bluuebunny/crossref_metadata_2025 huggingface dataset:
Ifosfamide, Methotrexate, Etoposide, and Prednisolone (IMEP) Plus L-Asparaginase As a First-Line Therapy Improves Outcomes In Stage III/IV NK/T-Cell Lymphoma, Nasal Type (NTCL)
Authors: Kim Miso , Kim Ki Hwan , Keam Bhumsuk , Lee Se-Hoon , Kim Dong-Wan , Lee Jong Seok , Heo Dae Seog , Kim Tae Min
Published: October 2019

Background

The prognosis of NTCL patients presenting in stage III/IV is extremely poor and there is no standard chemotherapy. Although L-asparaginase (L-asp) is known to be effective for NTCL, its significance has not been well demonstrated in a relatively homogenous subset. In addition, there were few studies to evaluate treatment outcomes and prognostic factors in stage III/IV NTCL. This study was undertaken to evaluate the efficacy of L-asparaginase-based combination chemotherapy (IMEP plus L-asp) and prognostic factors in stage III/IV NTCL.

Methods

A total of 70 patients with newly diagnosed NTCL at stage III/IV were enrolled from 3 Korean centers between Jan 2000 and Feb 2013. All patients received IMEP plus L-asp (N=22) regimens or combination chemotherapy without L-asp (N=48) as a first-line treatment. Recurrent cases were excluded. Clinical prognostic factors, treatment outcomes, and prognostic scores were compared between the groups. Independent prognostic factors for survivals were identified using multivariate analyses.

Results

The median age was 48.5 years (range, 18-73 years) with a male-to-female ratio of 2.2:1. After a median follow-up period of 12.8 months (range, 1.1-186.6 months), median progression-free survival (PFS) and overall survival (OS) were 5.6 months and 12.3 months, respectively. Clinical factors and treatment outcomes were compared between IMEP plus L-asp and chemotherapy without L-asp groups (Table 1). Higher response rate (RR) and complete response (CR) rates were observed in patients treated with IMEP plus L-asp compared with those treated with chemotherapy without L-asp (RR 90.0% vs. 34.8%, P< 0.0001; and CR rates 65.0% vs. 21.7%, P = 0.001). In addition, PFS and OS were significantly higher for IMEP plus L-asp group compared with chemotherapy without L-asp group (Table 1). Use of chemotherapy without L-asp (hazards ratio [HR]=2.29, 95% confidence interval [CI] 1.22-4.29; P = 0.010) and poor performance status (HR=2.10, 95% CI 1.23-3.59; P = 0.007) were independent predictors for reduced PFS. Independent factors adversely affecting OS were poor performance status (HR=1.99, 95% CI 1.08-3.65; P = 0.027), 2 or more extranodal sites (HR=2.91, 95% CI 1.25-6.77; P = 0.013), and chemotherapy without L-asp (HR=3.51, 95% CI 1.53-8.06; P= 0.003).

Conclusions

L-asparaginase-based combination chemotherapy (IMEP plus L-asp) is active against stage III/IV NTCL and an independent predictor for improved survivals. L-asp containing regimen might be useful as a first-line treatment for stage III/IV NTCL.

Disclosures:

No relevant conflicts of interest to declare.
Inhibition Of Wnt Signaling In Chronic Lymphocytic Leukemia Has Synergistic Cytotoxicity With Ibrutinib
Authors: Wu Christina C.N. , Choi Michael Y. , Lao Fitzgerald , Kipps Thomas J. , Carson Dennis A.
Published: October 2019

The Wnt pathway plays a major role in early embryonic development and in various cancers. We found that CLL cells have activated Wnt-signaling (Proc Natl Acad SciUSA 2004, PMID: 14973184) and express genes commonly associated with B-cell progenitors or stem cells, especially the Wnt factor-related genes such as LEF1, Wnt16, and Frizzled3 (FZD3). Also, compared to normal B lymphocytes, CLL cells express high levels of the putative cancer stem cell marker Aldehyde Dehydrogenase (ALDH), especially those CLL cells with high-risk prognostic features (Leuk and Lymph, 2013, PMID 22784365) and are highly sensitive to inhibitors of Wnt signaling (Proc Natl Acad SciUSA 2004, PMID: 3156152). Finally, next generation DNA sequencing studies have identified mutations in 12 different Wnt pathway genes in 15-20% of CLL patients. Collectively, the results of these studies imply that Wnt-signaling may be an excellent target for developing effective novel therapies for patients with CLL (Oncotarget 2011, PMID: 21860066).

We compared different classes of Wnt inhibitors identified by screening of natural compound and small molecule libraries for cytotoxicity in primary leukemic cells from patients with CLL. Among all the Wnt inhibitors tested, Salinomycin and Agelastatin (naturally occurring compounds targeting LRP5/6 degradation or LEF1 down-regulation as previously reported by our groups) consistently showed dose dependent cytotoxicity at concentrations lower than 1 µM. In contrast, small molecule Wnt inhibitors targeting more proximal elements of the Wnt pathway, porcupine (Wnt-C59) and tankyrase, (XAV-939) had little direct effect on in vitro CLL cell viability even at 10 µM.

The Wnt inhibitors were also utilized as tool compounds to evaluate the effect of combined inhibition of the Wnt pathway and other pathways. Interestingly, we identified synergistic activity between Wnt inhibitors and other inhibitors, including Ibrutinib and Idelalisib. By colorimetric and flow cytometry assays, we demonstrated that significant cell death was induced with combinations of the agents at concentrations at which little or no cytotoxicity was seen with either agent alone. The studies further demonstrate that the Wnt pathway is a viable target for the treatment of CLL and may potentiate other emerging CLL therapies.

Disclosures:

Kipps: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals: Speakers Bureau; Abbvie: Membership on an entity’s Board of Directors or advisory committees, Research Funding.
Visibility Of Bone Lesions In Relapsed Multiple Myeloma Can Be Improved By FDG-PET Scanning
Authors: De Waal Esther G.M. , Slart Riemer H.J.A. , Leene Marnix J. , Kluin Philip M. , Vellenga Edo
Published: October 2019

Osseous involvement is one the predominant features of patients with multiple myeloma (MM). Whole body X-ray (WBX) is the standard method for detecting skeleton abnormalities but has limited value in relapsing disease since it cannot make a distinction between old and new active skeleton lesions. Therefore changes in metabolic activity might be a more useful method to detect new skeleton lesions in MM. This can be assessed by [F-18] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. Consequently WBX and FDG-PET was studied in relapsing MM prior to treatment. In addition immunohistochemical staining on bone marrow biopsies was performed for glucose transport protein (GLUT) 3 expression, micro vessel density (MVD), and vascular endothelial growth factor (VEGF) to demonstrate whether these parameters might be predictive for the in vivo scanning results. This study included 44 patients (median age 62 yr (range 48-78)) with a median of 3.5 (range 2-12) relapses. Thus far 86% of the patients were treated with autologous stem cell transplantation in combination with bortezomib (78%) or lenalidomide (65%). New lesions on FDG-PET were more frequently demonstrated than new lesions on WBX (p=0.00001). In 78% of the patients FDG-PET demonstrated a median of 4 lesions (range 0-22) per patient with a median standard uptake value (SUV) max of 5.7 (range 0-24). In 42% of the patients new X-ray lesions (median 0 (range 0-7)) were demonstrated and these were concordant with the results of FDG-PET. In 5 % of the patients new X-ray lesions were observed without FDG-PET lesions. For the relapsing patients treatment consisted of dexamethasone in combination with bortezomib (65%) or lenalidomide (50%). CR was obtained in 27% of the patients, PR in 39% and progressive disease in 22%. Average time to next treatment (TTNT) was 11.7 months (2-43). However FDG-PET positivity was not predictive for PFS (p =0.55) and OS (p=0.40) neither if PET positivity was defined as more than 3 lesions nor if the cut off value of SUV max > 4.2 was applied. Immunohistochemical staining on bone marrow biopsies (n=20) with CD34 demonstrated a significant increased MVD of 39 ± 54 (mean ± SD, normal bone marrow MVD 3.5 ± 2.9), in particular when clusters of plasma cells were present. These enhanced MVD was associated with a significant increased expression of VEGF and GLUT-3. However MVD (p = 0.16), VEGF (p = 0.70) or GLUT-3 (p =0.70) expression were not predictive for having a positive or negative FDG-PET. In summary, our results demonstrate that FDG-PET is more informative than WBX for detecting skeleton lesions in relapsing MM patients. However, and in contrast to what was previously shown in patients with newly diagnosed MM, FDG-PET it is not predictive for treatment outcome. This might be due to heterogeneity in studied patients and treatments.

Disclosures:

No relevant conflicts of interest to declare.
Huachansu Injection Combined With Cemt Regimen On Patients With Relapsed Or Refractory Multiple Myeloma
Authors: Liu Qingchi , Zhang Huimin , Feng Xinwang , Wang Shujie
Published: October 2019

Objective

To observe the short-term treatment effect of Huachansu Injection combined with CEMT regimen on patients with relapsed or refractory multiple myeloma and evaluate the quality of life of the patients.

Methods

The 40 patients of relapsed or refractory multiple myeloma were divided into two groups, 20 patients were in the Chinese and western medicine treatment group, the rest in the control group. The patients in the control group received the CEMT regimen (Carboplatin, Etoposide, Methotrexate, and Thalidomide);and those in the Huachansu group received Huachansu injection on the basis of the CEMT treatment. The Huachansu injection in the 500ml 5% Glucose injection was given by intravenous drop once daily, 10'20ml for each time. The general treatment lasted 3 months and one treatment period was 4 weeks,during each period the patients received the  medicine treatment for 7 days and had a rest for 2 days. The patients in each group were given the syndrome differentiation type of traditional chinese medicinal broth,decoction, once a day. The QLQ-C30 Quality of Life Questionaire(Chinese Version V3.0for clinical use) worked out by EORTC(European Organization For Research And Treatment Of Cancer) was adopted to evaluate and research the patients’ quality of life before and after the treatment.

Results

5 cases had complete remission,6 had part remission, 2 had stable and 7 cases had progresss and the total effectiveness reaches 65.0%  in the Huachansu group group. In the control group, 3 cases had complete remission,4 had part remission, 1 had stable and 12 had progress and the total effectiveness reaches 40.0%. The effective rate of Huachansu group is higher than the control group,and the differences was statistically significant(P<0.05).  The quality of life questionaire result also shows that the overall health status and the overall life quality of the patients in both groups have been improved as well as the patients’ physical and mental status. The difference in the patients’ life quality is less obvious in both groups. The 3-month treatment on their role functions and social functions have no outstanding effects after comparation.

Conclusion

The Huachansu Injection combined with CEMT regimen not only  has excellent effect on on patients with relapsed or refractory multiple myeloma,but also improves the quality of life of patient.

Disclosures:

No relevant conflicts of interest to declare.
Comparison Between Bone Marrow Mesenchymal Stromal Cells (BM-MSC) and Lung Mesenchymal Stromal Cells (Lung-MSC) For Epithelial Regeneration
Authors: Ricciardi Mario , Midolo Martina , Bassi Giulio , Malpeli Giorgio , Bifari Francesco , Chilosi Marco , Zanotto Marco , Carusone Roberta , Zanoncello Jasmina , Pizzolo Giovanni , Krampera Mauro
Published: October 2019

Developing a therapeutic strategy for lung regeneration still remains complex. Stem cell-based therapeutical approaches have been suggested as a potential tool; among them, human mesenchymal stromal cells (MSC) possess some promising features to this aim. MSC are stem cells residing in many tissue, i.e. bone marrow (BM), adipose tissue, cord blood, lung, etc., and they are capable of differentiating into different cell types of mesodermal origin, such as fat, bone and cartilage.

To assess MSC epithelial differentiation potential, through a partially known process called Mesenchymal to Epithelial Transition (MET), MSC were collected from bone (BM) aspirates and lung biopsies after informed consent. MSC were characterized by immunophenotyping and clonogenicity assay. MSC mesodermal differentiation potential was assessed by testing their ability to differentiate into adipocytes, osteoblasts and chondrocytes. MSCs at different culture passages were induced to acquire the epithelial phenotype by culturing in presence of retinoic acid. The epithelial differentiation was checked by quantitative RT-PCR, immunofluorescence and a functional assay based on the Trans Epithelial Electrical Resistance Measurement (TEER).

In presence of retinoic acid, MSC from BM and, mostly, lung upregulated a panel of general epithelial genes (cytokeratin 18, occludin, tight junction protein and claudin) and downregulated some specific mesenchymal markers (smooth muscle actin, snail2, vimentin, THY1), as detected by quantitative RT-PCR. Immunofluorescence confirmed the presence of E-cadherin4, occludin and cytokeratin 18 in a small number of cells (about 0,2 %). Trans Epithelial Electrical Resistance (TEER) measurement confirmed that MSC can acquire in vitro partial epithelial polarization after retinoic acid treatment.

These data show that MSC can be induced to differentate into cells resembling some morphological, phenotypical and functional properties of epithelial cells. BM-MSC are less prone to acquire an epithelial phenotype as compared to hLung-MSC. Additional in vivo studies on mouse model with lung damage are in progress.

Disclosures:

No relevant conflicts of interest to declare.
Improved Vaccine Design For Adoptive Immunotherapy In Hematological Malignancies Through Chemically Modified Minor Histocompatibility Antigen Epitopes
Authors: Oostvogels Rimke , Hoppes Rieuwert , Lokhorst Henk , Spaapen Robbert M , Ovaa Huib , Mutis Tuna
Published: October 2019

Allogeneic stem cell transplantation (allo-SCT), alone or followed by donor lymphocyte infusion (DLI), is a potentially curative treatment for various hematological malignancies. In an HLA-matched transplantation setting, the therapeutic graft-versus-tumor (GvT) effect is mediated by donor T-cells directed at minor histocompatibility antigens (mHags), which are HLA-bound polymorphic peptides. Unfortunately, most patients don’t achieve complete response or relapse after allogeneic stem cell transplantation and thus still require additional therapies. Immunotherapy aimed at hematopoietically restricted mHags could theoretically provide an ideal method to augment the GvT effect, without causing GvHD. The most relevant mHags for immunotherapy are those antigens that are only expressed on hematopoietic tissue, are presented by frequent HLA molecules and display an equally balanced population frequency. UTA2-1 and HA-1 are two of these most broadly applicable mHags identified up until now and are therefore included in on-going clinical trials of mHag-peptide loaded dendritic cell vaccination in patients with various hematological malignancies. Another method for mHag-based immunotherapy could be adoptive transfer of ex vivo cultured mHag-specific cytotoxic T lymphocytes (CTL). However, initial results of both methods, also from preclinical models and trials in patients with solid tumors, postulate the necessity for improved strategies for efficient ex vivo and in vivo induction of tumour specific CTLs.

We here show for the HLA-A*02 restricted epitopes UTA2-1 and HA-1 that their MHC binding and consequent T cell reactivity can be improved through the incorporation of certain newly designed non-proteogenic amino acids at crucial MHC anchoring positions. With this novel approach we designed superior altered peptide ligands (APLs) for both epitopes, of which the best modifications not only increased MHC binding and stability, but also improved recognition by antigen specific T cells. Most importantly, these optimised peptides gave rise to superior antitumor T cell responses in vitro and in vivo in comparison to the native epitope, as they induced significantly enhanced proliferation of peptide-specific T cells with retained cytotoxic potential against malignant targets expressing the natural UTA2-1 antigen. Hence, these APLs designed with non-proteogenic amino acids with enhanced MHC-affinity and immunogenicity may improve the therapeutic outcome of mHag-based vaccination strategies, or can be utilized for ex vivo antigen-specific T cell enrichment and expansion for transfer into patients with haematological malignancies.

Disclosures:

Lokhorst: Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.
Prophylactic
Levofloxacin In Pediatric Neutropenic Patients During Autologous Hematopoietic Stem Cell Transplantation (HSCT)
Authors: Hafez Hanafy Ahmed , Yousef Dalia , Abbassi Maggie , Elborai Yasser , Elhaddad Alaa
Published: October 2019

Background

Bacterial sepsis continues to be a leading cause of morbidity and toxic death in children receiving myelosuppressive chemotherapy and for those undergoing hematopoietic stem cell transplants.

Using fluoroquinolones in prophylaxis against gram negative bacterial infection is not the standard of care in neutropenic pediatric patients, and till now it is a controversial issue. This study was conducted to assess the effect of levofloxacin prophylaxis on prevention of bacterial infection and on the duration of antibiotic use during profound neutropenia in pediatric patient with hematopoietic stem cell transplantation.

Methods

Non-randomized comparative study between 2 groups of pediatric neutropenic patients underwent autologous stem cell transplantation; one group didn’t receive prophylactic levofloxacin (control group), the other group received prophylactic levofloxacin (10mg/kg/day) starting from the first day of the conditioning till engraftment or 1stspike of fever.

Results

A total of 96 patients who underwent autologous stem cell transplantation were analyzed (46 patients in the control group and 50 patients taking levofloxacin). The median duration till onset of 1stfever was 11 days from the beginning of conditioning regimen in the control group as compared to 15 days in patients who were receiving levofloxacin, (p ≤ 0.001). Both groups had the same rate of bacteremia (30%) but the percentage of gram negative infections was higher in the control group (50%) as compared to (20%) in levofloxacin group, also the incidence of bacterial sepsis was higher in patients without levofloxacin (4/46) than those with levofloxacin (1/50). The median duration of antibiotic use was significantly lower in the levofloxacin group (10 days) as compared with (14 days) in patients on control group, (p <0.001).

Conclusion

Levofloxacin use can decrease the incidence of the gram negative bacteremia and their septic complications and will shorten the duration of antibiotic use, but its impact on emergence of resistant organisms should be closely monitored.

Disclosures:

No relevant conflicts of interest to declare.
Femoral Head Necrosis In Three Patients After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Zhao Gang , Li Zhi , Ding Jiahua , Wang Jun , Yu Zhengping , Chen Baoan , Zhu Han , Yu Xinnian
Published: October 2019

Femoral head necrosis (FHN) is one of common complications after hematopoietic stem cell transplantation (HSCT). It impacts on patients' normal life with severe pain. To investigate FHN after allogeneic HSCT, We performed retrospective analyses. Since 2003, our department has conducted 98 cases of allogeneic hematopoietic stem cell transplantation for patients with hematologic diseases. Chemotherapy regimens and transplant conditioning regimen before transplantation were steroid-free. FHN occurred in 3 out of 98 cases. The 3 patients were treated with steroid for preventing graft versus host disease (GVHD) after transplantation. However, all the three patients suffered from GVHD, which was cured with steroidal medication subsequently. Then, symptoms of FHN come out and were significantly improved after conservative treatment in all the three patients. The occurrence of FHN might be associated with GVHD and corticosteroids prescription. Early prevention might be helpful in reducing the incidence and improving outcomes.

Disclosures:

No relevant conflicts of interest to declare.
Zinc Deficiency In Patients Adults Undergoing To Hematopoietic Stem Cell Post-Transplantation
Authors: Pereira Andrea Z , Juliana Silva Bernardo , MF Pivocari Silvia , Tanaka Marcia , Ana Paula Barrere N , Lucio Fabiana , Castro Claudio Galvão , Feitosa Ribeiro Andreza Alice , Hamerschlak Nelson
Published: October 2019

Introduction

Zinc is an important trace mineral for the body, being a cofactor of enzymes responsible for the synthesis of nucleic acids, and maintaining the immune system. Symptoms of zinc deficiency, such as alopecia, diarrhea, skin rash and growth failure, can be confused with those of hematopoietic stem cell post-transplant (HSCT). Some studies show that zinc supplementation, with the purpose of increase of its serum level, reducing the incidence of mucositis, xerostomia, pain and loss of taste. Zinc deficiency is reported in children with leukemia, but there are very few studies in adults.

Material and methods

45 adult patients were evaluated, 22 women and 23 men, mean age 49 ± 16 years-old, undergoing HSCT in Hospital Israelita Albert Einstein during the period of 1 year (2012-2013). The serum zinc level, whose average was 69 ± 16 mg/dl, was evaluated in the first day of hospitalization for HSCT and no patient took zinc supplements before it.

Results

48% of patients had zinc deficiency, being most prevalent in patients > 60 years, which had 60%. There was no difference between the sexes.

Conclusion

Some studies believe that zinc, will be a very important agent in transplant medicine, due to its action on the improvement of the severity of mucositis induced by chemotherapy in patients with leukemia. In our study we found a high prevalence of zinc deficiency in adults and the elderly. Therefore, the assessment of zinc serum levels should be considered in patients submitted to HSTC, as a purpose of treatment and improvement of complications related to it.

Disclosures:

No relevant conflicts of interest to declare.
Surviving Stem Cell Transplantation Program In War Time In Syria
Authors: Rajeh Nabeel , Manchi Maha , Suliman Seham , Fahed Zahera , Barali Muhamad , Kalta Muhamad
Published: October 2019

Substantial medical care deterioration occurred during Syrian civil war, including complete destruction of over 50 hospitals and 400 medical centers. We report result of 17 cases of stem cell transplantation in private sector in Damascus in Syria in the period between 2012 and 2013 during major hardship and shortage of all medical care.

Stem cell transplantation is standard of care for certain hematologic malignancies. This sophisticated treatment has not been developed in Syria for economic and logistic reasons. Our group of six doctors adamantly worked hard over four years to establish local stem cell transplantation unit in private sector. We were able to start everything from scratch engineering the unit and training of all human resources. By the time we are ready to operate our first case of stem cell transplantation we had major obstacle, civil war eruption all over Syria. Some of our trained human resources has to leave the country other unable to reach the center. There was major medical supplies and medications shortage due to embargo and flight restrictions to Syria. With great difficulties and neighboring medical community assistance we were able to keep up the work and perform in the first year of operation seventeen cases of autologous stem cell transplantation.

From May2012 –June 2013 we admitted 17 cases for autologous stem cell transplantation. Median age 36 years half of them from Damascus and the rest from all other municipals. Relapse Hodgkin’s and none Hodgkin’s lymphoma, and consolidation multiple myeloma, are the majority of stem cell indication. CD 34 counts collected for patients ranged from 3-166 million cell/ KG (Median 66) with viability 90-99% (Median 95%) one week after freezing. Most conditioning regimens were standard BEAM and Melphelan 200. Median white blood cells engraftment to ANC 500 was D +13. Median platelets engraftment to platelets transfusion free was D +22. Infections are the major morbidity presented as febrile neutropenia. Grade III and IV Mucositis occurred in 35% of patient. All patient required transfusion support with PRBC’s and Random Donor Platelets while 25% of the required total parental nutrition. Two of the patients died during the first 100 days of transplant, one from massive pulmonary hemorrhage d+16, who was heavily pretreated with radiation and previous stem cell transplantation, the other case, none Hodgkin’s lymphoma who is heavily pretreated had engraftment failure and died from multi-organ failure on D+41.

Conclusion

Our group survived stem cell transplant program in extremely difficult time for Syria. During war economic deterioration of people is another obstacle were patients pay out of pocket for health care and medical insurances are underdeveloped. We were able to continue deliver high quality and technology edge treatment during civil war hardship for Syrian people.

Disclosures:

No relevant conflicts of interest to declare.
Development Of a New Regimen Function For Cancer Chemotherapy With a Computerized Physician Order Entry System Aimed At Reducing The Burden On Doctors In Japan
Authors: Komatsu Tsunehiko , Kimura Yuko Nishide , Takaba Yuji , Okubo Kensuke , Ishii Tomotaka , Yuji Koichiro , Nakagawa Masahiko
Published: October 2019

Background

Physician overwork has long been a problem in Japanese society. Mean weekly working durations are reportedly 70.6 hours. The working hours of hematologists are estimated to be especially long. In addition, there is no payment system for specialist medical care in Japan and there is no difference in payments for treatment between specialists and general physicians. The average hourly wage is $30 for both specialists and general physicians in Japan, while the respective values are $100 and $70 in the United States. Given this situation, we advocate that working hours of Japanese hematologists be reduced by improving their work efficiency. One of the problems lies in dose calculations for anticancer drugs. With the conventional ordering system, the method of rounding the dose fractions varies among physicians and there is a potential risk of incorrect administration. We developed an anticancer drug administration system designed to reduce hematologists’ workloads and improve the appropriateness of anticancer drug dosing. We then examined its efficacy.

Methods

EGMAIN-GX (Fujitsu Ltd., Japan) version 2 is an electronic medical record system incorporating an ordering function. We developed a drug administration system named Regimen version 4 in order to update the EGMAIN-GX version 2 ordering system. The new system allows dose calculation with a rounding function in which the dose is automatically rounded off to the nearest whole number. Seven hematologists were asked to order five regimens (IDR/araC, Flu/ivBU, R-CHOP, hyper-CVAD, R-ESAHP）for a patient (165 cm in height and weighing 52 kg) using the new and old systems. Times required for ordering and prescribed doses of anticancer drugs were compared between the two systems. Statistical analysis was performed using Student’s t test.

Results

The mean time and standard deviation (seconds) for ordering are shown in Table 1.

The time was significantly reduced with version 4 as compared to version 2, except for R-CHOP. The cumulative time was reduced by 54% with version 4. As to the prescribed doses of anticancer drugs, significant differences between the two systems were found in busulfan (42.0 mg vs. 40.7 mg, p < 0.0001; figures rounded off to the nearest whole number in the present system, i.e., 42.0 mg) and rituximab (529 mg vs. 583 mg, p= 0.002; figures rounded down to the nearest 100 in the present system, i.e., 500 mg).

Conclusions

The new drug administration system significantly reduced the time required for ordering and facilitated appropriate anticancer drug dosing. These results show that the new drug administration system can reduce hematologists’ workloads and also reduce the risk of incorrect administration of anticancer drugs.

Disclosures:

No relevant conflicts of interest to declare.
Disparities In Receipt Of Radiotherapy and Survival By Age, Sex and Ethnicity Among Patients With Localized Diffuse Large B-Cell Lymphoma
Authors: Shah Binay K. , Bista Amir
Published: October 2019

Background

Combination therapy with 3 cycles of chemotherapy followed by involved field radiotherapy has been a standard of care for treatment of localized diffuse large B-cell lymphoma (Miller TP NEJM 1998). This population based study evaluated ethnic disparities in receipt of radiotherapy (RT) and its effect on survival in patients with localized diffuse large B cell lymphoma (DLBCL) in the United States.

Methods

The Surveillance, Epidemiology, and End Results database was reviewed to identify patients with stage I DLBCL diagnosed between 1998 and 2008. We used unadjusted and adjusted odds ratio (OR) to analyze association of receipt of radiotherapy with age (<60 and 60+ years), sex and ethnicity (White, Black and Others). We calculated relative survival rates for different cohorts using SEER*Stat software. We used cox’s proportional hazard model to investigate the impact of age, sex and ethnicity on survival rates.

Results

A total of 11763 patients with localized DLBCL as the only primary malignancy were included in the study. Of the cohort, 38.2% received radiotherapy. Receipt of radiotherapy varied significantly by patient ethnicity - whites were more likely to receive RT compared to blacks and others. Similarly, age <60 years and females were more likely to receive radiotherapy compared with older patients and males (Table – 1).

The 1- and 5- year relative survival rates for patients receiving RT were higher compared to those who did not receive RT: 88.3±0.5% vs 73.4±0.6%, p-value <0.0001 at 1-year and 77.8±0.8% vs 62.5±0.7%, p-value <0.0001 at 5-years. Among patients who received RT, 1- and 5- year relative survival rates were significantly higher in whites compared to black or other- race patients.

Conclusions

This population based study showed that only 38.2% of patients with localized DLBCL received radiotherapy. White patients were more likely to receive RT compared to blacks and others. Survival rates are significantly higher for patients who received RT.

Disclosures:

No relevant conflicts of interest to declare.
Heterozygous Mutation Of Dynamin 2 Expands The Pool Of IL-7 Responsive Leukemic Stem Cells In T-Cell Acute Lymphoblastic Leukemia
Authors: Curtis David J. , Brown Fiona C. , Collett Michael , Lucas Sarah E. , Saw Jesslyn , Robinson Phillip J. , Tremblay Cedric Stevens
Published: October 2019

Early thymocyte progenitor T-cell acute lymphoblastic leukemia (ETP-ALL) is a poor prognosis malignancy that has a distinct genetic basis characterized by activating mutations of the IL-7 signaling pathway. Recurrent mutations spanning Dynamin 2 (Dnm2), a gene encoding a large GTPase required for clathrin-mediated endocytosis, have been identified in ETP-ALL although why these mutations are enriched in ETP-ALL remains obscure. We have utilized the Lmo2 transgenic mouse model to define the role of DNM2 mutations in ETP-ALL. Sequencing of 11 cases of Lmo2-derived T-ALL identified two novel Dnm2 mutations, a frameshift (Serine126fs) and a premature stop (Isoleucine135stop) mutation within the GTPase domain, which confirmed the relevance of this mouse model for studying Dnm2 mutations. We mated Lmo2 mice with mice carrying a germ-line missense mutation of Dnm2 in the GTPase domain (V235G), which impairs GTPase activity. This Dnm2 mutation had two important biologic effects on Lmo2-derived T-ALL: an increased penetrance (90% compared with 50% by 12 months of age; p<0.05) and a more immature phenotype (DN1-3 compared with ISP8). To address the mechanism of these effects, we examined the phenotype and expression profile of early leukemic stem cells harboring the Dnm2 mutation. The major abnormality was an expansion of IL-7 responsive leukemic stem cells with increased proliferation and survival. Intriguingly, the presence of Dnm2 mutations sensitized leukemic cells to killing by a small molecule inhibitor of Dnm2. Together, our data provide the first experimental evidence that Dnm2 mutations are enriched in ETP-ALL by expanding the pool of IL-7 responsive leukemic stem cells. Furthermore, our data supports further testing of Dynamin inhibitors in this subset of poor prognosis T-ALL.

Disclosures:

No relevant conflicts of interest to declare.
Persistence of Minimal Residual Disease Assessed By Multi-Parameter Flow Cytometry (MFC) at 30 and 90 Days after Achieving Complete Remission Predicts Outcome in Patients with Acute Myeloid Leukemia
Authors: Pinnamaneni Pramod , Jorgensen Jeffrey L. , Kantarjian Hagop M. , Jabbour Elias , Pierce Sherry R. , Brandt Mark , Wang Sa A. , Konoplev Sergej , Konopleva Marina , Kornblau Steven M. , Kadia Tapan , DiNardo Courtney D. , Pemmaraju Naveen , Andreeff Michael , Estrov Zeev , Garcia-Manero Guillermo , Cortes Jorge E. , Ravandi Farhad
Published: October 2019

Purpose – To determine the value of Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) after achieving initial response to therapy, in predicting outcome in patients with acute myeloid leukemia (AML)

Methods – We investigated the predictive value of MRD assessment by MFC in 191 patients with newly diagnosed AML treated between February 2010 and April 2014 at our institution who had available MRD assessment. MRD by MFC was assessed using an 8-color panel containing 19 distinct markers, on bone marrow specimens obtained at the time of achievement of CR and at approximately 30 days and 90 days after achieving CR. Residual leukemic blasts were identified based on phenotypic differences from normal myelomonocytic precursors. Sensitivity was estimated at 0.1% in most cases, with maximum achievable sensitivity of 0.01%, depending on the leukemic phenotype.

Results – Of the 191 patients, 167 (87%) achieved complete remission (CR) or CR without platelet recovery (CRp). Their median age was 58 years (Range, 17-85). 84 (44%) were older than 60 years. Median WBC at presentation was 3.2 x 109/L(Range, 0.5-100.2 x 109/L) and median bone marrow blast percentage was 43% (Range, 11-96%). Cytogenetics was favorable risk in 4 (2%), intermediate risk in130 (68%) and adverse risk in 57 (30%). Treatment included cytarabine plus anthracycline in 170 (89%) and hypomethylating agents-based strategies in 21 (11%). 48 patients had available samples at 30 days post CR and 32 (67%) became MRD negative. Achieving MRD negative status was associated with a statistically significant improvement in CR duration (p=0.02) and overall survival (OS) (p=0.0005). 56 patients were evaluated for MRD status at 90 days and 45 (80%) were negative. Again, achieving MRD negative status was associated with a significant improvement in CR duration (p=0.002) and OS (p=0.0009).

Conclusion – Achieving MRD negative status by MFC at 30 and 90 days post CR is associated with an improved outcome in patients with AML

Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures

No relevant conflicts of interest to declare.
Comprehensive Genetic Characterization of Pediatric T-Cell Acute Lymphoblastic Leukemia
Authors: Karrman Kristina , Castor Anders , Behrendtz Mikael , Forestier Erik , Olsson Linda , Ehinger Mats , Biloglav Andrea , Fioretos Thoas , Paulsson Kajsa , Johansson Bertil
Published: October 2019

A comprehensive genetic characterization comprising conventional chromosome banding, fluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) array analyses as well as large-scale sequencing of 75 genes were performed on a consecutive series of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. An abnormal karyotype was identified in 46% of the cases. Recurrent cytogenetic aberrations comprised T-cell receptor (TCR) translocations and deletions of 6q and 9p. FISH analyses of TCR rearrangements were positive in 26% of the investigated cases. The vast majority (37/39; 95%) of cases analyzed by SNP arrays displayed aberrations, with a median of 3 changes (range 0-11) per case. The genes recurrently deleted were CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. One case displayed chromothripsis involving 6q. No case had a whole chromosome uniparental isodisomy (wUPID); in fact, only one T-ALL of 123 informative cases in the literature has had a wUPID. However, segmental UPIDs (sUPIDs) were seen in 44% of the present cases, with most being sUPID9p. CDKN2A was homozygously deleted in all cases with sUPID9p, with a heterozygous deletion occurring prior to the sUPID9p in all instances. There was no evidence for chromosomal instability when comparing diagnostic and relapse samples. Among the genes sequenced, 14 were mutated in 28 cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse, showing that such mutations also can be secondary events. These findings support a multistep leukemogenic process.

Disclosures

No relevant conflicts of interest to declare.
Late Effects: An Evaluation of Contrasting Physical and Psychological Experiences Between Child and Adult Hodgkin Survivors
Authors: Sarker Shah-Jalal , George Gincy Elsa , Chowdhury Kashfia , Levitt Gill , Kingston Judith , Lister Andrew , Gribben John G. , Korszun Ania
Published: October 2019

Purpose

A retrospective study to assess the effect of age at diagnosis (AD) of patients with Hodgkin’s Lymphoma (HL) on the development of physical late effects (secondary malignancies, hyperthyroidism, fatigue), depressive symptoms and quality of life (QOL) using the Impact of Cancer (positive and negative scales) Questionnaire.

Methods

280 Hodgkin’s Lymphoma (HL) survivors from St. Bartholomew’s Hospital, London were divided into two groups; 57 Childhood (AD≤17 years) Hodgkin’s Lymphoma (CHL) and 223 Adult (AD≥18 years) Hodgkin’s Lymphoma (AHL). Chi-square/Fisher’s exact tests and logistic regression analyses were conducted to identify the effect of AD on late effects; adjusting for histological subtype (HS) and treatment modality (TM). For IOC, two separate hierarchical linear regression analyses were conducted to examine the combined association of; (i) AD, HS and TM (ii) AD, HS, TM and the late effects on IOC.

Results

CHL survivors were four times more likely to develop a secondary malignancy than AHL survivors (P=0.011). AD was not associated with hyperthyroidism, fatigue or depression. Higher negative IOC scores were significantly associated with lower levels of social support and two or more medical co-morbidities (P≤0.001). Although there was no significant association between AD and negative IOC, lower positive IOC scores were significantly associated with CHL (P=0.040).

Conclusions

CHL survivors may benefit from more vigorous screening for secondary malignancies to enable their early detection and treatment. QOL varies in different groups and those with less social support and more medical co-morbidities would benefit from interventions to reduce negative IOC. An early psychological intervention to increase positive IOC and resilience for young people with HL may also improve their future QOL as long-term CHL survivors.

Disclosures

Gribben: Celgene: Research Funding; Pharmacyclics: Honoraria; Roche: Honoraria.
The Role of ADAMTS13-Specific Circulating Immune Complexes in Prediction of Recurrence of Acquired Thrombotic Thrombocytopenic Purpura
Authors: Ferrari Barbara , Valsecchi Carla , Pontiggia Silvia , Mancini Ilaria , Lotta Luca Andrea , Mikovic Danijela , Meloni Giovanna , Peyvandi Flora
Published: October 2019

Introduction. Acquired thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy due to the development of autoantibodies against the VWF-cleaving protease ADAMTS13. We recently developed and validated a new ELISA method for the detection of ADAMTS13-specific circulating immune complexes (CICs) in acquired TTP patients. This study aims at investigating the clinical relevance of ADAMTS13-specific CICs at disease presentation in a large cohort of acquired TTP patients.

Methods. We measured ADAMTS13-specific CICs by ELISA in 51 patients from the Milan TTP Registry, at the first episode of acquired TTP. All patients presented anti-ADAMTS13 autoantibodies by western blotting and severe ADAMTS13 deficiency (i.e., <10% of normal) by FRETS-VWF73 or CBA assays. We studied the associations between ADAMTS13-specific CICs levels and (i) ADAMTS13-related measurements (i.e., ADAMTS13 antigen, anti-ADAMTS13 IgG), (ii) clinical and laboratory markers of disease severity (i.e., muco-cutaneous bleeding, neurological, renal and cardiovascular symptoms, number of platelets, LDH, hemoglobin, creatinine), (iii) short- and long-term clinical outcomes (i.e., number of plasma exchange procedures required to attain remission, recurrence). Statistical analyses were performed using linear, logistic and Cox regression models.

Results. The prevalence of ADAMTS13-specific CICs in patients experiencing a first episode of acquired TTP was 39% (95% confidence intervals [CI]: 26-52%). ADAMTS13-specific CICs were only associated with ADAMTS13 antigen levels at regression analyses (beta per 10% increase in ADAMTS13 antigen, 95% CI: 0.05, 0.02-0.08). The presence of ADAMTS13-specific CICs was associated with more than a four-fold increase in the risk of recurrence at 2 years after the first TTP episode (hazard ratio, 95%CI: 4.2, 1.1-16.4).

Conclusions. ADAMTS13-specific CICs are neither a biomarker of disease severity, nor a predictor of clinical outcome during acute phase. Conversely, ADAMTS13-specific CICs seem to have relevance in predicting the recurrence of acute TTP episodes.

Disclosures

Peyvandi: NovoNordisk: Research Funding; Kedrion : Research Funding; NovoNordisk: Speakers Bureau; CSL Behring : Speakers Bureau; Baxter: Speakers Bureau; Bayer: Speakers Bureau.
A Two-Site Interaction Underpins TRIM25 Activation of the RIG-I Anti-Viral Response
Authors: D'Cruz Akshay A , Kershaw Nadia J , Linossi Edmond M , Chiang Jessica J , Wang May K , Dagley Laura F , Croker Ben A , Zhang Jian-Guo , Gack Michaela U , Nicola Nicos A , Babon Jeffrey J , Nicholson Sandra E
Published: October 2019

SPRY/B30.2 domain-containing proteins are found in 103 human proteins that regulate numerous cellular processes including RNA processing, histone methylation, red blood cell membrane integrity, terminal erythroid cell differentiation and innate immune responses. Despite an increased understanding of SPRY/B30.2 domain function, some confusion remains as to the precise domain boundaries, the number and location of binding sites, and importantly how activation of these domains contribute to signal transduction. The B30.2 domain of tripartite motif 25 (TRIM25) interacts with the viral RNA sensor retinoic acid-inducible gene I (RIG-I), facilitating the formation of a RIG-I tetramer, which is required for activation of the innate immune response against RNA viruses such as influenza A, measles, HIV and hepatitis C. Here we have investigated the biochemical and structural changes associated with the activation of TRIM25 in the context of RIG-I binding. We solved a 1.8 Å crystal structure of the TRIM25 B30.2 domain and identified a putative RIG-I-binding site, which was confirmed by mutagenesis and functional analyses. Further mutagenesis identified a second site on the opposing face of the B30.2 domain that also specifically interacts with RIG-I. While the CARD1 domain of RIG-I is known to interact with the B30.2 domain of TRIM25, our data suggest that a conformational change within the CARD2 domain of RIG-I enables it to also interact with the B30.2 domain of TRIM25. We propose that both RIG-I CARDs interact with sites on opposing sides of the TRIM25 B30.2 domain to form a TRIM25/RIG-I complex that facilitates RIG-I tetramerisation and activation. The characterization of a dual binding mode for the TRIM25 B30.2 domain is a first for the SPRY/B30.2 domain family. Disease-associated polymorphisms of Pyrin, involved in Familial Mediterranean Fever, and mutational analyses of TRIM5a, required for HIV restriction, suggest that a second binding site may be a characteristic feature of other B30.2-containing TRIM proteins, and may facilitate the formation of large oligomeric complexes that are important for inflammasome function and HIV capsid destruction.

Disclosures

No relevant conflicts of interest to declare.
Proteomic Analysis Identifies Outcome-Predictive Clusters in Patients with Peripheral T-Cell Lymphoma, Not Otherwise Specified
Authors: Ludvigsen Maja , Pedersen Martin Bjerregaard , Hamilton-Dutoit Stephen Jacques , Bendix Knud , Møller Michael Boe , Nørgaard Peter H. , Poulsen Tim Svenstrup , Besenbacher Søren , d'Amore Francesco , Honoré Bent
Published: October 2019

Introduction: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of mature T-cell lymphomas, probably composed by different biologically related subsets that have not yet been conclusively identified. In the WHO classification, PTCL-NOS accounts for 25-30% of all mature T-/NK-cell malignancies. The clinical outcome is generally poor with a 5-yr overall survival of 30-35% after conventional treatment strategies. The aim of the study was to apply proteomic analysis in PTCL-NOS and to use the protein expression profiles to characterize clinically relevant subsets within this heterogeneous entity by means of unsupervised cluster analysis.

Methods: Archival frozen tumor tissue samples from 20 patients diagnosed with PTCL-NOS from 1991 to 2010 were analyzed for protein expression by high-resolution two-dimensional gel electrophoresis. Individual protein spots were visualized with fluorescence staining and the expression profiles were identified. All patients were homogeneously treated with curatively intended anthracycline-containing combination regimens. Clinico-pathological features were obtained from the Danish Lymphoma Registry (LYFO) and from patient records. Hyperplastic tonsils from healthy adults were included as reference tissue (n=8). Principal component analysis and unsupervised hierarchical cluster analysis were performed on the basis of the protein expression profiles. Differentially expressed (two-fold or higher, Mann-Whitney U-test) proteins between the detected clusters were identified by liquid chromatography - tandem mass spectrometry.

Results: Unsupervised cluster analysis defined three distinct clusters: one containing all reference samples and two additional ones further subdividing the PTCL-NOS cases in two separate subsets. Patients from these two PTCL-NOS subsets had significantly different responses to treatment and survival (p = 0.001). The differentially expressed proteins were primarily involved in (i) promotion of tumor growth, (ii) regulation of cellular metabolism, and (iii) immune responses.

Conclusion : Proteomic analysis identified shared protein expression patterns and potential prognostic markers in subsets of PTCL-NOS.

Disclosures

No relevant conflicts of interest to declare.