses of 0.93 x1012 to 2.56 x1013 vg/kg achieved mean peak levels of 0.546 and 21.7µg/ml of hFIX respectively (~11% to ~430% of normal levels). Biodistribution studies showed strong liver tropism following peripheral vein administration with minimal distribution to other organs at or below the level of detection. No vector associated lesions or adverse events were observed in the liver.

Conclusion

Collectively, these data support further evaluation of an AAVS3 pseudotyped vector in humans with the aim of achieving transduction of a larger proportion of hepatocytes using a lower, potentially safer dose of vector than achieved with AAV8.

Disclosures

Dane: Freeline: Employment. Sheridan:Freeline: Employment, Equity Ownership. Maginn:Freeline: Consultancy, Equity Ownership. Corbau:Freeline: Employment, Equity Ownership. Nathwani:Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioMarin: Consultancy, Patents & Royalties; UniQure: Patents & Royalties.
Prognostic Significance of FDG-PET/CT on Determining Upfront Autologous Stem Cell Transplantation for the Treatment of Peripheral T Cell Lymphomas
Authors: Ahn Seo-Yeon , Jung Seung-Yeon , Jung Sung-Hoon , Ahn Jae-Sook , Lee Je-Jung , Kim Hyeoung-Joon , Kang Sae-Ryung , Han Yeon-Hee , Kwak Jae-Yong , Yhim Ho-Young , Yang Deok-Hwan
Published: October 2019

Purpose: The clinical role of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) in performing upfront high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) remains unclear in peripheral T cell lymphomas (PTCLs). This study investigated the prognostic relevance of interim and final FDG-PET/CT in predicting the outcome of upfront ASCT for the treatment of PTCLs.

Method: The study conducted newly diagnosed 96 patients with PTCLs who aged under 65 years between January 2005 and December 2016 from two independent institutions. For making a comparison of clinical outcome between transplant and non-transplant patients according to interim or final FDG- PET/CT, 37 transplanted and 59 non-transplanted patients with the same populations were evaluated as a comparative group (non-ASCT). The enrolled patients were treated with mainly anthracycline-based chemotherapy except patients with NK/T cell lymphoma who were treated with non-anthracycline-based. If achieved complete or partial remission after primary treatment, patients proceeded to upfront ASCT. FDG-PET/CT was performed at the time of diagnosis, interim, and after primary treatment. The response of interim or final FDG-PET/CT was analyzed by visual assessment using Deauville five-point scale (5-PS).

Results: The characteristics of transplant patients were similar to non-transplant patients except two features (IPI score, CT response). Final FDG-PET/CT response (P<0.001, Hazard ratio (HR) 3.51), CT response (P<0.001, HR 2.11) and age (P=0.005, HR 1.07) were significant prognostic factors of progression-free survival (PFS) in transplant patients on multivariate analysis. In non-ASCT patients, final FDG-PET/CT response (P<0.001, HR 9.65), prognostic index for T-cell lymphomas (PITs) score (P=0.001, HR 5.24), and CT response (P<0.001, HR 2.34) were prognostic for PFS. After a median follow-up of 60.8 months, 5-year PFS rates of ASCT and non-ASCT patients according to interim FDG-PET/CT response were 75.5 vs 74.5% of Deauville score 1-2, 20% vs 22.2% of Deauville score 3 and 33.3% vs 42.2% of Deauville score 4, respectively (P=0.092, P=0.005; Figure 1A, 1C). 5-year PFS rates according to final FDG-PET/CT response of ASCT and non-ASCT patients were 70.2% vs 80.5% of Deauville score 1-2, 22.2% vs 25% of Deauville score 3 and 0% vs 0% of Deauville score 4, respectively (P<0.001, P<0.001; Figure 1B, 1D).

Conclusion: Final FDG-PET/CT response based on Deauville 5-PS had prognostic significance on the treatment outcome of PTCLs regardless of upfront ASCT. However, patients with ≥ 3 of Deauville score assessed by interim or final FDG-PET/CT had poor prognosis even though performing upfront ASCT.

Disclosures

No relevant conflicts of interest to declare.
Thromboembolic Complications in Patients with Sickle Cell Disease
Authors: Alkindi Salam , Al-Ghadani Anwaar , Al-zeheimi Samah , Pathare Anil
Published: October 2019

Background and Purpose: Venous thromboembolism (VTE) is common in patients with sickle cell disease (SCD). Traditional risk factors such as central venous catheters, frequent hospitalization, orthopedic surgeries for avascular necrosis, and pregnancy often leads to an increased incidence of VTE in the SCD. In addition, SCD itself appears to be a hypercoagulable state with many SCD-specific factors such as genotype, splenectomy and thrombophilia modifying the risk of VTE. This study aims to assess the clinical and pathological characteristics of VTE amongst a cohort of patients with SCD at the Sultan Qaboos University Hospital and determine its relation to morbidity and mortality.

Methodology: In this retrospective case control study, medical details of all patients with SCD who developed thromboembolic complications over the past decade were retrieved from the hospital information system. SCD patients matched for age and gender (2:1 ratio) who did not have thromboembolic complications but had a thrombophilia screen performed served as controls. The study was approved by the local Medical Research and Ethics Committee.

Results & Discussion: A total of 53 SCD patients were enrolled [34 cases, 19 controls] in this study. Amongst the 34 cases (mean age-30 yrs.), 18 had pulmonary embolism, eight had deep venous thrombosis, whereas, three each had cerebral venous thrombosis and portal venous thrombosis and one each had cerebral arterial thrombosis and VTE. A higher incidence of autosplenectomy(69.7% v/s 52.6%) and central venous catheters(42.4% v/s 5.3%) were significantly associated with thrombosis (p<0.05, Chi Square test). High LDH levels, WBC and Platelet counts were significant risk factors(p<0.05) for VTE. 21 patients [63.6%] amongst the cases developed acute chest syndrome, where 3[9%] had cerebrovascular accident. Mortality was seen in seven cases [21%].

Conclusions: The study shows that thromboembolic complications in SCD has a high impact on the morbidity and mortality. It confirms PE as the leading cause for VTE in SCD with asplenia, central venous catheter, high LDH, WBC and Platelet counts being significant risk factors.

Disclosures

No relevant conflicts of interest to declare.