bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of Multiple Myeloma 70-Gene Prognostic Risk Score As a Continuous Predicitor of Patient Outcome
Authors: van Laar Ryan , Bender Richard A , Zielinski Aga , Leigh Kenton , Barlogie Bart , Morgan Gareth J
Published: November 2019

Background: The 70-gene prognostic risk score (MyPRSR) for patients with multiple myeloma is conventionally used in a binary high/low risk fashion. The ability to more precisely estimate a patients' risk of 5-year relapse or death based on their specific risk score may increase the clinical utility of the assay.

Methods and Results: Logistic regression analysis of the 70-gene score in relation to event free and overall survival data from UAMS TT2/3 series was performed. 274 patients with at least 5 years' follow-up data were included in the analysis. A binary fitted line plot, which fits a model with one continuous predictor with an iterative reweighted least squares algorithm to obtain maximum likelihood estimates of the parameters, was generated for 5-year relapse-free and overall-survival. These plots correspond to the probability of a certain event occurring based on a specific 70-gene score.

The deviance R-square value for the relapse free survival analysis was 12.28% and the odds ratio for the 70-gene score as a continuous predictor was 1.03 (95% CI: 1.02 to 1.05). For overall survival the deviance R-square value was 15.5% and odds ratio 1.07 (95% CI: 1.05 to 1.10).

Conclusion: The 70-gene prognostic risk score is continuously associated with increased risk of 5-year relapse and death. Presentation of a patients' risk score in this format may enable superior risk-based management compared to binary high/low risk stratification. Further work is ongoing to investigate the association between GEP70 and risk of progression from precursor conditions, such as MGUS, to MM requiring treatment.

Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures

van Laar: Signal Genetics, Inc.: Employment. Bender:Signal Genetics, Inc.: Employment. Zielinski:Signal Genetics, Inc.: Employment. Leigh:Signal Genetics, Inc.: Employment. Barlogie:Mount Sinai Hospital: Employment. Morgan:Univ of AR for Medical Sciences: Employment; Bristol Meyers: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding.
Plasma Cell Leukemia in China: Retrospective Analysis of Clinical Characteristics and Prognosis
Authors: Yu Tengteng , Xu Yan , An Gang , Li Zengjun , Hao Mu , Qiu Lugui
Published: November 2019

Background: Plasma cell leukemia (PCL) is an aggressive malignancy characterized by the presence of ≥ 20% plasma cells in the peripheral blood or an absolute plasma cell count >2× 109/L. PCL exists in two forms: primary PCL (PPCL) presents de novo, whereas secondary PCL (SPCL) defined as a leukemic transformation from a previously diagnosed MM.

Materials and methods: We conducted a retrospective analysis in 46 cases with PCL patients enrolled in Blood Diseases Hospital, Chinese Academy of Medical Sciences from June 1997 to June 2016. Survival analysis and treatment response according to the response criteria of IMWG were analyzed to assess the efficacy of Bortezomib or Thalidomide based therapy combined with standard chemotherapy.

Results: Median age of 46 cases was 54.5 years (29-72 years), 28 males and 18 females; primary PCL 20 cases, secondary PCL 26 cases. Among those, 20 cases with kappa type, while 22 λ cases, 4 cases no secretion. Renal dysfunction occurs 51.4% of patients, 69.6% with osteolytic changes. D-S stage: I 1 case, 2 cases of stage II, stage III 43 cases. Complex karyotypes accounted for 45.2%, high frequency of cytogenetic abnormalities occur in IgH / CCND1 rearrangement with 8 cases, 1q21 amplification in 8 cases, RB-1 abnormalities in 6 cases, 4 cases of 17p deletion and 1 IgH / MAF rearrangement . 36 patients were evaluated in treatment responses, the overall reaction (≥MR) was 97.2%; 7 cases acquired complete remission (CR), 14 near complete remission (nCR), 6 very good partial response (VGPR), 8 cases of partial remission (PR), 1 case loss response. 16 cases of Bortezomib based therapy combined with chemotherapy; while 18 patients were treated with thalidomide combined with chemotherapy, 2 cases were conducted with allogeneic stem cell transplantation, 2 patients with chemotherapy underwent autologous stem cell transplantation after standard chemotherapy. Mean Overall survival (OS) was 19 months; primary and secondary PCL median OS was 15 months and 22 months separately (P = 0.098); Thalidomide based regimens and bortezomib-based regimen acquired a median OS 15 months and 30 months (P = 0.083). Median time to progression (TTP) of thalidomide and bortezomib based therapy was 6 months and 25 months (P = 0.03). The overall median TTP was 9 months.

Conclusions: Higher incidence in cytogenetic aberrations was observed in plasma cell leukemia. Combined chemotherapy with bortezomib can improve progression-free survival of patients, but cannot improve overall survival.

Disclosures

No relevant conflicts of interest to declare.
Correlation Analysis Between Serum Lactate Dehydrogenase and Prognosis in Old New Diagnosed Multiple Myeloma Patients
Authors: Yuan Yahui , Gu Yan , Qu Xiaoyan , Shi Qinglin , Bai Hua , Xu Ji , Xu Jiadai , Li Jianyong , Chen Lijuan
Published: November 2019

【Abstract】 Objective Multiple myeloma (MM) is a kind of plasma cell malignancy tumor with larger heterogeneity. Patient's survival varies greatly. This study retrospectively analyzed serum lactate dehydrogenase (LDH) in 107 cases of elderly MM patients, to discuss its correlation with other clinical indicators of MM and the prognostic significance. Methods 107 cases of elderly MM patients were selected from our hospital from July 2008 to January 2016 as the research objects, all of whom were above 60 years and were newly diagnosed. OLIPAS AU5400 fully automatic biochemical analyzer was used to assay serum LDH concentration, and prognosis analysis was carried out combined with patients' clinical data. On this basis, 73 cases of MM patients were given R-ISS staging. Results At primary diagnosis, about 9.4% patients had increased LDH (10/107), with the median follow-up time of 15 (1-88.5) months. Median overall survival (OS) was 52.5±6.9 months in normal LDH group, while 15.5±5.2 (months) in elevated LDH group, and there were statistically significant differences (p<0.001); Median progression free survival (PFS) was 24.0±3.5 months in normal LDH group, while 12.0±10.5 monthsin elevated LDH group, and there were statistically significant differences (p=0.008). Multiple factors analysis showed that LDH was an independent prognosis factor of elderly MM. Median OS of patients was 44 and 72 months (p=0.820) with stage II and stage III of ISS staging, while median PFS was 23 and 22 months (p=0.963); Median OS of patients was 44 and 22.5 months (p=0.308) with stage II and stage III of R-ISS staging, while median PFS was 24 and 14 months (p=0.105). Conclusions LDH is one of the important indicators for prognostic judgment of elderly MM patients. R-ISS staging based on LDH level is superior to the ISS staging system in prognostic judgment.

Disclosures

No relevant conflicts of interest to declare.
On the Redox Profile of B- Cell Terminal Differentiation and Multiple Myeloma: New Insights and Therapeutic Opportunities
Authors: Hassen Wafa , Kassambara Alboukadel , Jourdan Michel , Boireau Stephanie , Seckinger Anja , Hose Dirk , Kang Yubin , Klein Bernard , Moreaux Jerome
Published: November 2019

Redox homeostasis is fundamental for normal cellular functioning and is maintained by the net physiologic balance between production and removal of ROS. Redox signaling has been shown to coordinate the global signal transduction pattern critical for the control of key cellular processes including differentiation and tumorogenesis. In the present study, we review the systematic expression of ROS-producing and antioxidant genes and we draw up a full redox portrait of B cells all the way throughout B- cells expansion and differentiation and in malignant plasma cells. Our data firmly established that B-cells terminal differentiation entails drastic reshaping of the redox profile and underscore the stark transcriptional divide between B cells and plasma cells compartments with a major contribution of the Thioredoxin-Glutathione system in latter one. Furthermore, we advanced significant evidence that the most aggressive Multiple Myeloma cells (MMCs) witness increased expression of ROS producing genes and actively upregulated multiple antioxidant systems, which likely afforded high cytoprotective capacities and compromise chemotherapy efficacy. More importantly, we describe a transcriptional redox signature that enables the demarcation of good versus bad prognosis of MM patients and hold promise for robust molecular signature that could predict responsiveness. Finally, our data pinpointed the Thioredoxin-Glutathione system as actionable targets to circumvent drug resistance. Using Human Myeloma cell lines and primary cultures of MMCs, we validated Thioredoxin-Glutathione system as new critical, key functional node in the oncogenic network of MMCs whose depletion kill tumor cells and improve the response rate. We provided herein a preclinical data, which warrants further clinical investigation for the potential use of redox-modulators as a novel MM treatment strategy.

Disclosures

No relevant conflicts of interest to declare.
Low Pre-Transplant Vitamin D Levels Predict an Inferior Survival in Patients with Multiple Myeloma Undergoing an Autologous Stem Cell Transplant
Authors: Rakhee Vaidya , Ahlers Shane , Rodriguez Cesar , Lamar Zanetta S. , Hurd David D
Published: November 2019

Introduction

Nearly 40% of patients with newly diagnosed multiple myeloma are vitamin D deficient (Br J Haematol. 2008;142(3):492-4). Low vitamin D levels are associated with a higher ISS (International staging system) stage, higher creatinine, and higher serum C-reactive protein levels at diagnosis (Am J Hematol. 2009;84(7):397-400). Along with its key role in bone metabolism, vitamin D promotes differentiation, inhibits proliferation and is pro-apoptotic at the cellular level. In our retrospective study, we assessed the prognostic effect of pre-transplant vitamin D levels in patients with multiple myeloma (MM) undergoing their first autologous stem cell transplant (ASCT).

Methods

All patients who underwent an ASCT for MM since 2010 were identified from the Wake Forest University Comprehensive Cancer Center registry. 25-hydroxy vitamin D levels checked within 90 prior to ASCT were recorded, along with key clinical variables as noted in table 1. Receiver operating characteristic (ROC) analysis was employed to define best discriminant levels for predicting mortality. Survival was calculated from the date of transplant to the date of death or last follow up. The JMP (SAS Institute) statistical package was used for all calculations.

Results

A total of 176 patients received ASCT for MM from 2010 to 2015, of whom 158 (90%) had pre-transplant vitamin D levels checked within 90 days of ASCT and were included in the analysis. Most patients (140/158, 89%) underwent ASCT within one year of MM diagnosis. ROC analysis identified a 25-OH vitamin D level of ≤ 23 ng/mL (AUC 0.57) as best discriminant level for predicting mortality. Using this cut-off, vitamin D deficiency was identified in 60% (94/158) patients. Low vitamin D levels were significantly associated with younger age at MM diagnosis and ASCT (P =0.001). There were no other significant differences in the baseline characteristics of patients with low versus normal vitamin D levels (Table 1). Survival from the time of transplant was inferior in vitamin D deficient patients compared to those with normal levels (HR 2.55, 95% CI 1.08-7.03; P= 0.03). Median survival in vitamin D deficient patients was 25 months versus 32 months in those with normal vitamin D levels (P= 0.03). Multivariable analysis in the context of ISS and ASBMT disease risk confirmed the independent prognostic relevance of vitamin D levels (P= 0.01).

Conclusion

Low pre-transplant vitamin D levels are associated with an inferior survival in patients with multiple myeloma who undergo an ASCT. Further studies are needed to determine whether repleting vitamin D in vitamin D deficient patients improves outcomes.

Prognostic impact of pre-transplant vitamin D levels in MM patients undergoing an autologous stem cell transplant

Table 1 Table 1. Figure 1 Figure 1.

Disclosures

No relevant conflicts of interest to declare.
Bone Marrow CD4+ and CD8+ Lymphocyte Infiltration Patterns Define Overall- and Progression Free Survival in Multiple Myeloma and May Predict IMiD Response: an Analysis from the Austrian Myeloma Registry
Authors: Willenbacher Ella , Brunner-Veber Andrea , Weger Roman , Willenbacher Wolfgang
Published: November 2019

Introduction:

In Multiple Myeloma immune dysregulation with quantitative and qualitative changes in T-cell subpopulations is thought to result in a reduced anti-tumour immune response promoting disease progression.

Methods:

A retrospective cohort of 45 myeloma patients was analyzed for the extent of tumor infiltrating CD4+ and CD8+ lymphocytes by means of immunohistochemistry using sophisticated automated evaluation software.

Results:

Here, for the first time we analyzed trephine biopsies of myeloma patients and we report a significant association of different patterns of immune cell infiltrations with OS and PFS suggesting that these patients might particularly benefit from immune modulating therapeutic strategies:

CD4+ T-cells below a cutoff of 0.28% lymphocytes/total nucleated cells were associated with a significantly longer overall survival, while CD8+ T-cells above the cutoff of 6.51% predicted a longer progression free survival. Treatment with immunomodulatory drugs resulted in a significantly better overall- and progression free survival for patients with adverse local immunological features compared to those treated with proteasome inhibitors or non-novel agents.

We suggest that immune dysregulation in myeloma significantly influences overall- and progression free survival. We will now validate this immuno algorithm of lymphocyte infiltration patterns as a predictive biomarker of IMiD responsiveness in the framework of a large randomized phase III trial. If confirmed they might be used as a putative biomarker to guide rational therapy allocation in the future.

Disclosures

Willenbacher: Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Willenbacher:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commision: Research Funding.
Overexpression of Raf Kinase Inhibitor Protein (RKIP) in Multiple Myeloma and Its Molecular Signature
Authors: Shvartsur Anna , Garban Hermes , Bonavida Benjamin
Published: November 2019

Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS) that can evolve to asymptomatic pre-MM and later to symptomatic MM. MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) inhibits the Raf/MEK/ERK1/2 and NF-κB pathways and sensitizes resistant tumors to drug-induced apoptosis. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our prior findings demonstrated that RKIP is overexpressed (primarily in its inactive phosphorylated form) in MM cell lines and patients-derived tumor tissues (Baritaki et. al, FIDT 2:1-13, 2011). We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the expression of RKIP and several-associated gene products in both pre-MM and MM. Several gene products were found to be overexpressed such as RKIP, Bcl-2, and DR5 and underexpressed such as Bcl-6 and TNFR2 in both pre-MM and MM. A differentially expressed pro-apoptotic genes were observed in pre-MM versus expression of anti-apoptotic genes in MM. Based on these analyses on mRNA levels and on protein levels in published studies of the above differentially expressed genes, we have found a molecular signature each for pre-MM and MM. Once the molecular signatures are validated experimentally, they will be useful for a more precise diagnosis/prognosis of the disease stages and will also identify novel molecular therapeutic targets.

Disclosures

No relevant conflicts of interest to declare.
Bortezomib-Melphalan-Prednisone (VMP) Versus MP As Initial Treatment for Patients Older Than 75 Years with Newly Diagnosed Multiple Myeloma
Authors: Kim Min Kyoung , Kim Kihyun , Yoon Dok Hyun , Suh Cheolwon , Lee Jae Hoon , Jung Sung-Hoon , Lee Je-Jung , Kim Hyo Jung , Kim Jin Seok , Lee Jeong-Ok , Eom Hyeon Seok , Lee Won Sik , Mun Yeung-Chul , Do Young Rok , Kang Hye Jin
Published: November 2019

Although bortezomib-melphalan-prednisone (VMP) therapy is a well-established standard treatment for patients with multiple myeloma (MM) who are ineligible for high-dose therapy, it is not clear whether very elderly patients should be treated with VMP, considering the toxicities. The purpose of this case-control study was to compare the efficacy of VMP versus melphalan-prednisone or cyclophosphamide-prednisone (MP/CP) as initial therapy for very elderly patients.

We retrospectively studied 202 patients aged 75 years or older with newly diagnosed multiple myeloma between March 2007 and February 2015. One-hundred twenty two patients received VMP and eighty patients received MP/CP regimen were enrolled from 13 institutions throughout Korea.

Patient characteristics were comparable in these two groups. Overall response rate was 69.7% in VMP patients and 47.5% in MP/CP patients (P=0.002). Complete response rate was 24.6% in VMP patients and 10% in MP/CP patients (P=0.005). After a median follow-up for survivors of 28.4 months, progression-free survival was significantly different between the two groups (median 21.0 vs. 11.9 months in VMP and MP/CP group, respectively, P=0.037). Overall survival was also significantly different between the two groups (median 34.6 vs. 27.8 months in VMP and MP/CP group, respectively, P= 0.023). Hematologic grade 3-4 toxicities were more common with VMP (anemia: 29.1% vs 15.3%, P=0.077; thrombocytopenia: 39.3% vs. 15.3%, P < 0.001). Grade 2-4 diarrhea (22.5% vs. 2.8%, P = 0.001), vomiting (13.7% vs. 1.4%, P = 0.011), and peripheral sensory neuropathy (35.3% vs. 4.2%, P <0.001) were also more common with VMP.

Despite the presence of age-related comorbidities, VMP therapy was associated with modest toxicity, a better response rate and prolonged survival, supporting the use of this effective combination as frontline therapy for very elderly patients with MM.

Disclosures

Lee: Amgen: Membership on an entity's Board of Directors or advisory committees. Kim:Celltrion, Inc.: Research Funding.
Effect of Lenalidomide on Hepatitis C Viremia in Cancer Patients: A Case Series
Authors: Hosry Jeff , Samaniego Felipe , Turturro Francesco , Economides Minas P. , Torres Harrys A.
Published: November 2019

Background: T cells play an important role in controlling hepatitis C virus (HCV) infection. Immunomodulatory drugs affecting T cells such as thalidomide and lenalidomide are used in the treatment of some hematologic cancers (mainly multiple myeloma). Lenalidomide is up to 1000 times more potent than thalidomide in stimulating T cell proliferation, interferon-γ and interleukin-2 production. HCV reactivation (increase of HCV-RNA by at least 1 log10IU/mL) with hepatitis flare after thalidomide therapy was recently reported (Mahale et al., Open Forum Infect Dis. 2015); however, the effect of lenalidomide on HCV-viremia has not been studied yet.

Methods: HCV-infected cancer patients treated with lenalidomide at MD Anderson Cancer Center (11/2012-3/2016) were studied. HCV-RNA levels were measured before and after lenalidomide use. Since chronically infected patients have stable HCV-RNA levels that only varies ∼0.5 log10 IU/m, a significant change in HCV viremia was defined as a change of HCV-RNA ≥ 1 log10IU/ml from baseline. Hepatitis flare was defined by an increase of ALT level to ≥ 3 times upper limit of normal (or >170 IU/ml).

Results: Five HCV-infected cancer patients treated with lenalidomide were studied. All the patients were males with a median age of 56 years. They had multiple myeloma (n=4) or large B-cell lymphoma (n=1). Four patients had HCV genotype 1 (80%) and 1 had genotype 2 (20%). Two patients (40%) were cirrhotics. The 5 patients studied received 6 different lenalidomide-containing regimens: 2 with lenalidomide monotherapy, 2 lenalidomide + rituximab and 2 lenalidomide + steroids. HCV-RNA levels were measured between week 4 (1, 17%) and week 12 (5, 83%) on lenalidomide treatment. A decrease of HCV-RNA was seen with all the 6 regimens (100%) (Figs 1A, 1B and 1C). Nonetheless, a significant decrease (>1 log10IU/ml) was noted in 4 out of the 6 regimens: two on lenalidomide monotherapy (1.21 and 1.49 log10IU/ml) and two on lenalidomide + rituximab (1.15 and 1.3 log10IU/ml). Hepatitis flare was only seen in one patient treated with lenalidomide + rituximab but he did not have concomitant HCV-RNA changes.

Conclusion: Unlike thalidomide,lenalidomide does not cause HCV reactivation. On the contrary, this agent seems to inhibit HCV replication.

Figure 1 Figure 1.

Disclosures

Samaniego: Karus Therapeutics: Research Funding. Torres:Pfizer: Other: Scientific advisor; Theravance Biopharma: Other: Scientific advisor; Astellas Pharma: Other: Scientific advisor; Novartis: Other: Scientific advisor; Genentech: Other: Scientific advisor; Janssen Pharmaceuticals: Other: Scientific advisor; Vertex Pharmaceuticals: Other: Scientific advisor, Research Funding; Merck & Co.: Other: Scientific advisor, Research Funding; Gilead Sciences: Other: Scientific advisor, Research Funding.
Ticagrelor Modulates Proliferation in Multiple Myeloma Via P1 and P2 Receptor-Mediated Mechanisms
Authors: Meltzer Elan , Mediero Aranzazu , Whatling Carl , Berger Jeffrey S , Cronstein Bruce
Published: November 2019

Background:Multiple Myeloma (MM) is a hematologic malignancy involving uncontrolled proliferation of plasma cells and is particularly trophic to bone where it induces osteoclast-mediated bone destruction. Ticagrelor is a platelet inhibitor that blocks P2Y12 receptors and inhibits ENT1-mediated adenosine uptake, thereby increasing extracellular adenosine, which activates P1 receptors. Prior studies demonstrate that ticagrelor increases life span in a murine model of MM via its effect on extracellular adenosine. Prior studies also demonstrate an increase in proliferation, in vitro, and tumor growth, in vivo, of MM cells in the presence of platelet releasate. Ticagrelor blocks in vitro platelet-stimulated myeloma proliferation, suggesting a positive relationship and interaction between active platelets and multiple myeloma. We therefore determined whether the effect of ticagrelor on myeloma cells was mediated by extra-cellular adenosine or/and inhibition of platelet function.

Methods:Human primary myeloma cells (KMS) were incubated with ticagrelor (10-9-10-4 M) in the presence of 5ng/ml IL-6 in the absence/presence of an A2AR antagonist (ZM241385 10-6M) and platelets (1:500 myeloma cell:platelets). In other experiments MM cells were incubated in the presence of platelet releasate, releasate from platelets treated with ticagrelor, or ticagrelor alone. Proliferation was assayed by Cell Titer MTS assay (Promega).

Results: Ticagrelor inhibited MM cell proliferation by 20% (p<0.0001, IC50=0.5µM). This effect was abrogated by ZM241385 (48±6% increased vs. ticagrelor, p<0.0001). Platelet releasate increased MM proliferation by 33±6% (p<0.05) and ticagrelor inhibited the effect of platelet releasate on MM cell proliferation (IC50=0.12µM).

Conclusions:These results suggest that ticagrelor inhibits proliferation of malignant plasma cells by a mechanism dependent on both adenosine A2A and platelet P2Y12 receptors. Moreover, platelet releasate intensifies proliferation, and this effect is reversed when the P2Y12 receptor is blocked by ticagrelor.

Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3.

Disclosures

Meltzer: NIH: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding. Mediero:AstraZeneca: Research Funding; Celgene: Research Funding; NIH: Research Funding. Whatling:AstraZeneca: Employment. Berger:Merck: Membership on an entity's Board of Directors or advisory committees; AZ: Research Funding. Cronstein:AstraZeneca: Consultancy, Research Funding; CanFite: Equity Ownership; Gizmo Therapeutics: Consultancy; Eli Lilly & Co.: Consultancy; NIH: Research Funding; Celgene: Research Funding.
Impact of Switching from Intravenous to Subcutaneous Bortezomib in Real Life. Overlapping Toxicity and Efficacy in All Settings of Myeloma Patients Balancing Schedule and Way of Bortezomib Adminisration
Authors: Mangiacavalli Silvia , Cocito Federica , Ferretti Virginia Valeria , Cartia Claudio Salvatore , Ganzetti Maya , Cazzola Mario , Corso Alessandro
Published: November 2019

Background: Bortezomib

Disclosures

Corso: Janssen-Cilag: Honoraria.
Human CMVpp65-Specific Stem Cell-like Memory T-Cells (TSCM) Are a Principal Source for Rapid Repopulation of Immunodominant Central Memory (TCM) and Effector Memory (TEM) in the Circulation
Authors: Kuo Tzu-Yun , Hasan Aisha , Guerreiro Manuel , O'Reilly Richard J.
Published: November 2019

Latent CMV infection is controlled by a limited repertoire of immunodominant T-cells specific for viral peptides, particularly CMVpp65 and CMV IE-1. The antigen-specific T-cell subsets responsible for maintaining memory T-cells in this repertoire and repopulating them in response to periodic viral reactivations remain unclear. In this study, we generated T-cells specific for CMVpp65 from naïve (TN), TSCM, TCM and TEM subsets isolated from the blood of HLA-A*0201 normal seropositive donors and then comparatively characterized NLV-HLA-A*0201 Tetramer+ T-cells from each of these subsets. Following in vitro sensitization with artificial antigen-presenting cells transduced to express HLA-A*0201 and CMVpp65 and expansion with IL-7, IL-15 and IL-2, Tet+ T-cells were regularly generated from CD62L+CD45RO-CD95- TN and from CD62L+CD45RO-CD95+ TSCM, as well as TCM and TEM. Isolated Tet+ TN, TSCM, TCM and TEM were each able to generate IFN-γ, TNF-α and granzyme B. Each Tet+ subset also expressed similar level of PD-1 and KLRG-1. However, Tet+ TN and TSCM expressed higher levels of CD27 and lower levels of CD57 than TCM or TEM. Tet+ TSCM were distinguished from Tet+ TN, TCM and TEM by a significantly greater level of proliferation and by their rapid and selective expansion of NLV-specific T-cells bearing TCRs identical by amino acid sequences to those expressed by TEM and TCM in the blood. Thus, Tet+ TSCM rather than Tet+ TN constitute the principal repertoire for repopulation of immunodominant memory T-cells sustained in the circulation.

Disclosures

Hasan: Atara: Patents & Royalties.
A Comparison of Efficacy Following Two Different Doses of Granulocyte Colony Stimulating Factor (G-CSF) Alone for Mobilization of Peripheral Blood Stem Cells in 221 Multiple Myeloma Patients
Authors: Osmani Soufi , Brahimi Mohamed , Talhi Souad , Amani Kamila , Ouldjeriouat Hafida , Bouchama Samira , Charef Leila , Mazari Mohamed Amine , Entasoltan Badra , Yafour Nabil , Krim Amina , Bouhass Rachid Amar , Arabi Abdessamed , Bekadja Mohamed Amine
Published: November 2019

Introduction:

Intensive chemotherapy followed by autologous stem cell transplantation (ASCT) is currently the treatment of choice in multiple myeloma (MM). Mobilization of hematopoietic stem cell blood (HSCs) can be achieved either by the combination of chemotherapy plus growth factors or by growth factors alone. However, there is no consensus concerning the dose of growth factor alone that should be administered, with ranges varying from 5 microgr to 16 microgr/kg body weight.

In this context, we report our experience in mobilization of HSCs using growth factor alone at the dose between 15 microgr /kg and 10 microgr /kg in MM.

Patients and methods:

A total of 340 ASCT were performed in our center, from May 2009 until June the 31st 2016. These concerned 221 patients with MM. Patients were hospitalized at day -5 on which mobilization started with G-CSF alone (filgrastim) at the dose of 15 microgr /kg/daily subcutaneously for 5 days from May 2009 to October 2012 and at the dose of 10 microgr /kg from November 2012 to June 2016. The white blood cell count was assessed daily. Apheresis was performed at day -2 and day -1 using a Spectra Optia CMN device, and the CD34+ count was assessed by flow cytometry. A single leukapheresis was performed if the number of CD34+ cells was above 2.106/kg. Failure of mobilization was defined as a level of CD34+ less than 2.106/kg, after two leukapheresis.

In our study patients were divided into two groups: Group1 (G-CSF=15 microgr /kg) and Group 2 (G-CSF=10 microgr /kg) and the number of CD34+ were divided into three groups: optimal (³5.0 x 106 CD34+ cells/kg), suboptimal (2.0Ð5.0 x 106 CD34+ cells/kg) and poor (<2.0 x 106 CD34+ cells/kg) mobilization. Intensification was done using melphalan 200 mg/m2 on day -1.

Results:

Patient's characteristics are shown in Table 1. No significant difference was observed between the 2 groups. In this study, we found no significant difference in terms of optimal (p= 0.73), sub-optimal (p= 0.19) or poor (p= 0.11) harvest of stem cells between the 2 groups (table 2). Among the poor mobilizators with G-CSF, only 4 of them had a level of CD34+ harvest less than 0.5 x 106/kg. These patients did not receive an ASCT. 1,3% (4) of all apheresis failed to achieve acceptable harvest level.

Conclusion:

Our study showed that the mobilization regimen with G-CSF alone at the doses of 10 microgr/kg have the same efficacy as the doses of 15 microgr/kg and is interesting alternative to chemotherapy and G-CSF in patients with MM because it can be administered as an outpatient and is not associated with the risk of febrile neutropenia.

Disclosures

No relevant conflicts of interest to declare.
Safety and Efficacy of Donor-Derived Virus Specific Cytotoxic T Lymphocytes(CTL) Administered in Treatment for CMV/EBV Infections after Allogenetic Stem Cell Transplantation
Authors: Wang Jingbo , Huang Xiaojun , Hu Ying , Xue Song , Cheng Haoyu , Yin Yuming , Zhang Weijie , Gu Jiangying , He Junbao , Yang Fan
Published: November 2019

Objective:

To investigate the safety and efficacy of donor-derived cytomegalovirus(CMV) specific cytotoxic T lymphocytes(CTL) and Epstein-Barr virus(EBV) specific cytotoxic T lymphocytes(CTL) as immune therapy in CMV viremia and EBV viremia postallogeneic transplant.

Methods:

A total of fifty-three patients receiving haplo-identical allogeneic HSCT for hematological malignancy were eligible for recruitment to the study from February 2013 to December 2015. Thirty-eitht patients of CMV viremia postallogeneic transplant received CMV CTL. Fifteen patients of EBV viremia postallogeneic transplant received EBV CTL. The criteria for inclusion were: (1) plasma CMV/EBV DNA >1×103/ml. (2) Antiviral therapy (ganciclovir and foscaret) was not effective.(3) Antiviral therapy was not tolerated for pancytopenia. The criteria for exclusion were: (1) plasma CMV/EBV DNA <1×103/ml. (2) Prophylactically administered CMV-specific T cells and EBV-specific T cell. T-cell infusion: Patients were infused with a single dose of 2-3×105/kg weekly. Median number of infusion was 8(2-15). Criterion of therapeutical effect: Virus DNA copy number decreased by a log rank or above (Valid). Virus DNA copy number to zero(negative). Virus DNA copy number increased or not reduced ( Invalid).

Results:

38 cases of CMV viremia were effective in 28 cases, the effective rate was (73.7±7.1)%, the median onset time was 5 days (2-10). Plasma CMV was negative in 28 cases, the negative rate was (73.7±7.1)%, the median negative time was 11 days (2-24). 15 cases of EBV viremia were effective in 13 cases, the effective rate was (86.7±8.8)%, the median onset time was 5 days (2-11). Plasma EBV was negative in 13 cases, the negative rate was (86.7±8.8)%, the median negative time was 10 days (3-24). Adverse events: fever(n=1), skin rash(n=3), hypoxemia(n=2), diarrhea (n=1 uncertain), Tachycardia of sinus( n=1)

Conclusion:

Safety and efficacy of virus specific cytotoxic T lymphocytes(CTL) administered postallogenetic HSCT are exact. CTL can be used as second-line therapy of viral infections postallogenetic HSCT.

Disclosures

No relevant conflicts of interest to declare.
Impact of Muscle Mass, Evaluated By Ultrasound, and Muscle Strength in the Engraftment of Hematopoietic Stem Cell Transplantation(HSCT)
Authors: Pereira Andrea Z , Barban Juliana B S , Cocco Marister N , Pitito Bianca A , Hamerschlak Nelson
Published: November 2019

Introduction: In the HSCT, msucle mass and visceral fat are associated to comorbidities, mortality, length of stay, duration of use of immunosupressive drugs, the development of graft-versus host disease(GVHD) and survival. A recent study in patients undergone allogenic HSCT showed an inverse association between areas of visceral and peripherical fat with disease-free interval. In allogenic HSCT, decreased muscle mass is associated to higher prevalence of chronic GVHD and low performance. Objectives: To evaluate the muscle thickness(MT), visceral fat(VF) and muscle stregth(MS), correlating them with engraftment(EN). Methods: We studied 14 HSCT patients, adults(>=18 years), from Hospital Israelita Albert Einstein, Sao Paulo, Brazil. In the first day of hospitalization, before HSCT, we evaluated MT of right femoral quadriceps, 6 cm from the top edge of the patela; VF was measured in the abdominal area, and was characterized by the distance between the linea alba and the anterior wall of aorta artery. This measuments were evaluated by ultrasound in B-mode. In addition, all patients had their dominant upper limb strength evaluated by hand grip. Results: Most patients were women (57%) and the mean age was 50 years(+-16 years). We had haploidentical(57%), autologus(36%) and allogenic(7%). Most of our patients were overweight, mean 27 kg/m2(+-4 kg/m2). The EN average time was 16 days (+-6days). MT mean was 1,5 cm(+-0,3cm), VF 5,3 cm(+-1,4 cm) and MS 31 kgf(+-7,0 kgf). There was a negative and significant correlation between EN and MT(rs-0,8,p<0,05). We didn`t find any correlation with VF, MS and EN. Conclusion: The MT evaluated by ultrasound showed a strong correlation with EN. The ultrasound is pratical, low cost, no risk inHSCT, it could be more used for these patients.

Disclosures

No relevant conflicts of interest to declare.
Establishment of a Xenotransplantation Acute Myeloid Leukemia Model Using By Zebrafish
Authors: Ye Yongbin , Xu Xiaojun , Liu Qifa
Published: November 2019

Objecitve: To investigate the feasibility ofxenotransplant leukemia model using by zebrafish, and lay the foundation for the study of acute myeloid leukemia and the screening of the drugs for targeting therapy of acute myeloid leukemia.

Methods: Acute myeloid leukemia cell line KG1a was labeled with red fluorescent dye-MitoRed, then, the labeled cells was injected into the yolk sac of zebrafish embryos. Morphology observation, cell counting and histopathological detection were used to analysis the infiltration and metastasis of KG-1a cells in zebrafish.

Results: KG1a cells could proliferate and gradually spread to the entire abdominal cavity of the zebrafish After KG1a cells were injected into the yolk sac during 1-7 dpi, the results of cell counting in vitro also proved a signification proliferation of KG1a cells in zebrafish, suggesting that the implanted leukemia stem cells could survive, proliferate and spread in zebrafish. Further study detected the implanted cells could transfered to the liver of zebrafish, these cells showed the signature of KG1a cells by hematoxy -lin -eosin(HE) staining.

Conclusions: Human acute myeloid leukemia cells KG1a could survive, proliferate and migrate in zebrafish, suggesting xenotransplant leukemia model using by zebrafish is feasible. This model may provide benefit for the study of acute myeloid leukemia and the screening of the drugs for targeting therapy of acute myeloid leukemia.

Disclosures

No relevant conflicts of interest to declare.
Decreased Expression of PPARγ mRNA in Patients Correlates with aGVHD after Allo-HSCT
Authors: Wu Xiaojin , Zhang Jubin , Ma Shoubao , Ji Yuhan , Liu Shuangzhu , Bao Xiebing , Chen Jia , Wu Depei
Published: November 2019

Background and objective: Peroxisome proliferator-activated receptor (PPAR)-gamma(γ) is a member of superfamily of nuclear hormone receptors and involved in the lipids metabolism, adipocyte differentiation, atherosclerosis and anti-inflammation. The role of PPARγ in acute graft versus host disease (aGVHD ) remains unclear. In this study, we aimed to investigate the role of PPARγ during aGVHD after allogenic hematopoietic stem cell transplantation (allo-HSCT ).

Methods: 50 patients undering allo-HSCT and 20 healthy controls were enrolled in study. Peripheral blood (PB) of patients 30 days, 60 days, and 90 days were collected after allo-HSCT. We also collected PB samples at aGVHD onset and after aGVHD remission. Peripheral blood mononuclear cells (PBMCs) were isolated for real-time PCR to detect the mRNA expression of PPARγ, IFNγ, IL4, T-bet, GATA3, Foxp3, RORγt .

Results: Expression of PPARγmRNA in healthy controls were significant lower than that in patients after allo-HSCT(P<0.05). At the onset of aGVHD, the expression of PPARγmRNA was significantly lower than that in non-GVHD and increased when remission (P<0.05). PPARγexpression in severe aGVHD (grade 3 to 4) was lower than mild aGVHD (grade 1 to 2) patients (P<0.05). Gender, age, graft type, and the kind of disease showed no significant difference in the aGVHD and non-GVHD patients. The expression of IFNγ and T-bet increased after aGVHD and were negatively correlated with PPARγmRNA expression.

Conclusion: Our findings suggest that low expression of PPARγ is associated with aGVHD occurrence. PPARγ may be a useful indicator to predict aGVHD and follow-up.

Disclosures

No relevant conflicts of interest to declare.
Expandation of CD56-Bright NK Cell in Patients with Steroid-Refractory Graft-Versus-Host Disease Treated with Basiliximab and Etanercept
Authors: Sheng Lixia , Huang He , Tan Yamin , Luo Yi , Hu Yongxian , Fu Huarui , Shi Jimin
Published: November 2019

Objectives: Steroid-resistant aGVHD(SR-aGVHD) is a complication with high incidence of mortality following allogeneic stem cell transplantation. Our previous study has showed combined treatment by basiliximab and etanercept achieved high response in SR-aGVHD. The aim of this study is to investigate the changes of lymphocyte subsets in SR-aGVHD following treatment with basiliximab and etanercept.

Methods: We treated 11 SR-aGVHD patients with basiliximab 20mg on days 1, 4, 8, 15, and etanercept 25 mg twice a week for 4 weeks, followed by once weekly for 4 more weeks. Their peripheral blood lymphocyte subsets were assessed by flow cytometry before and after treatment.

Results: The overall response to treatment was 100% (11/11) with 72.7% (8/11) achieving a complete response. As expected, we found a significant depletion of both CD4+ and CD8+ T-cell subset at 4w following treatment. Conversely, the proportion of CD3-CD56+NK expanded significantly, accounting for 26.82±7.69% of PB lymphocytes at 6w following treatment, compared with 10.90±3.94% before treating. The increasement in NK proportion lasting from several weeks to several months. Moreover, the percentage of CD56bright and IFN-gamma-producing NK cell subsets also increased after combined treatments.

Conclusion: Expansion of CD56(bright) and IFN-gamma production NK cell subsets and contraction of CD4(+) and CD8(+) T cell numbers may contribute to the well control of SRaGVHD by basiliximab and etanercept. This finding provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during aGVHD.

Disclosures

No relevant conflicts of interest to declare.
Improved Survival of High Risk Patients with Parainfluenza Virus Following Hematopoietic Cell Transplantation: Role of Aerosolized Ribavirin
Authors: Nguyen Isabelle T , Shashidhar Sumana , Brown Janice (Wes) M.
Published: November 2019

Parainfluenza viruses (PIV) ARE associated with severe respiratory tract infections among immunocompromised patients. However, the most perplexing feature of PIV following hematopoietic cell transplantation (HCT) is the dichotomous nature of risk for life-threatening infection. Specifically, the vast majority of patients will not require treatment of any kind whereas a small subset appears to be at such high risk of death that it has been questioned if successful treatment is even possible.

In 2007, we implemented a standardized approach to patients diagnosed with Parainfluenza virus (PIV) following HCT at Stanford University Medical Center (Fig 1) based on the need for supplemental oxygen and/or specific risk factors. We performed both a prospective analysis of cases of lower respiratory tract infection and a retrospective review of all 2495 patients transplanted during this period. The epidemiology, risk factors, clinical status, and outcome of the 115 PIV patients using this protocol from September 2007 through May 2015 shows that prudent, risk-stratified application of antiviral therapies in can result higher survival rates among patients with PIV post-HCT. Moreover, high risk patients who received aerosolized ribavirin had a lower mortality rate than those who were either not treated or received oral ribavirin.

Disclosures

No relevant conflicts of interest to declare.
Retrospective Analysis of Post-Transplant Complications in Autologous Hematopoietic Cell Transplantation Patients Receiving Hyperbaric Oxygen Therapy
Authors: Abdelhakim Haitham , Bhatti Sajjad Akbar , Cantilena Amy Rose , Lin Tara L. , Ganguly Siddhartha , Singh Anurag K. , Abhyankar Sunil , Lipe Brea , McGuirk Joseph , Allin Dennis , Shune Leyla , Aljitawi Omar
Published: November 2019

High-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) is an established therapy for patients with multiple myeloma and lymphomas. Post-transplant complications during the neutropenia phase include pancytopenia requiring transfusions and G-CSF support, mucositis and infectious complications.

Previously, we have demonstrated that hyperbaric oxygen therapy (HBO) given day 0 prior to transplant reduced erythropoietin (EPO) levels and improved engraftment in umbilical cord blood transplantation. Subsequently, we conducted a pilot trial to study HBO effects EPO levels and engraftment in Auto-HCT setting. Herein, we review HBO effects on Auto-HCT post-transplant complications.

Methods:

Charts of patient who underwent HBO treatment prior to Auto-HCT on our pilot study and matched historic controls were retrospectively reviewed for post-transplant transfusion requirements, G-CSF support, mucositis and infectious complications

Results:

Nineteen patients completed HBO therapy and were compared to 118 patients in our historic cohort. Basic patient characteristics are listed in table-1. Average days of G-CSF use was 6.2 days in our HBO cohort compared to 9.16 days in the historic cohort (P=0.0007). Average number of transfused packed red cells was 2.1 and 2.58 units (P=0.22), while average number of platelet unit transfusions was 2.5 and 3.2 (P=0.17) in the HBO and historic cohorts, respectively. Mucositis incidence was 26.3% in the HBO cohort compared to 59.3% in controls (P=0.008). Similarly, the rate of neutropenic fever was 47% in the HBO cohort vs. 65% in controls (P=0.11). The rate of admissions, on the other hand, was 31.5% in the HBO cohort compared to 23.7% in controls (P=0.31) with an average length of hospital stay of 6.6 days in the HBO cohort compared to 7.68 days in controls (P=0.31).

Conclusions:

HBO therapy prior to Auto-HCT is associated with lower G-CSF use and lower incidence of mucositis in our retrospective study. Prospective studies are needed to determine HBO effects on Auto-HCT post-transplant complications.

Disclosures

Ganguly: Onyx: Speakers Bureau; Seattle Genetics: Speakers Bureau; Janssen: Research Funding.
Feasibility and Efficacy of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for HIV-Related Lymphoma: A Single-Institution Experience
Authors: Sleiman Elsa , Gomez Alexandra , Chavez Julio C. , Kharfan-Dabaja Mohamed A , Ayala Ernesto
Published: November 2019

Background: High dose therapy (HDT) followed by autologous hematopoietic cell transplantation (autoHCT) has been shown to be safe and effective in patients with HIV-related lymphoma (HRL). Data is limited to small case series, transplant registries and a single prospective multicenter observational study. Here we report our institutional experience with auto-HCT in patients with HRL.

Patients and methods: Twenty patients with HRL [non-Hodgkin=14 (70%), Hodgkin=6 (30%)] and treatable HIV infection underwent HDT consisting of carmustine, etoposide, cytarabine and melphalan (BEAM) followed by peripheral blood auto-HCT from 04/2006 to 07/2015. In 2 cases rituximab was administered as part of the preparative regimen. Patient-, disease-, and transplant-related characteristics are summarized in Table 1.

Results: Median age was 48 years (range 35-61). The median follow-up for surviving patients was 42 months (range 6-110). At transplant, median peripheral blood CD4 count was 226 cells/µl (range 41-761). HIV viral load was undetectable in 14 out of 20 patients and lower than 4 logs in all of them. The median time to neutrophil and platelet engraftment were 11 days (range 10-13) and 14 days (range 13-176), respectively. Response rates at day +100 post-autografting in 17 evaluable patients were as follows: complete remission (CR)=11/17 (65%), partial response (PR)=2/17 (12%), and relapse/progression=4/17 (24%). Median event-free survival (EFS) was 58.4 months. Median overall survival (OS) was 74.3 months. At 5-years post-transplantation, EFS and OS were 68% and 53%, respectively. Non-hematologic toxicities consisted of mucositis in 8 (grade 1=3, grade 2=5), and enteritis in 13 patients (grade 1=2, grade 2=3, and grade 3=8). There were 13 documented infections in 11 patients (bacterial=9, viral=2, fungal=2). Six patients died from disease relapse/progression (n=5) and infection (n=1). Non-relapse mortality was 0% at day 100 and 5% at 5 years.

Conclusion: Patients with HRL and treatable HIV infection should be offered autoHCT if indicated. HIV infection is no longer a contraindication for autoHCT in this population.

Disclosures

Chavez: Janssen: Speakers Bureau. Kharfan-Dabaja:Seattle Genetics: Speakers Bureau; Incyte: Speakers Bureau.