149 results on '"Steven I. Park"'
Search Results
2. High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles
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Kin Man Au, Rod Balhorn, Monique C. Balhorn, Steven I. Park, and Andrew Z. Wang
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Chemistry ,QD1-999 - Published
- 2018
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3. Novel Targeted Agents in Hodgkin and Non-Hodgkin Lymphoma Therapy
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Natalie S. Grover and Steven I. Park
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Hodgkin lymphoma ,non-Hodgkin lymphoma ,monoclonal antibody ,antibody-drug conjugates ,immune-checkpoint inhibitors ,small molecule inhibitors ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
There has been a recent emergence of novel targeted agents for treatment of Hodgkin and non-Hodgkin lymphoma. In particular, antibodies and antibody-drug conjugates directed against surface antigens, agents that block immune checkpoint pathways, and small molecule inhibitors directed against cell signaling pathways have shown significant promise in patients with relapsed and refractory disease and in the frontline setting. With the development of these new therapies, cytotoxic chemotherapy may be avoided entirely in some clinical settings. This review will present the latest information on these novel treatments in Hodgkin and non-Hodgkin lymphoma and will discuss both recently approved agents as well as drugs currently being studied in clinical trials.
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- 2015
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4. Impact of diagnosis to treatment interval in patients with newly diagnosed mantle cell lymphoma
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Narendranath, Epperla, Jeffrey M, Switchenko, Veronika, Bachanova, James N, Gerson, Stefan K, Barta, Max J, Gordon, Alexey V, Danilov, Natalie Sophia, Grover, Stephanie P, Mathews, Madelyn, Burkart, Reem, Karmali, Yazeed, Sawalha, Brian T, Hill, Nilanjan, Ghosh, Steven I, Park, David A, Bond, Mehdi, Hamadani, Timothy S, Fenske, Peter, Martin, Jin, Guo, Mary-Kate, Malecek, Brad S, Kahl, Christopher R, Flowers, Brian K, Link, Lawrence D, Kaplan, David J, Inwards, Andrew, Feldman, Eric D, Hsi, Kami, Maddocks, Kristie, Blum, Namcy L, Bartlett, James R, Cerhan, John P, Leonard, Thomas M, Habermann, Matthew J, Maurer, and Jonathon B, Cohen
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Hematology - Abstract
The prognostic relevance of diagnosis to treatment interval (DTI) in patients with newly diagnosed mantle cell lymphoma (MCL) is unknown. Hence, we sought to evaluate the impact of DTI on outcomes in MCL using 3 large datasets (1) the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource, (2) patients enrolled in the ALL Age Asthma Cohort/CALGB 50403, and (3) a multisitecohort of patients with MCL. Patients were a priori divided into 2 groups, 0 to 14 days (short DTI) and 15 to 60 days (long DTI). The patients in whom observation was deemed appropriate were excluded. One thousand ninety-seven patients newly diagnosed with MCL and available DTI were included in the study. The majority (73%) had long DTI (n=797). Patients with short DTI had worse eastern cooperative oncology group performance status (ECOG PS ≥2), higher lactate dehydrogenase, bone marrow involvement, more frequent B symptoms, higher MCL International Prognostic Index (MIPI ≥6.2), and were less likely to receive intensive induction therapy than long DTI group. The median progression-free survival (2.5 years vs 4.8 years, p
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- 2023
5. Supplementary Tables 1-7, Figures 1-3 from Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma
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Daniel O. Persky, Jack P. Higgins, Banmeet S. Anand, Eric T. Williams, Thomas Strack, Kristina Dabovic, Christine Burnett, Steven I. Park, Vasile Musteata, and Paul A. Hamlin
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Supplementary Table 1. Additional Study Eligibility Criteria. Supplementary Table 2. Pharmacokinetic Serum Sample Collection. Supplementary Table 3. Summary of Adverse Events and Discontinuations. Supplementary Table 4. Summary of Serum MT-3724 PK Parameters by Treatment on Cycle 1 Day 1. Supplementary Table 5. Summary of Serum MT-3724 PK Parameters by Treatment on Cycle 1 Day 12. Supplementary Table 6. Best Overall Response, Objective Response Rate, and Disease Control Rate (FAS). Supplementary Table 7. Summary of ADA Incidence by Actual Dose. Supplementary Figure 1. Study Design for Dose Escalation and Dose Expansion. Supplementary Figure 2. CONSORT diagram. Supplementary Figure 3. Individual CD19+ Nadir Percent Change from Baseline.
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- 2023
6. Data from Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma
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Daniel O. Persky, Jack P. Higgins, Banmeet S. Anand, Eric T. Williams, Thomas Strack, Kristina Dabovic, Christine Burnett, Steven I. Park, Vasile Musteata, and Paul A. Hamlin
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MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the MTD and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. Twenty-seven patients enrolled. MTD was 50 μg/kg/dose with 6,000 μg/dose cap. Thirteen patients experienced at least one grade ≥3 treatment-related adverse events; the most common grade ≥3 event was myalgia (11.1%). Two patients (75 μg/kg/dose) experienced grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL (n = 12), overall response rate was 41.7% (complete response, n = 2; partial response, n = 3). In patients with detectable baseline peripheral B cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADA) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events.Significance:This work describes the safety and efficacy of a new pharmaceutical pathway that could provide a treatment option for a subset of patients with a critical unmet therapeutic need. The study drug, MT-3724, is capable of targeting B-cell lymphomas via a unique, potent cell-killing mechanism that appears to be promising.
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- 2023
7. Tazemetostat in Combination with Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma: Phase 1b Results of Symphony-1
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Connie Lee Batlevi, Gilles Salles, Steven I. Park, Tycel J. Phillips, Jennifer E. Amengual, David Andorsky, Philip Campbell, Pamela McKay, John P. Leonard, Manu Sondhi, Yingxue Chen, Pamela L. Slatcher, Richard Lin, Attila Szanto, Sara Abbadi, and Franck Morschhauser
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
8. Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma
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Paul A. Hamlin, Vasile Musteata, Steven I. Park, Christine Burnett, Kristina Dabovic, Thomas Strack, Eric T. Williams, Banmeet S. Anand, Jack P. Higgins, and Daniel O. Persky
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hemic and lymphatic diseases - Abstract
MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design. Primary objectives were to determine the MTD and pharmacokinetics/pharmacodynamics. In a dose expansion study at MTD in serum rituximab-negative patients with diffuse large B-cell lymphoma (DLBCL), primary objectives were safety, tolerability, and pharmacokinetics/pharmacodynamics. Twenty-seven patients enrolled. MTD was 50 μg/kg/dose with 6,000 μg/dose cap. Thirteen patients experienced at least one grade ≥3 treatment-related adverse events; the most common grade ≥3 event was myalgia (11.1%). Two patients (75 μg/kg/dose) experienced grade 2 treatment-related capillary leak syndrome. Overall objective response rate was 21.7%. In serum rituximab-negative patients with DLBCL or composite DLBCL (n = 12), overall response rate was 41.7% (complete response, n = 2; partial response, n = 3). In patients with detectable baseline peripheral B cells, treatment resulted in dose-dependent B-cell depletion. The proportion of patients with anti-drug antibodies (ADA) increased during treatment and the majority appeared to be neutralizing based on an in vitro assay; nevertheless, tumor regression and responses were observed. MT-3724 demonstrated efficacy at the MTD in this population of previously treated patients with r/rDLBCL, with mild-to-moderate immunogenic safety events. Significance: This work describes the safety and efficacy of a new pharmaceutical pathway that could provide a treatment option for a subset of patients with a critical unmet therapeutic need. The study drug, MT-3724, is capable of targeting B-cell lymphomas via a unique, potent cell-killing mechanism that appears to be promising.
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- 2022
9. Data from Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma
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Daruka Mahadevan, E. Jane Leonard, Emily Sheldon-Waniga, Xiaofei Zhou, Karthik Venkatakrishnan, Susan Groshen, Catherine Spier, Monika Schmelz, Raul Mena, Ari VanderWalde, Gregory Monohan, Anand Karnad, Steven Weitman, Steven H. Bernstein, Alexandra Stefanovic, Swaminathan Padmanabhan Iyer, Peter Rosen, Soham Puvvada, Jia Ruan, Daniel Persky, John Hayslip, Kevin McDonagh, Steven I. Park, Jonathan W. Friedberg, and Kevin R. Kelly
- Abstract
Purpose:The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL.Patients and Methods:Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue.Results:Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non–germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL).Conclusions:The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.
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- 2023
10. Data from Pretargeted Radioimmunotherapy Using Genetically Engineered Antibody-Streptavidin Fusion Proteins for Treatment of Non-Hodgkin Lymphoma
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Oliver W. Press, John M. Pagel, Damian J. Green, Ajay K. Gopal, Amanda Axtman, Aimee L. Kenoyer, Franz Buchegger, Mark Hylarides, Nural Orgun, Patrick S. Stayton, D. Scott Wilbur, Yukang Lin, Donald K. Hamlin, Shani M. Frayo, Jaideep Shenoi, and Steven I. Park
- Abstract
Purpose: Pretargeted radioimmunotherapy (PRIT) using streptavidin (SAv)-biotin technology can deliver higher therapeutic doses of radioactivity to tumors than conventional RIT. However, “endogenous” biotin can interfere with the effectiveness of this approach by blocking binding of radiolabeled biotin to SAv. We engineered a series of SAv FPs that downmodulate the affinity of SAv for biotin, while retaining high avidity for divalent DOTA-bis-biotin to circumvent this problem.Experimental Design: The single-chain variable region gene of the murine 1F5 anti-CD20 antibody was fused to the wild-type (WT) SAv gene and to mutant SAv genes, Y43A-SAv and S45A-SAv. FPs were expressed, purified, and compared in studies using athymic mice bearing Ramos lymphoma xenografts.Results: Biodistribution studies showed delivery of more radioactivity to tumors of mice pretargeted with mutant SAv FPs followed by 111In-DOTA-bis-biotin [6.2 ± 1.7% of the injected dose per gram (%ID/gm) of tumor 24 hours after Y43A-SAv FP and 5.6 ± 2.2%ID/g with S45A-SAv FP] than in mice on normal diets pretargeted with WT-SAv FP (2.5 ± 1.6%ID/g; P = 0.01). These superior biodistributions translated into superior antitumor efficacy in mice treated with mutant FPs and 90Y-DOTA-bis-biotin [tumor volumes after 11 days: 237 ± 66 mm3 with Y43A-SAv, 543 ± 320 mm3 with S45A-SAv, 1129 ± 322 mm3 with WT-SAv, and 1435 ± 212 mm3 with control FP (P < 0.0001)].Conclusions: Genetically engineered mutant-SAv FPs and bis-biotin reagents provide an attractive alternative to current SAv-biotin PRIT methods in settings where endogenous biotin levels are high. Clin Cancer Res; 17(23); 7373–82. ©2011 AACR.
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- 2023
11. Supplementary Figure 1 from Pretargeted Radioimmunotherapy Using Genetically Engineered Antibody-Streptavidin Fusion Proteins for Treatment of Non-Hodgkin Lymphoma
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Oliver W. Press, John M. Pagel, Damian J. Green, Ajay K. Gopal, Amanda Axtman, Aimee L. Kenoyer, Franz Buchegger, Mark Hylarides, Nural Orgun, Patrick S. Stayton, D. Scott Wilbur, Yukang Lin, Donald K. Hamlin, Shani M. Frayo, Jaideep Shenoi, and Steven I. Park
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PDF file - 112K
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- 2023
12. Figure S2 from Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma
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Daruka Mahadevan, E. Jane Leonard, Emily Sheldon-Waniga, Xiaofei Zhou, Karthik Venkatakrishnan, Susan Groshen, Catherine Spier, Monika Schmelz, Raul Mena, Ari VanderWalde, Gregory Monohan, Anand Karnad, Steven Weitman, Steven H. Bernstein, Alexandra Stefanovic, Swaminathan Padmanabhan Iyer, Peter Rosen, Soham Puvvada, Jia Ruan, Daniel Persky, John Hayslip, Kevin McDonagh, Steven I. Park, Jonathan W. Friedberg, and Kevin R. Kelly
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Immunohistochemical staining of Bcl2, cMyc, Ki67, and CD3 in DLBCL subtype representative tumor samples (same as Supplementary Figure S1). Note that AD091967 is positive for both Bcl2 and cMyc. Cases AB189717, AD550620, and AE575816 show high proliferation rates (80%, 80%, 60%) Scale bars represent 50 µm.
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- 2023
13. Supplementary Table 1 from Pretargeted Radioimmunotherapy Using Genetically Engineered Antibody-Streptavidin Fusion Proteins for Treatment of Non-Hodgkin Lymphoma
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Oliver W. Press, John M. Pagel, Damian J. Green, Ajay K. Gopal, Amanda Axtman, Aimee L. Kenoyer, Franz Buchegger, Mark Hylarides, Nural Orgun, Patrick S. Stayton, D. Scott Wilbur, Yukang Lin, Donald K. Hamlin, Shani M. Frayo, Jaideep Shenoi, and Steven I. Park
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PDF file - 52K
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- 2023
14. Supplementary Table 2 from Pretargeted Radioimmunotherapy Using Genetically Engineered Antibody-Streptavidin Fusion Proteins for Treatment of Non-Hodgkin Lymphoma
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Oliver W. Press, John M. Pagel, Damian J. Green, Ajay K. Gopal, Amanda Axtman, Aimee L. Kenoyer, Franz Buchegger, Mark Hylarides, Nural Orgun, Patrick S. Stayton, D. Scott Wilbur, Yukang Lin, Donald K. Hamlin, Shani M. Frayo, Jaideep Shenoi, and Steven I. Park
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PDF file - 63K
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- 2023
15. Equal access to care and nurse navigation leads to equitable outcomes for minorities with aggressive large B‐cell lymphoma
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Lisa M. Pye, Rupali Bose, Ryan Jacobs, Derek Raghavan, James T. Symanowski, Danielle Boselli, Nilanjan Ghosh, Edward A. Copelan, Kris Blackley, Bei Hu, Amy Soni, Steven I. Park, Belinda R. Avalos, Tommy Chen, and Tamara K. Moyo
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Cancer Research ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Immunotherapy, Adoptive ,Health Services Accessibility ,symbols.namesake ,International Prognostic Index ,Nursing ,Refractory ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Fisher's exact test ,Retrospective Studies ,Chemotherapy ,business.industry ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,medicine.disease ,Progression-Free Survival ,Lymphoma ,Clinical trial ,Oncology ,symbols ,Lymphoma, Large B-Cell, Diffuse ,business - Abstract
Background Aggressive large B-cell lymphomas (LBCLs) are curable, but previous studies have shown inferior outcomes in minorities. Nurse navigation programs can improve patient outcomes by providing patient support. This study presents the outcomes of White and minority patients with aggressive LBCL at an institution with an active nurse navigation program. Methods The authors prospectively collected baseline characteristics, treatment regimens, and outcome data for patients with aggressive LBCL. Navigation encounters were characterized as low or high intensity. Overall survival (OS) and progression-free survival (PFS) were calculated with Kaplan-Meier methods. Baseline characteristics were compared with Fisher exact tests. Results Two hundred four consecutive patients (47 minority patients and 157 White patients) were included. Results were presented as minorities versus Whites. There were no differences in prognostic scores (Revised International Prognostic Index score of 3-5, 43% vs 47%; P = .50), frontline chemotherapy (98% vs 96%; P = .68), or the incidence of relapsed/refractory disease (40% vs 38%; P = .74). For relapsed/refractory LBCL, similar proportions of patients underwent hematopoietic stem cell transplantation (32% vs 29%; P > .99) or chimeric antigen receptor T-cell therapy (16% vs 19%; P > .99). Enrollment in clinical trials was comparable (17% vs 14%; P = .64). More than 85% received nurse navigation, but minorities had higher intensity navigation encounters (42% vs 21%; P = .01). The 2-year OS rates were 81% and 76% for minorities and Whites, respectively (P = .27); the 2-year PFS rates were 62% and 65%, respectively (P = .78). Conclusions This study shows similar survival between Whites and minorities with aggressive LBCL, which was likely due to equal access to guideline-concordant therapy. Minorities received higher intensity navigation encounters, which may have helped them to overcome socioeconomic disadvantages.
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- 2021
16. Intensive induction regimens after deferring initial therapy for mantle cell lymphoma are not associated with improved survival
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Timothy S. Fenske, Jin Guo, Brian T. Hill, Natalie S Grover, Krithika Shanmugasundaram, Madelyn Burkart, Brad S. Kahl, Stefan K. Barta, J. Switchenko, Alexey V. Danilov, Subir Goyal, Mehdi Hamadani, Max J. Gordon, Christopher R. Flowers, Oscar Calzada, Peter Martin, David A. Bond, Jonathon B. Cohen, Yazeed Sawalha, Nilanjan Ghosh, Steven I. Park, Kristie A. Blum, James N. Gerson, Bhaskar Kolla, Reem Karmali, Stephanie Mathews, Michael C. Churnetski, Talha Badar, Veronika Bachanova, Mary Malecek, and Narendranath Epperla
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Male ,Oncology ,medicine.medical_specialty ,Improved survival ,Lymphoma, Mantle-Cell ,Disease ,Transplantation, Autologous ,Article ,Dexamethasone ,Disease-Free Survival ,Time-to-Treatment ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,Intensive therapy ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Initial therapy ,Prospective cohort study ,Cyclophosphamide ,Aged ,Proportional Hazards Models ,Retrospective Studies ,business.industry ,Proportional hazards model ,Remission Induction ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Doxorubicin ,Vincristine ,030220 oncology & carcinogenesis ,Female ,Mantle cell lymphoma ,business ,030215 immunology - Abstract
INTRODUCTION: While most patients with mantle cell lymphoma (MCL) receive therapy shortly after diagnosis, a subset of patients with indolent-behaving disease can safely defer treatment. In this subgroup, we evaluated the importance of treatment intensity in patients with MCL who defer initial therapy. METHODS: Out of 1134 patients with MCL from 12 academic centers, we analyzed 219 patients who initiated therapy at least 90 days after diagnosis. Patients who received induction with high-dose cytarabine and/or autologous stem cell transplantation (ASCT) in first remission were considered to have received intensive therapy (n = 88) while all other approaches were non-intensive (n = 131). RESULTS: There was no difference in progression-free (PFS; P = .224) or overall survival (OS; P = .167) in deferred patients who received non-intensive vs. intensive therapy. Additionally, univariate and multivariate Cox proportional hazards models were performed for PFS and OS. Treatment at an academic center (HR 0.43, P = .015) was associated with improved OS in both univariate and multivariate models, while intensity of treatment was not associated with improved OS in either model. CONCLUSIONS: These results indicate that intensified initial treatment is not associated with improved survival after deferring initial therapy, although prospective studies are needed to determine which of these patients with MCL may benefit from intensive therapy.
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- 2021
17. Heterodimerization of CSF3R Splice Variants and Mutants Alter Receptor Function
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Sara L. Seegers, Amanda Lance, Steven I. Park, Belinda R. Avalos, and Lawrence J Druhan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
18. Clinical Activity of Anti-PD-1 Therapy Following CD30 CAR-T Cell Therapy in Relapsed Hodgkin Lymphoma
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Timothy J. Voorhees, Anne W. Beaven, Christopher Dittus, George E Hucks, J. Kaitlin Morrison, Catherine Joyce Arago Cheng, Tammy Cavallo, Steven I. Park, Gianpietro Dotti, Jonathan S. Serody, Barbara Savoldo, and Natalie S. Grover
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
19. Frontline PET-Directed Therapy with Brentuximab Vedotin Plus AVD Followed By Nivolumab Consolidation in Patients with Limited Stage Hodgkin Lymphoma
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Steven I. Park, Stephen M. Ansell, Sharmila Giri, Jakub Svoboda, Stephen D Smith, Tatyana Feldman, Elizabeth L. Budde, Andrew J Ness, Yunsik Choi, Philip J Bierman, and Hun Ju Lee
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
20. Positron Emission Tomography–Directed Therapy for Patients With Limited-Stage Diffuse Large B-Cell Lymphoma: Results of Intergroup National Clinical Trials Network Study S1001
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Paul M. Barr, Hongli Li, Brad S. Kahl, Jerome D. Winegarden, Louis S. Constine, Lode J. Swinnen, Michael LeBlanc, Jonathan W. Friedberg, Joo Y. Song, Thomas P. Miller, Thomas J. Fitzgerald, John P. Leonard, Richard I. Fisher, Steven I. Park, Daniel O. Persky, Sonali M. Smith, Deborah M. Stephens, Lisa M. Rimsza, and Nancy L. Bartlett
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Male ,Oncology ,Cancer Research ,Time Factors ,hemic and lymphatic diseases ,Positron Emission Tomography Computed Tomography ,Antineoplastic Combined Chemotherapy Protocols ,Prospective Studies ,Young adult ,Prospective cohort study ,Aged, 80 and over ,medicine.diagnostic_test ,Antibodies, Monoclonal ,ORIGINAL REPORTS ,Chemoradiotherapy ,Middle Aged ,Treatment Outcome ,Vincristine ,Positron emission tomography ,Predictive value of tests ,Disease Progression ,Female ,Lymphoma, Large B-Cell, Diffuse ,Rituximab ,Adult ,medicine.medical_specialty ,Adolescent ,Clinical Decision-Making ,Young Adult ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Cyclophosphamide ,Aged ,Neoplasm Staging ,Limited Stage ,business.industry ,Patient Selection ,Radioimmunotherapy ,medicine.disease ,United States ,Lymphoma ,Clinical trial ,Doxorubicin ,Prednisone ,Radiopharmaceuticals ,business ,Diffuse large B-cell lymphoma - Abstract
PURPOSE Diffuse large B-cell lymphoma (DLBCL) presents as a limited-stage disease in 25% to 30% of patients, with better overall survival (OS) than that for advanced-stage disease but with continuous relapse regardless of treatment approach. The preferred treatment is abbreviated rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and radiation therapy. On the basis of promising results of positron emission tomography (PET)–directed treatment approaches, we designed a National Clinical Trials Network (NCTN) study to improve outcomes and decrease toxicity. METHODS Patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received 3 cycles of standard R-CHOP therapy and underwent a centrally reviewed interim PET/computed tomography scan (iPET). Those with a negative iPET proceeded with 1 additional cycle of R-CHOP, whereas those with a positive iPET received involved field radiation therapy followed by ibritumomab tiuxetan radioimmunotherapy. RESULTS Of 158 patients enrolled, 132 were eligible and 128 underwent iPET, which was positive in 14 (11%) of the patients. With a median follow-up of 4.92 years (range, 1.1-7.7 years), only 6 patients progressed and 3 died as a result of lymphoma. Eleven patients died as a result of nonlymphoma causes at a median age of 80 years. The 5-year progression-free survival estimate was 87% (95% CI, 79% to 92%) and the OS estimate was 89% (95% CI, 82% to 94%), with iPET-positive and iPET-negative patients having similar outcomes. CONCLUSION To our knowledge, S1001 is the largest prospective study in the United States of limited-stage DLBCL in the rituximab era, with the best NCTN results in this disease subset. With PET-directed therapy, 89% of the patients with a negative iPET received R-CHOP × 4, and only 11% had a positive iPET and required radiation, with both groups having excellent outcomes. The trial establishes R-CHOP × 4 alone as the new standard approach to limited-stage disease for the absolute majority of patients.
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- 2020
21. ABVD followed by BV consolidation in risk-stratified patients with limited-stage Hodgkin lymphoma
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Oludamilola Olajide, Allison M. Deal, Nilanjan Ghosh, Jeanne F. Noe, Stephen M. Ansell, Thomas C. Shea, Nishitha Reddy, Steven I. Park, and Lihua E. Budde
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Dacarbazine ,medicine.medical_treatment ,Vinblastine ,Bleomycin ,Young Adult ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Doxorubicin ,Brentuximab vedotin ,Aged ,Neoplasm Staging ,Brentuximab Vedotin ,Lymphoid Neoplasia ,business.industry ,Hematology ,Middle Aged ,Hodgkin Disease ,Confidence interval ,Radiation therapy ,ABVD ,chemistry ,Female ,business ,medicine.drug - Abstract
Approximately 90% of limited-stage Hodgkin lymphoma (HL) patients are projected to be cured with standard therapy, but many do not live their expected life span because of late treatment–related complications. New treatment paradigms are needed to reduce the use of radiation therapy (RT) as well as conventional chemotherapy drugs while improving upon current standard-of-care survival outcomes. In this phase 2 multicenter study, patients with non-bulky limited-stage HL received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin (BV) consolidation. Forty-one patients were enrolled, and patient characteristics included median age of 29 years (range, 19 to 67 years), 58% were female, 45% had unfavorable disease, and 98% had stage II disease. Based on positron emission tomography (PET)–based risk stratification, patients received 2 to 6 cycles of ABVD followed by 6 cycles of BV. After ABVD followed by BV, 95% of evaluable patients (37 out of 39; 95% confidence interval [CI], 83%-99%) achieved PET-negative status. In the intent-to-treat patient population, the estimated 3-year progression-free survival (PFS) rate was 92%, and the overall survival (OS) rate was 97%, with a median follow-up of 47 months. All 37 patients who achieved negative PET status after BV consolidation effectively avoided RT and remain in remission with estimated 3-year PFS and OS rates of 100%. In conclusion, BV demonstrates encouraging clinical activity when it follows ABVD therapy in limited-stage HL. Early incorporation of BV may reduce the use of RT as well as conventional chemotherapy drugs while achieving favorable survival outcomes in risk-stratified patients with non-bulky limited-stage HL. This trial was registered at www.clinicaltrials.gov as #NCT01578967.
- Published
- 2020
22. Mogamulizumab: An Anti-CC Chemokine Receptor 4 Antibody for T-Cell Lymphomas
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Joseph B. Elmes, Steven I. Park, Chris Larck, Priscila A Shibu, and Donald C Moore
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Adult ,Oncology ,medicine.medical_specialty ,Receptors, CCR4 ,Skin Neoplasms ,Refractory Mycosis Fungoides ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Lymphoma, T-Cell ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Mogamulizumab ,Humans ,Leukemia-Lymphoma, Adult T-Cell ,T-cell lymphoma ,Pharmacology (medical) ,Adverse effect ,Vorinostat ,business.industry ,Middle Aged ,medicine.disease ,Lymphoma, T-Cell, Cutaneous ,Lymphoma ,Drug eruption ,Leukemia ,030220 oncology & carcinogenesis ,Drug Eruptions ,business ,030215 immunology ,medicine.drug - Abstract
Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, dosing, and administration of mogamulizumab for the treatment of T-cell lymphomas. Data Sources: A literature search of PubMed (1966 to September 2019) was conducted using the keywords mogamulizumab, KW-0761, and lymphoma. Data were also obtained from package inserts and meeting abstracts. Study Selection and Data Extraction: All relevant published articles, package inserts, and unpublished meeting abstracts on mogamulizumab for the treatment of T-cell lymphomas were reviewed. Data Synthesis: Mogamulizumab is an anti-CC chemokine receptor 4 (CCR4) monoclonal antibody that has demonstrated activity in various T-cell lymphomas. It was approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have been treated with at least 1 prior line of therapy. Mogamulizumab demonstrated significant improvement in progression-free survival compared with vorinostat in patients with relapsed or refractory MF or SS. Serious adverse events associated with mogamulizumab include infusion-related reactions, cutaneous drug eruption, and autoimmune complications. Mogamulizumab administration in the preallogeneic hematopoietic stem cell transplant setting can increase the risk for severe posttransplant graft-versus-host disease. Relevance to Patient Care and Clinical Practice: Mogamulizumab is a first-in-class CCR4 inhibitor, providing a new option in the treatment of relapsed or refractory cutaneous T-cell lymphomas. Although not currently FDA approved for this indication, mogamulizumab may have some utility for the treatment of relapsed adult T-cell leukemia/lymphoma. Conclusion: The recent approval of mogamulizumab represents an important addition to the armamentarium of pharmacotherapies for T-cell lymphomas.
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- 2019
23. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy
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Stephanie P. Mathews, Michael C. Churnetski, Steven I. Park, Kami J. Maddocks, Talha Badar, Narendranath Epperla, Kristie A. Blum, Mary-Kate Malecek, Veronika Bachanova, Alexey V. Danilov, Jin Guo, Natalie S Grover, James N. Gerson, Brad S. Kahl, Max J Gordon, Stefan K. Barta, Brian T. Hill, Alina S. Gerrie, Madelyn Burkart, Oscar Calzada, Mehdi Hamadani, Yazeed Sawalha, Bhaskar Kolla, Nilanjan Ghosh, Edward Maldonado, Jeffrey M. Switchenko, Peter Martin, Reem Karmali, Krithika Shanmugasundaram, Christopher R. Flowers, Jonathon B. Cohen, Diego Villa, Subir Goyal, Timothy S. Fenske, and David A. Bond
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Adult ,medicine.medical_specialty ,Lymphoma ,Population ,Early Relapse ,Lymphoma, Mantle-Cell ,Rare Diseases ,Recurrence ,Internal medicine ,Medicine ,Humans ,In patient ,Prospective Studies ,Prospective cohort study ,education ,Cancer ,education.field_of_study ,business.industry ,Prevention ,Hematology ,Mantle-Cell ,medicine.disease ,Prognosis ,Point of delivery ,Treatment Outcome ,Cohort ,Mantle cell lymphoma ,business ,Progressive disease - Abstract
Although an expanding array of effective treatments has resulted in recent improvement in survival of patients with mantle cell lymphoma (MCL), outcomes remain heterogeneous, and identification of prognostic factors remains a priority. We assessed the prognostic impact of time to progression of disease (POD) after first-line therapy among 455 patients with relapsed MCL. Patients were categorized by duration of first remission as PRF/POD6, defined as progressive disease during induction or POD within 6 months of diagnosis (n = 65; 14%); POD6-24, defined as POD between 6 and 24 months after diagnosis (n = 153; 34%); and POD>24, defined as POD >24 months after diagnosis (n = 237; 53%). The median overall survival from POD (OS2) was 1.3 years (95% confidence interval [CI], 0.9-2.4) for patients with PRF/POD6, 3 years (95% CI, 2-6.8) for those with POD6-24, and 8 years (95% CI, 6.2-NR) for those with POD>24. Median OS2 was inferior in patients with early POD (defined as PRF/POD6 or POD6-24) after both intensive and less intensive frontline treatment. The prognostic performance of time until POD was replicated in an independent cohort of 245 patients with relapsed MCL, with median OS2 of 0.3 years (95% CI, 0.1-0.5) for PRF/POD6, 0.8 years (95% CI, 0.6-0.9) for POD6-24, and 2.4 years (95% CI 2.1-2.7) for POD>24. Early POD is associated with inferior OS2 in patients with relapsed MCL, identifying a high-risk population for future prospective studies.
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- 2021
24. Rituximab, lenalidomide, and ibrutinib in relapsed/refractory primary cutaneous diffuse large B‐cell lymphoma, leg type
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Amy Soni, Donald C Moore, Bei Hu, Ryan Jacobs, Jonathan Levine, Steven I. Park, Nilanjan Ghosh, Elton T. Smith, and Tamara K. Moyo
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business.industry ,Hematology ,Leg type ,chemistry.chemical_compound ,chemistry ,Ibrutinib ,Relapsed refractory ,Primary Cutaneous Diffuse Large B-Cell Lymphoma ,medicine ,Cancer research ,Rituximab ,business ,Lenalidomide ,medicine.drug - Published
- 2021
25. Combination of Atezolizumab and Obinutuzumab in Patients with Relapsed/Refractory Follicular Lymphoma and Diffuse Large B-Cell Lymphoma: Results from a Phase 1b Study
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M. Lia Palomba, Brian G. Till, Steven I. Park, Franck Morschhauser, Guillaume Cartron, Reinhard Marks, Mahesh Shivhare, Wan-Jen Hong, Aparna Raval, Alice C. Chang, Elicia Penuel, and Leslie L. Popplewell
- Subjects
Cancer Research ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Hematology ,Lymphoma, Large B-Cell, Diffuse ,Antibodies, Monoclonal, Humanized ,Lymphoma, Follicular - Abstract
This was an open-label, phase 1b study assessing the safety, tolerability, preliminary efficacy and pharmacokinetics of the combination of atezolizumab and obinutuzumab in patients with relapsed/refractory follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL). There is a mechanistic rationale suggesting that this combination may enhance recruitment of both innate and adaptive immunity and be effective against CD20+ B-cell malignancies.The study consisted of a safety evaluation stage and an expansion stage. Patients received obinutuzumab 1000 mg intravenously (IV) in cycle (C) 1, obinutuzumab plus atezolizumab 1200 mg IV for C2-8, and atezolizumab only from C9. Primary endpoints were to identify a recommended phase 2 dose (RP2D) for atezolizumab, and safety and tolerability in the safety and expansion stages.A total of 49 patients were enrolled (FL, n = 26; DLBCL, n = 23), with a median of 2 prior lines of treatment. The RP2D for atezolizumab was 1200 mg IV every 3 weeks. Adverse events reported in ≥ 20% of patients were fatigue (15 patients [31%]), nausea (13 patients [27%]), cough, and diarrhea (10 patients [20%] each). Objective response rate was 54% in the FL cohort (complete response [CR] rate: 23%) and 17% in the DLBCL cohort (CR: 4%). Median progression-free survival was 9 months for FL and 3 months for DLBCL. Median overall survival was not estimable for FL and 9 months for DLBCL.The combination of obinutuzumab and atezolizumab was determined to be safe and tolerable, with no new toxicities observed.
- Published
- 2021
26. Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era
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Max J. Gordon, Timothy S. Fenske, Peter Martin, Natalie S Grover, Mary Malecek, Bhaskar Kolla, Brian T. Hill, Jeffrey M. Switchenko, Madelyn Burkart, Reem Karmali, Kami J. Maddocks, Jin Guo, David A. Bond, Stephanie Mathews, Narendranath Epperla, Michael C. Churnetski, Alexey V. Danilov, Talha Badar, Nilanjan Ghosh, Jonathon B. Cohen, Subir Goyal, Steven I. Park, Kristie A. Blum, Krithika Shanmugasundaram, James N. Gerson, Veronika Bachanova, Brad S. Kahl, Stefan K. Barta, Christopher R. Flowers, Yazeed Sawalha, and Mehdi Hamadani
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Oncology ,Male ,medicine.medical_specialty ,Multivariate analysis ,Lymphoma, Mantle-Cell ,Blastoid ,Article ,Antineoplastic Agents, Immunological ,Internal medicine ,Medicine ,Humans ,Progression-free survival ,Aged ,Retrospective Studies ,Univariate analysis ,biology ,Practice patterns ,business.industry ,Age Factors ,Hematology ,Middle Aged ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Progression-Free Survival ,Treatment Outcome ,Cytarabine ,Mantle cell lymphoma ,Rituximab ,Female ,business ,medicine.drug - Abstract
Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.
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- 2021
27. Elevated cytokines and chemokines in peripheral blood of patients with SARS-CoV-2 pneumonia treated with high-titer convalescent plasma
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Joshua Zenreich, Michele L. Donato, Stacey L. Fanning, Melissa Baker, Bingsong Zhang, Robert Korngold, Phyllis McKiernan, Kira Goldgirsh, David S. Perlin, Ming Tan, Zheng Yang, and Steven I. Park
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Male ,RNA viruses ,Viral Diseases ,Pulmonology ,Physiology ,Coronaviruses ,Cancer Treatment ,medicine.disease_cause ,Antibodies, Viral ,Biochemistry ,Medical Conditions ,Immune Physiology ,Blood plasma ,Medicine and Health Sciences ,Biology (General) ,Pathology and laboratory medicine ,Coronavirus ,Aged, 80 and over ,Innate Immune System ,Immune System Proteins ,biology ,Middle Aged ,Medical microbiology ,Body Fluids ,Immunoglobulin Isotypes ,Blood ,Infectious Diseases ,Oncology ,Viruses ,Cytokines ,Female ,Antibody ,medicine.symptom ,Chemokines ,Anatomy ,SARS CoV 2 ,Pathogens ,Research Article ,Adult ,SARS coronavirus ,QH301-705.5 ,Immunology ,Inflammation ,Surgical and Invasive Medical Procedures ,Cytokine Therapy ,Microbiology ,Blood Plasma ,Antibodies ,Proinflammatory cytokine ,Respiratory Disorders ,Immune system ,Virology ,Genetics ,medicine ,Humans ,Molecular Biology ,COVID-19 Serotherapy ,Aged ,business.industry ,SARS-CoV-2 ,Immunization, Passive ,Organisms ,Viral pathogens ,COVID-19 ,Biology and Life Sciences ,Proteins ,Covid 19 ,RC581-607 ,Molecular Development ,medicine.disease ,Microbial pathogens ,Pneumonia ,Immune System ,Respiratory Infections ,biology.protein ,Parasitology ,Immunologic diseases. Allergy ,Cytokine storm ,business ,Intubation ,Developmental Biology - Abstract
The global SARS-CoV-2 coronavirus pandemic continues to be devastating in many areas. Treatment options have been limited and convalescent donor plasma has been used by many centers to transfer passive neutralizing antibodies to patients with respiratory involvement. The results often vary by institution and are complicated by the nature and quality of the donor plasma itself, the timing of administration and the clinical aspects of the recipients. SARS-CoV-2 infection is known to be associated with an increase in the blood concentrations of several inflammatory cytokines/chemokines, as part of the overall immune response to the virus and consequential to mediated lung pathology. Some of these correlates contribute to the cytokine storm syndrome and acute respiratory distress syndrome, often resulting in fatality. A Phase IIa clinical trial at our institution using high neutralizing titer convalescent plasma transfer gave us the unique opportunity to study the elevations of correlates in the first 10 days after infusion. Plasma recipients were divided into hospitalized COVID-19 pneumonia patients who did not (Track 2) or did (Track 3) require mechanical ventilation. Several cytokines were elevated in the patients of each Track and some continued to rise through Day 10, while others initially increased and then subsided. Furthermore, elevations in MIP-1α, MIP-1β and CRP correlated with disease progression of Track 2 recipients. Overall, our observations serve as a foundation for further study of these correlates and the identification of potential biomarkers to improve upon convalescent plasma therapy and to drive more successful patient outcomes., Author summary COVID-19, the disease caused by the SARS-CoV-2 virus, has a varied clinical course with limited treatment options. While some patients mount a productive immune response leading to recovery, others progress to rapid respiratory deterioration that may require hospitalization and mechanical ventilation. Our institution conducted a clinical trial to evaluate the efficacy of convalescent plasma therapy (CPT) to treat patients hospitalized with COVID-19 pneumonia. In this arm of the study, we sought to examine immune analytes in donor plasma as well as evaluate the recipients’ plasma before CPT infusion, and at Day 3 and Day 10 post-CPT infusion. We found some analytes to be elevated in plasma donors, compared to healthy controls, even after recovery. Plasma composition in CPT recipients prior to infusion showed elevations in several analytes associated with immune activation. Some significant differences were seen in plasma composition in patients in our Track 2 cohort (hospitalized without mechanical ventilation) compared to the Track 3 cohort (hospitalized with mechanical ventilation). In addition, we obtained plasma samples for hospitalized COVID-19 patients that did not receive CPT and noted several differences in the course of immune analyte production over time compared to the CPT-treated patients.
- Published
- 2021
28. Extracellular Vesicle Capture by AnTibody of CHoice and Enzymatic Release (EV‐CATCHER): A customizable purification assay designed for small‐RNA biomarker identification and evaluation of circulating small‐EVs
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Kar Chow, Megan Mitchell, Ehsan Manouchehri Doulabi, Masood Kamali-Moghaddam, Andrew B. Ramnauth, Olivier Loudig, Steven I. Park, Emily Bhoy, Anju Gangadharan, David S. Perlin, Michael Poulos, Kenny Ye, Yael Kramer, Michele L. Donato, Iddo Z. Ben-Dov, Christina Liu, and Seán Fitzgerald
- Subjects
0301 basic medicine ,Bodily Secretions ,Small RNA ,Histology ,Cell- och molekylärbiologi ,Technical Reports ,Severity of Illness Index ,Mice ,03 medical and health sciences ,Technical Report ,0302 clinical medicine ,micro‐RNA profiling ,Chlorocebus aethiops ,Animals ,Humans ,Circulating MicroRNA ,Vero Cells ,exosome purification ,chemistry.chemical_classification ,biology ,QH573-671 ,Chemistry ,micro-RNA profiling ,COVID-19 ,High-Throughput Nucleotide Sequencing ,Cell Biology ,Extracellular vesicle ,sequencing ,In vitro ,Blot ,Titer ,RAW 264.7 Cells ,030104 developmental biology ,Enzyme ,Biochemistry ,030220 oncology & carcinogenesis ,Immunologic Techniques ,MCF-7 Cells ,Nucleic acid ,biology.protein ,TEM ,Antibody ,extracellular vesicles ,Cytology ,Cell and Molecular Biology - Abstract
Circulating nucleic acids, encapsulated within small extracellular vesicles (EVs), provide a remote cellular snapshot of biomarkers derived from diseased tissues, however selective isolation is critical. Current laboratory‐based purification techniques rely on the physical properties of small‐EVs rather than their inherited cellular fingerprints. We established a highly‐selective purification assay, termed EV‐CATCHER, initially designed for high‐throughput analysis of low‐abundance small‐RNA cargos by next‐generation sequencing. We demonstrated its selectivity by specifically isolating and sequencing small‐RNAs from mouse small‐EVs spiked into human plasma. Western blotting, nanoparticle tracking, and transmission electron microscopy were used to validate and quantify the capture and release of intact small‐EVs. As proof‐of‐principle for sensitive detection of circulating miRNAs, we compared small‐RNA sequencing data from a subset of small‐EVs serum‐purified with EV‐CATCHER to data from whole serum, using samples from a small cohort of recently hospitalized Covid‐19 patients. We identified and validated, only in small‐EVs, hsa‐miR‐146a and hsa‐miR‐126‐3p to be significantly downregulated with disease severity. Separately, using convalescent sera from recovered Covid‐19 patients with high anti‐spike IgG titers, we confirmed the neutralizing properties, against SARS‐CoV‐2 in vitro, of a subset of small‐EVs serum‐purified by EV‐CATCHER, as initially observed with ultracentrifuged small‐EVs. Altogether our data highlight the sensitivity and versatility of EV‐CATCHER., ‘A customizable, low background, high‐affinity assay for specific immuno‐capture and release of circulating small extracellular vesicles prior to small‐RNA sequencing for identification of miRNA biomarkers or in‐vitro evaluation: The EV‐CATCHER assay (Extracellular Vesicle Capture by AnTibody of CHoice and Enzymatic Release)’.
- Published
- 2021
29. Pretherapy metabolic tumor volume is associated with response to CD30 CAR T cells in Hodgkin lymphoma
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Jonathan S. Serody, Timothy J Voorhees, Natalie S Grover, Anne W. Beaven, Amir H. Khandani, Jennifer S. Smith, Catherine Cheng, J. Kaitlin Morrison, Anastasia Ivanova, George E Hucks, Beibo Zhao, Thomas B. Shea, Barbara Savoldo, Jorge Oldan, Gianpietro Dotti, Steven I. Park, and Christopher Dittus
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medicine.medical_specialty ,Receptors, Chimeric Antigen ,CD30 ,business.industry ,T-Lymphocytes ,Ki-1 Antigen ,Hematology ,Gastroenterology ,Hodgkin Disease ,Chimeric antigen receptor ,Tumor Burden ,Log-rank test ,Cell therapy ,Antigen ,Refractory ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Progression-free survival ,Neoplasm Recurrence, Local ,business - Abstract
Our group has recently demonstrated that chimeric antigen receptor T-cell therapy targeting the CD30 antigen (CD30.CAR-T) is highly effective in patients with relapsed and refractory (r/r) classical Hodgkin lymphoma (cHL). Despite high rates of clinical response, relapses and progression were observed in a subset of patients. The objective of this study was to characterize clinical and correlative factors associated with progression-free survival (PFS) after CD30.CAR-T cell therapy. We evaluated correlatives in 27 patients with r/r cHL treated with lymphodepletion and CD30.CAR-T cells. With a median follow-up of 9.5 months, 17 patients (63%) progressed, with a median PFS of 352 days (95% confidence interval: 116-not reached), and 2 patients died (7%) with a median overall survival of not reached. High metabolic tumor volume (MTV, >60 mL) immediately before lymphodepletion and CD30.CAR-T cell infusion was associated with inferior PFS (log rank, P = .02), which persisted after adjusting for lymphodepletion and CAR-T dose (log rank, P = .01 and P = .006, respectively). In contrast, receiving bridging therapy, response to bridging therapy, CD30.CAR-T expansion/persistence, and percentage of CD3+PD-1+ lymphocytes over the first 6 weeks of therapy were not associated with differences in PFS. In summary, this study reports an association between high baseline MTV immediately before lymphodepletion and CD30.CAR-T cell infusion and worse PFS in patients with r/r cHL. This trial was registered at www.clinicaltrials.gov as #NCT02690545.
- Published
- 2021
30. Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma
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Jason P. Wong, H. Shelton Earp, Rachele Bigi, Blossom Damania, Ariana G. Bravo Cruz, Steven I. Park, Jichen Zhao, Timothy J. Stuhlmiller, Carolina Lin, Weihe Zhang, Gary L. Johnson, Dirk P. Dittmer, Stephen V. Frye, Louise Giffin, and Xiaodong Wang
- Subjects
Proteome ,Cell Survival ,viruses ,Apoptosis ,Mice ,Phosphatidylinositol 3-Kinases ,immune system diseases ,Cell Line, Tumor ,Lymphoma, Primary Effusion ,hemic and lymphatic diseases ,Animals ,Medicine ,Kinome ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Cell Proliferation ,B-Lymphocytes ,Multidisciplinary ,business.industry ,Kinase ,Cell growth ,Lymphoma, Non-Hodgkin ,Receptor Protein-Tyrosine Kinases ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Up-Regulation ,Lymphoma ,PNAS Plus ,Cell culture ,Tumor progression ,Cancer research ,Female ,Primary effusion lymphoma ,business ,Signal Transduction ,TYRO3 - Abstract
Non-Hodgkin lymphomas (NHLs) make up the majority of lymphoma diagnoses and represent a very diverse set of malignancies. We sought to identify kinases uniquely up-regulated in different NHL subtypes. Using multiplexed inhibitor bead-mass spectrometry (MIB/MS), we found Tyro3 was uniquely up-regulated and important for cell survival in primary effusion lymphoma (PEL), which is a viral lymphoma infected with Kaposi’s sarcoma-associated herpesvirus (KSHV). Tyro3 was also highly expressed in PEL cell lines as well as in primary PEL exudates. Based on this discovery, we developed an inhibitor against Tyro3 named UNC3810A, which hindered cell growth in PEL, but not in other NHL subtypes where Tyro3 was not highly expressed. UNC3810A also significantly inhibited tumor progression in a PEL xenograft mouse model that was not seen in a non-PEL NHL model. Taken together, our data suggest Tyro3 is a therapeutic target for PEL.
- Published
- 2019
31. A phase 1 trial of ibrutinib plus palbociclib in previously treated mantle cell lymphoma
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Steven I. Park, Nancy L. Bartlett, Kristie A. Blum, Zhengming Chen, Christopher Dittus, Peter Martin, Xiangao Huang, LeAnn Ridling, Jia Ruan, John P. Leonard, Selina Chen-Kiang, Giorgio Inghirami, Maurizio DiLiberto, and Kami J. Maddocks
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Immunology ,Palbociclib ,Neutropenia ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Survival rate ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Rash ,Lymphoma ,030104 developmental biology ,chemistry ,Ibrutinib ,Mantle cell lymphoma ,medicine.symptom ,business ,Febrile neutropenia ,030215 immunology - Abstract
Single-agent ibrutinib is active in patients with previously treated mantle cell lymphoma (MCL); however, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human MCL cells and MCL cell lines expressing wild-type Bruton’s tyrosine kinase (BTK). Therefore, we conducted a phase 1 trial to evaluate the dosing, safety, and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. From August 2014 to June 2016, a total of 27 patients (21 men, 6 women) were enrolled. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1 to 21 of each 28-day cycle. The dose-limiting toxicity was grade 3 rash. The most common grade 3 to 4 toxicities included neutropenia (41%), thrombocytopenia (30%), hypertension (15%), febrile neutropenia (15%), and lung infection (11%). The overall and complete response rates were 67% and 37%, and with a median follow-up of 25.6 months, the 2-year progression-free survival was 59.4% and the 2-year response duration was 69.8%. A phase 2 multicenter clinical trial to further characterize efficacy is now ongoing. The current trial was registered at www.clinicaltrials.gov as #NCT02159755.
- Published
- 2019
32. Updated interim analysis of the randomized phase 1b/3 study of tazemetostat in combination with lenalidomide and rituximab in patients with relapsed/refractory follicular lymphoma
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Connie Lee Batlevi, Steven I. Park, Tycel Jovelle Phillips, Jennifer Amengual, David Jacob Andorsky, Philip Campbell, Pamela McKay, John Paul Leonard, Manu Sondhi, Jay Yang, Yingxue Chen, Heather O'Connor, Pamela Slatcher, and Franck Morschhauser
- Subjects
Cancer Research ,Oncology - Abstract
7572 Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, showed antitumor activity as monotherapy in patients with relapsed or refractory (R/R) follicular lymphoma (FL) who received ≥2 prior lines of therapy. In clinical studies in patients with R/R FL, lenalidomide and rituximab (R2) demonstrated an objective response rate (ORR) of 73%–78% and median progression-free survival (PFS) of 36–39 months. This global, multicenter phase 1b/3 study is designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + R2 in patients with R/R FL after ≥1 prior therapy. We report an updated interim analysis of the phase 1b safety run-in where we assess the clinical activity and pharmacokinetics (PK) of TAZ when administered with R2 in patients with R/R FL. Methods: Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily) in 28-day cycles with standard-dose R2 (NCT04224493). In addition to PK and safety, preliminary efficacy analysis was performed on the response-evaluable population, including best overall response, PFS, and duration of response (DOR) per investigator assessment according to Lugano 2014 response criteria. Results: As of January 22, 2022, 43 patients were enrolled and receiving TAZ + R2 (400 [n = 4], 600 [n = 18], and 800 mg [n = 21]). These patients had a median age of 67 years (range, 39–83) and received a median of 1 prior therapy (range, 1–4). Overall, 15/43 (34.9%) patients were refractory to rituximab, 10/39 (25.6%) had POD24, and 6/41 (14.6%) had mutant-type EZH2. Median duration of treatment exposure was 32.0 weeks (range, 4.1–68.1). Mean Cmax and AUC0–t of TAZ 800 mg + R2 at steady state were similar to those found for TAZ as monotherapy. PK of TAZ was not altered by concomitant administration of daily oral lenalidomide 20 mg, and PK of lenalidomide was not altered by concomitant administration of TAZ. No dose-limiting toxicities were observed in phase 1b, and no new safety signals were identified as of the January 2022 data cutoff. Serious treatment-emergent adverse events (TEAEs) were observed in 14 (32.6%) patients. Grade 3–4 TEAEs were observed in 24 (55.8%) patients; the most common grade 3–4 TEAE was neutrophil count decrease (n = 13; 30.2%). Of 38 patients evaluable for tumor assessment, 19 (50.0%) had a complete response, 17 (44.7%) had a partial response, and 2 (5.3%) had stable disease. ORR was 94.7% (n = 36). With a median follow-up of 5.8 months, median PFS and DOR were not reached and appeared to be similar, regardless of mutation status. Conclusions: TAZ + R2 combination demonstrates consistent and unaltered PK for TAZ and lenalidomide as well as a favorable safety profile and efficacy trend. The 2-arm randomized phase 3 portion will further explore the efficacy and safety of TAZ RP3D 800 mg + R2 in ≈500 patients with R/R FL. Clinical trial information: NCT04224493.
- Published
- 2022
33. High-Performance Concurrent Chemo-Immuno-Radiotherapy for the Treatment of Hematologic Cancer through Selective High-Affinity Ligand Antibody Mimic-Functionalized Doxorubicin-Encapsulated Nanoparticles
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Andrew Z. Wang, Rod Balhorn, Kin Man Au, Monique Cosman Balhorn, and Steven I. Park
- Subjects
010405 organic chemistry ,Chemistry ,General Chemical Engineering ,Cell ,technology, industry, and agriculture ,Cancer ,General Chemistry ,010402 general chemistry ,medicine.disease ,01 natural sciences ,0104 chemical sciences ,3. Good health ,Cell killing ,medicine.anatomical_structure ,In vivo ,Cancer cell ,medicine ,Cancer research ,Cytotoxic T cell ,Immunogenic cell death ,Doxorubicin ,QD1-999 ,Research Article ,medicine.drug - Abstract
Non-Hodgkin lymphoma is one of the most common types of cancer. Relapsed and refractory diseases are still common and remain significant challenges as the majority of these patients eventually succumb to the disease. Herein, we report a translatable concurrent chemo-immuno-radiotherapy (CIRT) strategy that utilizes fully synthetic antibody mimic Selective High-Affinity Ligand (SHAL)-functionalized doxorubicin-encapsulated nanoparticles (Dox NPs) for the treatment of human leukocyte antigen-D related (HLA-DR) antigen-overexpressed tumors. We demonstrated that our tailor-made antibody mimic-functionalized NPs bound selectively to different HLA-DR-overexpressed human lymphoma cells, cross-linked the cell surface HLA-DR, and triggered the internalization of NPs. In addition to the direct cytotoxic effect by Dox, the internalized NPs then released the encapsulated Dox and upregulated the HLA-DR expression of the surviving cells, which further augmented immunogenic cell death (ICD). The released Dox not only promotes ICD but also sensitizes the cancer cells to irradiation by inducing cell cycle arrest and preventing the repair of DNA damage. In vivo biodistribution and toxicity studies confirm that the targeted NPs enhanced tumor uptake and reduced systemic toxicities of Dox. Our comprehensive in vivo anticancer efficacy studies using lymphoma xenograft tumor models show that the antibody-mimic functional NPs effectively inhibit tumor growth and sensitize the cancer cells for concurrent CIRT treatment without incurring significant side effects. With an appropriate treatment schedule, the SHAL-functionalized Dox NPs enhanced the cell killing efficiency of radiotherapy by more than 100% and eradicated more than 80% of the lymphoma tumors., Antibody mimic Selective High-Affinity Ligand-functionalized doxorubicin-encapsulated nanoparticles have been engineered for concurrent chemo-immuno-radiotherapy of hematological cancer.
- Published
- 2018
34. Diagnosis, clinical characteristics, and outcomes of COVID-19 patients from a large healthcare system in northern New Jersey
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Marcus H Cunningham, Seán Fitzgerald, Caixin Zhan, José R. Mediavilla, Kar Fai Chow, Yanan Zhao, Tao Hong, David S. Perlin, Gary Munk, Steven I. Park, Hee Sang Ahn, and Xiangyang Li
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Adult ,Male ,medicine.medical_specialty ,Science ,Population ,MEDLINE ,Diseases ,030204 cardiovascular system & hematology ,Microbiology ,Article ,03 medical and health sciences ,Medical research ,0302 clinical medicine ,Interquartile range ,Internal medicine ,Pandemic ,Health care ,Humans ,Medicine ,Serologic Tests ,030212 general & internal medicine ,Medical diagnosis ,education ,Aged ,Retrospective Studies ,Aged, 80 and over ,education.field_of_study ,Multidisciplinary ,New Jersey ,Clinical Laboratory Techniques ,business.industry ,COVID-19 ,Retrospective cohort study ,Middle Aged ,Hospitalization ,Female ,business ,Viral load - Abstract
New Jersey was an early epicenter for the COVID-19 pandemic in the United States, yet information on hospitalized COVID-19 patients from this area is scarce. This study aimed to provide data on demographics and clinical features of a hospitalized patient population who were confirmed with infection by our in-house (CDI) real-time reverse-transcription polymerase chain reaction (RT-PCR) test. We included consecutive patients who were admitted to Hackensack Meridian Health system hospitals with laboratory-confirmed diagnoses of COVID-19 at Hackensack University Medical Center by the CDI virus test between March 12, 2020, and April 8, 2020. Clinical data and viral testing results were collected and analyzed for characteristics associated with outcomes, as well as the correlation with viral load. A total of 722 patients were included in the study, with a median age of 63 (interquartile range (IQR), 51–75) and 272 (37.7%) females. Mortality of this case series was 25.8%, with a statistically significant linear increase observed from age 40 to ≥ 80 by 10-year intervals. Viral load, as indicated by the cycle of threshold (Ct) values from the RT-PCR test, was significantly higher in the oldest patient group (≥ 80), and inversely correlated with survival. This is the first report to describe the clinical characteristics and outcomes in a large hospitalized COVID-19 patient series from New Jersey. Findings from this study are valuable to the ongoing response of both nationwide healthcare networks and the medical research community.
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- 2021
35. Clinical and laboratory evaluation of patients with SARS-CoV-2 pneumonia treated with high-titer convalescent plasma
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Samit Desai, Alison Morawski, Joshua Zenreich, Michele Boonstra, Rena Feinman, Sean Sadikot, Xue Geng, Samuel Singer, Laura J. Long, Ming Tan, David S. Siegel, Scott D. Rowley, Michele L. Donato, Steven I. Park, Sukhdeep Kaur, Alfred P. Gillio, Mariefel Vendivil, Elizabeth Tam, Andrea Ricourt, Melissa Baker, Abdulla Al-Khan, Marlo Kemp, Rani Sebti, Andre Goy, David S. Perlin, Martin Gutierrez, Emily Brown, Kar F. Chow, Ernest Richards, Bindu Balani, Noa Biran, Andrew Ip, Steven J. Sperber, Anna Ullrich, Stacey L. Fanning, Danit Arad, Kathryn Buttner, Cristina Cicogna, Ronaldo C. Go, Robert Korngold, Stuart L. Goldberg, Andrew L. Pecora, Tatyana Feldman, Phyllis McKiernan, Lori A. Leslie, Sarah L. Timmapuri, Hyung C. Suh, and Keith M. Rose
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0301 basic medicine ,Male ,medicine.medical_specialty ,media_common.quotation_subject ,medicine.medical_treatment ,Antibodies, Viral ,Gastroenterology ,Severity of Illness Index ,03 medical and health sciences ,Immunocompromised Host ,Plasma ,0302 clinical medicine ,Internal medicine ,medicine ,Intubation ,Humans ,Adverse effect ,Survival rate ,COVID-19 Serotherapy ,media_common ,Aged ,business.industry ,SARS-CoV-2 ,Mortality rate ,Convalescence ,Immunization, Passive ,COVID-19 ,General Medicine ,Pneumonia ,Middle Aged ,medicine.disease ,Rash ,Antibodies, Neutralizing ,Respiration, Artificial ,Titer ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunoglobulin G ,Medicine ,Female ,Immunotherapy ,medicine.symptom ,business ,Research Article - Abstract
Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti–SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response., Patients with COVID-19 pneumonia receiving high-titer convalescent plasma showed antibody transfer with preservation of endogenous production, and database survival comparison is promising for the early group.
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- 2020
36. Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry
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Lisa A. Bellm, Frederick Lansigan, John P. Greer, Massimo Federico, Anil Tulpule, Christian Gisselbrecht, Steven M. Horwitz, Marc Schwartz, Lauren C. Pinter-Brown, Steven T. Rosen, Neil Morganstein, Eric D. Hsi, Michael Craig, Francine M. Foss, Brad S. Kahl, Andrei R. Shustov, Barbara Pro, Mark Acosta, Tatyana Feldman, Ranjana H. Advani, Carla Casulo, Sonali M. Smith, Steven I. Park, Joseph W. Leach, and Mary Jo Lechowicz
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Male ,medicine.medical_specialty ,Combination ,Drug therapy ,Peripheral T-cell lymphoma ,Prospective cohort studies ,Salvage therapy ,Kaplan-Meier Estimate ,Stable Disease ,Pharmacotherapy ,Refractory ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Registries ,Treatment Failure ,Prospective cohort study ,Aged ,business.industry ,Lymphoma, T-Cell, Peripheral ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Lymphoma ,Female ,business ,Progressive disease - Abstract
Background: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. Objectives: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. Methods: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. Results: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. Conclusions: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.
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- 2020
37. Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma
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Birju Mehta, Helen E. Heslop, Adrian P. Gee, Jonathan S. Serody, Paul Eldridge, Faith Brianne Buchanan, Kathryn McKay, Cliona M. Rooney, Anne W. Beaven, Premal Lulla, Bambi Grilley, Steven I. Park, Gianpietro Dotti, Meng Fen Wu, Malcolm K. Brenner, Kaitlin Morrison, Barbara Savoldo, Anastasia Ivanova, Tao Wang, Catherine Cheng, Carlos A. Ramos, Christopher Dittus, Natalie S Grover, and Thomas C. Shea
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Adult ,Male ,Cancer Research ,CD30 ,Adolescent ,medicine.medical_treatment ,T-Lymphocytes ,Cell- and Tissue-Based Therapy ,Ki-1 Antigen ,Immunotherapy, Adoptive ,Combination drug therapy ,Epitope ,Lymphocyte Depletion ,Epitopes ,Young Adult ,Cancer immunotherapy ,Antigen receptor ,Antineoplastic Combined Chemotherapy Protocols ,Refractory Hodgkin Lymphoma ,Medicine ,Combined Modality Therapy ,Bendamustine Hydrochloride ,Humans ,Young adult ,Receptor ,Cyclophosphamide ,Aged ,Receptors, Chimeric Antigen ,business.industry ,Immunotherapy ,ORIGINAL REPORTS ,Middle Aged ,Hodgkin Disease ,Oncology ,Cancer research ,Hodgkin lymphoma ,CAR T-cell therapy ,Female ,Car t cells ,business ,Vidarabine ,Stem Cell Transplantation - Abstract
PURPOSE Chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies has proved to be effective. We show how the same approach of CAR T cells specific for CD30 (CD30.CAR-Ts) can be used to treat Hodgkin lymphoma (HL). METHODS We conducted 2 parallel phase I/II studies (ClinicalTrials.gov identifiers: NCT02690545 and NCT02917083 ) at 2 independent centers involving patients with relapsed or refractory HL and administered CD30.CAR-Ts after lymphodepletion with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. The primary end point was safety. RESULTS Forty-one patients received CD30.CAR-Ts. Treated patients had a median of 7 prior lines of therapy (range, 2-23), including brentuximab vedotin, checkpoint inhibitors, and autologous or allogeneic stem cell transplantation. The most common toxicities were grade 3 or higher hematologic adverse events. Cytokine release syndrome was observed in 10 patients, all of which were grade 1. No neurologic toxicity was observed. The overall response rate in the 32 patients with active disease who received fludarabine-based lymphodepletion was 72%, including 19 patients (59%) with complete response. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival for all evaluable patients were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. CAR-T cell expansion in vivo was cell dose dependent. CONCLUSION Heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30.CAR-Ts had a high rate of durable responses with an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond canonical B-cell malignancies.
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- 2020
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38. Hodgkin Lymphoma With Multiple Autoimmune Disorders: Case Report and Review of the Literature
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Alice D. Ma, Natalie S Grover, Christopher Dittus, and Steven I. Park
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Adult ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Gastroenterology ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Primary biliary cirrhosis ,Hashimoto thyroiditis ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,business.industry ,Hematology ,Prognosis ,medicine.disease ,Hodgkin Disease ,Immune thrombocytopenia ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Hodgkin lymphoma ,Female ,business - Published
- 2018
39. A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma
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Hong Li, David Smith, Thomas E. Boyd, Paul M. Barr, Cindy Yu, Anne Sophie Carret, Steven I. Park, Robert T. Chen, Kathryn S. Kolibaba, Saurabh Chhabra, Tycel Phillips, Edwin C. Kingsley, Paolo Caimi, and Elaina M. Gartner
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0301 basic medicine ,Male ,Immunoconjugates ,CD70 antigen ,Lymphoma, Mantle-Cell ,Gastroenterology ,Benzodiazepines ,0302 clinical medicine ,hemic and lymphatic diseases ,Phase I Studies ,Grade 3b Follicular Lymphoma ,Pyrrolobenzodiazepine dimer (PBD) ,Pharmacology (medical) ,Tissue Distribution ,Aged, 80 and over ,Antibodies, Monoclonal ,Diffuse, large B cell, lymphoma (DLBCL) ,Middle Aged ,Prognosis ,Gene Expression Regulation, Neoplastic ,Mantle-cell lymphoma ,Oncology ,030220 oncology & carcinogenesis ,Female ,Lymphoma, Large B-Cell, Diffuse ,medicine.symptom ,Adult ,medicine.medical_specialty ,Lymphoma, B-Cell ,Maximum Tolerated Dose ,Anemia ,Nausea ,03 medical and health sciences ,Refractory ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Pyrroles ,Adverse effect ,Antibody-drug conjugate ,Aged ,Pharmacology ,Salvage Therapy ,business.industry ,medicine.disease ,Grade 3 follicular lymphoma ,Lymphoma ,030104 developmental biology ,Drug Resistance, Neoplasm ,Mantle cell lymphoma ,Neoplasm Recurrence, Local ,business ,Diffuse large B-cell lymphoma ,CD27 Ligand ,Follow-Up Studies - Abstract
Summary Purpose This first-in-human study evaluated SGN-CD70A, an antibody-drug conjugate (ADC) directed against the integral plasma membrane protein CD70 and linked to a pyrrolobenzodiazepine (PBD) dimer, in patients with relapsed or refractory (R/R) CD70-positive non-Hodgkin lymphoma (NHL) including diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and Grade 3b follicular lymphoma (FL3b). Methods SGN-CD70A was administered intravenously on Day 1 of 3-week cycles beginning at 8 mcg/kg with planned dose escalation to 200 mcg/kg. Due to observations of prolonged thrombocytopenia, the study was amended to dose every 6 weeks (q6wk). Results Twenty patients were enrolled and treated with SGN-CD70A. The maximum tolerated dose of SGN-CD70A was 30 mcg/kg q6wk. The most common adverse events (AEs) reported were thrombocytopenia (75%), nausea (55%), anemia (50%), and fatigue (50%). The onset for treatment-related thrombocytopenia typically occurred during Cycle 1. Most of the treatment-related events of thrombocytopenia were ≥ Grade 3. Antitumor activity in patients included 1 complete remission (CR) and 3 partial remissions (PRs), 2 of which were ongoing for at least 42.9 weeks. SGN-CD70A exposures were approximately dose proportional, with a mean terminal half-life of 3 to 5 days. Conclusions While modest single-agent activity was observed in heavily pretreated NHL patients, the applicability of SGN-CD70A is limited by the frequency and severity of thrombocytopenia, despite the long-term response with limited drug exposure. Electronic supplementary material The online version of this article (10.1007/s10637-018-0655-0) contains supplementary material, which is available to authorized users.
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- 2018
40. Pretargeted delivery of PI3K/mTOR small-molecule inhibitor-loaded nanoparticles for treatment of non-Hodgkin's lymphoma
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Andrew Z. Wang, Steven I. Park, and Kin Man Au
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medicine.medical_treatment ,Drug Compounding ,Targeted therapy ,Immunophenotyping ,03 medical and health sciences ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Antigen ,In vivo ,immune system diseases ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Tissue Distribution ,Health and Medicine ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Research Articles ,030304 developmental biology ,CD20 ,0303 health sciences ,Multidisciplinary ,biology ,Chemistry ,Lymphoma, Non-Hodgkin ,TOR Serine-Threonine Kinases ,Imidazoles ,SciAdv r-articles ,HLA-DR Antigens ,medicine.disease ,Antigens, CD20 ,Xenograft Model Antitumor Assays ,3. Good health ,Lymphoma ,Non-Hodgkin's lymphoma ,Disease Models, Animal ,Treatment Outcome ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Quinolines ,Nanoparticles ,Drug carrier ,Research Article - Abstract
Dual pretargeting with anti-CD20 and anti–HLA-DR allows effective therapeutic delivery of a BEZ235 nanoformulation to NHL cells., Overactivation of the PI3K/mTOR signaling has been identified in non-Hodgkin’s lymphoma. BEZ235 is an effective dual PI3K/mTOR inhibitor, but it was withdrawn from early-phase clinical trials owing to poor solubility and on-target/off-tumor toxicity. Here, we developed a nanoparticle (NP)–based pretargeted system for the therapeutic delivery of BEZ235 to CD20- and HLA-DR–expressing lymphoma cells for targeted therapy. The pretargeted system is composed of dibenzocyclooctyne-functionalized anti-CD20 and anti-Lym1 antibodies as the tumor-targeting components and azide-functionalized BEZ235-encapsulated NPs as the effector drug carrier. Using lymphoma cell lines with different CD20 and HLA-DR antigen densities as examples, we demonstrate that the dual antibody pretargeted strategy effectively raises the number of NPs retained on the target tumor cells and improves the in vitro and in vivo antitumor activity of BEZ235 through the inhibition of the PI3K/mTOR pathway. Our data demonstrate that the NP-based pretargeted system improves the therapeutic window of small-molecule kinase inhibitor.
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- 2019
41. Inhibition of Aurora A Kinase in Combination with Chemotherapy Induces Synthetic Lethality and Overcomes Chemoresistance in Myc-overexpressing Lymphoma
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Daniel P. Roth, Marissa L. Cann, Blossom Damania, Yuri Fedoriw, Michael B. Foote, Steven P. Angus, Trevor Parton, Steven I. Park, Carolina Lin, Gary L. Johnson, Natalie Ren, Aadra P. Bhatt, and Dirk P. Dittmer
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0301 basic medicine ,Cancer Research ,Cyclophosphamide ,medicine.medical_treatment ,Aurora A kinase ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Mice, Transgenic ,Synthetic lethality ,Article ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Propidium iodide ,Aurora Kinase A ,Chemotherapy ,business.industry ,Lymphoma, Non-Hodgkin ,Cell Cycle ,Drug Synergism ,Azepines ,Cell cycle ,medicine.disease ,Lymphoma ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Pyrimidines ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Heterografts ,Drug Therapy, Combination ,business ,medicine.drug - Abstract
BACKGROUND: Aberrant Myc expression plays a critical role in various tumors, including non-Hodgkin lymphoma (NHL). Myc-positive lymphoma is clinically aggressive, more resistant to chemotherapy, and associated with high mortality. OBJECTIVE: The current study aimed to show inhibition of aurora A kinase (AURKA) may overcome resistance to chemotherapy and improve outcomes in Myc-overexpressing lymphoma. METHODS: Myc-overexpressing lymphoma cell lines were evaluated by trypan blue, annexin V/propidium iodide staining, and western blotting for cytotoxicity, cell cycle, apoptosis, and Myc-associated protein expression, respectively, in the presence of cyclophosphamide with or without MLN8237, an AURKA inhibitor. Immunofluorescence for apoptosis-inducing factor (AIF) and acridine orange staining were used to analyze levels of autophagy. EμMyc genetically modified mouse model and xenograft models bearing Myc-overexpressing lymphoma cells were used to determine the efficacy of cyclophosphamide, MLN8237, or the combination in chemosensitive and chemoresistant tumors. RESULTS: In our in vitro experiments using chemoresistant lymphoma cells, MLN8237 and cyclophosphamide showed synergistic effects. Mice bearing lymphoma xenograft had rapid disease progression with median survival of ~ 35 days when treated with cyclophosphamide alone. In contrast, the combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, which led to improvement in survival compared to the single agent control (p=0.022). Kinome analysis of tumors treated with MLN8237 showed global suppression of various kinases. CONCLUSION: Our data demonstrate that AURKA inhibition induces synthetic lethality and overcomes chemoresistance in Myc-overexpressing lymphoma. The combination of MLN8237 and conventional chemotherapy showed promising safety and anti-tumor activities in preclinical models of Myc-positive NHL.
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- 2019
42. Deferred treatment is a safe and viable option for selected patients with mantle cell lymphoma
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Narendranath Epperla, Christopher R. Flowers, Alexey V. Danilov, Jonathon B. Cohen, Mehdi Hamadani, Timothy S. Fenske, Oscar Calzada, Jeffrey M. Switchenko, Stephanie P. Mathews, Natalie S Grover, Joseph Maly, Steven I. Park, Kristie A. Blum, and Max J. Gordon
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lymphoma, Mantle-Cell ,Severity of Illness Index ,Article ,Time-to-Treatment ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Prospective Studies ,Watchful Waiting ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Patient Selection ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Progression-Free Survival ,humanities ,Non-Hodgkin's lymphoma ,body regions ,Deferred treatment ,030220 oncology & carcinogenesis ,Cohort ,Disease Progression ,Female ,Mantle cell lymphoma ,business ,030215 immunology - Abstract
Prospective identification of candidates for deferred therapy is not standardized and many patients receive immediate therapy regardless of risk. We conducted a retrospective, multi-center cohort analysis of MCL patients with comprehensive clinical data to examine the use and safety of deferred therapy for newly diagnosed patients. Previously untreated patients ≥18 years-old with MCL diagnosed in 1993-2015 at five academic sites were included. Of 395 patients, 72 (18%) received deferred therapy (defined as receipt of first treatment90 days following initial diagnosis). Patients receiving deferred therapy were more likely to have an ECOG performance status of 0 (67 versus 44% p = .001), have no B symptoms (83 versus 65% p = .003) and have normal LDH levels at diagnosis (87 versus 55% p .001). In multivariable analysis, deferred therapy was not associated with a significant difference in OS (HR 0.64: 95% CI 0.22-1.84, p = .407).
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- 2018
43. Complex karyotype in patients with mantle cell lymphoma predicts inferior survival and poor response to intensive induction therapy
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Jonathon B. Cohen, Ashley D. Staton, Alexey V. Danilov, Natalie S Grover, Jeffrey M. Switchenko, Michael J. Lee, Stephanie P. Mathews, Timothy S. Fenske, Debra Saxe, Max J. Gordon, Christopher R. Flowers, Joseph Maly, Mehdi Hamadani, I. Brian Greenwell, Narendranath Epperla, Steven I. Park, and Kristie A. Blum
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Proliferative index ,business.industry ,medicine.medical_treatment ,Cytogenetics ,Cancer ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,International Prognostic Index ,030220 oncology & carcinogenesis ,Induction therapy ,Internal medicine ,Complex Karyotype ,medicine ,Mantle cell lymphoma ,business ,030215 immunology - Abstract
Background Risk stratification of newly diagnosed patients with mantle cell lymphoma (MCL) primarily is based on the MCL International Prognostic Index (MIPI) and Ki-67 proliferative index. Single-center studies have reported inferior outcomes in patients with a complex karyotype (CK), but this remains an area of controversy. Methods The authors retrospectively reviewed 483 patients from 5 academic centers in the United States and described the effect of a CK on survival outcomes in individuals with MCL. Results A CK was found to be associated with inferior overall survival (OS) (4.5 vs 11.6 years; P 30% (HR, 1.86; 95% CI, 1.06-3.28 [P = .03]) were associated with inferior PFS. Multivariable analysis did not identify any specific cytogenetic abnormalities associated with inferior survival. Conclusions CK appears to be independently associated with inferior outcomes in patients with MCL regardless of the intensity of induction therapy and receipt of ASCT. Cytogenetics should be incorporated into the workup of a new diagnosis of MCL and novel therapeutic approaches should be investigated for patients with CK. Cancer 2018;124:2306-15. © 2018 American Cancer Society.
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- 2018
44. Bespoke Pretargeted Nanoradioimmunotherapy for the Treatment of Non-Hodgkin Lymphoma
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Ashutosh Tripathy, Andrew Z. Wang, Seungpyo Hong, Steven I. Park, Kyle Wagner, Carolina Lin, and Kin Man Au
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0301 basic medicine ,Dendrimers ,Immunoconjugates ,General Physics and Astronomy ,Article ,Mice ,03 medical and health sciences ,Drug Delivery Systems ,0302 clinical medicine ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Tissue Distribution ,Yttrium Radioisotopes ,General Materials Science ,Pretargeted Radioimmunotherapy ,Pretargeting ,biology ,Effector ,business.industry ,Lymphoma, Non-Hodgkin ,Immunogenicity ,General Engineering ,Antibodies, Monoclonal ,Radioimmunotherapy ,Antigens, CD20 ,medicine.disease ,Lymphoma ,Clinical trial ,Nanomedicine ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Radiopharmaceuticals ,Antibody ,business ,Ligation - Abstract
Non-Hodgkin lymphoma (NHL) is one of the most common types of hematologic malignancies. Pretargeted radioimmunotherapy (PRIT), the sequential administration of a bispecific antibody-based primary tumor-targeting component followed by a radionucleotide-labeled treatment effector, has been developed to improve the treatment efficacy and to reduce the side effects of conventional RIT. Despite the preclinical success of PRIT, clinical trials revealed that the immunogenicity of the bispecific antibody as well as the presence of competing endogenous effector molecules often compromised the treatment. One strategy to improve PRIT is to utilize bio-orthogonal ligation reactions to minimize immunogenicity and improve targeting. Herein, we report a translatable pretargeted nanoradioimmunotherapy strategy for the treatment of NHL. This pretargeting system is composed of a dibenzylcyclooctyne (DBCO)-functionalized anti-CD20 antibody (α-CD20) tumor-targeting component and an azide- and yttrium-90-((90)Y) dual-functionalized dendrimer. The physicochemical properties of both pretargeting components have been extensively studied. We demonstrated that an optimized dual-functionalized dendrimer can undergo rapid strain-promoted azide–alkyne cycloaddition with the DBCO-functionalized α-CD20 at the physiological conditions. The treatment effector in our pretargeting system can not only selectively deliver radionucleotides to the target tumor cells but also increase the complement-dependent cytotoxicity of α-CD20 and thus enhance the antitumor effects, as justified by comprehensive in vitro and in vivo studies in mouse NHL xenograft and disseminated models.
- Published
- 2018
45. OUTCOMES FOR PATIENTS WITH MANTLE CELL LYMPHOMA EXPERIENCING FRONTLINE TREATMENT FAILURE: A MULTICENTER RETROSPECTIVE STUDY
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Michael C. Churnetski, Talha Badar, Nilanjan Ghosh, Jonathan Cohen, David A. Bond, Madelyn Burkart, Brian T. Hill, Jeffrey M. Switchenko, Timothy S. Fenske, Reem Karmali, Stephanie P. Mathews, Steven I. Park, Kristie A. Blum, Narendranath Epperla, Alexey V. Danilov, Edward Maldonado, Veronika Bachanova, Subir Goyal, Peter Martin, James N. Gerson, Y. Salwaha, Mary Malecek, Christopher R. Flowers, Jin Guo, Bhaskar Kolla, Krithika Shanmugasundaram, Mehdi Hamadani, Natalie S Grover, Brad S. Kahl, Stefan K. Barta, Kami J. Maddocks, Max J. Gordon, and Oscar Calzada
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Retrospective cohort study ,Hematology ,General Medicine ,medicine.disease ,Treatment failure ,Internal medicine ,medicine ,Mantle cell lymphoma ,business - Published
- 2019
46. MAINTENANCE RITUXIMAB IS ASSOCIATED WITH IMPROVED OVERALL SURVIVAL IN MANTLE CELL LYMPHOMA PATIENTS RESPONDING TO INDUCTION THERAPY WITH BENDAMUSTINE + RITUXIMAB (BR)
- Author
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Jonathon B. Cohen, Jeffrey M. Switchenko, Jin Guo, Reem Karmali, Yazeed Sawalha, Brad S. Kahl, Stefan K. Barta, Bhaskar Kolla, Nilanjan Ghosh, Alexey V. Danilov, Stephanie P. Mathews, Mehdi Hamadani, Natalie S Grover, Michael C. Churnetski, Kami J. Maddocks, Talha Badar, Oscar Calzada, Max J. Gordon, Steven I. Park, Brian T. Hill, Kristie A. Blum, James N. Gerson, Narendranath Epperla, Christopher R. Flowers, David A. Bond, Mary Malecek, Subir Goyal, Veronika Bachanova, Madelyn Burkart, Edward Maldonado, Peter Martin, Timothy S. Fenske, and Krithika Shanmugasundaram
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Hematology ,General Medicine ,Bendamustine/rituximab ,medicine.disease ,Induction therapy ,Internal medicine ,medicine ,Overall survival ,Mantle cell lymphoma ,Rituximab ,business ,medicine.drug - Published
- 2019
47. Aurora Kinase Inhibition Overcomes Primary Venetoclax Failure and Leads to Synthetic Lethality in BCL2-Positive Lymphomas Via Upregulation of P53/P21/BAX Axis
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David M. Foureau, Edward A. Copelan, Lawrence J. Druhan, Scott C Jaros, Sarah E Teague, Rajeswaran Mani, Donald L. Durden, Samon Benrashid, Nilanjan Ghosh, Hsih-Te Yang, Steven I. Park, Belinda R. Avalos, and Nury Steuerwald
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chemistry.chemical_compound ,Aurora kinase ,Downregulation and upregulation ,chemistry ,Venetoclax ,hemic and lymphatic diseases ,Immunology ,Cancer research ,Cell Biology ,Hematology ,Synthetic lethality ,Biochemistry - Abstract
Venetoclax (VEN), a BCL2 specific inhibitor, has shown excellent clinical activities in various types of non-Hodgkin lymphoma, and it is FDA-approved in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, its efficacy has been mostly disappointing in BCL2-positive (BCL2+) lymphomas harboring classic BCL2 rearrangements, including follicular lymphoma (FL), double-hit lymphoma (DHL), and triple-hit lymphoma (THL). The mechanism by which BCL2+ lymphomas evade BCL2 inhibition remains elusive although it has shown to be in part due to overexpression of anti-apoptotic proteins like BCLxL or MCL1. Aurora kinases (AURK) are serine threonine kinases involved in mitotic regulation and have functional role in stabilization of regulatory proteins such as MYC. Here in we investigated potential mechanisms of primary resistance to VEN and the effect of AURK inhibition in overcoming primary VEN failure in BCL2+ lymphomas. BCL2+ lymphoma cells, WSU-NHL (single hit; BCL2 only), DoHH2 (DHL; BCL2 and MYC), and VAL (THL; BCL2, MYC, and BCL6) were evaluated for cell viability (ATP quantification) and apoptosis (Annexin V/7AAD staining), after treatment with various concentrations of VEN with or without MLN8237 (AURK-A inhibitor), LY3295668 (AURK-A inhibitor), or AZD2811 (AURK-B inhibitor). Addition of an AURK-A or B inhibitor to VEN induced robust killing and displayed synergism only in BCL2+ but not in BCL2-negative Raji and Ramos Burkitt lymphoma cells (MYC only). AURK-A inhibition using MLN8237 was chosen for further in-depth functional analysis. Immunoblotting revealed increased caspase-3 cleavage in DoHH2 cells treated with VEN+MLN8237 combination than either agent alone. No significant changes in BCL2, BCLxL or MCL1 protein levels were noticed in DoHH2 and VAL cells after single or combined treatments. However, MLN8237 resulted in elevated levels of proapoptotic proteins BAX and PUMA. MYC degradation occurred later in cells after treatment with MLN8237 or combination implying that MYC degradation may be a delayed and independent effect. Furthermore, VEN+MLN8237 combination completely cleared tumors in two different BCL2+ lymphoma mouse models where mice were randomized into four groups and treated with vehicle, VEN, MLN8237, or VEN+MLN8237 combination via oral gavage for 15 days. First, in a DoHH2 DHL xenograft SCID mouse model, VEN+MLN8237 combination resulted in complete tumor regression and 100% tumor-free survival on day 100 (p < 0.0001; N=8/group) with no discernable toxicity, while all mice in other groups were euthanized due to disease progression within 45 days. Next, in a disseminated THL model using VAL cells intravenously infused into NCG mice, all animals receiving combination therapy survived with no evidence of disease on day 100 (p < 0.0001; N=6-8/group), while all except one in other groups were euthanized due to removal criteria, including hindlimb paralysis and weight loss, by day 60. To investigative the tumor response to BCL2 and AURK inhibitions, we performed transcriptome sequencing (RNA seq) of DoHH2 tumors harvested from SCID mice (N=6-7/group) treated for 3 days under the 4 conditions as described above. Comparison of VEN with VEN+MLN8237 combination identified 41 genes of which 33 increased and 8 decreased in combination therapy compared to VEN alone (Fold change >2 and FDR < 0.05). Most notably, CDKN1A (p21) level was decreased by 2-fold in VEN monotherapy compared to vehicle control while the concurrent inhibition of AURK-A by MLN8237 reversed this process by upregulating p21 by > 4-fold compared to VEN monotherapy. Ingenuity pathway analysis subsequently revealed that VEN+MLN8237 combination induced significant upregulation of p53/p21/BAX network. Additional assays confirmed an early characteristic downregulation of p53 protein levels in response to VEN treatment in BCL2+ lymphoma cells. The induction of p53, p21, PUMA, and BAX in VEN+MLN8237 combination was further confirmed by immunoblotting. In contrast, VEN reduced p21, PUMA and BAX expression levels compared to vehicle treated cells. p53 knockdown in DoHH2 cells resulted in similar resistance to VEN and combination treatment. Taken together these data suggest AURK inhibition overcomes downregulation of p53/p21/BAX axis by BCL2+ lymphomas in response to BCL2 inhibition, hence lay the groundwork for further evaluation of this combination in clinical settings. Figure 1 Figure 1. Disclosures Foureau: Cytognos: Honoraria; TeneoBio, Celgene: Research Funding. Ghosh: Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding. Copelan: Amgen: Consultancy. Durden: SignalRx Pharmaceuticals: Current holder of individual stocks in a privately-held company. Avalos: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMJ Best Practice: Patents & Royalties: Royalties from a co-authored article on evaluation of neutropenia. Park: Takeda: Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Morphosys: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding, Speakers Bureau; Gilead: Speakers Bureau; G1 Therapeutics: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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- 2021
48. Interim Analysis of the Randomized Phase 1b/3 Study Evaluating the Safety and Efficacy of Tazemetostat Plus Lenalidomide and Rituximab in Patients with Relapsed/Refractory Follicular Lymphoma
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Heather O'Connor, Jay Yang, John M. Pagel, Connie Lee Batlevi, Pamela McKay, Anthony Hamlett, Loretta J. Nastoupil, Jennifer E Amengual, Deyaa Adib, David Andorsky, Tycel Phillips, Franck Morschhauser, John P. Leonard, Philip Campbell, and Steven I. Park
- Subjects
Oncology ,medicine.medical_specialty ,Tazemetostat ,business.industry ,Immunology ,Follicular lymphoma ,Cell Biology ,Hematology ,Interim analysis ,medicine.disease ,Biochemistry ,Internal medicine ,Relapsed refractory ,medicine ,Rituximab ,In patient ,business ,medicine.drug ,Lenalidomide - Abstract
Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 inhibitor, showed antitumor activity as monotherapy in patients with wild-type and mutant EZH2 relapsed or refractory (R/R) follicular lymphoma (FL) who received ≥2 prior lines of therapy. In clinical studies in patients with R/R FL, lenalidomide and rituximab (R 2) demonstrated an objective response rate (ORR) of 73%-78% and median progression-free survival of 36-39 months. Preclinical data demonstrated synergistic activity of TAZ + lenalidomide, and clinical experience with TAZ + rituximab in diffuse large B-cell lymphoma supports the combination of TAZ + R 2 in patients with R/R FL. This global, multicenter phase 1b/3 study (NCT04224493) is designed to determine the recommended phase 3 dose (RP3D), efficacy, and safety of TAZ + R 2 in patients with R/R FL after ≥1 prior therapy. We report an interim analysis of the phase 1b safety run-in. Methods: The methods of this randomized, double-blind, 3-stage study were previously described (Leonard JP, et al. ASH 2020). Phase 1b evaluated TAZ at 3 dose levels (400, 600, and 800 mg orally twice daily [BID]) in 28-day cycles with standard-dose R 2 using a 3+3 design. The RP3D of TAZ will be selected at the dose level with a target dose-limiting toxicity (DLT; NCI CTCAE v5) rate of Results: As of February 26, 2021, 15 patients were enrolled and receiving treatment with TAZ + R 2 (400 mg [n=4], 600 mg [n=4], and 800 mg [n=6]). Data for the 15th patient enrolled at 800 mg BID were not available as of the cutoff date; thus, this patient is not included in the current safety analysis. The 14 patients included had a median age of 65.5 years (range, 51-83) and received a median of 2 prior therapies (range, 1-5). Median duration of treatment exposure was 16.9 weeks (range, 8-28); dose modifications for treatment-emergent adverse events (TEAEs) are shown in the Table. No DLTs were observed in phase 1b, and no new safety signals were identified as of the February 2021 data cutoff. A summary of TEAEs is provided in the Table. Serious TEAEs were observed in 3 (21.4%) patients. Grade 3/4 TEAEs were observed in 7 (50.0%) patients; the most common grade 3/4 TEAE (≥20%) was decreased neutrophil count (21.4%). Febrile neutropenia and severe cytopenias have not been reported to date. Treatment-related TEAEs (TR-TEAEs) of any grade were observed in 12 (85.7%) patients; grade 3/4 TR-TEAEs were observed in 5 (35.7%) patients. The TR-TEAEs were attributable to either study agent. Of the 12 patients evaluable for tumor assessment, 5 (41.7%) had a complete response, 6 (50.0%) had a partial response, and 1 (8.3%) had stable disease. The ORR was 91.7% (n=11). Conclusions: The TAZ + R 2 combination demonstrates a favorable safety profile that is consistent with the respective safety information for TAZ and for R 2. The high response rates reported from the preliminary efficacy analysis support a benefit with the combination of TAZ + R 2. The randomized phase 3 portion will further explore the efficacy and safety of TAZ + R 2 in ~500 patients with R/R FL. Figure 1 Figure 1. Disclosures Batlevi: Dava Oncology: Honoraria; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Medscape: Honoraria; TouchIME: Honoraria; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Park: Seattle Genetics: Research Funding, Speakers Bureau; Takeda: Research Funding; Gilead: Speakers Bureau; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Morphosys: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nastoupil: MorphoSys: Honoraria; Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Bayer: Honoraria; Takeda: Honoraria, Other: DSMC, Research Funding; Genentech: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; IGM Biosciences: Research Funding; Denovo Pharma: Other: DSMC; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Phillips: ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Amengual: Daiichi Sankyo, Inc: Consultancy; Epizyme, Inc.: Speakers Bureau; Seagen: Consultancy; Appia Pharmaceuticals: Research Funding. Andorsky: AbbVie: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding; AstraZeneca: Other: served on steering committees; AbbVie: Consultancy. Campbell: Novartis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; CSL Behring: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy, Research Funding; BMS/Celgene: Research Funding. McKay: Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pagel: Epizyme: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Yang: Epizyme, Inc.: Current Employment, Other: May own stock/options. O'Connor: Epizyme, Inc.: Current Employment, Other: May own stock/options . Hamlett: Epizyme: Current Employment. Adib: Epizyme, Inc.: Consultancy. Morschhauser: Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Chugai: Honoraria; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy. OffLabel Disclosure: Tazemetostat is not approved in combination with other therapies.
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- 2021
49. TAK-981, a First-in-Class SUMO-Activating Enzyme Inhibitor, Combined with Rituximab in Adult Patients (Pts) with CD20-Positive Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL): Phase 1 Data
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Alejandro Gomez-Pinillos, Alonzo Martinez, Allison Berger, Amitkumar Mehta, Deborah Berg, Stephane Doucet, Paolo Caimi, Tycel Phillips, Lapo Alinari, Brenda W. Cooper, Bo Chao, Christine K. Ward, Igor Proscurshim, John Gibbs, Sarit Assouline, Alexey V. Danilov, Sharon Friedlander, and Steven I. Park
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CD20 ,Adult patients ,biology ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Relapsed refractory ,Cancer research ,medicine ,biology.protein ,Hodgkin lymphoma ,Rituximab ,SUMO-activating enzyme ,business ,medicine.drug - Abstract
Background: TAK-981 is the first small-molecule inhibitor of SUMOylation to enter clinical trials. SUMOylation is a post-translational modification in which small ubiquitin-like modifier (SUMO) proteins are activated and covalently attached to substrate proteins. SUMOylation has a central role in constraining type I interferon (IFN-I)-dependent responses (Decque Nat Immunol 2016). By blocking SUMOylation, TAK-981 promotes IFN-I production and increases innate immunity. The ability of TAK-981 to promote activation of macrophages and NK cells and increase their cytotoxic/phagocytic activity provides a mechanistic rationale for its use in combination with monoclonal antibodies (mAbs) reliant on antibody-dependent cellular cytotoxicity and phagocytosis. Preclinical studies have demonstrated synergistic antitumor activity between TAK-981 and the anti-CD20 monoclonal antibody rituximab in xenograft models of human B cell lymphoma (Nakamura AACR 2019). Based on these data, and a single-agent TAK-981 study (TAK-981-1002), this phase 1b/2, open-label, dose-escalation and expansion study is investigating the safety and efficacy of TAK-981 plus rituximab in adults with CD20-positive R/R NHL (NCT04074330); here, we report data from the phase 1b dose-escalation part of the study. Methods: Eligible pts were aged ≥18 years with CD20-positive, R/R aggressive B-cell NHL (aNHL) or indolent NHL (iNHL). aNHL included diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and grade 3b follicular lymphoma (FL); iNHL included grade 1-3a FL and marginal zone lymphoma. aNHL pts had to have received prior R-CHOP or equivalent plus 1 additional line of therapy in the R/R setting; iNHL pts had to be refractory to rituximab or another anti-CD20 mAb, and to have received at least 1 prior therapy for R/R disease. TAK-981 IV was given at increasing doses (starting: 10 mg) on days 1 and 8 (QW) or days 1, 4, 8, and 11 (BIW) of 21-day cycles. Rituximab 375 mg/m 2 IV was given on days 1, 8, and 15 of cycle 1 and on day 1 thereafter. Dose escalation was based on adaptive Bayesian logistic regression modelling with overdose control based on the posterior probability of having a dose-limiting toxicity (DLT). Primary phase 1b objectives were safety, tolerability, and recommended phase 2 dose (RP2D) of TAK-981 in combination with rituximab; data cutoff was 28 June 2021. Results: 24 pts have been enrolled and treated: 19 QW (10-120 mg) and 5 BIW (90 mg); 4 are currently on treatment. Enrollment continues in the 90 mg BIW and 120 mg QW cohorts. Median age was 65 years (range 29-80); 67% were male. No DLTs have been reported to date. RP2D and schedule will be determined based on safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Treatment-emergent adverse events (TEAEs) are shown in the Table. Most common TEAEs (≥15%) were similar between the QW/BIW schedules with the exception of dizziness (2 pts at 10 mg, 2 at 40 mg, and 1 at 90 mg) and hypokalemia (1 pt at 40 mg, 2 at 90 mg, and 1 at 120 mg); all QW. TEAEs were consistent with induction of IFN signalling (transient flu-like symptoms: fever, chills, fatigue) and with those observed in the single-agent study (data on file); no further TAK-981- or immune-related TEAEs were observed. Grade ≥3 TEAEs related to TAK-981 were reported in 2 pts: grade 3 atrial fibrillation (ongoing cardiac history) and grade 4 neutropenia; both in the 40 mg QW cohort and transient. In this population of rituximab-refractory pts, there were 5 objective responses in 17 response-evaluable pts: 4 partial responses (2 at 10 mg, FL and DLBCL; 1 at 60 mg, DLBCL; 1 at 90 mg, primary mediastinal thymic large B-cell lymphoma) and 1 complete response (40 mg, MCL), all in the QW cohort. TAK-981 PK was linear and declined in a tri-phasic manner. TAK-981 exhibited PD activity in peripheral blood including target engagement, decreased SUMOylation, and increased IFN-regulated gene expression (Figure). Conclusion: The combination of TAK-981 and rituximab was well tolerated in pts across each dose level and schedule. TAK-981 PK showed minimal accumulation after repeat dosing and PD assays confirmed inhibition of SUMOylation and activation of IFN-I signalling. More importantly, the combination of TAK-981 and rituximab resulted in promising clinical activity (ORR 29%) in the R/R setting, supporting the continued development of this combination in pts with NHL. Figure 1 Figure 1. Disclosures Assouline: Johnson&Johnson: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Roche/Genentech: Research Funding; Eli Lilly: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Jewish General Hospital, Montreal, Quebec: Current Employment. Mehta: Affirmed; Kite/Gilead; Roche-Genetech; Celgene/BMS; Oncotartis; Innate Pharmaceuticals; Seattle Genetics; Incyte; Takeda; Fortyseven Inc/Gilead; TG Therapeutics; Merck; Juno Pharmaceuticals/Bristol Myers Squibb: Research Funding; Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy. Phillips: Bayer: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Danilov: Rigel Pharm: Honoraria; Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding. Doucet: Amgen: Consultancy; Novartis: Consultancy; Astra-Zeneca: Consultancy; BMS: Consultancy; Jannsen: Consultancy; Servier: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Gilead: Consultancy. Park: Morphosys: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Gilead: Speakers Bureau; Takeda: Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Seattle Genetics: Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees. Berg: Takeda: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Gomez-Pinillos: Takeda: Current Employment. Martinez: Takeda: Current Employment. Chao: Takeda: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Gibbs: Takeda: Current Employment. Friedlander: Takeda: Current Employment. Ward: Takeda: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Caimi: TG Therapeutics: Consultancy; Kite: Consultancy; ADC Therapeutics: Consultancy; Verastem: Consultancy; Amgen: Consultancy; XaTek Inc.: Patents & Royalties; Celgene: Speakers Bureau.
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- 2021
50. Very Few Interventions after Tumor Lysis Monitoring in Patients with Chronic Lymphocytic Leukemia Who Are Started on Venetoclax in the Real-World Setting- Suggests Less Intensive Monitoring Maybe Safe for Low-Risk Patients
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Ashley Matusz-Fisher, Nilanjan Ghosh, Tommy Chen, Amy Soni, James T. Symanowski, Danielle Boselli, Ryan Jacobs, Bei Hu, Derek Raghavan, Rupali Bose, Steven I. Park, Belinda R. Avalos, Edward A. Copelan, Tamara K. Moyo, and Gray Magee
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medicine.medical_specialty ,Venetoclax ,business.industry ,Chronic lymphocytic leukemia ,Immunology ,Psychological intervention ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,In patient ,business ,health care economics and organizations - Abstract
Background: Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies in adults. Venetoclax, an orally administered B-cell lymphoma 2 (BCL2) inhibitor, is a FDA approved therapy offering durable responses. Due to risk of tumor lysis syndrome (TLS) upon venetoclax initiation, a strict dose escalation schedule with frequent laboratory monitoring is recommended in the package insert (PI). Real world data reflecting adherence to this schedule and frequency of interventions resulting from intense monitoring are not described. Methods: Retrospective review of the Levine Cancer Institute database identified 73 consecutive patients with CLL who were initiated on venetoclax between July 2017 and March 2021. This included those initiated at the central academic site and regional academic-hybrid community sites. In the first two weeks of venetoclax, ramp up dosing and TLS labs (creatinine, potassium, calcium, phosphorous and uric acid) were evaluated for compliance consistent with the PI. Compliance required labs to be performed pre-dose, and at 6-8 hours and 24 hours after the initial 20 mg and 50 mg doses on weeks 1 and 2. The consequent interventions within these first 2 weeks, based on TLS labs, were then recorded. Patients who strictly adhered to all these laboratory checks at the various timepoints were considered compliant. Those who missed even a single lab or time point were considered non-compliant. Tumor lysis was measured by standard criteria using the Cairo-Bishop definition. The following Interventions were recorded: rasburicase administration, renal replacement therapy, ED visits, unplanned hospitalizations, ICU admissions, unplanned administration of IV fluids, the use of calcium supplementation, phosphate binders, treatment for hyperkalemia, dose reduction or holding of venetoclax. Baseline patient, disease, and treatment characteristics were summarized and described; rates of compliance were compared between tumor burden categories using Fisher's Exact test. Results : Baseline characteristics of the 73 identified patients were: 64% male, 79% white and 19% black, median age at venetoclax initiation was 67 (44 - 84). There were 49% of patients in the low tumor burden category, 44% in the medium tumor burden category and 6% in the high tumor burden category. Compliance with TLS labs during the first 2 weeks was 66% overall (n=48), with compliance between the tumor burden categories being 75% in high, 66% in medium and 67% in low (P>0.99). Interventions occurred in 6 (8%) of the patients, with all interventions occurring in the medium or high tumor burden group. These interventions included administration of IV fluids (n=2), calcium supplementation (n=1), phosphate binders (n=2) and holding of venetoclax (n=1). None of these 6 patients requiring an intervention had clinical or laboratory TLS. None of the 73 patients required rasburicase administration, renal replacement therapy, ED visits, unplanned hospitalizations, or ICU admissions during this 2 week ramp up period. Of the 6 patients requiring interventions, 4 patients had TLS labs performed by the PI versus 2 patients who did not. Clinical and laboratory TLS in the PI-compliant group was recorded. None of these patients had clinical TLS and 1 patient met the criteria for laboratory criteria TLS based on a 25% change from baseline in phosphorus and uric acid, however, labs remained in normal range. There were no deaths during the venetoclax ramp up. Conclusion: Compliance with the strict TLS lab monitoring during venetoclax initiation is not universal, likely due to real world patient and institutional barriers. The intervention rates during the first 2 weeks were low, with no patients in the low tumor burden category requiring an intervention. These results suggest that a less strict laboratory monitoring schedule may be safe in patients with low tumor burden CLL. If the safety is confirmed prospectively, it would make the venetoclax initiation less cumbersome and result in increased access to venetoclax for patients with low burden CLL. Disclosures Hu: Kite: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees; Cellectar: Membership on an entity's Board of Directors or advisory committees. Moyo: Seattle Genetics: Consultancy. Park: Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; G1 Therapeutics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Takeda: Research Funding. Copelan: Amgen: Consultancy. Avalos: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMJ Best Practice: Patents & Royalties: Royalties from a co-authored article on evaluation of neutropenia. Symanowski: Carsgen: Consultancy; Immatics: Consultancy, Other: DSMB Member; Eli Lilly: Consultancy, Other: DSMB Member. Jacobs: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; Verastem: Consultancy; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; MEI Pharma: Research Funding; TeneoBio: Research Funding; SecuraBio: Consultancy, Speakers Bureau; Genentech: Consultancy; Jannsen: Speakers Bureau. Ghosh: Genmab: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Epizyme: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Genentech: Research Funding.
- Published
- 2021
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