42 results on '"Pei, Lin"'
Search Results
2. Single Cell Profiling of BCMA Naïve Vs Refractory Relapsed Myeloma Patients Reveals Unique Transcriptomic Profiles in Tumor and Microenvironment
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Minghao Dang, Li Qin, Wei Tan, Liping Dong, Hans C. Lee, Krina Patel, Luz Yurany Moreno Rueda, Pei Lin, Hima Bansal, David Berrios, Sheeba K Thomas, Donna M. Weber, David E. Symer, Linghua Wang, Elisabet E. Manasanch, and Robert Z. Orlowski more...
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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3. Comparative Effectiveness and Safety of Extended Anticoagulant Therapy Among Medicare Beneficiaries with Venous Thromboembolism
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Park, Haesuk, primary, Kang, Hye-Rim, additional, Huang, Pei-Lin, additional, Lo-Ciganic, Wei-Hsuan, additional, Dietrich, Eric A, additional, Murphy, Martina C, additional, and DeRemer, Christina E, additional more...
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- 2021
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4. Adherence Trajectories of Extended Direct-Acting Oral Anticoagulants and Risk of Recurrent Venous Thromboembolism and Major Bleeding: A Retrospective Cohort Study
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Kang, Hye-Rim, primary, Jones, Bobby L, additional, Lo-Ciganic, Wei-Hsuan, additional, DeRemer, Christina E, additional, Dietrich, Eric A, additional, Huang, Pei-Lin, additional, Murphy, Martina C, additional, and Park, Haesuk, additional more...
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- 2021
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5. Acute myeloid leukemia with erythroid and megakaryocytic differentiation associated with Down syndrome
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Beenu Thakral and Pei Lin
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Leukemia, Myeloid, Acute ,Erythroid Cells ,Immunology ,Humans ,Infant ,Cell Biology ,Hematology ,Down Syndrome ,Biochemistry ,Megakaryocytes - Published
- 2021
6. A Genotype Validated Bimodal Method for the Large-Scale Identification and Phenotyping of Persons with Sickle Cell Disease Using Electronic Health Record Data
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Wuichet, Kristin, Takemoto, Clifford M, Cronin, Robert, Barton, Martha, Chen, Pei-Lin, Saraf, Santosh L., Weiss, Mitchell J., and DeBaun, Michael R.
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- 2023
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7. Duffy-Null Patients with Sickle Cell Disease Are at Risk for Low Neutrophil Counts with HU Treatment
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Zheng, Yan, Chen, Pei-Lin, Gossett, Jeffery, Kang, Guolian, and Takemoto, Clifford M
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- 2023
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8. Disease Characteristics of Multiple Myeloma Involving BRAF Mutations
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Pei Lin, Andrés E. Quesada, Muzaffar H. Qazilbash, Koji Sasaki, Junsheng Ma, Naveen Pemmaraju, C. Cameron Yin, Shehab F. Mohamed, Gautam Borthakur, Qaiser Bashir, Maliha Khan, Gregory P. Kaufman, and Melody R. Becnel more...
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business.industry ,Immunology ,Cancer research ,Medicine ,Disease characteristics ,Cell Biology ,Hematology ,business ,medicine.disease ,Biochemistry ,Multiple myeloma - Abstract
Introduction In multiple myeloma (MM), the RAS-RAF-MEK-ERK pathway plays a key role in regulation of cell growth, differentiation, proliferation, and cell death. The BRAF gene, located on chromosome 7, is the most potent component of the RAF group, and usually involves missense mutations clustered in exons 11 and 15. In this retrospective study, we investigated the prevalence of BRAF mutations in MM, the clinical and pathological significance of these mutations, and whether these BRAF mutations occur as initial or acquired mutations. Methods Patient data was retrieved from the clinical database of patients with MM who had been diagnosed and/or treated at The University of Texas MD Anderson Cancer Center during January 2015 through December 2020. To be included, participants had to be aged >18 years, have been diagnosed with MM, and have a positive BRAF mutation, identified using an 81-gene panel that had been performed on their bone marrow samples. The primary outcome variable was overall survival (OS) time. The secondary outcome variable was progression-free survival (PFS). Patients were classified as sustained when repeat bone marrow in relapse or refractory patient showed a persistent BRAF mutation, and as non-sustained when repeat bone marrow in relapse or refractory patient did not have a persistent BRAF mutation. Results Of the 22 patients in our study, most were men (73%), and the median age at diagnosis, for all patients, was 66 years (range, 28-79 years). Half of patients (50%) had a monoclonal immunoglobulin G as part of their MM, while 9 (40.9%) patients had monoclonal immunoglobulin A MM. Most patients (68.4%) had stage III disease. For BRAF mutation, only 3 (13.6%) patients had the V600E variant, and 5 (22.7%) had the G469A variant which was the most common. Other prominent variants were D594N (13.6%), G466A (9.1%), and G466E (9.1%). Of the 11 patients who had a sustained BRAF mutation, 8 (72.7%) patients had remission after first-line therapy, and 9 underwent an autologous stem cell transplant. Seven patients (31.8%) had only a BRAF mutation. Other commonly mutated genes were KRAS in 5 (22.7%), DNMT3A in 4 (18.2%), NRAS in 4 (18.2%), and TP53 in 3 (13.6%). We found that exon 11 (72.7%) was more frequently affected than exon 15 (27.3%). The most common chromosomal change was diploid (30.0%), and complex in 6 patients (30.0%). Complete response was achieved in 7 (31.8%) patients, a partial response was seen in 8 (36.4%) patients, and 4 (18.2%) patients had stable disease. Overall, 14 (63.6%) patients underwent an autologous stem cell transplant. The median follow-up time was 45.5 months (range, 12.0-280.9 months), and the median survival time was 72.7 months (95% CI, 29.7 months-not reached). The 5-year OS rate was 52.3% (95% CI, 0.337-0.811). For patients with sustained BRAF mutations and patients without a sustained BRAF mutations, the 5-year OS rates were 77.8% (95% CI, 54.9%-100.0%) and 27.8% (95% CI: 8.9%-86.9%), respectively. In univariable analysis, patients in whom BRAF was not sustained had marginally significantly poorer OS (HR, 4.20; 95% CI, 1.01-17.39; P=0.048). The median PFS time was 16.6 months (95% CI, 11.2-44.5 months), and the 5-year PFS rate was 14.3% (95% CI, 5.0%-40.7%). On univariate analysis, we observed significantly worse PFS rates in patients who had initial disease (HR, 2.84; 95% CI, 1.05-7.68; P=0.049), did not have sustained BRAF mutations (HR, 2.74; 95% CI, 0.98-7.69; P=0.037), or achieved stable disease (HR, 6.82; 95% CI, 1.51-30.73; P=0.012). Patients who achieved remission after first-line therapy (HR, 0.14; 95% CI, 0.04-0.49; P=0.002) had significantly better PFS. Conclusion In our study, patients with sustained BRAF mutations versus those who did not have sustained BRAF mutations, had higher 5-year OS rates (77.8% vs. 27.8%); and had better 5-year PFS rates, 27.3% versus all patients showing progression within 3 years. We have shown that the loss of BRAF mutations negatively affects patient outcomes and survival. However, the small size of our study limits the generalizability of our results to BRAF mutation-positive MM. We encourage other studies to assess the prognostic value of BRAF mutations in MM, and recommend the use of a routine panel to check for BRAF mutations in order to appropriately adjust therapy for such MM patients. Also, despite the low incidence of BRAF-mutated MM, more trials are needed to accurately evaluate the response to BRAF-targeting therapy. Figure 1 Figure 1. Disclosures Sasaki: Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; GSK: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Protagonist: Consultancy. Pemmaraju: Roche Diagnostics: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Incyte: Consultancy; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; LFB Biotechnologies: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; DAVA Oncology: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Celgene Corporation: Consultancy; Affymetrix: Consultancy, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Qazilbash: Angiocrine: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Biolline: Research Funding; Janssen: Research Funding; NexImmune: Research Funding; Amgen: Research Funding. more...
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- 2021
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9. Adherence Trajectories of Extended Direct-Acting Oral Anticoagulants and Risk of Recurrent Venous Thromboembolism and Major Bleeding: A Retrospective Cohort Study
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Bobby L Jones, Hye-Rim Kang, Eric Dietrich, Martina Murphy, Christina E. DeRemer, Pei-Lin Huang, Wei-Hsuan Lo-Ciganic, and Haesuk Park
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medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Retrospective cohort study ,Cell Biology ,Hematology ,business ,Biochemistry ,Venous thromboembolism ,Direct acting ,Major bleeding - Abstract
Introduction: The optimal duration of extended oral anticoagulant treatment for patients with venous thromboembolism (VTE) beyond the initial 3 to 6 months of the treatment remains undetermined. Group-based trajectory modeling (GBTM) is a data-driven method that can categorize patients with similar longitudinal adherence patterns over time into distinct subgroups. This study identified distinct patient subgroups with similar adherence trajectories of extended treatment of direct-acting oral anticoagulants (DOACs), and then examined the association between adherence trajectories and the risk of recurrent VTE and major bleeding among patients with VTE. Methods: We identified patients ≥18 years with a diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE) from inpatient claims using 2013-2019 Truven Commercial and Medicare Supplemental database. Patients were included if they initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of therapy-defined as ≥83% proportion days covered (PDC) with oral anticoagulants during the initial 6-month treatment period, and had extended treatment with any DOACs or no extended therapy. Based on the monthly PDC as the DOAC adherence measure, we used GBTM to identify DOAC adherence trajectories during 6 months of the extended treatment. The final trajectory model was chosen by assessing the Bayesian information criteria, Nagin's criteria, and having at least 10% of patients in each trajectory group for improving clinical utility. We compared recurrent VTE and major bleeding among adherence trajectory subgroups. Patients were followed up from the initiation of the extended treatment until the occurrence of the study outcomes, discontinuation of DOACs, switching to warfarin, end of study period, or end of enrollment, whichever occurred first. Cox proportional hazard modeling with inverse probability treatment weighting (IPTW) was used to obtain hazard ratios (HR) and 95% confidence intervals (95% CI). Results: The study cohort (mean age=58.7 years and 51.1% males) consisted of 10,960 patients with extended treatment of DOACs (4,294 apixaban, 6,409 rivaroxaban, 238 dabigatran, and 19 edoxaban users) with a mean treatment duration of 7.7 months and 5,133 patients with no extended treatment following completion of an initial 6 months of anticoagulant treatment. The final GBTM models identified four distinct adherence trajectories for extended therapy including (1) patients with consistent adherence (group 1, 40.7%), (2) patients with gradually declining adherence (group 2, 14.3%), (3) patients with rapidly declining adherence (group 3, 13.1%), and (4) patients with no extended treatment (reference group, 31.9%) (Figure 1). The incidence rates of recurrent VTE were 18.6, 46.9, 84.1, and 160.7 per 10,000 person-years, and those of major bleeding were 61.0, 125.1, 168.3, and 48.7 per 10,000 person-years in group 1, group 2, group 3, and the reference group, respectively. After IPTW, demographics and clinical characteristics (e.g., HAS-BLED bleeding risk score, provoked VTE) were comparable across the four trajectory groups with Conclusions: We identified 4 distinct trajectories of DOAC adherence during the 6 months of extended therapy among patients who completed 6 months of initial treatment. Compared to no extended treatment, persistent use of DOACs during extended treatment was associated with a lower risk of recurrent VTE without increasing major bleeding risk, whereas a rapid decline in adherence was associated with an increased risk of major bleeding with no difference in the risk of recurrence. Our findings provide evidence on the benefits of continuing and being adherent to extended anticoagulant treatment in patients with VTE without increasing the risk of major bleeding. Figure 1 Figure 1. Disclosures Kang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Jones: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Lo-Ciganic: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding; MERCK: Research Funding. DeRemer: BMS advisory board attendee: Honoraria; Portola Pharmaceuticals: Current equity holder in publicly-traded company; BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Dietrich: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Huang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Murphy: North American Thrombosis Foundation: Honoraria. Park: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. more...
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- 2021
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10. Comparative Effectiveness and Safety of Extended Anticoagulant Therapy Among Medicare Beneficiaries with Venous Thromboembolism
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Wei-Hsuan Lo-Ciganic, Christina E. DeRemer, Hye-Rim Kang, Eric Dietrich, Pei-Lin Huang, Martina Murphy, and Haesuk Park
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medicine.medical_specialty ,business.industry ,General Neuroscience ,Immunology ,Medicare beneficiary ,General Medicine ,Cell Biology ,Hematology ,Biochemistry ,General Biochemistry, Genetics and Molecular Biology ,Anticoagulant therapy ,medicine ,General Pharmacology, Toxicology and Pharmaceutics ,Intensive care medicine ,business ,Venous thromboembolism - Abstract
Introduction: Approximately 30% of patients with venous thromboembolism (VTE) experience a recurrence within 10 years of the initial event with their recurrence risk peaking during the first 6-12 months. Two large randomized clinical trials AMPLIFY-EXT and PADIS-PE reported that extended treatment with apixaban and warfarin beyond 6 months of initial treatment reduced recurrent VTE without increasing the rate of major bleeding compared to placebo, respectively. Little is known about real-world effectiveness and safety of extended oral anticoagulation beyond 6 months of initial treatment for Medicare beneficiaries with VTE, despite the fact that VTE disproportionately affects the elderly. We assessed the effectiveness and safety of extended use of apixaban and warfarin beyond 6 months of initial treatment for prevention of recurrent VTE and adverse major bleeding events among Medicare beneficiaries with newly diagnosed VTE. Methods: A retrospective cohort study using 2014-2018 Medicare data (5% samples in 2014-2016 and 15% samples of Medicare beneficiaries in 2017-2018) was conducted for patients aged ≥18 years with a diagnosis of deep vein thrombosis or pulmonary embolism ascertained from inpatient claims. Patients were included if they initiated anticoagulants within 30 days of their first VTE diagnosis, completed 6 months of therapy defined as ≥83% proportion days covered with oral anticoagulants during the initial 6-month period, and received extended treatment with either apixaban or warfarin or no extended therapy. We compared the risks of recurrent VTE and major bleeding between apixaban, warfarin, and no treatment groups. To adjust for differences in baseline characteristics and clinical factors (e.g., HAS-BLED score, active cancer, and provoked VTE) between groups, we used the stabilized inverse probability treatment weighting (IPTW) method. Follow-up continued until the occurrence of the first event, switch to the comparator, disenrollment, death, or end of the study period. Multivariable Cox proportional hazards modeling with IPTW was used to obtain adjusted hazard ratios (aHR) and 95% confidence intervals (95%CI). Results: The study cohort (mean age=74 ±12 years, 40% male, 76% White) consisted of 2,315 users of extended apixaban treatment (83% with 5 mg twice a day and 17% with 2.5 mg twice a day; mean duration=6.2 months), 2,757 users of extended warfarin treatment (mean duration=8.2 months), and 2,328 patients with no extended treatment following completion of an initial 6 months of anticoagulant treatment. The incidence rates of recurrent VTE were 0.42, 1.73, and 1.72 per 100 person-years, and those of major bleeding were 2.28, 3.62, and 1.43 per 100 person-years in the apixaban, warfarin, and no treatment groups, respectively (Table 1). Compared to no extended treatment, the use of apixaban was associated with an 80% decreased risk of recurrent VTE (aHR=0.19, 95%CI=0.06-0.55) without increasing the risk of major bleeding (aHR=1.19, 95%CI=0.65-2.19); the use of warfarin did not lower the risk of recurrent VTE (aHR=0.75, 95%CI=0.42-1.37) but increased the risk of major bleeding (aHR=1.92, 95%CI=1.13-3.25). Compared to the use of warfarin, the use of apixaban was associated with a decreased risk of recurrent VTE (aHR=0.26, 95% CI=0.09-0.76) and no difference in major bleeding risk (aHR=0.61, 95%CI=0.36-1.06). These findings remained consistent in subgroup (e.g., patients with provoked vs. unprovoked VTE, patients with active cancer vs. those without, and patients with chronic kidney diseases vs. those without) and sensitivity analyses (e.g., ≥92% proportion days covered with oral anticoagulants during the initial 6-month period). Conclusions: Compared to no extended therapy, extended anticoagulation with apixaban was associated with a reduced risk of recurrent VTE without increasing the risk of major bleeding, whereas warfarin did not lower risk of recurrent VTE but increased the risk of major bleeding among Medicare beneficiaries with VTE. In the head-to-head comparison, the use of apixaban was more effective than warfarin in preventing recurrent VTE, without increasing the risk of major bleeding events. Our findings suggest that apixaban is an effective and safer option for extended treatment of VTE when compared to warfarin or no treatment among Medicare beneficiaries with VTE. Figure 1 Figure 1. Disclosures Park: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Kang: BMS/Pfizer Alliance American Thrombosis InvestigatorInitiated Research Program: Research Funding. Huang: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Lo-Ciganic: MERCK: Research Funding; BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Dietrich: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding. Murphy: North American Thrombosis Foundation: Honoraria. DeRemer: BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program: Research Funding; Portola Pharmaceuticals: Current equity holder in publicly-traded company; BMS advisory board attendee: Honoraria. more...
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- 2021
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11. Extensive Changes of the Immune Microenvironment Are Associated with Progression from Precursor Stages to Multiple Myeloma
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Minghao Dang, Sattva S. Neelapu, Samer A. Srour, Pei Lin, Guangchun Han, Donald A. Berry, Krina K. Patel, Robert Z. Orlowski, Yago Nieto, Linghua Wang, Manisha Singh, Zuzana Berkova, Donna M. Weber, Gregory P. Kaufman, Qaiser Bashir, Sheeba K. Thomas, Behrang Amini, P. Andrew Futreal, Maliha Khan, Hans C. Lee, Shubhra Singh, Elisabet E. Manasanch, Muzaffar H. Qazilbash, and Zheng Zhang more...
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business.industry ,Immune microenvironment ,Immunology ,Cancer research ,Medicine ,Cell Biology ,Hematology ,business ,medicine.disease ,Biochemistry ,health care economics and organizations ,Multiple myeloma - Abstract
Myeloma precursors (monoclonal gammopathy of unknown significance (MGUS) and smoldering myeloma (SMM)) precede the development of active multiple myeloma. Understanding the genomic and immune mechanisms that underlie transformation to MM may be key to identifying a successful therapy. To this end, we designed a prospective observational study of MGUS/SMM patients to identify genomic, immunological, and clinical parameters that may predict disease progression, and to recognize potential therapeutic targets for MGUS and SMM patients at high-risk of progression. From December 2015 until April 2019, 132 patients were consented, 100 patients were eligible for the study (41 MGUS, 59 SMM) and included in this analysis. Patients met the current definition of MGUS/SMM per IMWG criteria and were followed at a minimum of every 6 months with standard blood work and urine studies. All patients had advanced imaging/bone marrow biopsy at baseline and after 3 years of follow up. Median follow up time is 24 months (12-48 months). As of 07/01/2020, ten patients (17%, 10/59 SMM and 0%, 0/41 MGUS) progressed to MM and two patients progressed to systemic AL amyloidosis (3%, 2/59 SMM and 0%, 0/41 MGUS). Eight pairs of CD138+ bone marrow samples at baseline and at progression were available and analyzed by flow cytometry using a pre-designed antibody panel. Whole exome sequencing has been performed on 76 samples (matched germline and tumor) from 38 patients (15 MGUS, 17 SMM without progression and 6 SMM that progressed). A total of 24/39 (62%) tumor samples were covered at >100x and 20/37 (54%) germline samples were covered at >50x. After quality control analysis, bulk RNASeq of 144 samples from tumor and microenvironment (TME) cells from 90 patients (38 MGUS and 52 SMM) were included in the analysis. Flow analysis showed upregulation of inhibitory ligands (PD-L1/PD-L2) and B7-H3, CD200, HLA-E, HLA-G and CD59 at progression compared to baseline in 8 paired tumor samples from SMM patients that progressed. (Figure 1A). WES data analysis showed mutations in KMT2C/E (6/38, 4 SMM, 2 MGUS), NRAS/KRAS (5/38, 2 SMM progressors, 1 SMM, 2 MGUS), and FOXO3 (5/38, 1 SMM progressor, 2 SMM, 2 MGUS). Notably, 5/6 mutations in KMT2C/2E were deleterious mutations, all FOXO3 mutations were truncating, and mutations in KMT2C/2E, FOXO3, and NRAS were mutually exclusive. Unsupervised clustering of CD138+ tumor cells RNAseq at baseline identified 3 distinct clusters (C1-C3). All SMM that progressed (n=6) belonged to C2. CD138- TME RNAseq baseline samples were separated into 4 clusters (C1-C4) and 9/11 progressed patients belonged to C2 with distinct expression profiles (Figure 1 panel B/C). Immune deconvolution of TME samples showed lower baseline counts of CD8+ and CD4+ memory resting T cells and higher CD4+ memory activated, gamma delta T cells and dendritic cells in patients with PD (n=11) vs no PD (n=73)(p Overall, we found extensive changes in the TME composition, in the expression of genes in immune pathways, and in the expression of immune checkpoints, both in tumor and TME samples at baseline and during disease progression. The results of clustering analysis suggest that the features of both tumor and TME at baseline could be possibly used to predict risk of disease progression. Larger studies and validation are needed. Treatment that targets changes in the cell composition and expression of immune checkpoints in myeloma precursor disease may be entertained as a possible therapeutic option. Disclosures Manasanch: Novartis: Research Funding; Sanofi: Research Funding; Takeda: Honoraria; JW Pharma: Research Funding; Merck: Research Funding; Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Quest Diagnostics: Research Funding. Lee:Genentech: Consultancy; Regeneron: Research Funding; Daiichi Sankyo: Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Patel:Cellectis: Research Funding; Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Oncopeptides: Consultancy; Precision Biosciences: Research Funding; Poseida: Research Funding; Celgene: Consultancy, Research Funding. Kaufman:Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Honoraria. Bashir:Celgene: Research Funding; KITE: Other: Advisory Board; Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding; StemLine: Research Funding. Nieto:Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support. Qazilbash:Angiocrine: Research Funding; Bioline: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding; Janssen: Research Funding. Berry:Berry Consultants LLC.: Other: Co-owner. Thomas:BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards; Genentech: Research Funding. Orlowski:STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Neelapu:Cell Medica/Kuur: Other: personal fees; Legend Biotech: Other; Calibr: Other; Incyte: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Unum Therapeutics: Other, Research Funding; Karus Therapeutics: Research Funding; Novartis: Other: personal fees; N/A: Other; Precision Biosciences: Other: personal fees, Research Funding; Cellectis: Research Funding; Acerta: Research Funding; Allogene Therapeutics: Other: personal fees, Research Funding; Poseida: Research Funding; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Adicet Bio: Other. more...
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- 2020
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12. Clinical and prognostic significance of 3q26.2 and other chromosome 3 abnormalities in CML in the era of tyrosine kinase inhibitors
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Wei Wang, Pei Lin, Hagop M. Kantarjian, Michael W. Beaty, Jorge E. Cortes, Shimin Hu, L. Jeffrey Medeiros, Timothy J. McDonnell, Di Ai, Hesham M. Amin, and Chi Young Ok
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Immunology ,Locus (genetics) ,Kaplan-Meier Estimate ,Biology ,Biochemistry ,Tyrosine-kinase inhibitor ,Young Adult ,Myelogenous ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,neoplasms ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Chromosome Aberrations ,Myeloid Neoplasia ,Cytogenetics ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia ,Chromosome 3 ,Cancer research ,Female ,Chromosomes, Human, Pair 3 ,Chronic myelogenous leukemia - Abstract
Chromosome 3q26.2 abnormalities in acute myeloid leukemia, including inv(3)/t(3;3) and t(3;21), have been studied and are associated with a poor prognosis. Their prevalence, response to tyrosine kinase inhibitor (TKI) treatment, and prognostic significance in chronic myelogenous leukemia (CML) are largely unknown. In this study, we explored these aspects using a cohort of 2013 patients with CML diagnosed in the era of TKI therapy. Chromosome 3 abnormalities were observed in 116 (5.8%) of 2013 cases. These cases were divided into 5 distinct groups: A, inv(3)(q21q26.2)/t(3;3)(q21;q26.2), 26%; B, t(3;21)(q26.2;q22), 17%; C, other 3q26.2 rearrangements, 7%; D, rearrangements involving chromosome 3 other than 3q26.2 locus, 32%; and E, gain or loss of partial or whole chromosome 3, 18%. In all, 3q26.2 rearrangements were the most common chromosome 3 abnormalities (50%, groups A-C). 3q26.2 rearrangements emerged at different leukemic phases. For cases with 3q26.2 rearrangements that initially emerged in chronic or accelerated phase, they had a high rate of transformation to blast phase. Patients with 3q26.2 abnormalities showed a marginal response to TKI treatment, and no patients achieved a long-term sustainable response at a cytogenetic or molecular level. Compared with other chromosomal abnormalities in CML, patients with 3q26.2 rearrangements had poorer overall survival. The presence or absence of other concurrent chromosomal abnormalities did not affect survival in these patients, reflecting the predominant role of 3q26.2 rearrangements in determining prognosis. Interestingly, although heterogeneous, chromosome 3 abnormalities involving non-3q26.2 loci (groups D, E) also conferred a worse prognosis compared with changes involving other chromosomes in this cohort. more...
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- 2015
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13. Insights from response to tyrosine kinase inhibitor therapy in a rare myeloproliferative neoplasm with CALR mutation and BCR-ABL1
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Raja Luthra, L. Jeffrey Medeiros, Keyur P. Patel, Hagop M. Kantarjian, Sanam Loghavi, Jorge E. Cortes, Meenakshi Mehrotra, Srdan Verstovsek, Naveen Pemmaraju, Yang Huh, Pei Lin, and Rashmi Kanagal-Shamanna more...
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Pathology ,medicine.medical_specialty ,biology ,Essential thrombocythemia ,business.industry ,medicine.drug_class ,Immunology ,Context (language use) ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tyrosine-kinase inhibitor ,Dasatinib ,Bcr abl1 ,medicine ,biology.protein ,Cancer research ,CALR Mutation ,business ,Calreticulin ,Myeloproliferative neoplasm ,medicine.drug - Abstract
To the editor: Calreticulin ( CALR ) mutations have been reported primarily in the context of JAK2 and MPL wild-type essential thrombocythemia and primary myelofibrosis.[1][1][⇓][2][⇓][3][⇓][4]-[5][5] CALR mutations are exceedingly rare in the setting of t(9;22)/ BCR-ABL1 ,[4][4],[5][5] with more...
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- 2015
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14. A Multicenter Phase II Single Arm Trial of Isatuximab in Patients with High Risk Smoldering Multiple Myeloma (HRSMM)
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Elisabet E. Manasanch, Sattva S. Neelapu, Sundar Jagannath, Neha Korde, Donna M. Weber, Ola Landgren, Behrang Amini, Hans C. Lee, Connor Graham, Pei Lin, Robert Z. Orlowski, Michelle A.T. Hildebrandt, Sham Mailankody, Sheeba K. Thomas, Swami P. Iyer, Gregory P. Kaufman, Krina K. Patel, Nikoletta Lendvai, Feng Lei, and Zuzana Berkova more...
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Isatuximab ,education.field_of_study ,medicine.medical_specialty ,business.industry ,Immunology ,Population ,Phases of clinical research ,Cell Biology ,Hematology ,Pomalidomide ,medicine.disease ,Biochemistry ,Quality of life ,Family medicine ,Clinical endpoint ,Medicine ,business ,education ,health care economics and organizations ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
Background High risk smoldering multiple myeloma (HRSMM), defined as having immunoparesis and at least 95% abnormal plasma cells/all plasma cells by advanced flow cytometry, has a risk of progression to multiple myeloma of about 75% after 5 years of diagnosis. These patient have no symptoms and current standard is to follow them without treatment. Isatuximab is an IgG1 monoclonal antibody that binds to CD38 highly expressed in myeloma cells. Isatuximab has activity as monotherapy (overall response rate (ORR) 35%), with lenalidomide/dexamethasone (ORR 56%) and pomalidomide/dexamethasone (ORR 62%) in relapsed MM. We designed a phase II study to test the efficacy of isatuximab in high risk smoldering myeloma. Our study is registered in clinicaltrials.gov as NCT02960555. Methods The primary endpoint of the study is the ORR of isatuximab 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6 and day 1 cycles 7-30 in high risk smoldering myeloma. 24 patients were accrued in the first stage (of maximum 61 patients). Secondary endpoints are PFS, OS, clinical benefit rate (CBR). Exploratory endpoints are quality of life analysis (QoL), MRD, molecular/immune characterization using DNA/RNA sequencing of myeloma cells and the microenvironment before and after treatment. Results 24 patients with HRSMM were accrued from 02/08/2017 until 12/21/2018 (Table 1). All patients are evaluable for response. Best responses: ORR (≥PR) 15(62.5%), CR MRD- flow at 10-5 1 (5%), VGPR 4 (17%), PR 10 (42%), minor response (MR) 4 (18%), stable disease 5 (21%); CBR (≥MR) 79%. Median number of cycles received were 11.5 (range 6-30). Five patients have stopped treatment (one has completed the study, one with heavy history of smoking was diagnosed with squamous cell cancer of the tongue, one could no longer travel to treatments due to relocation, two progressed to active multiple myeloma after 16 and 6 cycles of treatment, respectively). There have been no deaths. DNA/RNA seq is ongoing for biomarkers of response. There were 5 grade 3 severe treatment-related adverse events (RAE) which resolved to baseline: dyspnea -related to infusion reaction (n=2), headache (n=1), ANC decrease (n=1), urinary tract infection (n=1). Most common grade 1-2 related adverse events (n): nausea (7), vomit (5), WBC decrease (3), diarrhea (3), fatigue (6), headache (4), mucositis (4), myalgia (4) and infusion reaction (3). In patients with available QoL functional scores (n=9 at baseline and n=7 after 6 months of therapy), isatuximab was effective in reducing their anxiety and worry of progression to multiple myeloma. Isatuximab also improved general QoL scores by the end of cycle 6 of treatment which were now comparable to those in the general population (Figure 1). Conclusion Isatuximab is very well tolerated, results in high response rates in HRSMM and has the potential to change the natural history of this disease. In ongoing QoL analysis, initial data shows improvement in QoL and decreased cancer worry after isatuximab treatment. Immune-genomic analysis is ongoing and may identify patients that benefit the most from treatment. Disclosures Manasanch: celgene: Honoraria; merck: Research Funding; quest diagnostics: Research Funding; sanofi: Research Funding; BMS: Honoraria; Sanofi: Honoraria. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Merck: Consultancy. Lee:Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Mailankody:Takeda Oncology: Research Funding; Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; CME activity by Physician Education Resource: Honoraria. Lendvai:Janssen: Employment. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Allogene: Consultancy; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC. OffLabel Disclosure: Isatuximab for the treatment of smoldering myeloma more...
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- 2019
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15. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma
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Donna M. Weber, Caimiao Wei, R. Eric Davis, Deborah J. Kuhn, Zuzana Berkova, Timothy Madden, Sheeba K. Thomas, Veerabhadran Baladandayuthapani, Robert Z. Orlowski, Richard Woessner, Michael Wang, Hua Wang, Chad C. Bjorklund, Richard J. Jones, Jatin J. Shah, Wencai Ma, and Pei Lin more...
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medicine.medical_treatment ,Blotting, Western ,Immunology ,Antineoplastic Agents ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Mice, SCID ,Pharmacology ,Biochemistry ,Receptor, IGF Type 1 ,Bortezomib ,Mice ,Paracrine signalling ,Insulin-like growth factor ,immune system diseases ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Insulin-Like Growth Factor I ,Autocrine signalling ,Receptor ,Multiple myeloma ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Lymphoid Neoplasia ,biology ,Cell growth ,Gene Expression Profiling ,Imidazoles ,Drug Synergism ,Cell Biology ,Hematology ,Flow Cytometry ,medicine.disease ,Boronic Acids ,Xenograft Model Antitumor Assays ,Survival Rate ,Insulin receptor ,Drug Resistance, Neoplasm ,Pyrazines ,biology.protein ,Multiple Myeloma ,medicine.drug - Abstract
Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)–1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA–mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bor-tezomib. Importantly, OSI-906 in combination with bortezomib also overcame bor-tezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic. more...
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- 2012
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16. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype
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Hagop M. Kantarjian, Jorge E. Cortes, Farhad Ravandi, Sherry Pierce, Joseph D. Khoury, Pei Lin, Nitin Jain, Deborah A. Thomas, Susan O'Brien, Audrey Lamb, Tapan M. Kadia, Jeffrey L. Jorgensen, Michael Rytting, Marina Konopleva, Gautam Borthakur, Zhuang Zuo, and Elias Jabbour more...
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Myeloid ,Adolescent ,CD3 Complex ,Clinical Trials and Observations ,medicine.medical_treatment ,Immunology ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,Biochemistry ,Disease-Free Survival ,Immunophenotyping ,Antigens, CD1 ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Recurrence ,Risk Factors ,Acute lymphocytic leukemia ,Internal medicine ,medicine ,Humans ,Aged ,Proportional Hazards Models ,Chemotherapy ,Precursor Cells, T-Lymphoid ,business.industry ,Remission Induction ,Cancer ,Cell Differentiation ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Lymphoma ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,CD5 ,business ,CD8 ,030215 immunology ,Follow-Up Studies - Abstract
Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a recently recognized high-risk T lymphoblastic leukemia/lymphoma (T-ALL/LBL) subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL/LBL are poorly characterized. In this study, we compared the outcomes of adults with ETP-ALL/LBL who received treatment on frontline regimens with those of patients with other T-ALL/LBL immunophenotypic subtypes. Patients with newly diagnosed T-ALL/LBL who received frontline chemotherapy between the years 2000 and 2014 at The University of Texas MD Anderson Cancer Center were identified and immunophenotypically categorized into early, thymic, and mature per the World Health Organization (WHO) classification using CD1a and surface CD3 status. Patients with ETP-ALL/LBL were identified on the basis of the following immunophenotypes: CD1a(-), CD8(-), CD5(-)(dim), and positivity for 1 or more stem cell or myeloid antigens. A total of 111 patients with T-ALL/LBL (68% T-ALL; 32% T-LBL) with adequate immunophenotype data were identified. The median age was 30 years (range, 13-79). There was no difference in the outcomes of patients based on the WHO subtypes. Nineteen patients (17%) had ETP-ALL/LBL. The complete remission rate /complete remission with incomplete platelet recovery rate in patients with ETP-ALL/LBL was significantly lower than that of non-ETP-ALL/LBL patients (73% vs 91%;P= .03). The median overall survival for patients with ETP-ALL/LBL was 20 months vs not reached for the non-ETP-ALL/LBL patients (P= .008). ETP-ALL/LBL represents a high-risk disease subtype of adult ALL. Novel treatment strategies are needed to improve treatment outcomes in this T-ALL/LBL subset. more...
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- 2015
17. NY-ESO-1 is highly expressed in poor-prognosis multiple myeloma and induces spontaneous humoral and cellular immune responses
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Pei Lin, Guido J Tricot, Susann Szmania, Ramesh B. Batchu, Fenghuang Zhan, Frits van Rhee, Sushil K. Gupta, Guilio C. Spagnoli, Amberly Moreno, John D. Shaughnessy, and Mindy Pomtree
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Cytotoxicity, Immunologic ,Biopsy ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Biology ,Biochemistry ,Antibodies ,Immune system ,Antigen ,Antigens, Neoplasm ,Recurrence ,medicine ,Humans ,Cytotoxic T cell ,Cells, Cultured ,Multiple myeloma ,Immunobiology ,Membrane Proteins ,Cell Biology ,Hematology ,Immunotherapy ,Prognosis ,medicine.disease ,Molecular biology ,Gene Expression Regulation, Neoplastic ,Antibody Formation ,biology.protein ,NY-ESO-1 ,Antibody ,Multiple Myeloma ,CD8 - Abstract
The presence of a metaphase cytogenetic abnormality (CA) is the key negative predictor of outcome in patients with multiple myeloma (MM). Gene expression profiling (GEP) of such patients showed increased expression of NY-ESO-1 compared to patients with normal cytogenetics (60% versus 31%; P = .004). NY-ESO-1 was also highly expressed in relapsing MM especially patients with CA (100% versus 60.7%; P < .001). GEP findings were confirmed at the protein level by immunostaining of marrow biopsies for NY-ESO-1. We detected spontaneous NY-ESO-1–specific antibodies by enzyme-linked immunosorbent assay in 33% of patients with NY-ESO-1+ MM, especially in CA patients (9 of 13; 70%), but in none of the NY-ESO-1- patients with MM (n = 27) or healthy donors (n = 21). Spontaneous NY-ESO-1157-165–specific T cells (0.2%-0.6% of CD8+ T cells) were found in the peripheral blood of NY-ESO-1+ MM with HLA-A*0201/NY-ESO-1157-165 tetramers. These NY-ESO-1–specific T cells, when expanded, killed primary MM cells (50% lysis, effector-target [E/T] ratio, 10:1). Our data demonstrate that NY-ESO-1 is frequently expressed in MM with CA and is capable of eliciting spontaneous humoral and T-cell immunity. The pool of NY-ESO-1–specific cytotoxic T cells expands easily on NY-ESO-1 peptide stimulation and is functionally active. NY-ESO-1 should therefore be an ideal tumor target antigen for immunotherapy of patients with poor-prognosis MM. more...
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- 2005
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18. A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance
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Jing Yang, Pei Lin, Yong Lu, Qing Yi, Jingda Xu, Jin He, Zhiqiang Liu, Jianfei Qian, Yuhuan Zheng, Haiyan S. Li, and Donna M. Weber
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animal structures ,Stromal cell ,Cell Survival ,Biopsy ,Immunology ,Gene Expression ,Antineoplastic Agents ,Apoptosis ,Biology ,Biochemistry ,Zinc Finger Protein GLI1 ,Syndecan 1 ,immune system diseases ,GLI1 ,Bone Marrow ,hemic and lymphatic diseases ,Cell Line, Tumor ,Animals ,Humans ,Hedgehog Proteins ,Sonic hedgehog ,Autocrine signalling ,Hedgehog ,Cell Proliferation ,Oncogene Proteins ,Cell Biology ,Hematology ,Xenograft Model Antitumor Assays ,Hedgehog signaling pathway ,Tumor Burden ,Autocrine Communication ,Disease Models, Animal ,Proto-Oncogene Proteins c-bcl-2 ,Drug Resistance, Neoplasm ,Case-Control Studies ,embryonic structures ,Cancer research ,biology.protein ,Trans-Activators ,Female ,Syndecan-1 ,Stem cell ,Multiple Myeloma ,Signal Transduction - Abstract
Hedgehog (Hh) signaling plays an important role in the oncogenesis of B-cell malignancies such as multiple myeloma (MM). However, the source of Hh ligand sonic hedgehog (SHH) and its target cells remains controversial. Previous studies showed that stromally induced Hh signaling is essential for the tumor cells and that CD19(+)CD138(-) MM stem cells are the target cells of Hh signaling. Here we demonstrate that SHH was mainly secreted by human myeloma cells but not by stromal cells in MM bone marrow. Autocrine SHH enhanced CD138(+) myeloma cell proliferation and protected myeloma cells from spontaneous and stress-induced apoptosis. More importantly, autocrine SHH protected myeloma cells against chemotherapy-induced apoptosis in vitro and in vivo. Combinational treatment with chemotherapy and SHH-neutralizing antibody displayed synergistic antimyeloma effects. Mechanistic studies showed that SHH signaling activated the SHH/GLI1/BCL-2 axis, leading to the inhibition of myeloma cell apoptosis. Thus, this study identifies the myeloma autocrine Hh signaling pathway as a potential target for the treatment of MM. Targeting this pathway may improve the efficacy of chemotherapy in MM patients. more...
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- 2014
19. MYC Copy Number Aberrancies Predict a Worse Prognosis in Patients with Diffuse Large B-Cell Lymphoma
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Nishitha Reddy, Adam C. Seegmiller, Jie Xu, Pei Lin, Guilin Tang, Jason R. Westin, Parth Desai, L. Jeffrey Medeiros, Wei Wang, Shaoying Li, Andrés E. Quesada, Roberto N. Miranda, and C. Cameron Yin
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Oncology ,medicine.medical_specialty ,Immunology ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,In patient ,medicine.diagnostic_test ,business.industry ,Cell Biology ,Hematology ,BCL6 ,medicine.disease ,Chemotherapy regimen ,Lymphoma ,Exact test ,030220 oncology & carcinogenesis ,Immunohistochemistry ,business ,Diffuse large B-cell lymphoma ,030215 immunology ,Fluorescence in situ hybridization - Abstract
Introduction: It is known that patients with double hit (DHL) and triple hit lymphoma (THL) have a significantly worse prognosis compared to patients with diffuse large B-cell lymphoma (DLBCL) without MYC rearrangement (MYC-R). Some studies have shown that DLBCL patients with MYC rearrangement only (single hit lymphoma; SHL) also have a poor prognosis similar to those with DHL/THL. However, it is not uncommon for fluorescence in situ hybridization (FISH) to detect extra copies (EC) of MYC, BCL2 or BCL6 in the absence of rearrangement. The potential role of these extra copies (EC) on survival has not been fully explored. In the current study, we focused on the prognostic significance of MYC-EC in comparison with MYC-R in patients with de novo DLBCL treated with rituximab-chemotherapy. Materials and Methods: A total of 664 de novo DLBCL cases with MYC/8q24, BCL2/18q21 and BCL6/3q27status confirmed by FISH and/or karyotype from 2010-2015 were included. MYC SHL, DHL and THL were identified if they had rearrangements of MYC only, both MYC and BCL2 or BCL6, or concurrent MYC, BCL2, and BCL6, respectively. Positive expression for MYC or BCL2 by immunohistochemistry was defined by >40% and >50% staining in the lymphoma cells, respectively.Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test.Fisher's exact test was used to compare the clinicopathologic features.Statistical analysis was performed using SPSS 23 software. Results: 105 DLBCL had MYC-R, 77 had MYC-EC, and 482 had no MYC abnormality (MYC-NL). The 105 MYC-R cases included 28 SHL, 45 DHL (39 MYC/BCL2 and 6 MYC/BCL6 DHL), 11 THL, and 21 with unknown BCL2 or BCL6 status. Overall, the clinicopathologic features including overall survival (OS) were similar among SHL, DHL, and THL patients (Figure 1A, p=0.92). Patients with DLBCL harboring MYC-R had more aggressive clinicopathologic features than those with MYC-EC or MYC-NL (p Although both the MYC-R and MYC-EC groups demonstrated a worse OS than MYC-NL patients (p By multivariate analysis, MYC-R (HR=2.55, p=0.0001) but not MYC-EC was an independent prognostic factor in de novo DLBCL patients. Conclusion: Patients with DLBCL harboring extra copies of MYC have clinicopathologic features more in common to DLBCL patients with normal MYC status than those with MYC rearrangement. The OS in patients with DLBCL harboring extra copies of MYC was significantly worse than in DLBCL patients without MYC abnormality; however, it was not as poor as that seen in patients with DLBCL with MYC-R. Compared to R-CHOP, intensive induction regimens (R-EPOCH & R-Hyper-CVAD) showed only a trend towards better prognosis in DLBCL patients with MYC rearrangement or extra copies. Figure 1 Figure 1. Disclosures Westin: Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; ProNAi: Membership on an entity's Board of Directors or advisory committees. Reddy:GILEAD: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. more...
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- 2016
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20. Phase I/II Trial of Lenalidomide and High-Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma: Updated Results
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Denái R. Milton, Robert Z. Orlowski, Ruby Delgado, Partow Kebriaei, Qaiser Bashir, Amanda Cornelison, Nina Shah, Chitra Hosing, Pei Lin, Yago Nieto, Peter F. Thall, Simrit Parmar, Uday R. Popat, Elizabeth J. Shpall, Muzaffar H. Qazilbash, and Richard E. Champlin more...
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medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Urology ,Hematopoietic stem cell transplantation ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Maintenance therapy ,Median follow-up ,medicine ,Multiple myeloma ,Lenalidomide ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Surgery ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Bone marrow ,business ,Progressive disease ,030215 immunology ,medicine.drug - Abstract
Introduction While high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In light of data suggesting safety and synergy in combining novel therapeutics with traditional cytotoxic chemotherapy, we hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control. Methods We conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant. Initial results after 12.3 months of follow-up were published in 2015; we now present an update with 39.8 months of follow-up. Results 57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose-limiting toxicities were seen, both at dose level 75 mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 4%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). 63% received maintenance therapy, (54% lenalidomide-based). By day +90, 8 patients (14%) had achieved a complete response (CR), 17 (30%) a very good partial response (VGPR), and 17 (30%) a partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. Best responses were PR: 26%, VGPR: 18%, near CR: 18%, CR: 7%, stringent CR: 23% for a ≥VGPR rate of 66. 23% achieved bone marrow minimal residual disease negativity by flow cytometry. Median time to achieve best response was 92 days (range: 16-732). One patient (2%) had progressive disease and 3 patients (5%) achieved only stable disease. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, (deletion 13q, t(4:14) or del 17p) by conventional cytogenetics or (t(4:14), t(14:16) or del17p by fluorescent in-situ hybridization), bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 39.8 months (range: 0.5- 66.9), median PFS was 17.1 months (95% CI: 10.8 - 23.0, Figure 1) and median OS was 48.0 months (95% CI: 22.6 months, not estimated, Figure 2). There was no significant effect of dose level on PFS or OS. Multivariable Bayesian survival time models found high-risk cytogenetics to be significantly harmful to both OS and PFS. In addition, degree of plasma cell infiltration of bone marrow before auto-HCT was significantly harmful to PFS. Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Longer follow-up demonstrates PFS and OS as comparable to other salvage treatments for MM, suggesting that this regime can be applied as a part of the sequence of therapies for these patients. Figure 1 PFS of 17.1 months (95% CI: 10.8 - 23.0; N=57, Events=48) Figure 1. PFS of 17.1 months (95% CI: 10.8 - 23.0; N=57, Events=48) Figure 2 OS of 48.0 months (95% CI: 22.6 months, not estimated; N=57, Deaths=28) Figure 2. OS of 48.0 months (95% CI: 22.6 months, not estimated; N=57, Deaths=28) Disclosures Orlowski: Takeda Pharmaceuticals: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties. more...
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- 2016
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21. CD5 Negative Mantle Cell Lymphoma: Clinicopathologic Correlations and Outcome in 58 Cases
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Shaoying Li, Pei Lin, Annapurna Saksena, C. Cameron Yin, Yuan Miao, Jingyi Li, L. Jeffrey Medeiros, and Michael Wang
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Oncology ,medicine.medical_specialty ,Vincristine ,business.industry ,Immunology ,Induction chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Log-rank test ,Transplantation ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Rituximab ,Mantle cell lymphoma ,business ,Progressive disease ,Survival analysis ,medicine.drug - Abstract
Introduction: Mantle cell lymphoma (MCL) is a B-cell neoplasm that has a characteristic immunophenotype of being positive for CD5, B-cell antigens and cyclin D1. A small subset of cases of MCL can be negative for CD5, approximately 5% in the literature. The clinicopathologic features and prognosis of patients with CD5-negative MCL are poorly characterized. Here, we study a group of patients with CD5- MCL and compare them with a group patients with CD5+ MCL. Methods: From a total of 270 cases of MCL accessioned from 2004-2015, 58 CD5- cases (study group) and 212 CD5+ cases (control group) were identified. All cases of MCL were positive for cyclin D1 by immunohistochemistry and, in most patients, CCND1-IGH was shown FISH. Cases negative for CD5 were assessed by flow cytometry and/or immunohistochemistry. Fisher exact test was utilized to analyze differences between the CD5- and CD5+ groups. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazards model analyses for OS and PFS were performed (SPSS 22 software). A P-value of less than 0.05 was considered statistically significant. Results: The CD5- group included 39 men and 19 women with a median age of 66 years (range, 36- 88 years) at time of diagnosis. The CD5- and CD5+ groups shared overlapping clinicopathological features, but CD5- cases showed a lower percentage of men (P=0.006) than CD5+ cases. Treatment information was available for 50 patients. Twenty-nine (58%) patients were treated initially with R-Hyper CVAD therapy (rituximab, fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose methotrexate and cytarabine). Seventeen (34%) patients were treated initially with less aggressive therapy: 7 with R-CHOP; 8 had other rituximab-based chemotherapy regimens; 2 received rituximab as a single agent. Four patients (8%) were observed without therapy. After induction, 34 patients achieved complete remission (CR), 5 patients achieved partial remission (PR), 6 patients showed no response (NR) or progressive disease (PD), and 5 patients lost follow-up. Ten patients also underwent stem cell transplantation (SCT): 5 patients received allogeneic SCT, the other 5 autologous SCT. With a median follow-up of 45.7 months (range, 2.0-174.3 months), 13 of 56 (23.2%) patients died, 43 of 56 (76.8%) patients were alive at last follow-up, and the rest of 2 patients lost follow up. The induction chemotherapy regimens and CR and PR rate were not significantly different between the CD5- and CD5+ groups (p>0.05). Survival analysis showed patients with CD5- MCL had a tendency for longer OS (Figure 1A, P=0.078). Further analysis showed that lack of CD5 expression predicted a superior OS in a few subsets of MCL patients defined with 1) normal WBC count (p=0.049); 2) Stage I/II disease (p=0.046); 3) Low/intermediate MIPI (p=0.041) and 4) Ki67≥30% (at a borderline p value of 0.05). Patients with CD5- MCL also showed a significantly longer progression-free survival (PFS) (Figure 1B, P=0.01). Absence of CD5 expression was associated with a better PFS in MCL patients with advanced disease (stage III-IV) (P=0.035), a normal leukocyte count (P=0.018), a normal serum lactate dehydrogenase level (P=0.046), classical morphology (P=0.029), and low/intermediate MIPI (p=0.0004). Multivariate Cox regression analysis revealed that MIPI was the only independent prognostic factor for both OS and PFS (P=0.026 and P=0.001 respectively) and CR/PR also predict a better OS (P=0.004) in CD5- MCL patients. Conclusion: The clinicopathologic features were similar between patients with CD5- MCL and those with CD5+ MCL, except that less men in the CD5- MCL group. Lack of CD5 expression was associated with a favorable PFS in MCL patients. Recognizing this subgroup of CD5- MCL has not only a diagnostic significance, but also a prognostic significance. Figure Figure. Disclosures Wang: Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Onyx: Research Funding. more...
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- 2016
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22. Resistin Induces Multidrug Resistance in Myeloma By Inhibiting Cell Death and Upregulating ABC Transporter Expression
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Robert Z. Orlowski, Zhiqiang Liu, Huan Liu, Jianan Pang, Pei Lin, Jin He, Qiaofa Shi, Jing Yang, and Jiuwei Cui
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Stromal cell ,business.industry ,Bortezomib ,Immunology ,Adipokine ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Apoptosis ,hemic and lymphatic diseases ,Cancer research ,Medicine ,Resistin ,Bone marrow ,business ,PI3K/AKT/mTOR pathway ,Multiple myeloma ,medicine.drug - Abstract
Chemoresistance is a major hurdle in multiple myeloma. Most patients are prone to develop resistance to a wide spectrum of anticancer agents, significantly hampers the patients' long term outcome. Many studies point to bone marrow microenvironment as an important player in myeloma chemoresistance, in which marrow stromal cells and stromal-secreted soluble factors are shown to promote myeloma cell growth and survival. Our previous study has demonstrated that marrow-derived adipocytes protect myeloma cells against chemotherapy-induced apoptosis through adipocyte-secreted adipokines, one of such is leptin. However, the level of leptin expression in myeloma patients is not significantly changed, indicating the involvement of additional adipokines in this process. Interestingly, in a clinical study, an elevation of the adipokine resistin in the serum of myeloma patients after thalidomide treatment were observed as compared with that in patients before treatment, suggesting a potential role of this adipokine in response to chemotherapy. As a 12.5-kDa hormone that is mainly secreted by adipocytes and also secreted by other cells, resistin has a function in production of inflammatory cytokines that are important for cancer development. We thus hypothesized that resistin protects myeloma cells against chemotherapy. In our experiments, human myeloma cell lines and primary myeloma cells isolated from patient bone marrow aspirates were cultured in medium with addition of the recombinant human resistin and chemotherapy drugs melphalan or bortezomib for 24 hours. Cells without resistin served as a control. After cultures, an annexin-V binding assay for assessing apoptosis, western blot analysis for assessing cleavage of caspases and phosphorylation of signaling kinases, and the eFluxx-ID Gold uptake assay for examining ABC transporters activity were performed. In the animal study, myeloma-bearing SCID mice were treated with or without resistin and/or melphalan. Our results showed that resistin treatment reduced melphalan- or bortezomib-induced apoptosis both in vitro and in vivo. This protective effect has been further confirmed by the reduced cleavage of caspase-9, caspase-3, and poly (ADP-ribose) polymerase in myeloma cells. Mechanistic studies showed that culturing myeloma cells with resistin upregulated expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL and downregulated expression of the pro-apoptotic protein Bax via the NF-kB and the PI3K/Akt signaling pathways. Addition of resistin also reduced the intracellular accumulation of eFluxx-ID gold fluorescence in myeloma cells ARP-1 and MM.1S, when compared to that in cells without resistin. In addition, resistin significantly increased the mRNA and protein expression of ATP-binding cassette (ABC) transporters in myeloma cells by downregulating the expression of DNA methyltransferase 1 and 3a, and CpG methylation in the promoters of ABC transporters. Thus, our study demonstrates that resistin is a novel factor contributing to myeloma chemoresistance, and also implicates that disruption of its protective effect can be a potential strategy to improve current chemotherapy in patients and prolong survival. Disclosures No relevant conflicts of interest to declare. more...
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- 2016
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23. Clinical Implementation of a Testing Algorithm for the Diagnosis of Ph-like B-Cell Acute Lymphoblastic Leukemia
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Zhenya Tang, Marina Konopleva, Alexandra Reynolds, Jeffrey L. Jorgensen, Patrick A. Zweidler-McKay, L. Jeffrey Medeiros, Sa Wang, Keyur P. Patel, Charles G. Mullighan, Sergej Konopleva, Guilin Tang, Xinyan Lu, Pei Lin, Nitin Jain, and Kathryn G. Roberts more...
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medicine.diagnostic_test ,business.industry ,Concordance ,Immunology ,PDGFRB ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Acute lymphocytic leukemia ,Medicine ,B Acute Lymphoblastic Leukemia ,Multiplex ligation-dependent probe amplification ,CRLF2 Positive ,business ,Algorithm ,Fluorescence in situ hybridization ,SNP array - Abstract
Introduction: Philadelphia chromosome-like (Ph-like) B acute lymphoblastic leukemia (B-ALL) is characterized by a specific gene expression profile similar to that of Ph positive B-ALL, but lacks the BCR-ABL1 fusion. Ph-like B-ALL is known to frequently carry translocations and/or point mutations in various kinases and/or the cytokine receptor CRLF2 that activate a multi-kinase cascade and is often associated with poorer clinical outcomes. Recent reports have shown that patients with Ph-like B-ALLs respond to ABL1 or JAK2 inhibitors. However, timely diagnosis of Ph-like B-ALL cases remains clinically challenging. Methods: A panel of seven fluorescence in situ hybridization (FISH) probes targeting CRLF2, ABL1, ABL2, JAK2, PDGFRB, CSF1R and EPOR were designed and validated for the detection of rearrangements in Ph-like B-ALL. Of these, FISH for CRLF2was performed on both metaphase and interphase cells and the results were correlated with levels of CRLF2 expression assessed by multiparameter flow cytometry (MFC). Additional comprehensive analysis of fusion transcripts was conducted by PCR based testing. DNA copy number analyses were assessed using SNP microarray and/or MLPA and technologies. Results: For the initial validation, CRLF2 FISH was tested in 10 relapsed and 5 de novo B-ALL cases with CRLF2 overexpression by MFC and 100% concordance was achieved. FISH validation of other probes was successful in detecting known positive rearrangements. Using this panel, we tested a cohort of 57 B-ALL cases with a median age of 31 years old (range 13-81) and unknown Ph-like status, including 14 relapsed and 43 de novo. CRLF2 FISH was positive in all 17 (29.8%) MFC CRLF2 positive cases including 3 co-existing with the BCR-ABL1 fusion, showing 100% concordance. Of the 17 CRLF2 positive cases, five of nine cases tested (55.6%) were positive for JAK2 mutation. IGH-CRLF2 fusion was the most prevalent seen in 10 (58.9%) by metaphase FISH whereas P2RY8-CRLF2 was seen in two (11.8%) cases by metaphase FISH and/or SNP array analysis. One case had a novel fusion PAX5/ZCCHC7-CRLF2 detected by metaphase FISH analysis and the remaining 4 cases showed unknown fusion partners. In 40 (70.2%) CRLF2 negativecases, five (5/57, 8.8%) were positive with our FISH panel including two with CSF1R/PDGFRB, one with JAK2 and one with EPOR rearrangements, while one with NUP214-ABL1fusion was detected by PCR. Conclusions: Using the integrated MFC, FISH and Molecular testing, we demonstrated Ph-like B-ALL in 38.6% (22/57) of unselected B-ALL cases, including 17 CRLF2, 2 CSF1R/PDGFRB, 1 JAK2, 1 EPOR and 1 ABL1 rearrangements. Based on our clinical experience, we further implemented a clinical testing algorithm (Figure 1) for the diagnosis of Ph-like B-ALL. It is noteworthy that BCR-ABL1 fusion and CRLF2 rearrangement are not mutually exclusive and all B-ALL patients should be screened for both rearrangements simultaneously. Figure 1 Figure 1. Disclosures Mullighan: Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Loxo Oncology: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Jain:Servier: Consultancy, Honoraria; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Novartis: Consultancy, Honoraria; Novimmune: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. more...
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- 2016
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24. MYC/BCL2 Double Hit Lymphoma: What Really Matters
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Zhuang Zuo, Shaoying Li, Guilin Tang, Annapurna Saksena, Roberto N. Miranda, C. Cameron Yin, Nishitha Reddy, L. Jeffrey Medeiros, Pei Lin, Adam C. Seegmiller, Parth Desai, Jeffrey L. Jorgensen, and Jie Xu more...
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Oncology ,medicine.medical_specialty ,Pathology ,Immunology ,Follicular lymphoma ,Cell Biology ,Hematology ,Gene rearrangement ,Biology ,medicine.disease ,BCL6 ,Biochemistry ,Lymphoma ,International Prognostic Index ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,B-cell lymphoma ,Burkitt's lymphoma ,Diffuse large B-cell lymphoma - Abstract
Introduction: MYC/BCL2 double hit lymphoma (DHL), defined as a large B-cell lymphoma with concurrent MYC and BCL2 translocations, is the most common type of DHL. Although multiple studies focused on DHL have been published, several issues regarding impact on prognosis remain controversial including: 1) history of low grade B cell lymphoma; 2) morphology (diffuse large B-cell lymphoma [DLBCL] versus B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma [BCLU)]; 3) Absence or low expression of MYC or BCL2; 4) MYC translocation partner gene; and especially 5) most effective therapy. The aim of this study was to attempt clarify the prognostic importance of these factors in DHL. Methods: 157 patientsdiagnosed with MYC/BCL2 DHL between 2003 and April 2015 at two institutions were included in this study. MYC and BCL2 gene rearrangement were confirmed by FISH using a MYC breakapart probe and BCL2 and IGH dual color dual fusion probes. BCL6 /3q27gene status was tested either by FISH using breakapart probe or by karyotype. MYC partner gene was identified by karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2 but not BCL6 . Positive for MYC or BCL2 by immunohistochemistry was defined by >40% and >50% of lymphoma cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the clinicopathologic features. Statistical analysis was performed using SPSS 23 software. Results : There were 103 men and 54 women with a median age of 61 years (range, 18-87). 110 patients had de novo disease and 47 patients had a history of low-grade B-cell NHL, mostly follicular lymphoma. The clinicopathologic features were similar (P>0.05) between patients with a history of low-grade B-cell NHL and patients with de novo NHL, and therefore analysis was performed on all 157 DHL cases. Using the 2008 WHO classification, there were 91 DLBCL, 61 BCLU, and 5 composite lymphoma (4 DLBCL + follicular lymphoma and 1 DLBCL + B-lymphoblastic lymphoma). 99% of cases had a germinal center B-cell immunophenotype by the Hans algorithm. MYC expression was observed in 39/47 (83%) and BCL2 in 129/141(91%) of cases. MYC and BCL2 dual expression was present in 34/46(74%) cases. Of the 39 cases assessed, the MYC translocation partner was IGH in 13, IG light chain in 19, and a non-IG gene in 7 cases. 144 patients had complete treatment information: 61 received the R-CHOP regimen initially, 31 R-EPOCH, 29 R-HCVAD, and 23 various other chemotherapy regimens. 39 patients also received stem cell transplant (SCT) including 31 autologous and 8 allogeneic. 62 patients reached complete remission (CR) after initial chemotherapy. The median overall survival was 19 months. In a univariate analysis that evaluated 17 clinicopathologic parameters including those mentioned in introduction, extranodal sites of disease, bone marrow involvement, CNS involvement, advanced stage, and high/high-intermediate International Prognostic Index score were associated with a worse overall survival (OS, P more...
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- 2015
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25. Phase I/II Trial of Lenalidomide and High Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma
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Simrit Parmar, Chitra Hosing, Muzaffar H. Qazilbash, Partow Kebriaei, Robert Z. Orlowski, Elizabeth J. Shpall, Nina Shah, Uday R. Popat, Patricia S. Fox, Jatin J. Shah, Pei Lin, Peter F. Thall, Amanda Cornelison, Richard E. Champlin, Yago Nieto, and Qaiser Bashir more...
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Oncology ,Melphalan ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Population ,Hematopoietic stem cell transplantation ,Pharmacology ,Biochemistry ,Article ,Autologous stem-cell transplantation ,immune system diseases ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,education ,neoplasms ,Multiple myeloma ,Lenalidomide ,education.field_of_study ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Surgery ,Clinical trial ,Thalidomide ,Transplantation ,surgical procedures, operative ,business ,Progressive disease ,medicine.drug - Abstract
Introduction While high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In the era of modern therapeutics, it is reasonable to consider that the advantages gained for relapsed patients in the conventional setting may also extend to auto-HCT. We thus hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control. Methods We conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier curves were used to estimate PFS and OS and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant. Results 57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose limiting toxicities were seen, both at dose level 75mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 3%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). By day +90, 8 patients (14%) had achieved a CR, 25 (44%) a CR or very good partial response (VGPR), and 42 (74%) a CR, VGPR or partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. By day 180, 12 patients (21%) had achieved a CR. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 12.3 months (range 0.5-41), median PFS was 23.7 months and median OS had not yet been reached. The 1-year progression-free rate was 64% (95% CI: 49-75%). Multivariable Bayesian survival time models found both dose level and longer time between diagnosis and transplant to be significantly beneficial to both OS and PFS. In addition, high risk cytogenetics and LDH were significantly harmful to OS, and LDH was moderately harmful for PFS as well (Figures 1 and 2). Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Our previous data has shown a median PFS of 12.3 months in a comparable population. Thus this treatment regimen yields an encouraging PFS, offering relapsed or refractory patients another option for disease control. Figure 1. PFS by lenalidomide dose level (N=57, Events=24) Figure 1. PFS by lenalidomide dose level (N=57, Events=24) Figure 2. OS by lenalidomide dose level (N=57, Deaths=12) Figure 2. OS by lenalidomide dose level (N=57, Deaths=12) Disclosures Shah: Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Off Label Use: This presentation discusses lenalidomide in a transplant preparative chemotherapy combination. . Shah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Orlowski:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum Pharmaceuticals: Research Funding; JW Pharmaceutical: Research Funding; Array BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Champlin:Celgene: Consultancy, Research Funding. more...
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- 2014
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26. Myeloma Cells Switch Osteoblastogenesis to Adipogenesis and Suppress Bone Formation
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Larry W. Kwak, Zhiqiang Liu, Robert F. Gagel, Jin He, Robert Z. Orlowski, Huan Liu, Pei Lin, Qiang Tong, and Jing Yang
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medicine.medical_specialty ,Palliative care ,business.industry ,Immunology ,Mesenchymal stem cell ,Wnt signaling pathway ,Osteoblast ,Cell Biology ,Hematology ,Biochemistry ,Bone resorption ,chemistry.chemical_compound ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Adipogenesis ,hemic and lymphatic diseases ,Adipocyte ,Internal medicine ,Cancer research ,Medicine ,Bone marrow ,business - Abstract
Bone destruction is a hallmark of myeloma, and has a severe impact on patients’ quality of life and survival. Unfortunately, current treatment only offers moderate palliative effects, and this disease remains incurable. The bone changes in myeloma patients results from increased osteoclast-mediated bone resorption and decreased osteoblast-mediated bone formation. In particular, new bone formation that usually occurs at sites of previously resorbed bones is deeply suppressed; as a result, areas of bone destruction rarely heal. Previous studies have shown that myeloma cells inhibit osteoblast differentiation from mesenchymal stem cells (MSCs), and the Wnt/b-catenin signaling pathway is suppressed via myeloma-produced Wnt antagonists such as dickkopf-1. However, the role of dickkopf-1 in myeloma-induced inhibition of bone formation remains controversial since myeloma cells alone do not produce sufficient dickkopf-1 to suppress osteoblast differentiation. In addition, the administration of an antibody against dickkopf-1 in myeloma patients failed to restore new bone formation, indicating there must be an additional mechanism for inhibition of osteoblast differentiation seen in myeloma. While MSCs can differentiate into mature osteoblasts, they are also capable of differentiating into adipocytes, which is a major cell type in marrow stroma. We observed that myeloma cells (cell lines and primary cells isolated from myeloma patients’ bone marrow) injected into human or mouse bone not only reduced osteoblast number, but also increased adipocyte number and activity in bone marrow. Similar observations were seen in the clinical setting where collections of adipocytes were found in the bone marrow of newly diagnosed, untreated myeloma patients. Patients with greater bone destruction had higher adipocyte numbers than those in patients with less bone destruction, indicating a relationship among myeloma cells, adipogenesis, and osteoblastogenesis. We hypothesized that inhibition of osteoblast differentiation is a consequence of myeloma-dependent alterations in the control of the MSCs’ fate into osteoblasts or into adipocytes. In our studies, we co-cultured MSCs with myeloma cells in a mixed medium (that contained both adipocyte and osteoblast media), and we observed co-culture with myeloma cells induced more adipocyte than osteoblast formation. Moreover, co-culture with myeloma cells enhanced adipocyte differentiation in vitro. Interestingly, separation of the cells by transwell inserts significantly reduced such effect. By analysis of the adhesion molecules in myeloma cells, we identified integrin α4β1 as a novel contributor in regulation of adipogenesis and osteoblastogenesis. Thus, our studies indicate that in the presence of myeloma cells, MSCs may be more prone to differentiate into adipocytes than into osteoblasts via α4β1. Our studies also suggest the development of new strategies to improve the care of myeloma patients with bone destruction by targeting α4β1 and its signaling pathways. Disclosures No relevant conflicts of interest to declare. more...
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- 2014
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27. The TRUST Trial: Anti-Drug Antibody Formation In a Patient With Hemophilia With Inhibitors After Receiving The Activated Factor VII Product Bay 86-6150
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Mahlangu, Johnny N., primary, Koh, Pei Lin, additional, Ng, Heng Joo, additional, Lissitchkov, Toshko, additional, Hardtke, Marion, additional, and Schroeder, Jens, additional
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- 2013
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28. Regulation Of DKK-1 Expression By p38 MAPK Signaling Via CREB Myeloma Cells
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Yuping Zhong, Zhiqiang Liu, Robert Z. Orlowski, Larry W. Kwak, Huan Liu, Jin He, Pei Lin, and Jing Yang
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MAPK/ERK pathway ,biology ,Activator (genetics) ,business.industry ,Immunology ,Wnt signaling pathway ,Cell Biology ,Hematology ,Transfection ,CREB ,Biochemistry ,chemistry.chemical_compound ,chemistry ,DKK1 ,biology.protein ,Cancer research ,Medicine ,Signal transduction ,business ,Anisomycin - Abstract
Bone destruction is a hallmark of multiple myeloma and severely compromises a patient’s quality of life. Recently, we have demonstrated that p38 mitogen-activated protein kinase (MAPK), which is constitutively activated in myeloma cells, is a master regulator of myeloma-mediated bone destruction. We have observed that myeloma cell p38 MAPK upregulated the production of dickkopf-1 (DKK-1), of which inhibits osteoblast differentiation and bone formation by inhibiting Wnt signaling and enhances osteoclast differentiation and bone resorption by upregulating RANKL production. Our results have shown that treatment of SB203580 (SB20), a p38 MAPK inhibitor, downregulated, while treatment of anisomycin, a p38 MAPK activator, upregulated DKK-1 expression. However, the mechanism underlying the regulation of DKK-1 expression by p38 MAPK in myeloma cells remains poorly elucidated. Previous studies have suggested that CREB is a p38 MAPK-targeted transcriptional factor. We therefore hypothesized that myeloma cell p38 MAPK may upregulate the transcriptional levels of DKK-1 through CREB. To verify whether p38 MAPK regulates CREB phosphorylation in myeloma cells, ARP-1 and U266 cells were treated with SB20 or anisomycin. Western blotting results showed that SB20 treatment significantly reduced, while anisomycin treatment enhanced phosphorylation of CREB in both cell lines. Database analysis of DKK-1 promoter regions predicted a couple of potential CREB-binding sites localized around 1.3 kb upstream from the starting codons. CHIP assay further indicated that CREB specifically bound to the one of the putative binding sites (-1,354 bp). To validate the CHIP assay results, we designed three constructs: construct 1 containing the whole promoter (-2,542 bp to -220 bp), which has previously been shown to have strong transcriptional activity; construct 2, as a truncated portion of the promoter containing the putative CREB-binding sites (-1,392 bp to -220 bp); and construct 3, as a truncated portion of the promoter containing neither CREB-binding sites (-1073 bp to -220 bp). These constructs were amplified by PCR and cloned into a luciferase reporter gene vector (pGL2) respectively. To examine the effect of CREB on the transcription activities of DKK1 in myeloma cells, reporter constructs were transfected into ARP-1 and U266 cells. In line with our findings in CHIP assay, we observed that in both myeloma cells, the construct 2 had similar strong transcriptional activity as the construct 1 did, the construct 3 had little activity. These results demonstrated that there was a CREB-binding site in DKK-1 promoter, and is required for p38 MAPK-upregulated DKK-1 expression in myeloma cells. In conclusion, our results uncover a mechanism of myeloma cell p38 MAPK in osteoblast inhibition and osteoclast activation by which p38 MAPK transcriptionally upregulates DKK-1 expression via CREB. Disclosures: Orlowski: Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. more...
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- 2013
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29. The TRUST Trial: Anti-Drug Antibody Formation In a Patient With Hemophilia With Inhibitors After Receiving The Activated Factor VII Product Bay 86-6150
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Johnny N. Mahlangu, Pei Lin Koh, Heng Joo Ng, Toshko Lissitchkov, Marion Hardtke, and Jens Schroeder
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medicine.medical_specialty ,Factor VII ,business.industry ,Surrogate endpoint ,Immunology ,Cell Biology ,Hematology ,Bethesda unit ,Biochemistry ,Surgery ,Clinical trial ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Cohort ,Medicine ,Data monitoring committee ,business ,Adverse effect ,Factor IX ,medicine.drug - Abstract
Introduction Up to 30% of patients with hemophilia A and 5% of patients with hemophilia B develop neutralizing antibodies (inhibitors) against replacement factor VIII or factor IX, respectively. Acute bleeding episodes in these patients with inhibitors are treated with bypassing agents, which include activated recombinant factor VII (rFVIIa). BAY 86-6150 is a modified rFVIIa which in preclinical studies was shown to have prolonged half-life and improved potency compared with currently available rFVIIa. In a phase 1, randomized, double-blind trial, BAY 86-6150 was not associated with any clinically significant adverse events (AEs). We report the immunologic response to BAY 86-6150 in a phase 2/3 clinical trial in patients with hemophilia with inhibitors. Methods TRUST (Treatment with Unique Recombinant FVII Study) was a multicenter, open-label, 2-part study (part A and part B) which included males aged 12−62 years with moderate or severe hemophilia A or B, with a history of high-titer inhibitors (≥5 Bethesda units), and ≥4 bleeding episodes in the 6 months prior to enrollment. Part A was a sequential dose-escalation study of 4 BAY 86-6150 dose levels (6.5, 20, 50, and 90 μg/kg body weight; n≥10/cohort). Dose escalation was dependent on both efficacy and an Independent Data Monitoring Committee (IDMC) approval of safety in 10 patients per cohort who had ≥1 bleeding episode treated with BAY 86-6150. Part B was designed as a single-arm investigation of the efficacy and safety of the recommended dose of BAY 86-6150 determined in all patients from Part A. Safety endpoints were AEs and immunogenicity. Anti-drug antibody testing was performed at screening (prior to exposure), after the second exposure, then every fifth exposure, and at the end of study visit in both part A and part B. Anti-BAY 86-6150 binding antibodies were measured using a validated enzyme-linked immunosorbent assay (ELISA). Samples that revealed a specific immunoreactivity in this assay were further characterized for neutralizing activity using a validated platelet-activated clotting assay. Additional functional assays were performed to determine the cross-reactive neutralizing effect on rFVIIa (NovoSeven®) of any detected anti-BAY 86-6150 antibodies. The presence of neutralizing antibodies was considered a serious adverse event (SAE) requiring prompt IDMC review. Results In cohort 1, 10 patients (mean age, 27.4 years) were treated with 6.5 mg/kg BAY 86-6150. These patients had a total of 73 bleeding events and received a total of 84 study drug injections. No anti-drug antibodies or anti-FVIIa was detected in the patients at screening prior to exposure to the study drug. BAY 86-6150 was well tolerated in all patients with no clinical or laboratory symptoms or signs of venous thromboembolism. Binding antibodies to BAY 86-6150 were detected on a scheduled screening visit in 1 patient after 3 exposures to BAY 86-6150; these anti-BAY 86-6150 antibodies displayed neutralizing activity against BAY 86-6150 and were also cross-reactive and neutralizing for rFVIIa. The affected patient had received rFVIIa before entry into the study. At the time of diagnosis of binding and neutralizing antibodies, the affected patient was not bleeding and did not require emergency treatment. Exposure to BAY 86-6150 was stopped and the trial was terminated at the first cohort. Subsequent bleeding episodes in this patient were successfully managed with FEIBATM (Factor Eight Inhibitor Bypass Activity). No other treatment-related AEs or SAEs were reported in this study. Additionally, the IDMC has recommended safety follow-up assessments for all the patients who actively participated in the trial. Conclusions The TRUST trial has been discontinued as a precautionary measure because of potential safety concerns related to the detection of the antidrug antibodies in 1 patient. Development of neutralizing antibodies against BAY 86-6150 that had a cross-reactive neutralizing effect on rFVIIa was considered a serious risk because of the limited treatment options in patients with inhibitors. These results underline the fact that it is currently not possible to predict immunologic response based on preclinical and phase 1 studies. Disclosures: Hardtke: Bayer Pharma AG: Employment. Schroeder:Bayer Pharma AG: Employment. more...
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- 2013
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30. Activation Of Autophagy By Bone Marrow Adipocytes Protects Myeloma Cells From Chemotherapy-Induced Apoptosis
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Robert Z. Orlowski, Huan Liu, Jin He, Larry W. Kwak, Pei Lin, Qing Yi, Zhiqiang Liu, Jing Yang, and Jingda Xu
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medicine.medical_specialty ,Stromal cell ,business.industry ,Immunology ,ATG5 ,Autophagy ,Mesenchymal stem cell ,Cell Biology ,Hematology ,Biochemistry ,Endocrinology ,medicine.anatomical_structure ,Apoptosis ,Cell culture ,Internal medicine ,medicine ,Cancer research ,Tumor necrosis factor alpha ,Bone marrow ,business - Abstract
Currently, chemotherapy is the most effective treatment for multiple myeloma (MM). Although some new drugs have been shown to prolong survival in MM patients, these patients are prone to rapid relapse after high-dose treatment. Recent studies show that several bone marrow (BM) stromal cells are potentially involved in drug resistance. However, the role of other stromal cells is unclear. Adipocytes (ADs) are a major component of BM stromal cells. ADs have been shown to be involved in tumor rapid growth, metastasis, and apoptosis. Clinical studies suggest that BM ADs are associated with an increased risk of MM. Moreover, ADs isolated from patient BM biopsies were shown to support MM proliferation and migration. However, no published study has examined the importance of ADs in MM drug resistance. In addition, autophagy activation has been shown to induce drug resistance in cancer patients. We hypothesized that BM ADs protect MM cells from chemotherapy drug-induced apoptosis by autophagy activation. To examine the role of ADs in MM drug resistance, MM cells were cocultured with ADs at a ratio of 1:5 for 24 hours in medium with melphalan, dexamethasone, or bortezomib, the commonly used drugs for the treatment of MM. MM cells included primary MM cells isolated from BM aspirates of 5 MM patients and 6 MM cell lines. Human ADs were generated from mesenchymal stem cells derived from the BM mononuclear cells of healthy human fetal bones or BM aspirates of MM patients or healthy adult donors, cultured in AD medium for 2 weeks. ADs generated in vitro contained cytoplasmic Oil red O+ lipid droplets and produced triglycerol. Our results showed less drug-induced MM apoptosis in cocultures of MM cells and ADs compared with cultures of MM cells alone. Western blot analysis showed that treatment with melphalan upregulated the levels of cleaved caspase-9 and -3, but not -8, and PARP in MM cells. Compared with cultures alone, cocultures with ADs showed significantly lower levels of cleaved caspase-9, -3, and PARP in melphalan-treated MM cells. Mechanistic studies further showed that cocultures of ADs, compared with cultures alone, significantly upregulated the expression of autophagy proteins LC3B, Atg3, Atg5, and LAMP-1, but not Beclin-1. The addition of autophagy inhibitors 3-methyl adenine and chloroquine diphosphate to the cocultures remarkably enhanced apoptosis and caspase activation. Furthermore, we observed that cocultures of MM cells and ADs with either cell-cell contact or those separated by transwell inserts conferred similar protection from drug-induced apoptosis. We identified that AD-produced adipokines such as adiponection, leptin, adipsin, IL-6, MCP-1, TNF-a, and IGF-1, but not VEGF and CRP, were abundant in all examined ADs. Among these adipokines, adiponection, leptin, and adipsin were mainly produced from ADs and not from BM stromal cells, whereas other adipokines were produced from both cells. The addition of antibodies against these adipokines to the cocultures enhanced apoptosis and reduced autophagy, whereas addition of these adipokines to the cultures alone inhibited apoptosis and enhanced autophagy. In vivo studies validated these findings that injection of BM-derived ADs into the implanted human bones of SCID-hu mice bearing primary MM cells reduced response to treatment with melphalan and induced autophagy activation. Taken together, our findings elucidate a novel mechanism of MM drug resistance, through BM ADs. Our studies also provide evidence that targeting BM ADs may be a new approach to improve the efficacy of chemotherapy for the treatment of MM. Disclosures: No relevant conflicts of interest to declare. more...
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- 2013
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31. Targeted Therapy Of Acute Myeloid Leukemia By A CD117-Specific Aptamer-Drug-Conjugate
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Nianxi Zhao, Sung-nan Pei, Jianjun Qi, Pei Lin, and Youli Zu
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Cell growth ,Aptamer ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,Targeted therapy ,Transplantation ,Cell culture ,LNCaP ,medicine ,Stem cell ,Diffuse large B-cell lymphoma - Abstract
The current treatment paradigm for acute myeloid leukemia (AML) is remission induction chemotherapy, followed by either consolidation chemotherapy or allogeneic stem cell transplantation. As most patients diagnosed with AML are in their sixth or seventh decade of life, many are not candidates for standard remission induction chemotherapy because of the risk of toxicities, such as profound myelosuppression, life-threatening infections, and cardiotoxicity. The development of new effective and safe treatments for AML is therefore needed. The “ideal” therapy should specifically target AML tumor cells with no side-effect on normal cells. Since CD117 (c-Kit) is a transmembrane receptor on tumor cells surface and expresses in 70% cases of AML, it is a potential molecule for developing new targeted therapy. Aptamers are single-stranded oligonucleotides (DNA or RNA), which have the ability to specifically bind to their targets with high affinity. As a “chemical antibody”, aptamers can be chemically synthesized, easily conjugated with therapeutic drugs, and more importantly, less or not immunogenic. In this study, we developed single strand DNA (ssDNA) aptamer specific for CD117 by using a unique hybrid SELEX approach with both cell-selection and protein-enrichment. When sequencing the enriched ssDNA library with million reads, one dominant sequence had over 80% copies of total sequence reads. Cell binding analysis of the aptamer by flow cytometry and fluorescent microscopy (figure 1) demonstrated that, the aptamer molecule specifically bound to CD117-expressing AML cells, but did not react to CD117-negative control cells including Histiocytic lymphoma Cell line: U937, Burkitt's lymphoma cell line: CA46, Breast adenocarcinoma cell line: 468 and human prostate carcinoma cell line: LNCap. In addition, the presence of aptamers inhibited cell binding anti-CD117 antibody, indicating that aptamer targeted CD117 receptor on leukemic cells. Notably, this aptamer specifically targeted CD117-positve AML cells of clinical specimens with an identical staining pattern to that observed with anti-CD117 antibody (figure 2), indicating potential for in clinical use. For targeted therapy, an aptamer -drug-conjugate was formulated by chemical conjugation of ssDNA CD117 aptamer (Apt) to chemotherapeutic drug, Methotrexate (MTX). For treatment study, cell mixture of leukemic cells HEL (CD117+) and U937 (CD117-), which showed the same sensitivity to free MTX, were used (figure 3A). Exposure of cells to the Apt-MTX revealed that the formed aptamer-drug-conjugate specifically killed CD117 positive cells, but had no effect on the growth of the off-target cells in the same cultures. For therapeutic effect, Apt-MTX killed 60% of positive cells at as low as 10nM final concentration (figure 3B). In contrast, under the same condition, free MTX had no effect on cell growth (figure 3A). Our study demonstrated that the aptamer-drug-conjugate could be a new targeted therapeutics in addition to current antibody-drug-conjugate. Disclosures: No relevant conflicts of interest to declare. more...
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- 2013
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32. P38 MAPK Activity in Myeloma Cells Regulates Osteoclast and Osteoblast Activity and Induces Bone Destruction in Vivo
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Jin He, Yuhuan Zheng, Pei Lin, Bangxing Hong, Zhiqiang Liu, Yong Lu, Robert Z. Orlowski, Jingda Xu, Mingjun Zhang, Larry W. Kwak, Haiyan S. Li, Qing Yi, Jing Yang, Jianfei Qian, and Zhen Cai
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MAPK/ERK pathway ,medicine.medical_specialty ,Osteolysis ,Stromal cell ,biology ,business.industry ,medicine.medical_treatment ,Immunology ,Osteoblast ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Bone resorption ,medicine.anatomical_structure ,Endocrinology ,Cytokine ,Osteoclast ,RANKL ,Internal medicine ,medicine ,Cancer research ,biology.protein ,business - Abstract
Abstract 566 Bone destruction is a hallmark of multiple myeloma (MM). More than 80% of MM patients have osteolysis, which is characterized by pathological fractures, severe bone pain, spinal cord compression, and hypercalcemia. These symptoms can severely compromise a patient's quality of life and performance status. It has been proposed that MM cells activate osteoclast (OC)-mediated bone resorption and inhibit osteoblast (OB)-mediated bone formation. However, the mechanism underlying the association of MM cells with development of bone lesions remains poorly elucidated. Our previous studies showed that p38 mitogen-activated protein kinase (MAPK), which is constitutively activated in MM cells, is a master regulator of MM-mediated bone destruction. Knocking down or inhibiting p38 MAPK activity in MM cells prevented MM-induced bone destruction in vivo. In the present study, we further investigated the mechanism of MM cell p38 MAPK-induced bone destruction. We hypothesized that p38 MAPK activity in MM cells can regulate OB and OC differentiation and activity by upregulating cytokine production by MM cells. In a cytokine array analysis, we examined the expression and secretion of MM-derived cytokines that regulate OB and OC differentiation. Our results showed for the first time that either knockdown or inhibition of p38 MAPK activity by p38 MAPK short hairpin RNAs or inhibitors significantly downregulated the production of dickkopf-1 (DKK-1) and monocyte chemotactic protein-1 (MCP-1) by MM cells. Real-time PCR and ELISA quantified and confirmed the array analysis results. To determine the role of p38 MAPK-upregulated DKK-1 and MCP-1 production in bone destruction, we administered treatment with neutralizing antibodies to SCID mice injected intravenously with ARP-1 or MM.1S cells. Our results showed that neutralization of DKK-1 and MCP-1 led to fewer bone lesions in these mice. Furthermore, we examined the impact of MM cell p38 MAPK activity on OB and/or OC differentiation. Our results showed that knockdown or inhibition of MM cell p38 MAPK significantly downregulated osteoclastogenesis but upregulated osteoblastogenesis in vitro and in vivo. Although DKK-1 is well known to inhibit OB differentiation, we found that DKK-1, together with MCP-1, promoted OC differentiation and bone resorption. Mechanistic studies further showed that MCP-1 upregulated RANK expression in OC precursors and that DKK-1 increased RANKL secretion from stromal cells and mature OBs, all of which led to activation of the NF-kB and MAPK signaling pathways in OCs. Thus, our study uncovered a novel mechanism by which p38 MAPK signaling in MM cells regulates osteoblastogenesis, osteoclastogenesis, and bone destruction in patients with this disease. These findings strongly suggest that disrupting and targeting MM cell p38 signaling are effective approaches to treating osteolytic bone lesions in MM patients. Disclosures: No relevant conflicts of interest to declare. more...
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- 2012
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33. Myeloma Cells Exhibit Inhibitory Effect On Osteoclastogenesis
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Pei Lin, Larry W. Kwak, Eryong Huang, Mingjun Zhang, Yong Lu, Jingda Xu, Jing Yang, Jungsun Park, Qing Yi, Haiyan S. Li, Bangxing Hong, Jin He, Yuhuan Zheng, Zhiqiang Liu, and Jianfei Qian
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Pathology ,medicine.medical_specialty ,Stromal cell ,CD40 ,biology ,Chemistry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Plasma cell ,Biochemistry ,Molecular biology ,medicine.anatomical_structure ,Cytokine ,Osteoclast ,RANKL ,biology.protein ,medicine ,Bone marrow ,Interleukin 3 - Abstract
Abstract 439 In multiple myeloma (MM), an incurable bone malignancy characterized by plasma cell accumulation in the bone marrow (BM), patients have increased osteoclast (OC) activity. As a result, more than 80% of MM patients develop osteolytic bone lesions during the course of the disease. Osteolytic bone lesions cause morbidity, such as pathological fractures, bone pain, and hypercalcemia, and therefore, severely affect the patients' quality of life. A better understanding of the mechanism of MM cell-induced OC activation could lead to a novel approach to treating MM bone disease. It is commonly accepted that MM cells are responsible for OC activation. Cocultures of MM cells with monocyte-derived OC precursors (preOCs) induce OC formation and bone resorption. In addition, previous studies have demonstrated the critical roles of receptor activator of nuclear factor κB ligand (RANKL) and receptor activator of nuclear factor κB (RANK) in aberrant OC activity upregulation in MM BM. Moreover, MM-derived cytokines, such as IL-3, IL-7, and MIP-1d, have been shown to enhance OC formation in a RANKL-dependent or -independent manner. When we cocultured MM cells with monocytes, but not preOCs, and treated them with RANKL, we made the novel observation that MM cells inhibited RANKL-induced OC differentiation. Specifically, human monocytes, isolated from five different healthy donor PBMCs or murine monocytic/macrophage cell line RAW264.7 cells, were transwell-cocultured with MM cells, either human MM cell lines or primary MM cells isolated from patients, in mediums with or without RANKL (50 mg/mL) for 14 days. Mature OCs, characterized as TRAP+ multinuclear cells, were detected by TRAP staining and further confirmed by quantitative RT-PCR for the expressions of mature OC marker genes, such as CTSK, CALCA, and TRAP. Our results showed that coculture with MM cells inhibited the development of mature OCs from monocytes, and suppressed RANKL-induced NFκB and JNK activation. By ELISA, we analyzed the levels of soluble cytokines in the conditioning medium of MM cells and found that MM cells produced large amounts of IL-10. Adding neutralizing antibody against IL-10 significantly abrogated MM inhibition of osteoclastogenesis, whereas adding IL-10 inhibited OC differentiation and downregulated the mRNA and protein levels of RANK on monocytes/preOCs. As MM cells grow in the BM, we wondered whether bone marrow stromal cells (BMSCs) could regulate the MM cell inhibitory effect on osteoclastogenesis. Our results showed that although BMSC itself did not affect osteoclastogenesis, cocultures of monocytes with both MM cells and BMSCs significantly restored RANKL-induced osteoclastogenesis. Analysis of soluble cytokines by ELISA showed that the levels of MCP-1, but not IL-10, were significantly upregulated in medium from MM/BMSC cocultures. Adding neutralizing antibody against MCP-1 highly inhibited OC activation, while adding MCP-1 enhanced OC differentiation and upregulated the expression of RANK on monocytes/preOCs. Overall, our findings are the first to elucidate a novel mechanism by which MM cells inhibit osteoclastogenesis by producing IL-10 and the presence of BMSCs suppresses MM inhibitory effects by up-regulating MCP-1. Regulation of RANK expression on monocytes/preOCs by MCP-1 and IL-10 determines osteoclastogenesis. Our studies provide evidence that targeting BM microenvironmental cells and/or factors may be a new approach to treating MM bone lesions. Disclosures: No relevant conflicts of interest to declare. more...
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- 2012
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34. Clinicopathologic Characterization of Acute Myeloid Leukemia and Myelodysplastic Syndrome with Inv(3)(q21q26.2)/t(3;3)(q21;q26.2) Reveals That Complex Karyotype but Not Blast Percentage Is Associated with Poor Survival; A Bone Marrow Pathology Group Study
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Athena M. Cherry, Adam Bagg, Erika Moore, Daniel A. Arber, Pei Lin, Jennifer J.D. Morrissette, Kathryn Foucar, Robert P. Hasserjian, Susan Mathew, Natasha M. Savage, Sa A. Wang, John Anastasi, Attilio Orazi, Eric D. Hsi, James W. Vardiman, Yen-Chun Liu, Carlos E. Bueso-Ramos, Gordana Raca, and Heesun J. Rogers more...
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Pathology ,medicine.medical_specialty ,Leukopenia ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Normocytic anemia ,medicine.disease ,Biochemistry ,Lymphoma ,medicine.anatomical_structure ,International Prognostic Scoring System ,Dysplasia ,hemic and lymphatic diseases ,Complex Karyotype ,Medicine ,Bone marrow ,medicine.symptom ,business - Abstract
Abstract 3847 Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2); RPN1-EVI1 [inv3/t3] is a distinct type of AML with recurrent genetic abnormalities (RGA) in the 2008 WHO classification, with poor response to therapy and poor prognosis. The resulting dysregulation of EVI1 plays an important role in stem cell self-renewal and leukemogenesis. Although myelodysplastic syndrome (MDS) with inv3/t3 has a high risk of progression to AML, inv3/t3 is not among the genetic abnormalities sufficient for diagnosis of AML, irrespective of blast percentage (%) in the WHO classification. The revised International Prognostic Scoring System (IPSS-R) includes comprehensive cytogenetic subgrouping to better define prognosis in MDS patients. In this system, inv3/t3 is included in a poor risk karyotype group. The objective of this multicenter study was to evaluate a series of patients with MDS/AML and inv3/t3 in order to characterize their clinicopathologic features and outcome, and to apply the IPSS-R to inv3/t3 MDS patients. 111 patients (40 MDS and 71 AML with inv3/t3) were gathered from 8 medical centers. The median age at diagnosis was 56.5 years and was significantly older in MDS than AML with inv3/t3 patients (65 vs 54.5, p=0.03). Patients typically presented with normocytic anemia, thrombocytopenia and mild leukopenia (median Hb 9.1 g/dL, platelet 91 x109/L, WBC 3.6 x109/L). MDS with inv3/t3 patients had lower WBC than AML with inv3/t3 (median 3.1 vs 5.5, p There was no significant difference in overall survival (OS) between MDS and AML with inv3/t3 (12.9 vs 8.0 mo, Cox PH p=0.11, Figure 1). There was no OS difference between MDS and AML after excluding Ph+ cases (Cox PH p=0.17) nor between de novo and therapy related MDS/AML with inv3/t3 (Cox PH p=0.89). Patients with isolated inv3/t3, one additional cytogenetic abnormality, and a complex karyotype showed progressively shorter OS (12.9, 10.0 and 4.3 mo, Cox PH p MDS with inv3/t3 patients were classified into IPSS Intermediate (Int)-1 (21), Int-2 (13), and high (6) risk groups. IPSS-R categorized MDS patients into low (3), Int (6), high (14) and very high (17) risk groups. 57% of IPSS Int-1 risk group patients (expected OS 3.5 year) were reclassified to high or very high risk group in IPSS-R (expected OS The IPSS-R better reflects the OS of inv3/t3 than IPSS but may not fully reflect the generally dismal prognosis. Patients with MDS and AML with inv3/t3 follow a similarly aggressive clinical course, supporting classification of MDS with inv3/t3 as an AML with RGA irrespective of blast%. Additional cytogenetic abnormalities are associated with shorter OS in AML/MDS with inv3/t3 and our data suggest that aggressive therapy with SCT should be considered in these patients. Disclosures: Vardiman: Celgene Corporation: review of slides for clinical trials not relevant to this abstract Other. Foucar:e. Honoraria–Scientific Symposium Pathology Education: ASCP Press; ARP, Amirsys, ASCP Press; ARP, Amirsys Patents & Royalties, Honoraria, Not relevant to this abstract Other. more...
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- 2012
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35. Cyclin D1 as a Universally-Expressed Mantle Cell Lymphoma-Associated aTumor Antigen for Immunotherapy
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Michael Wang, Jianfei Qian, Liang Zhang, Pei Lin, Qing Yi, Xiaohong Han, and Luhong Sun
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CD40 ,biology ,Immunology ,Cell Biology ,Hematology ,Natural killer T cell ,Biochemistry ,Interleukin 21 ,Cyclin D1 ,Cancer research ,biology.protein ,Interleukin 12 ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell - Abstract
Mantle cell lymphoma (MCL) accounts for 5% to 10% of all non-Hodgkin lymphomas and has the worst prognosis among all lymphomas. The hallmark of MCL is a t(11;14) translocation resulting in overexpression of cyclin D1 by tumor cells of virtually all patients. In this study we examined whether cyclin D1 could be an effective tumor-associated antigen for immunotherapy. We identified a cyclin D1 peptide (P101) for HLA-A*0201, created heteroclitic peptide (Py101) for better binding, and generated peptide-specific T-cell lines from HLA-A*0201+ blood donors and MCL patients. After 5 to 7 rounds of in vitro stimulation with peptide-pulsed autologous dendritic cells (DCs), T-cell lines were obtained, which contained about 45% CD4+ and 55% CD8+ T cells. As exemplified by the results of peptide-tetramer staining, the frequencies of peptide-specific CD8+ T cells increased during in vitro stimulation, from 5.7% of specific T cells at fourth stimulation to 19.7% at sixth stimulation. These cell lines proliferated in response to autologous DCs pulsed with cyclin D1 peptide Py101 (but not unpulsed), as measured by 3[H]-thymidine incorporation and CFSE-dilution assays. These results indicate that the T cells are indeed specific for cyclin D1 Py101 peptide. Moreover, the T cells efficiently lysed peptide-pulsed but not unpulsed T2 cell and autologous DCs, and cyclin D1+ and HLA-A*0201+ human MCL lines MINO, SP53, Jeko-1, and Granta 519, and more importantly, HLA-A*0201+ primary lymphoma cells from MCL patients. No killing was observed on HLA-A*0201− primary lymphoma cells or HLA-A*0201+ normal blood cells including B cells. These results indicate that these T cells are potent cytotoxic T cells and recognize cyclin D1 peptides naturally presented by patient lymphoma cells in the context of surface HLA-A*0201 molecules. Flow cytometry analysis was used to examine the expression of granzymes, perforin, and Fas ligand (FasL) by the T cells. Based on these results, T cells may kill their target cells via the perforin/granzyme pathways, because they express perforin and high levels of granzymes but not FasL. Two independent methods were used to examine the cytokine expression profiles of the T cells. Upon restimulation with DCs pulsed with Py101 peptide, but not with unpulsed DCs, 11.2% of the T cells expressed IFN-γ by intracellular cytokine staining. IL-4-expressing T cells were very few (0.3%). To detect cytokine secretion, an ELISPOT assay was used to enumerate IFN-γ-secreting cells. After restimulation with DCs pulsed with cyclin D1 peptides, or with cyclin D1+/HLA-A*0201+ SP53 and cyclin D1+/HLA-A*0201+ primary lymphoma cells from patients, large numbers of IFN-γ-secreting cells were detected. Taken together, our work identifies cyclin D1 as a potentially important antigen for immunotherapy in MCL. more...
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- 2008
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36. DEAH-Box Splicing Factor Gene, Prp16 Amplification in Acute Myeloid Leukemia.
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Ma, Yupo, primary, Barnett, Tammy, primary, Chai, Li, primary, Yang, Jianchang, primary, Alipio, Zaida, primary, Pei, Lin, primary, Amin, Hesham M., primary, Fink, Louis, primary, Di, Chunhui, primary, Yan, Hai, primary, and Ward, David, primary more...
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- 2006
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37. A SCID-hu In Vivo Mouse Model of Human Primary Mantle Cell Lymphoma
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Sungyoul Hong, Xiaohong Han, Michael Wang, Liang Zhang, Jianfei Qian, Jorge E. Romaguera, Jing Yang, Pei Lin, Larry W. Kwak, Qing Yi, and Yuankai Shi
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CD20 ,Pathology ,medicine.medical_specialty ,Severe combined immunodeficiency ,biology ,business.industry ,Immunology ,Spleen ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,In vivo ,hemic and lymphatic diseases ,Atiprimod ,biology.protein ,Medicine ,Bone marrow ,Lymph ,business ,Homing (hematopoietic) - Abstract
Introduction: Mantle cell lymphoma (MCL) has a poor outcome and is a therapeutic challenge. Preclinical evaluation of investigational agents for MCL has been limited by lack of suitable animal models that mimic the natural history of human MCL and provide the microenvironment in which MCL cells thrive. Since MCL usually involves the bone marrow, we developed an in vivo mouse model for primary human MCL cells in severe combined immunodeficient mice (SCID-hu), which have been implanted with human fetal bone. Materials and Methods: Human primary MCL cells were obtained and isolated from spleen, lymph nodes, bone marrow aspirates, or peripheral blood of six different MCL patients. Purified patient primary MCL cells were directly inoculated into human fetal bone chip or injected into mouse tail vein. Immunohistochemical staining with anti-human CD20 or cyclin D1 antibodies and detection of circulating human beta 2-microglobulin (B2M) in mouse serum were used to monitor the engraftment, growth, and immigration of human primary MCL cells in SCID-hu mice. Results: A total of 30 SCID-hu mice and 5 SCID mice were used. Twenty of SCID-hu mice received inoculation of 0.5 – 5 × 106 of patient primary MCL cells (2–5 SCID-hu mice/patient sample) into human fetal bone chips implanted in mice subcutaneously. Five of SCID-hu mice and 5 of SCID mice (without human fetal hone chips) were injected intravenously with 5 × 106 of patient MCL cells. The same number of cells were injected into human bone chips in 5 SCID-hu mice with equal volume of PBS as controls. Successful primary MCL cell engraftment was observed in 15 out of 20 SCID-hu mice after injection of these cells into human fetal bones. But only one out of 5 SCID-hu mice had successful engraftment after the intravenous injection of primary MCL cells into mouse tail vein. Importantly, none of SCID mice had successful engraftment after intravenous injection of 5 × 106 of primary MCL cells. These data indicated that human fetal bone provides a critical microenvironment for the survival and growth of primary MCL cells. Increasing levels of circulating human B2M in mouse serum were found after successful engraftment and growth of human primary MCL cells in SCID-hu mice. Immunohistochemical staining with anti-human CD20 and cyclin D1 antibodies confirmed that, similar to the human disease, primary MCL cells homed to mouse lymph nodes, spleen, bone marrow, and gastrointestinal tract but not to mouse liver. Treatment of MCL-bearing SCID-hu mice with atiprimod suppressed B2M secreted by functioning human MCL cells and induced tumor regression. Conclusion: Human primary MCL cells from patient were able to successfully engraft in SCID-hu mice, and mimiced the natural organ involvement of human disease homing to mouse lymph node, spleen, bone marrow, and gastrointestinal tract but not to liver. This in vivo model mimiced the natural biological features of human MCL and is therefore useful for preclinical evaluation of new therapeutic agents. more...
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- 2007
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38. Gene Expression Profiling of Paired Pre- and Post-Prednisolone (PRED) BM Samples from Childhood ALL Identifies Robust Signatures for PRED Response and Eventual Outcome
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Pei Lin Koh, Ying Xu, Allen Eng Juh Yeoh, Limsoon Wong, Huiqing Liu, Yi Lu, and Ariffin Hany
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Oncology ,medicine.medical_specialty ,Immunology ,Treatment outcome ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Blast Count ,Bioinformatics ,Biochemistry ,Gene expression profiling ,Leukemia ,Internal medicine ,Gene expression ,medicine ,Prednisolone ,Childhood all ,Pre and post ,medicine.drug - Abstract
Early response to therapy is the most important prognostic factor for childhood ALL. CCG investigators have shown that Day-7 and Day-14 BM blast counts were prognostically important although there is great inter-observer variability. BFM group have shown that day 8 prednisolone (PRED) response is highly predictive of the treatment outcome. While gene expression profiling (GEP) of diagnostic marrow can discern a pattern of PRED sensitivity as determined by in vitro MTT assay, the accuracy was low at only 70%. We hypothesized that changes in global GEP after therapy have a higher likelihood to predict response as the signatures of sensitivity and resistance may be unmasked during the therapy. We prospectively studied the changes in GEP using Affymetrix HG-U133A or Plus 2 chips on paired BM samples before and after 7-day course of PRED and one dose IT MTX in 58 patients with newly diagnosed or relapsed ALL. Unsupervised hierarchical clustering revealed that pre- and post- PRED samples in the patients still tended to cluster together, indicating that expression profiles of molecular subgroups were still most important. To remove intrinsic influence of molecular subtypes and identify potential signatures independent of genetic abnormalities, we subtracted Day-0 GEP from its paired Day-8 profile and retained probe sets with significant changes (≥ 10-fold). To avoid the ambiguity of variation in BM blast counting at Day-8, we divided the samples into a stringently reproducible group where “Good” PRED response was defined as that Day-8 blast count in PBL < 109/L and BM lymphoblasts ≤ 30% (n=16). “Poor” response was when Day 8 PBL ≥ 109/L (n=11). This stringently reproducible group (n=27) formed the training group to help define a distinct signature while the rest (n=31 pairs) were used as a blinded test set. 54 and 19 discriminating genes were identified by 2 independent statistical methods respectively, and an integrated predictor model was constructed based on shortlisted entries. This model predicted the PRED response with 100% accuracy for the training set using the leave-one-out cross validation but was less accurate in predicting the BM blast count in blinded test set. But intriguingly, in the blinded test set, this model predicted correctly 19 out of 21 reliable “Good” PRED responses are in CCR (91%), while among 8 predicted as “Poor” responses, only 2 are in CCR (25%). This suggests that as gene expression profiling as early as day 8 of PRED could discern the beginning of leukaemia cell death even before morphological changes are discernable and is highly correlated to eventual outcome. In conclusion, we have shown that analyses on the relative changes of gene expression profile can identify real genetic signatures indicating the sensitivity to PRED administration which is highly correlated with outcome. more...
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- 2006
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39. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype.
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Jain, Nitin, Lamb, Audrey V., O'Brien, Susan, Ravandi, Farhad, Konopleva, Marina, Jabbour, Elias, Zhuang Zuo, Jorgensen, Jeffrey, Pei Lin, Pierce, Sherry, Thomas, Deborah, Rytting, Michael, Borthakur, Gautam, Kadia, Tapan, Cortes, Jorge, Kantarjian, Hagop M., and Khoury, Joseph D. more...
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T-cell lymphoma , *T cell receptors , *IMMUNOPHENOTYPING , *ANTIGENS , *STEM cells - Abstract
Early T-cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a recently recognized high-risk T lymphoblastic leukemia/lymphoma (T-ALL/LBL) subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL/LBL are poorly characterized. In this study, we compared the outcomes of adults with ETP-ALL/LBL who received treatment on frontline regimens with those of patients with other T-ALL/LBL immunophenotypic subtypes. Patients with newly diagnosed T-ALL/LBL who received frontline chemotherapy between the years 2000 and 2014 at The University of Texas MD Anderson Cancer Center were identified and immunophenotypically categorized into early, thymic, and mature per the World Health Organization (WHO) classification using CD1a and surface CD3 status. Patients with ETP-ALL/LBL were identified on the basis of the following immunophenotypes: CD1a-, CD8-, CD5- (dim), and positivity for 1 or more stem cell or myeloid antigens. A total of 111 patients with T-ALL/LBL (68% T-ALL; 32% T-LBL) with adequate immunophenotype data were identified. The median age was 30 years (range, 13-79). There was no difference in the outcomes of patients based on the WHO subtypes. Nineteen patients (17%) had ETP-ALL/LBL. The complete remission rate /complete remission with incomplete platelet recovery rate in patients with ETP-ALL/LBL was significantly lower than that of non-ETP-ALL/LBL patients (73% vs 91%; P = .03). The median overall survival for patients with ETP-ALL/LBL was 20 months vs not reached for the non-ETP-ALL/LBL patients (P = .008). ETP-ALL/LBL represents a high-risk disease subtype of adult ALL. Novel treatment strategies are needed to improve treatment outcomes in this T-ALL/LBL subset. [ABSTRACT FROM AUTHOR] more...
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- 2016
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40. Insights from response to tyrosine kinase inhibitor therapy in a rare myeloproliferative neoplasm with CALR mutation and BCR-ABL1.
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Loghavi, Sanam, Pemmaraju, Naveen, Kanagal-Shamanna, Rashmi, Mehrotra, Meenakshi, Jeffrey Medeiros, L., Luthra, Raja, Pei Lin, Yang Huh, Kantarjian, Hagop M., Cortes, Jorge E., Verstovsek, Srdan, and Patel, Keyur P. more...
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MYELOPROLIFERATIVE neoplasms , *CALRETICULIN , *GENE fusion , *CHROMOSOME abnormalities , *MORPHOGENESIS , *DIAGNOSIS ,BONE marrow cancer - Abstract
The article presents a case study of a 67-year-old hypertensive man with atypical myeloproliferative neoplasm (MPN) in which calreticulin (CALR) preceded BCR/ABL1 fusion. It indicates that bone marrow (BM) morphologic features were dominated by the presence of BCR/ABL1 fusion, despite the presence of CALR mutation. Also revealed is the importance of BM morphology and expanded molecular testing in the patient's workup. more...
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- 2015
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41. A critical role of autocrine sonic hedgehog signaling in human CD138+ myeloma cell survival and drug resistance.
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Zhiqiang Liu, Jingda Xu, Jin He, Yuhuan Zheng, Haiyan Li, Yong Lu, Qian, Jianfei, Pei Lin, Weber, Donna M., Jing Yang, and Qing Yi
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SUPERINFECTION , *DRUG resistance , *PHARMACOLOGY , *NEOPLASTIC cell transformation , *SURVIVAL behavior (Humans) - Abstract
Hedgehog (Hh) signaling plays an important role in the oncogenesis of B-cell malignancies such as multiple myeloma (MM). However, the source of Hh ligand sonic hedgehog (SHH) and its target cells remains controversial. Previous studies showed that stromally induced Hh signaling is essential for the tumor cells and that CD19+CD138- MM stem cells are the target cells of Hh signaling. Here we demonstrate that SHH was mainly secreted by human myeloma cells but not by stromal cells in MM bone marrow. Autocrine SHH enhanced CD138+ myeloma cell proliferation and protected myeloma cells from spontaneous and stress-induced apoptosis. More importantly, autocrine SHH protected myeloma cells against chemotherapy-induced apoptosis in vitro and in vivo. Combinational treatment with chemotherapy and SHH-neutralizing antibody displayed synergistic antimyeloma effects. Mechanistic studies showed that SHH signaling activated the SHH/GLI1/BCL-2 axis, leading to the inhibition of myeloma cell apoptosis. Thus, this study identifies the myeloma autocrine Hh signaling pathway as a potential target for the treatment of MM. Targeting this pathway may improve the efficacy of chemotherapy in MM patients. [ABSTRACT FROM AUTHOR] more...
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- 2014
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42. Targeting the insulin-like growth factor-1 receptor to overcome bortezomib resistance in preclinical models of multiple myeloma.
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Kuhn, Deborah J., Berkova, Zuzana, Jones, Richard J., Woessner, Richard, Bjorklund, Chad C., Ma, Wencai, Davis, R. Eric, Pei Lin, Hua Wang, Madden, Timothy L., Caimiao Wei, Baladandayuthapani, Veerabhadran, Michael Wang, Thomas, Sheeba K., Shah, Jatin J., Weber, Donna M., and Orlowski, Robert Z. more...
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GENE targeting , *SOMATOMEDIN C , *DRUG resistance , *PROTEASOME inhibitors , *MULTIPLE myeloma treatment , *CELL lines - Abstract
Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no Β 5 subunit muta-tions. Instead, up-regulation of the insulin-like growth factor (IGF)-1 axis was identi-fied, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellu-lar sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA-mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and po-tently resensitized bortezomib-resistant ceil lines and patient samples to bor-tezomib. Importantly, OSI-906 in combination with bortezomib also overcame bor-tezomib resistance in an in vivo model of myeloma. Taken together, these data sup-port the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and pro-vide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to over-come or possibly prevent the emergence of bortezomib-refractory disease In the clinic. [ABSTRACT FROM AUTHOR] more...
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- 2012
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