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1. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory mantle cell lymphoma (CITADEL-205): a phase 2 studyResearch in context

Author

Pier Luigi Zinzani, Marek Trněný, Vincent Ribrag, Vittorio Ruggero Zilioli, Jan Walewski, Jacob Haaber Christensen, Vincent Delwail, Guillermo Rodriguez, Parameswaran Venugopal, Morton Coleman, Caroline Dartigeas, Caterina Patti, Fabrizio Pane, Wojciech Jurczak, Michal Taszner, Shankara Paneesha, Fred Zheng, Douglas J. DeMarini, Wei Jiang, Aidan Gilmartin, and Amitkumar Mehta

Subjects
Mantle cell lymphoma, B-cell lymphoma, Non-Hodgkin lymphoma, PI3K inhibitor, Parsaclisib, Medicine (General), R5-920
Abstract

Summary: Background: Parsaclisib is a potent and highly selective PI3Kδ inhibitor that has shown clinical benefit in patients with relapsed/refractory (R/R) B-cell malignancies. In this phase 2 study (CITADEL-205; NCT03235544, EudraCT 2017-003148-19), the efficacy and safety of parsaclisib was evaluated in patients with R/R mantle cell lymphoma (MCL). Methods: Patients ≥18 years old with pathologically confirmed R/R MCL and prior treatment with 1–3 systemic therapies, with (cohort 1) or without (cohort 2) previous Bruton kinase inhibitor (BTKi) treatment, received oral parsaclisib 20 mg once-daily (QD) for 8 weeks, then either parsaclisib 20 mg once-weekly (weekly dosing group [WG]) or parsaclisib 2.5 mg QD (daily dosing group [DG]). The primary endpoint was objective response rate (ORR). Findings: At the primary analysis data cutoff on January 15, 2021, 53 patients in cohort 1 (BTKi-experienced) (WG, n = 12; DG: n = 41) and 108 patients in cohort 2 (BTKi-naive) (WG, n = 31; DG: n = 77) had received parsaclisib monotherapy. The BTKi-experienced cohort was closed after an interim analysis demonstrated limited clinical benefit. In the BTKi-naive cohort, the ORR (95% CI) for DG (dosing selected for further study) was 70.1% (58.6%–80.0%), with a complete response rate (95% CI) of 15.6% (8.3%–25.6%) and a median duration of response (95% CI) of 12.1 (9.0–not evaluable) months. Treatment-emergent adverse events (TEAEs) occurred among 90.7% (98/108) of all treated patients in the BTKi-naive cohort. Grade ≥3 TEAEs occurred among 62.0% (67/108) of patients, including diarrhoea (13.9%, 15/108) and neutropenia (8.3%, 9/108). Parsaclisib interruption, reduction, or discontinuation due to TEAEs occurred among 47.2% (51/108), 8.3% (9/108), and 25.0% (27/108) of patients, respectively. Fatal TEAEs were experienced by six patients and determined to be treatment-related in one patient. Interpretation: Parsaclisib, a potent, highly selective, PI3Kδ inhibitor demonstrated meaningful clinical benefits and a manageable safety profile (25.0% discontinuation rate, low incidences of individually reported grade ≥3 or serious adverse events) in R/R MCL patients with no prior BTKi therapy. Limited clinical benefit was observed with parsaclisib monotherapy in patients who had previously received BTKi treatment. Future development of PI3K inhibitors for NHL will require further investigation of dose optimisation to improve safety and long-term survival. Funding: Incyte Corporation.

Published
2023
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2. Premature Ventricular Contractions and Cardiomyopathy while on Ofatumumab for Treatment of Chronic Lymphocytic Leukaemia

Author

Oladipo Odeyinka, Mitchell Collins, Michael Sunnaa, Parameswaran Venugopal, and Tochukwu Okwuosa

Subjects
premature ventricular contraction, ofatumumab, chronic lymphocytic leukemia, Medicine
Abstract

Ofatumumab is a monoclonal antibody used in the treatment of recurrent and progressive chronic lymphocytic leukaemia (CLL) and was recently approved for the treatment of multiple sclerosis. We describe the case of a 68-year-old man who presented with complaints of irregular pulse readings while undergoing ofatumumab treatment for recurrent CLL. Electrocardiograms (ECGs) demonstrated premature ventricular contractions (PVCs) which eventually caused cardiomyopathy and failed to resolve despite ablative therapy. Ofatumumab-induced PVCs are confirmed in this case by the existence of documented PVCs on ECGs and the disappearance of these PVCs after the completion of ofatumumab treatment. To the best of our knowledge, there have been no previously reported cases of PVCs associated with ofatumumab in the literature.

Published
2022
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3. Prediction of doxorubicin cardiotoxicity by early detection of subclinical right ventricular dysfunction

Author

Maria Isabel Camara Planek, Ahmad Manshad, Kyaw Hein, Mohamad Hemu, Fatima Ballout, Rajiv Varandani, Parameswaran Venugopal, and Tochukwu Okwuosa

Subjects
RV strain, Doxorubicin, Cardiotoxicity, Diseases of the circulatory (Cardiovascular) system, RC666-701, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Doxorubicin remains one of the most common causes of cardiotoxicity in patients with lymphoma, leading to significant morbidity and mortality. Early decline in left ventricular (LV) ejection fraction predicts chemotherapy-induced cardiotoxicity and mortality, but limited data exist on doxorubicin-induced subclinical right ventricular (RV) dysfunction. We investigated dose-dependent subclinical doxorubicin-induced RV dysfunction in lymphoma patients. Methods Thirty-five patients with adult lymphoma treated with doxorubicin were studied. All patients had normal baseline LV ejection fraction (LVEF > 55%), and no known cardiopulmonary disease. We studied the dose-dependent effect of doxorubicin on RV strain by 2D speckle-tracking echocardiography (STE) using a vendor-independent software (TomTec). Images were analyzed offline by two independent observers blinded to the clinical characteristics of the study population. Baseline LVEF, RV fractional area change (RV FAC), RV free wall strain (RV FWS), and RV global longitudinal strain (RV GLS) were measured prior to chemotherapy initiation and compared with echo studies obtained at a 6-month follow-up interval. Patients served as their own controls. Comparisons between pre- and post-therapy were achieved using paired Student’s t-tests or Chi-Square test. Results The Interobserver Intraclass Correlation Coefficient for RV GLS, RV FAC and RV FWS, was 0.87, 0.81 and 0.79, respectively. The mean age was 51 ± 13 years, 40% women, 60% white. The mean cumulative doxorubicin dose was 239 ± 104 mg m− 2. There was there was significant decline in RV FAC (47.3 ± 4.4% vs. 43.7 ± 3.9%), RV FWS (− 24.9 ± 3.3 vs. -22.2 ± 2.9), and RV GLS (− 22.4 ± 4.1 vs. -20.6 ± 3.4) (all p

Published
2020
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5. Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study

Author

Adam S. Zayac, Andrew M. Evens, Alexey Danilov, Stephen D. Smith, Deepa Jagadeesh, Lori A. Leslie, Catherine Wei, Seo-Hyun Kim, Seema Naik, Suchitra Sundaram, Nishitha Reddy, Umar Farooq, Vaishalee P. Kenkre, Narendranath Epperla, Kristie A. Blum, Nadia Khan, Daulath Singh, Juan P. Alderuccio, Amandeep Godara, Maryam Sarraf Yazdy, Catherine Diefenbach, Emma Rabinovich, Gaurav Varma, Reem Karmali, Yusra Shao, Asaad Trabolsi, Madelyn Burkart, Peter Martin, Sarah Stettner, Ayushi Chauhan, Yun Kyong Choi, Allandria Straker-Edwards, Andreas Klein, Michael C. Churnetski, Kirsten M. Boughan, Stephanie Berg, Bradley M. Haverkos, Victor M. Orellana-Noia, Christopher D'Angelo, David A. Bond, Seth M. Maliske, Ryan Vaca, Gabriella Magarelli, Amy Sperling, Max J. Gordon, Kevin A. David, Malvi Savani, Paolo Caimi, Manali Kamdar, Matthew A Lunning, Neil Palmisiano, Parameswaran Venugopal, Craig A. Portell, Veronika Bachanova, Tycel Phillips, Izidore S. Lossos, and Adam J. Olszewski

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P

Published
2021
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6. Orbital Mucosa-Associated Lymphoid Tissue Lymphoma and Primary Cutaneous Classical Hodgkin Lymphoma: A Rare Case Report and Review of the Literature

Author

Nicole Yun, James Coggan, Ira Miller, and Parameswaran Venugopal

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

A 60-year-old woman was diagnosed with isolated mucosa-associated lymphoid tissue (MALT) lymphoma of the ocular adnexa and treated with two years of weekly rituximab for eight doses followed by rituximab maintenance. After nearly two years of maintenance therapy, she developed a tender, indurated mass on the left neck. Biopsy results were consistent with primary cutaneous classical Hodgkin lymphoma (PCCHL).

Published
2020
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8. Bone Marrow and Peripheral Blood AML Cells Are Highly Sensitive to CNDAC, the Active Form of Sapacitabine

Author

Sucheta Jagan, Laura A. Paganessi, Robin R. Frank, Parameswaran Venugopal, Melissa Larson, and Kent W. Christopherson

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated the in vitro efficacy of the active form of novel agent sapacitabine, CNDAC, compared to current chemotherapeutic drugs Ara-C and mitoxantrone using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from AML patients. Cell lines were exposed to compound for 3–6 days and primary cells for 4 days. The viability of primary cells was additionally evaluated 3, 7, and 31 days after removal of tested compound to determine the durability of the response. Our studies indicate that CNDAC and mitoxantrone have a greater impact on viability than ara-C in primary AML cells and AML cell lines. CNDAC is more effective at reducing viability and inducing apoptosis than ara-C at equivalent concentrations in the THP-1 cell line, which is defined as displaying resistance to ara-C. As sapacitabine has shown in vivo activity at clinically achievable doses, future studies are warranted to assess the potential for combining it with ara-C and/or mitoxantrone, with an emphasis on cells and patients insensitive to ara-C treatment.

Published
2012
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9. Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 <scp>U.S.</scp> cancer centers

Author

Kevin A. David, Suchitra Sundaram, Seo‐Hyun Kim, Ryan Vaca, Yong Lin, Samuel Singer, Mary‐Kate Malecek, Jordan Carter, Adam Zayac, Myung Sun Kim, Nishitha Reddy, Douglas Ney, Alma Habib, Christopher Strouse, Jerome Graber, Veronika Bachanova, Sidra Salman, Jean Alyxa Vendiola, Nasheed Hossain, Mazie Tsang, Ajay Major, David A. Bond, Prashasti Agrawal, Angel Mier‐Hicks, Pallawi Torka, Priya Rajakumar, Parameswaran Venugopal, Stephanie Berg, Michael Glantz, Samuel A. Goldlust, Matthew Folstad, Pallavi Kumar, Thomas A. Ollila, Johnny Cai, Stephen Spurgeon, Alex Sieg, Joseph Cleveland, Julie Chang, Narendranath Epperla, Reem Karmali, Seema Naik, Peter Martin, Sonali M. Smith, James Rubenstein, Brad Kahl, and Andrew M. Evens

Subjects
Hematology
Published
2023
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10. EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort

Author

Prashasti Agrawal, Kevin A. David, Zhengming Chen, Suchitra Sundaram, Seo-Hyun Kim, Ryan Vaca, Yong Lin, Samuel Singer, Mary-Kate Malecek, Jordan Carter, Adam Zayac, Myung Sun Kim, Nishitha Reddy, Douglas Ney, Alma Habib, Christopher Strouse, Jerome Graber, Veronika Bachanova, Sidra Salman, Jean A. Vendiola, Nasheed Hossain, Mazie Tsang, Ajay Major, Maher K. Gandhi, Colm Keane, David A. Bond, Matthew Folstad, Julie Chang, Angel Mier-Hicks, Pallawi Torka, Priya Rajakumar, Parameswaran Venugopal, Stephanie Berg, Michael Glantz, Samuel A. Goldlust, Rahul Matnani, Pallavi Kumar, Thomas A. Ollila, Johnny Cai, Stephen E. Spurgeon, Alex G. Sieg, Joseph Cleveland, Narendranath Epperla, Reem Karmali, Seema Naik, Sonali M. Smith, James L. Rubenstein, Brad S. Kahl, Amy Chadburn, Andrew M. Evens, and Peter Martin

Subjects
Cancer Research, Oncology, Hematology
Published
2023
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14. Prevention of Thromboembolic Events in Patients with COVID-19

Author

Parameswaran Venugopal, Elizabeth Behrens, Surbhi Warrior, Joshua Thomas, Sefer Gezer, and Shivi Jain

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Mortality rate, Incidence (epidemiology), Population, Hydroxychloroquine, medicine.disease, Thrombosis, chemistry.chemical_compound, Tocilizumab, chemistry, RC666-701, Internal medicine, medicine, Coagulopathy, Diseases of the circulatory (Cardiovascular) system, Dosing, business, education, Letter to the Editor, medicine.drug
Abstract

Background: COVID-19 has developed into a global pandemic with respiratory compromise and systemic coagulopathy causing significant morbidity and mortality. Methods: A retrospective analysis was performed on all COVID-19 patients hospitalized between March and June 2020. Findings: Of 1265 COVID-19 positive hospitalized patients identified, 138 (10.9%) had a thromboembolism. Mortality rate in COVID-19 patients with thrombosis was 31.9%, significantly higher than COVID-19 patients who did not have thrombosis 10% (p

Published
2021
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15. Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study

Author

Craig A. Portell, Seo-Hyun Kim, Catherine Wei, Neil Palmisiano, Catherine Diefenbach, Manali Kamdar, Madelyn Burkart, Nadia Khan, Seth M. Maliske, Izidore S. Lossos, Andreas K. Klein, Paolo Caimi, Narendranath Epperla, Amandeep Godara, Alexey V. Danilov, Victor M. Orellana-Noia, Max J. Gordon, Adam Zayac, Maryam Sarraf Yazdy, Allandria Straker-Edwards, Michael C. Churnetski, Ayushi Chauhan, Umar Farooq, Deepa Jagadeesh, Daulath Singh, Matthew A. Lunning, Suchitra Sundaram, Sarah Stettner, Kirsten M Boughan, Lori A. Leslie, Yusra F. Shao, Peter Martin, Amy Sperling, Stephen D. Smith, Reem Karmali, Bradley M. Haverkos, Parameswaran Venugopal, Veronika Bachanova, Tycel Phillips, Yun Kyong Choi, Malvi Savani, Seema Naik, Gaurav Varma, Vaishalee P. Kenkre, Gabriella Magarelli, Ryan Vaca, Asaad Trabolsi, Andrew M. Evens, Juan Pablo Alderuccio, Emma Rabinovich, Christopher D'Angelo, Nishitha Reddy, Adam J. Olszewski, Kristie A. Blum, Stephanie Berg, David A. Bond, and Kevin A. David

Subjects
Oncology, medicine.medical_specialty, business.industry, Incidence (epidemiology), Hazard ratio, Hematology, medicine.disease, Lower risk, Lymphoma, 03 medical and health sciences, Regimen, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Cumulative incidence, Young adult, business, 030215 immunology, Cohort study
Abstract

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P

Published
2021
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17. The Burkitt Lymphoma International Prognostic Index (BL-IPI)

Author

Andreas K. Klein, Deepa Jagadeesh, Tarec Christoffer El-Galaly, Umar Farooq, Catherine Zhu, Nicolas Martinex-Calle, Craig A. Portell, Xiao-Yin Zhang, Adam J. Olszewski, Manali Kamdar, Andrew M. Evens, Neil Palmisiano, Tycel Phillips, Nadia Khan, Chan Yoon Cheah, Stephen D. Smith, Catherine Diefenbach, Vaishalee P. Kenkre, Reem Karmali, Silvia Montoto, Izidore S. Lossos, Graham P. Collins, Lasse Hjort Jakobsen, Alexey V. Danilov, Adam Zayac, Alina S. Gerrie, Matthew A. Lunning, Narendranath Epperla, Parameswaran Venugopal, Knut B. Smeland, Scott E. Smith, Kirsten M Boughan, Maryam Sarraf Yazdy, Suchitra Sundaram, Peter Martin, Kevin A. David, Anna Santarsieri, Alessia Dalla Pria, Nishitha Reddy, Seema Naik, Veronika Bachanova, Kristie A. Blum, David Peace, Kate Cwynarski, Elizabeth H Phillips, Shireen Kassam, Mark Bower, Tatyana Feldman, and Fredrik Ellin

Subjects
Oncology, medicine.medical_specialty, International Prognostic Index, business.industry, Internal medicine, Immunology, medicine, Cell Biology, Hematology, medicine.disease, business, Biochemistry, Lymphoma
Abstract

Background. BL is a rare, high-grade B-cell lymphoma that is often studied in trials with small sample sizes. Historical definitions of "low-risk BL" vary between studies, use arbitrary cutoffs for lactate dehydrogenase (LDH), and identify a small favorable group, leaving >80-90% of patients (pts) in an undifferentiated "high-risk" category. A validated prognostic index will help compare study cohorts and better define good-prognosis pts for whom reduced treatment would be appropriate vs a poor-prognosis group in need of new approaches. Herein, we constructed and validated a simplified prognostic model for BL applicable to diverse clinical settings across the world. Methods. We derived the BL-IPI from a large real-world evidence cohort of US adults treated for BL in 2009-2018 (Evens A, Blood 2020). Progression-free survival (PFS) from diagnosis until BL recurrence, progression, death, or censoring was the primary outcome. We first determined the best prognostic cutoffs for age, LDH (normalized to local upper limit normal, ULN), hemoglobin (Hgb), and albumin. Independent risk factors were ascertained by forward stepwise selection into Cox regression from candidate variables: age, sex, HIV+ status, ECOG performance status (PS) ≥2, advanced stage (3/4), involvement of >1 extranodal site, bone marrow, central nervous system (CNS), values of LDH, Hgb, and albumin. Derivation models used multiple imputation to mitigate bias from missing data and reported hazard ratios (HR) with 95% confidence interval (CI). BL-IPI groups, defined by inspection of survival curves, were compared using log-rank test for trend. We validated performance of the BL-IPI in an external retrospective dataset of BL pts treated contemporaneously in centers from the United Kingdom, Scandinavia, Canada, and Australia. Results. Characteristics of pts in the derivation (N= 633) and validation (N=457) cohorts are shown in the Table. Age ≥40 years (yr), LDH >3xULN, Hgb 3xULN, low Hgb, and low albumin were associated with inferior PFS in univariate tests. In the multivariable model age ≥40 yr, LDH >3xULN, PS ≥2, and CNS involvement were selected as 4 independent prognostic factors; adding stage did not enhance the model. The model was simplified to 3 groups with 0 (low risk; 18% of pts), 1 (intermediate risk; 36% of pts; HR=3.14; 95%CI, 1.61-6.14), or 2-4 factors (high risk; 46% of pts; HR=6.52; 95%CI, 3.48-12.20; Fig A) with 3 yr PFS of 92%, 72%, and 53%, respectively (P Among pts with stage III/IV (historically classified as "high-risk" and constituting 78% of all pts in the cohort), the BL-IPI further discriminated subgroups with 3 yr PFS of 87%, 71%, and 52%, respectively (P In the international validation cohort, fewer pts had CNS involvement; most received CODOX-M/IVAC+R; and PFS/OS estimates at 3 yr were higher. BL-IPI categories were of similar size (low-risk 15%, intermediate-risk 35%, high-risk 50%), and provided similar risk discrimination (Harrell's C=.65 in both datasets). PFS at 3 yr was 96%, 82%, and 63%, respectively (P Conclusions. BL-IPI is a novel prognostic index specific to BL, which was validated to allow for simplified stratification and comparison of risk distribution in geographically diverse cohorts. The index identified a low-risk group with PFS >90-95%, which could be targeted with future strategies for treatment de-escalation. Conversely, only about 55-60% of pts in the high-risk group achieved cure with currently available immunochemotherapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Jakobsen:Takeda: Honoraria. Collins:ADC Therapeutics: Consultancy, Honoraria; Celleron: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Research Funding; BeiGene: Consultancy; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding. Cwynarski:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau. Bachanova:Incyte: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Danilov:Abbvie: Consultancy; BeiGene: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Gilead Sciences: Research Funding; Takeda Oncology: Research Funding; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Karyopharm: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Denovo: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Farooq:Kite, a Gilead Company: Honoraria. Feldman:Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Cell Medica: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding. Gerrie:AbbVie: Consultancy, Honoraria, Research Funding; Astrazeneca: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Sandoz: Consultancy. Jagadeesh:Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Kamdar:BMS: Consultancy; Abbvie: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Speakers Bureau. Karmali:Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Honoraria; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Khan:Seattle Genetics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Lossos:Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy, Other; Janssen Biotech: Honoraria; NCI: Research Funding; Janssen Scientific: Consultancy, Other. Lunning:ADC Therapeutics: Consultancy; Legend: Consultancy; Acrotech: Consultancy; AstraZeneca: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; TG Therapeutics: Research Funding; Novartis: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Curis: Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding. Martin:I-MAB: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy. Martinex-Calle:Abbvie: Other: Travel grant. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Phillips:Beigene: Honoraria; Roche: Research Funding. Phillips:Seattle Genetics: Consultancy; Incyte: Consultancy, Other: travel expenses; AstraZeneca: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy, Research Funding; Cardinal Health: Consultancy. Portell:Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; Bayer: Consultancy; Amgen: Consultancy; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Xencor: Research Funding; BeiGene: Consultancy, Research Funding. Reddy:Celgene: Consultancy; BMS: Consultancy, Research Funding; Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy. Yazdy:Abbvie: Consultancy; Genentech: Research Funding; Octapharma: Consultancy; Bayer: Honoraria. Smith:Bristol Meyers Squibb: Research Funding; Ayala: Research Funding; Seattle Genetics: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Karyopharm: Consultancy. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Evens:Research To Practice: Honoraria, Speakers Bureau; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Published
2020
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18. Venetoclax ramp-up with concurrent voriconazole in a patient with chronic lymphocytic leukemia

Author

Aaron Krapfl, Caleb McLeod, Rebecca Myers, Parameswaran Venugopal, and Amanda Seddon

Subjects
Male, Sulfonamides, Oncology, Humans, Pharmacology (medical), Antineoplastic Agents, Voriconazole, Middle Aged, Bridged Bicyclo Compounds, Heterocyclic, Leukemia, Lymphocytic, Chronic, B-Cell
Abstract

Introduction Chronic lymphocytic leukemia (CLL) is commonly treated with the B-cell lymphoma 2 inhibitor (BCL-2) venetoclax. Venetoclax is associated with an increased risk of tumor lysis syndrome in this patient population. Because venetoclax undergoes CYP3A4 metabolism, strong CYP3A4 inhibitors are contraindicated during the ramp-up phase of venetoclax in patients with CLL. Case report Our case report describes a 58 year old male initially diagnosed with CLL in 2013, whose first-line treatment consisted of ibrutinib. The patient developed a central nervous system (CNS) aspergillosis infection in 2018, and was initiated on voriconazole. He was subsequently under active surveillance until his disease progressed. The patient was started on venetoclax therapy, while on concomitant voriconazole, for management of his CLL. Management and outcome The patient's initial venetoclax dose was 10 mg daily, and he received rasburicase on day 1 of therapy. He tolerated a modified ramp-up phase without complication. After receiving 9 days of inpatient therapy, the patient was discharged on 50 mg of venetoclax to continue outpatient dose escalation. His dose was ultimately escalated to 100 mg daily. Discussion Although this report describes the safe administration of venetoclax with voriconazole, extreme caution should be exercised when administering venetoclax with any strong CYP3A4 inhibitor during the ramp-up phase in patients with CLL.

Published
2022

19. Real World (RW) Outcomes and Prognostication of Older Patients with Primary Central Nervous System Lymphoma (PCNSL) in the Contemporary Era

Author

Parameswaran Venugopal, Angel Mier-Hicks, Kevin A. David, Johnny Cai, Adam Zayac, Ajay Major, Samuel Singer, Narendranath Epperla, Michael Glantz, Joseph C. Cleveland, Seo-Hyun Kim, Andrew M. Evens, Mazie Tsang, Prashasti Agrawal, Mary-Kate Malecek, Reem Karmali, Ryan Vaca, Thomas A Ollila, Pallawi Torka, Alma Habib, Alex G Sieg, Yong Lin, Suchitra Sundaram, Veronika Bachanova, David A. Bond, Sonali M. Smith, Myung S. Kim, Priya Rajakumar, Stephen E. Spurgeon, Brad S. Kahl, Jerome J. Graber, Pallavi Kumar, Christopher Strouse, Nishitha Reddy, Seema Naik, Rahul Matnani, Peter Martin, Samuel Goldlust, Jordan Carter, and James L. Rubenstein

Subjects
Pediatrics, medicine.medical_specialty, Older patients, business.industry, Immunology, Primary central nervous system lymphoma, Medicine, Cell Biology, Hematology, business, medicine.disease, Biochemistry
Abstract

Introduction: Treatment of older patients (pts) with PCNSL is challenging due to the prevalence of comorbidities, frailty, and complexities with delivery of chemotherapy (CT). The optimal induction CT and consolidation regimens for older PCNSL pts is unknown. Moreover, there are few large scale prognostication studies available, including analysis of geriatric assessments (GA). We analyzed detailed characteristics, treatment patterns and outcomes with prognostication across 17 academic centers. Methods: We conducted a large, RW retrospective study of newly diagnosed PCNSL pts (1/2008-1/2019) ages ≥ 60 years (yrs). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. We detailed Cumulative Index Rating Scale-Geriatric (CIRS-G) scores & other GAs. Univariate associations were derived via Cox model with variables p Results: Among 491 initial cases, n=450 cases were verified for diagnosis & follow-up. Clinical features included: median age 71 yrs (60-88); male 47%; elevated LDH 30%; creatinine clearance 1 site). Cerebral involvement predominated in 75% with deep structure involvement in 20% & cerebellum in 5%. CSF involvement was documented in 13% of pts (unchecked in 26%). For GA at diagnosis, the median CIRS-G score was 6 (range 0-27) and impaired self-care activities of daily living (ADLs) were noted in 36%. Furthermore, geriatric syndrome (ie, dementia, delirium, depression, and/or falls) was present in 45% of pts. Induction therapy included CT in 91% of pts (of whom 82% had rituximab (Rtx)) and radiation therapy (RT) in 8%. The most common chemotherapy regimens were: high-dose methotrexate (HD MTX) or HD MTX with Rtx (MR) in 38%; HD MTX/procarbazine/vincristine (MPV) +/- Rtx 30%; HD MTX/temozolomide/Rtx (MTR) 22%; Rtx alone 2%; and HD MTX/cytarabine/thiotepa/Rtx (MATRIX) in 2%. Median MTX dosing for all pts was 3.5 g/m2 (range 1-8 g/m2), and by 3 most common regimens (all g/m2): MTR 5.1; MR 5.4; MPV 3.1 (P With 42 month median follow-up (1-125), 3-yr PFS & OS for all pts were 38% & 52%, respectively (Fig 1A/1B). On MVA, factors associated with inferior PFS were: advancing age (continuous HR 1.05, P Conclusions: Older pts with PCNSL have suboptimal outcomes, with 2/3 progressing in the first several years. GA is an important prognostic tool, and could be used to stratify pts in future investigations. In addition, use of Rtx, increasing MTX dose, and the MTR regimen were associated with improved outcomes. Disclosures Reddy: Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy; Celgene: Consultancy; BMS: Consultancy, Research Funding. Bachanova:Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:COTA: Other; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau; Boston Biomedical: Consultancy; Cortice Bio: Consultancy, Other: travel; WEX: Consultancy, Other: travel. Spurgeon:Beigene: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; VelosBio: Consultancy, Research Funding; Cardinal Health: Honoraria; Verastem: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Martin:Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Teneobio: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy. Smith:Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding. Rubenstein:Kymera: Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Evens:Merck: Consultancy, Honoraria, Research Funding; Research To Practice: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria.

Published
2020
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20. EBV-Positive Primary CNS Lymphomas in Older Patients: Incidence, Characteristics, Tumor Pathology, and Outcomes across a Large Multicenter Cohort

Author

Michael Glantz, Andrew M. Evens, Alex G Sieg, Kevin A. David, Christopher Strouse, Veronika Bachanova, Suchitra Sundaram, Sonali M. Smith, Samuel Goldlust, Jordan Carter, Johnny Cai, Adam Zayac, Pallavi Kumar, Prashasti Agrawal, Thomas A Ollila, James L. Rubenstein, Priya Rajakumar, Mazie Tsang, David A. Bond, Stephen E. Spurgeon, Peter Martin, Alma Habib, Myung S. Kim, Angel Mier-Hicks, Narendranath Epperla, Amy Chadburn, Ryan Vaca, Yong Lin, Samuel Singer, Joseph C. Cleveland, Seo-Hyun Kim, Parameswaran Venugopal, Pallawi Torka, Jerome J. Graber, Zhengming Chen, Mary-Kate Malecek, Reem Karmali, Ajay Major, Brad S. Kahl, Nishitha Reddy, Seema Naik, and Rahul Matnani

Subjects
Oncology, medicine.medical_specialty, business.industry, Incidence (epidemiology), Immunology, Cell Biology, Hematology, Tumor Pathology, Biochemistry, Older patients, hemic and lymphatic diseases, Internal medicine, Cohort, medicine, EBV Positive, business, health care economics and organizations, Cns lymphomas
Abstract

Background Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin lymphoma that is often associated with immunosuppressed states. The Epstein-Barr Virus (EBV) may play a role in tumor pathogenicity in some cases. The objective of this study was to examine the patient characteristics, tumor pathology, and survival outcomes associated with EBV tumor status in patients with PCNSL. Methods This was a retrospective subset analysis from 17 academic medical centers that included 439 patients of ages 60 years and above with PCNSL (David K et al. ASH 2020). The associations between EBV status and clinical or demographical variables were tested by Fisher's exact test, Wilcoxon rank-sum test, or CMH trend test. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test for statistical significance. Confidence interval of survival rate was calculated using Greenwood's formula. Results A total of 247 patients with available EBV status were included in this analysis. Median age was 71 (range 60-84) and 44.5% were male. Notably, none of the patients were HIV-positive. Twenty-five patients (10.1%) had EBV positive tumors as detected by EBER (EBV-encoded RNA) in-situ hybridization or LMP1 immunohistochemistry (IHC), 17 of which were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD) and 8 of which were not PTLD. All EBV-positive non-PTLDs were diffuse large B-cell lymphoma. Three (15%) SOT-related PTLDs were EBV-negative. Patient characteristics analyzed included age at diagnosis, sex, ECOG performance status, history of prior or concurrent malignancies, history of solid organ transplant or autoimmune disease, history of allogeneic stem cell transplant, and immunosuppressive treatment. Of these, only a history of solid organ transplant or autoimmune disease (P Tumor characteristics analyzed included expression of C-MYC, BCL2, CD5, cell of origin markers (BCL6, MUM1, CD10), and CD20 through IHC, C-MYC and BCL2 translocation through FISH, histology, and involvement of brain parenchyma, CSF, spinal cord, and eyes. EBV-positive tumors were associated with low C-MYC (p=0.047) and BCL6 (p=0.0006) expression on immunohistochemistry, but not other factors. There were no significant differences in tumor characteristics between those with EBV-positive PTLD and EBV-positive non-PTLD. Among patients with PTLD, 30% (n=6) did not receive primary chemotherapy, and the most common treatment regimens were high-dose methotrexate (HD-MTX) with or without rituximab (n=5) and rituximab alone (n=3). However, there was no significant difference in outcomes among PTLD patients who received chemotherapy or those who did not. Among EBV-positive non-PTLD patients, only 12.5% (n=1) did not receive primary chemotherapy and the most common treatment regimens were methotrexate/rituximab/temozolomide (n=3) and HD-MTX with or without rituximab (n=3). There was no difference in overall or progression free survival between patients with EBV-positive and EBV-negative tumors, or in outcomes among SOT-related PTLD patients regardless of EBV status. However, patients with EBV-positive non-PTLD PCNSL had better overall survival compared to patients with EBV-positive PTLD and EBV-negative tumors (p=0.033, Figure). Conclusions In this large observational study of older patients with PCNSL, the incidence of EBV positive tumors was overall low and was most commonly associated with SOT-related PTLD. Mycophenolate mofetil was the most common immunosuppressive medication. In those without PTLD, there were no patient or tumor factors that were associated with EBV status. Unexpectedly, non-PTLD EBV-positive PCNSL had superior outcomes to EBV-positive PTLD and EBV-negative PCNSL. Future studies of EBV-positive non-PTLDs are warranted to further evaluate the potential impact of EBV latency and the immune response on the tumor microenvironment. Disclosures Reddy: BMS: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; KITE Pharma: Consultancy. Bachanova:Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; WEX: Consultancy, Other: travel; Cortice Bio: Consultancy, Other: travel; Boston Biomedical: Consultancy; COTA: Other; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau. Spurgeon:Gilead: Research Funding; Genentech: Research Funding; Cardinal Health: Honoraria; Bristol-Myers Squibb: Research Funding; VelosBio: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy; Beigene: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BeiGene: Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Smith:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding. Rubenstein:Kymera: Research Funding. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy. Evens:Abbvie: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy.

Published
2020
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21. When Monoclonal Gammopathy is of Renal Significance: A Case Study of Crystalglobulinemia From Chicago Multiple Myeloma Rounds

Author

Luis David Sumoza, Brendan A. Gilmore, Tulio E. Rodriguez, David Cimbaluk, Parameswaran Venugopal, Agne Paner, Kevin Barton, Pritesh R. Patel, Michael R. Bishop, Patrick Hagen, Binod Dhakal, Parameswaran Hari, and Roger A. Rodby

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Biopsy, Paraproteinemias, Symptom assessment, Kidney Function Tests, Monoclonal Gammopathy of Undetermined Significance, Severity of Illness Index, Internal medicine, medicine, Humans, Multiple myeloma, business.industry, Disease Management, Hematology, medicine.disease, Combined Modality Therapy, Immunoglobulin A, Monoclonal gammopathy, Female, Kidney Diseases, Symptom Assessment, medicine.symptom, business, Biomarkers, Monoclonal gammopathy of undetermined significance
Published
2019
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22. Durable Response to Venetoclax Monotherapy in Richter’s Syndrome: A Case Report and Review of Literature

Author

Brett Mahon, Kelly Grant‐ Szymanski, Parameswaran Venugopal, and Revathi Kollipara

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Lymph node biopsy, Case Report, Aggressive lymphoma, Ofatumumab, Venetoclax, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Biopsy, medicine, medicine.diagnostic_test, business.industry, medicine.disease, Lymphoma, Richter transformation, 030104 developmental biology, B symptoms, chemistry, 030220 oncology & carcinogenesis, medicine.symptom, business
Abstract

In 2017, 20,110 people in the United States were diagnosed with chronic lymphocytic leukemia (CLL). Of these patients, 5-15% will ultimately undergo Richter’s syndrome (RS), a transformation to a more aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL) type. Particularly when the transformation is clonally related, prognosis is poor in these individuals with a median survival of only 5 - 14 months. This is an area of unmet need, and as such, the benefits of novel approaches with targeted therapies should be explored. Our patient is a 70-year-old female who was diagnosed with CLL in 2010. In 2016, she presented to her general practitioner with new B symptoms and leukocytosis. Cytogenetics on peripheral blood was notable for known trisomy 12 (52.8% of cells) and new 17p deletion (93.4% of cells). She received five cycles of ofatumumab with complete resolution of systemic symptoms but mixed response on interim computed tomography (CT) scan with ensuing rise in her white blood cell (WBC) and lactic acid dehydrogenase (LDH). A positron emission tomography (PET) scan had disproportionate uptake in the porta hepatis lymph nodes and subsequent lymph node biopsy confirmed transformation. She was started on R-CHOP chemotherapy but tolerated it very poorly. She was transitioned to venetoclax monotherapy in April 2017 and achieved a partial response by CT and bone marrow biopsy. This has been maintained over the last 12 months allowing the patient to travel and maintain a high quality of life. While the pathogenesis to RS is poorly understood, there have been several studies to identify tumor genetic changes predisposing to transformation. Of the proposed factors, a review of the literature consistently suggests p53 tumor suppressor gene mutation and/or 17p deletion to be associated with RS. Venetoclax is a selective BCL-2 inhibitor that is now approved for CLL patients with 17p deletion. This case serves as an example encouraging the use and study of novel agents such as venetoclax alone or in combination with traditional regimens or other novel agents to mitigate the poor prognosis of 17p deletion associated RS. Further research, however, is required to clarify the pathogenesis of RS and identify optimal treatment strategies.

Published
2019
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23. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS)

Author

Pau Montesinos, Farhad Ravandi, Martha Arellano, Karen Seiter, Ellin Berman, Jessica K. Altman, Lori J. Maness, Donald P. Quick, Parameswaran Venugopal, Judy H. Chiao, Scott R. Solomon, Rakesh Gaur, Mikkael A. Sekeres, Maria R. Baer, Marc Buyse, Aleksandra Butrym, David A. Rizzieri, Stephen A. Strickland, Stuart L. Goldberg, Tapan M. Kadia, Marc Gautier, David F. Claxton, Gary J. Schiller, Gianluca Gaidano, Kebede H. Begna, Selina M. Luger, Hagop M. Kantarjian, and Xavier Thomas

Subjects
Myeloid, Cancer Research, medicine.medical_specialty, Randomization, Clinical Trials and Supportive Activities, Oncology and Carcinogenesis, Phases of clinical research, Decitabine, sapacitabine, Acute, acute myeloid leukemia, Sapacitabine, Gastroenterology, Article, chemistry.chemical_compound, Cytosine, Rare Diseases, acute myeloid leukemia (AML), decitabine, hypomethylation, sapacitabine, therapy, Clinical Research, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Oncology & Carcinogenesis, Cancer, Aged, therapy, Leukemia, business.industry, Myelodysplastic syndromes, Induction chemotherapy, Evaluation of treatments and therapeutic interventions, Hematology, medicine.disease, humanities, Regimen, Leukemia, Myeloid, Acute, Treatment Outcome, Oncology, chemistry, Hypomethylating agent, 6.1 Pharmaceuticals, Public Health and Health Services, Azacitidine, Arabinonucleosides, business, medicine.drug, hypomethylation
Abstract

BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (

Published
2021

24. Impact of blood type on thrombosis and disease severity in adult COVID-19 patients

Author

Shivi Jain, Shivani Rao, Surbhi Warrior, Parameswaran Venugopal, Shengyuan Luo, and Sefer Gezer

Subjects
Blood type, Adult, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Letter to the Editors-in-Chief, COVID-19, Thrombosis, Hematology, medicine.disease, Viral infection, Severity of Illness Index, Disease severity, Immunology, Severity of illness, Medicine, Humans, business
Published
2021

25. Heparin Induced Thrombocytopenia in Patients with COVID-19

Author

Parameswaran Venugopal, Sefer Gezer, Shivi Jain, Surbhi Warrior, and Elizabeth Behrens

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, medicine.drug_class, 311.Disorders of Platelet Number or Function, medicine.medical_treatment, Immunology, Population, Low molecular weight heparin, Cell Biology, Hematology, medicine.disease, Biochemistry, Pre- and post-test probability, Heparin-induced thrombocytopenia, Internal medicine, medicine, Platelet activation, Renal replacement therapy, business, Prospective cohort study, education, Platelet factor 4
Abstract

Background The Coronavirus disease-2019 (COVID-19) is a global pandemic caused by novel coronavirus SARS-CoV-2. Acute respiratory and renal failure as well as systemic coagulopathy are critical aspects of the morbidity and mortality in patients with COVID-19. Heparin Induced Thrombocytopenia (HIT) occurs when IgG antibodies form against platelet factor 4-Heparin complex, resulting in platelet activation and removal, leading to a prothrombotic state. HIT is suspected when there is a platelet count decrease of more than 50% after exposure to heparin, along with hypercoagulability. Clinical Scoring systems like 4T Score (Thrombocytopenia, Timing, Thrombosis, no other cause of Thrombocytopenia) have been developed to assess the pretest probability of HIT. The use of unfractionated heparin, post-orthopedic and post-cardiac surgery state, female gender, and old age are recognized as risk factors for HIT. There is a nine-fold increased risk of developing HIT in patients requiring hemodialysis. ICU patients and patients with VTE without thrombocytopenia are considered to have low pre-test probability for HIT. Studies have shown that only 6% who are investigated serologically for HIT actually have the diagnosis. We conducted this study to assess the incidence and risk factors for HIT in COVID-19 positive patients and its impact on mortality. Methods A retrospective analysis was performed on all patients who were COVID-19 positive and hospitalized between March 1, 2020 and June 26, 2020 at our institution. Patients with intermediate or high suspicion for HIT, based on 4T score of 4 or higher, underwent IgG-specific platelet factor 4(PF4)-dependent enzyme immune assay (EIA). Washed platelet assays such as serotonin release assay (SRA) and heparin-induced platelet aggregation (HIPA) were used as confirmatory tests in cases with intermediate or low optical density (OD) with EIA. The incidence of HIT, its impact on mortality, and positivity of IgG-specific PF4-EIA in COVID-19 patients were studied, and statistical analysis was done with X2 testing. Subgroup analysis was performed based on demographic factors and risk factors for HIT, including exposure to heparin or low molecular weight heparin (LMWH), history of or cancer, recent orthopedic or cardiac surgery, exposure to renal replacement therapy (RRT), and severity of disease (D-dimer >6 ULN, Acute Kidney Injury, ICU admission, and mechanical ventilation requirement). These factors were analyzed by Fisher's exact test to determine their impact on mortality. The hospital course for HIT antibody-positive patients was further analyzed to study the impact of COVID-19 related therapy, such as Remdesivir, Tocilizumab, Hydroxychloroquine, Steroids, and anticoagulation after diagnosis of HIT. Results WEight out of 1265 hospitalized COVID-19 positive patients tested positive for IgG-specific platelet factor 4(PF4)-dependent enzyme immune assay (EIA+). Incidence of EIA+ in COVID-19 patients was 0.6%, which is significantly higher than in the general population 0.2% (p1, 1 was SRA positive) which is significantly higher than confirmation of HIT in nonCOVID-19 patients 6% (p Conclusion Our study indicates incidence of HIT is higher in the COVID-19 population. The incidence of positive EIA for patients with intermediate to high 4T scores is also higher in COVID-19 positive patients. This can be attributed to the cytokine storm and severe sepsis seen in critically ill COVID-19 patients. Our study also suggests that development of HIT can contribute to increased risk for thromboembolic events as well as mortality of COVID-19 patients, however, our study is limited due to small sample size. Therefore, prospective studies are needed to analyze the impact of HIT on morbidity, mortality and long-term outcomes in COVID-19 patients. Table Disclosures No relevant conflicts of interest to declare.

Published
2021
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26. HIV-associated Burkitt lymphoma: outcomes from a US-UK collaborative analysis

Author

Madelyn Burkart, Nishitha Reddy, Suchitra Sundaram, Victor M. Orellana-Noia, Adam Zayac, Andrew M. Evens, Andreas K. Klein, Alessia Dalla Pria, Catherine Diefenbach, Ayushi Chauhan, Kristie A. Blum, Umar Farooq, Frank A. Post, Stephanie Berg, Michael C. Churnetski, Graham P. Collins, Deepa Jagadeesh, Agrima Mian, Alexey V. Danilov, David A. Bond, Yun Kyong Choi, Seema Naik, Vaishalee P. Kenkre, Scott E. Smith, Kirsten M Boughan, Craig A. Portell, Yong Lin, Seth M. Maliske, Izidore S. Lossos, Tatyana Feldman, Andrzej Stadnik, Adam J. Olszewski, Stephen D. Smith, Amandeep Godara, Gaurav Varma, Shireen Kassam, Peter Martin, Christopher D'Angelo, Mark Bower, Albert Ren, Reem Karmali, Narendranath Epperla, Bradley M. Haverkos, Silvia Montoto, Parameswaran Venugopal, Manali Kamdar, Nadia Khan, Kate Cwynarski, Maryam Sarraf Yazdy, Juan Pablo Alderuccio, Catherine Zhu, Amy Sperling, Seo-Hyun Kim, Ryan Vaca, Emma Rabinovich, Daniel Rector, Allandria Straker-Edwards, Catherine Wei, and Paolo Caimi

Subjects
Oncology, medicine.medical_specialty, Vincristine, Cyclophosphamide, Clinical Trials and Observations, HIV Infections, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Median follow-up, Internal medicine, Medicine, Humans, Etoposide, Ifosfamide, business.industry, Hematology, medicine.disease, Burkitt Lymphoma, United Kingdom, United States, Lymphoma, 030220 oncology & carcinogenesis, Cytarabine, Neoplasm Recurrence, Local, business, Rituximab, Burkitt's lymphoma, 030215 immunology, medicine.drug
Abstract

Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.

Published
2021

27. Impact of Treatment and Anticoagulation on Thrombosis in COVID-19 Patients

Author

Surbhi Warrior, Elizabeth Behrens, Sefer Gezer, Priya Rajakumar, Shivi Jain, Joshua Thomas, and Parameswaran Venugopal

Subjects
medicine.medical_specialty, business.industry, Incidence (epidemiology), Mortality rate, Deep vein, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Thrombosis, Pulmonary embolism, chemistry.chemical_compound, Tocilizumab, medicine.anatomical_structure, chemistry, Internal medicine, medicine, Coagulopathy, 331.Pathophysiology of Thrombosis, business, Stroke
Abstract

Background The Coronavirus disease-2019 (COVID-19) is a global pandemic. Acute respiratory compromise and systemic coagulopathy cause significant morbidity and mortality. Venous thromboembolism (VTE), which encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as arterial thromboembolism (ATE), which includes stroke, are common sequelae described in this patient population. COVID-19 coagulopathy is attributed to severe inflammation and endothelial dysfunction resulting in a prothrombotic state. COVID-19 related treatment has focused on targeting the unregulated inflammatory state in an attempt to decrease incidence of COVID-19 related complications, such as thrombosis. Prophylactic anticoagulation is recommended, and many suggest intermediate to therapeutic anticoagulation in severe COVID-19. However, there is no clear data showing impact of anticoagulation on morbidity and mortality in patients with COVID-19. Methods A retrospective analysis was performed on all COVID-19 patients hospitalized between March 2020 and June 2020 at our institution. Patient charts were individually reviewed to ensure accuracy of data. Thromboembolic events (VTE or ATE) verified by imaging were included in the analysis. The impact of COVID-19 specific treatments such as Remdesivir, Tocilizumab, Hydroxychloroquine, and steroids on incidence of thrombosis was analyzed by using X2 testing. Using logistics regression, we analyzed the effect of prophylactic versus therapeutic anticoagulation received before development of thrombosis on mortality. Results Out of 1265 COVID-19 positive hospitalized patients during our time frame, 138 (10.9%) had thromboembolism. Incidence of 6.3% VTE, 5.6% DVT, 4.8% PE in COVID-19 patients was significantly higher than 0.24% VTE, 0.15% DVT, 0.12% PE in non COVID-19 hospitalized patients as reported by CDC (p Conclusion In Our study the incidence of thrombosis in hospitalized COVID-19 patients was significantly higher than non-COVID-19 hospitalized patients. COVID-19 patients with thrombosis had higher mortality compared to COVID-19 patient without thrombosis, particularly patients with PE. Hispanic patients with COVID-19 and thrombosis experienced a higher mortality rate compared to non-Hispanic patients. The lowest incidence of thrombosis occurred in COVID-19 patients who received steroids, followed by Tocilizumab suggesting that steroids and Tocilizumab may reduce the pro-inflammatory state leading to thrombosis. However, mortality rate was higher in patients who received COVID-19 related treatment, suggesting that these patients likely had severe disease. There was no mortality difference in patients who received prophylactic versus therapeutic anticoagulation prior to thrombosis. Randomized control trials will address the impact of anticoagulation dosing on morbidity and mortality in COVID-19 patients and study the post discharge prophylaxis and long-term outcomes in these patients. Disclosures No relevant conflicts of interest to declare.

Published
2021

28. Outcomes of COVID-19 Infection in Patients with Hematologic Malignancies

Author

Ankur Varma, Seo-Hyun Kim, Deborah A. Katz, Yoona Rhee, Alexander Yerkan, Elizabeth Behrens, Melissa C. Larson, Celalettin Ustun, Agne Paner, Irene Dehghan-Paz, Parameswaran Venugopal, Shivi Jain, Jamile M. Shammo, Anne Timmermann, and Sefer Gezer

Subjects
medicine.medical_specialty, education.field_of_study, business.industry, Mortality rate, Incidence (epidemiology), Immunology, Population, Subgroup analysis, Cell Biology, Hematology, Neutropenia, medicine.disease, Biochemistry, Intensive care unit, 901.Health Services Research-Non-Malignant Conditions, law.invention, law, Internal medicine, Cohort, Medicine, business, Prospective cohort study, education
Abstract

The coronavirus disease 2019 (COVID-19) outbreak, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic on March 11, 2020. This novel virus can cause a rapid progression from cough to acute respiratory distress syndrome and death. Cancer patients infected with COVID-19 were reported to have a 39% incidence of severe events, including admission to intensive care unit (ICU), mechanical ventilation, or death. Patients with hematologic malignancies, especially those undergoing treatment, are a particularly at-risk population due to disease-related impairment of the immune system and chemotherapy-induced neutropenia. The goal of this study is to analyze outcomes of COVID-19 infected patients with hematologic malignancies in order to better understand the impact of SARS-CoV-2 on this vulnerable population. Methods We performed a retrospective analysis on 26 COVID-19 positive patients with hematologic malignancies identified at our center. On July 22, 2020, there were 264 COVID-19 positive patients with hematologic malignancies (including our center's 26 patients) reported to the American Society of Hematology Research Collaborative COVID-19 Registry (ASH RC), a global public reference tool. We extracted our patient's data from each category reported to the ASH RC and compared hospitalization, ICU admissions, and mortality rates between our cohort and the remaining 238 cases. Chi-square test was used for analyses. We also performed a subgroup analysis comparing demographics; type and status of hematologic malignancy, as well as COVID-19 directed treatments between our center's patients and the patients reported to the ASH RC. Results Between March and June 2020, a total of 1265 COVID-19 positive patients were hospitalized at our institution. A significantly higher percentage of COVID-19 patients with hematologic malignancies were hospitalized at our institution compared to the ASH RC (61.5% versus 35.3%, P=. 009). There was no difference in ICU admission rate at our center compared to the ASH RC (23.1% versus 30.2%, P=.45). Significantly less COVID-19 directed therapies were administered at our center compared to the ASH RC (46.2% versus 66.4%, P=.041). Our patients received: 7.7% Remdesivir, 11.5% Tocilizumab, 15.4% hydroxychloroquine, 11.5% azithromycin, 0% convalescent plasma, compared to the ASH RC: 1.7% Remdesivir, 5.5% Tocilizumab, 30.3% hydroxychloroquine, 25.6% azithromycin, 4.6% convalescent plasma. Lastly, our institution had a significantly decreased mortality rate compared to the ASH RC (11.5% versus 29.8%, P=.049). Demographics as well as type and status of hematologic malignancy comparing the two cohorts are shown in Table 1. Conclusions In our comparative analysis, we found that our center's patients were hospitalized significantly more than the ASH RC cohort yet had lower mortality rates. These differences were seen despite similar distribution of malignancy types between the two groups. It should be noted that more patients in our cohort were in remission and none presented at initial cancer diagnosis at the time of infection, which may have contributed to better outcomes. The difference in mortality rates may also be attributed to variance in provider experience, higher percentage of patients >80 years of age reported to the ASH RC, and closer patient monitoring at our center due to a higher hospitalization rate. Differences in ICU admissions were not significant, suggesting a similar rate of severe COVID-19 infection between the two cohorts. Our demographics reflect the urban population we serve with more African Americans and Hispanics compared to the ASH RC. The greater number of COVID-19 directed therapies in the ASH RC cohort compared to ours is likely attributed to the use of convalescent plasma, which was not commonly used as COVID-19 directed treatment at our institution. Limitations of our study include a restricted time frame, small sample size, and the possibility of incomplete datasets within the ASH RC, as stated on the registry's website. In conclusion, we recommend close monitoring and a lower threshold for hospitalizing patients with hematologic malignancies in the setting of COVID-19 infection; however, additional prospective studies are needed to confirm our findings, and further investigate the complications and outcomes of SARS-CoV-2 on this at-risk population. Disclosures Ustun: Kadmon: Honoraria. Shammo:Celgene: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Onconova: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy; Regeneron: Consultancy; Novartis: Consultancy; Agios: Consultancy; Sanofi: Speakers Bureau; Abbive: Current equity holder in publicly-traded company; Baxter: Current equity holder in publicly-traded company; Takeda: Current equity holder in publicly-traded company; Alexion: Consultancy, Research Funding, Speakers Bureau.

Published
2021

29. Thrombosis and Mortality in Pregnant Patients with COVID-19

Author

Parameswaran Venugopal, Elizabeth Behrens, Surbhi Warrior, Xavier Pombar, Joshua Thomas, Sefer Gezer, and Shivi Jain

Subjects
2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Virology, Thrombosis, Medicine, 331.Pathophysiology of Thrombosis, business
Abstract

Background Coronavirus disease-2019 (COVID-19) has become a global pandemic causing respiratory compromise, coagulopathy and renal failure in severe cases. Studies demonstrate a high incidence of venous thromboembolism (VTE), up to 69% in patients with severe COVID-19 infection. Coagulopathy in COVID-19 patients is attributed to excessive inflammation and endotheliopathy. Pregnant patients have approximately a 4-fold increase of VTE incidence. This is in part due to an increase in clotting factors and fibrinogen and a decrease in fibrinolytic activity and protein S. Increased stasis and the presence of acquired and inherited thrombophilias can contribute to increased VTE incidence during pregnancy and postpartum period (PP). Risk factors for thrombosis in pregnancy include African American race, heart disease, diabetes, smoking, multiparity, age >35 years, and obesity. Pregnancy/PP state and COVID-19 infection independently increase the risk of VTE which raises concern for an even higher incidence of thromboembolic events in pregnant/PP patients with COVID-19. Data pertaining to hypercoagulability in COVID-19 infected pregnant patients is currently limited. We conducted this study to evaluate the incidence of thrombosis and mortality in pregnant/PP COVID-19 positive patients. Methods A retrospective analysis was performed on all COVID-19 positive hospitalized patients between March 2020-June 2020 at our institution. Pregnant and PP patients were extracted from this cohort and individually chart reviewed by clinicians. Data from the Centers for Disease Control and Prevention on COVID-19 positive pregnant women in the United States from January 22-July 7, 2020 was utilized for comparison analyses. Statistical analysis was performed with chi-square testing. The incidences of thrombosis and mortality were compared between hospitalized COVID-19 positive pregnant/PP patients and hospitalized adult COVID-19 positive women of childbearing age (18-51 years). A subgroup analysis was performed to evaluate risk factors for thrombosis such as demographics, trimester of pregnancy, and single/multiple gestation (Table 1). Anticoagulation and COVID-19 related therapies administered in this cohort were also studied. Results Forty-three pregnant/PP COVID-19 positive patients were identified out of 1265 hospitalized COVID-19 positive patients at our institution. Thrombosis (DVT, PE, or stroke) incidence in our cohort was 0%, which was not significantly different compared to 6.12% incidence of thrombosis in hospitalized COVID-19 positive women of childbearing age (P = .097). The mortality rate of COVID-19 positive pregnant/PP patients was 0%, which was not significantly different compared to the mortality rate of 3.06% in hospitalized COVID-19 women of childbearing age (P = .25). Further, VTE incidence of 0% in hospitalized COVID-19 positive pregnant/PP patients was not significantly different from the 0.1% incidence of VTE in the non COVID-19 pregnant population in the United States (P=.84). Lastly, the 0% mortality rate in COVID-19 positive pregnant/PP patients at our institution was no different than the 0.0169% mortality rate of pregnant women without COVID-19 infections in the United States (P = .93). Conclusion Our study demonstrates no significant difference in incidence of thrombosis and mortality rate between hospitalized COVID-19 positive pregnant/PP patients and hospitalized COVID-19 positive women of childbearing age. There was also no difference in VTE incidence between hospitalized COVID-19 positive pregnant/PP patients and non COVID-19 pregnant women in the United States. The lack of significant difference in both thrombosis incidence and mortality rate in patients who are both COVID-19 positive and pregnant/PP is reassuring and may imply that pregnancy might play a role in decreasing the inflammatory response of COVID-19. During certain phases of pregnancy a high number of macrophages, natural killer cells, and T regulator cells in the decidua have been identified, which could indicate an overall increased systemic immune response, potentially decreasing the dysregulation of the cytokine storm seen in critically ill COVID-19 patients. However, the systemic immunologic changes in pregnancy and the postpartum period remain largely unknown and prospective studies are needed to further investigate the effects of COVID-19 on pregnant patients. Disclosures No relevant conflicts of interest to declare.

Published
2021

30. Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers

Author

Allandria Straker-Edwards, Catherine Wei, Paolo Caimi, Andreas K. Klein, Michael C. Churnetski, Suchitra Sundaram, Deepa Jagadeesh, Andrew M. Evens, Neil Palmisiano, Catherine Diefenbach, Matthew A. Lunning, Kevin A. David, Agrima Mian, Adam J. Olszewski, Parameswaran Venugopal, Manali Kamdar, Nadia Khan, Albert Ren, Veronika Bachanova, Umar Farooq, Vaishalee P. Kenkre, Craig A. Portell, Nishitha Reddy, Tatyana Feldman, Victor M. Orellana-Noia, Alexey V. Danilov, Gaurav Varma, Jeremy Ramdial, Seema Naik, Yun Kyong Choi, Ayushi Chauhan, Tycel Phillips, Kristie A. Blum, Madelyn Burkart, Andrzej Stadnik, Reem Karmali, Stephen D. Smith, Ryan Vaca, Christopher D'Angelo, Daniel Rector, Brad M. Haverkos, Narendranath Epperla, Amy Sperling, Juan Pablo Alderuccio, Yong Lin, Seth M. Maliske, Stephanie Berg, Izidore S. Lossos, Malvi Savani, Seo-Hyun Kim, Maryam Sarraf Yazdy, Amandeep Godara, David A. Bond, Peter Martin, Adam Zayac, Scott E. Smith, Emma Rabinovich, and Kirsten M Boughan

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Immunology, Perforation (oil well), Kaplan-Meier Estimate, Biochemistry, Gastroenterology, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Progression-free survival, Aged, Gene Rearrangement, Performance status, L-Lactate Dehydrogenase, business.industry, Proportional hazards model, Cancer, Cell Biology, Hematology, Middle Aged, medicine.disease, Prognosis, Burkitt Lymphoma, Progression-Free Survival, United States, Lymphoma, 030104 developmental biology, Treatment Outcome, Respiratory failure, Rituximab, Female, business, 030215 immunology, medicine.drug
Abstract

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

Published
2020

31. Significance of isolated deletion (20q) in donor cells after allogeneic hematopoietic cell transplantation

Author

Jamile M. Shammo, Sunita Nathan, Celalettin Ustun, Mohammad Junaid Hussain, Sushma Bharadwaj, Parameswaran Venugopal, Laura Kalas, Ira Miller, Deborah A. Katz, Wei-Tong Hsu, and Kristy Luke

Subjects
Cancer Research, Hematopoietic cell, business.industry, Hematopoietic Stem Cell Transplantation, De novo Myelodysplastic Syndrome, Graft vs Host Disease, Hematology, Long arm, Transplantation, 03 medical and health sciences, 0302 clinical medicine, Oncology, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, Chromosomal Abnormality, Cancer research, Medicine, Humans, Transplantation, Homologous, Chromosome 20, business, 030215 immunology
Abstract

Deletion of the long arm of chromosome 20 [del(20q)] is a well-described chromosomal abnormality in de novo myelodysplastic syndrome (MDS); however, findings of isolated del(20q) is not considered ...

Published
2020

32. Phase 1 study of the protein deubiquitinase inhibitor VLX1570 in patients with relapsed and/or refractory multiple myeloma

Author

Jesus G. Berdeja, Joachim Gullbo, Agne Paner, Paul G. Richardson, Eric K. Rowinsky, Ola Landgren, Angelica Loskog, Kimmo Porkka, Claudia E. Paba-Prada, Parameswaran Venugopal, Stig Linder, HUS Comprehensive Cancer Center, Department of Medicine, University of Helsinki, and Hematologian yksikkö

Subjects
0301 basic medicine, Male, UCHL5, Pulmonary toxicity, Protein deubiquitinase inhibitor, Pharmacology, Pharmaceutical Sciences, 0302 clinical medicine, Recurrence, Multiple myeloma, Phase I Studies, Pharmacology (medical), Pharmaceutical sciences, Infusions, Intravenous, PROTEASOME, Deubiquitinating Enzymes, Bortezomib, Azepines, Middle Aged, 3. Good health, APOPTOSIS, Oncology, Tolerability, 030220 oncology & carcinogenesis, Toxicity, Female, VLX1570, 19S proteasome, Respiratory Insufficiency, medicine.drug, 3122 Cancers, Antineoplastic Agents, Benzylidene Compounds, 03 medical and health sciences, Pharmacokinetics, medicine, Humans, Aged, business.industry, medicine.disease, Farmaceutiska vetenskaper, USP14, 030104 developmental biology, Proteasome, Drug Resistance, Neoplasm, business
Abstract

This phase 1 study sought to characterize the safety, tolerability, and pharmacokinetic behavior of VLX1570, a small molecule inhibitor of the deubiquitinases (DUBs) that remove sterically bulky ubiquitin chains from proteins during processing in the19S regulatory subunit of the proteasome, in patients with relapsed and refractory multiple myeloma (MM). Fourteen patients were treated with escalating doses of VLX1570 ranging from 0.05 to 1.2 mg/kg as a brief intravenous (IV) infusion on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Due to its poor aqueous solubility, VLX1570 was formulated in polyethylene glycol, polyoxyethylated castor oil, and polysorbate 80 and administered as a brief intravenous (IV) infusion via a central venous catheter. Anti-myeloma effects were noted at doses at or above 0.6 mg/kg, however, two patients treated at the 1.2 mg/kg dose level experienced severe, abrupt, and progressive respiratory insufficiency, which was associated with diffuse pulmonary infiltrates on imaging studies, similar to those rarely noted with bortezomib and other inhibitors of the 20S proteasome, culminating in death. Although the contribution of VLX1570s formulation to the pulmonary toxicity could not be ruled out, the severity and precipitous nature of the toxicity and the steep relationship between dose and toxicity, the study was discontinued. Despite the severe pulmonary toxicity noted with VLX1570, efforts directed at identifying DUB inhibitors with greater therapeutic indices appear warranted based on the unique mechanism of action, robustness of preclinical antitumor activity, and activity of the DUB inhibitors in MM resistant to PIs targeting the 20S proteasome subunit. Funding Agencies|Uppsala University; Vivolux, AB

Published
2020

33. Orbital Mucosa-Associated Lymphoid Tissue Lymphoma and Primary Cutaneous Classical Hodgkin Lymphoma: A Rare Case Report and Review of the Literature

Author

Ira Miller, James Coggan, Nicole K. Yun, and Parameswaran Venugopal

Subjects
Pathology, medicine.medical_specialty, Mucosa-Associated Lymphoid Tissue Lymphoma, Case Report, 03 medical and health sciences, 0302 clinical medicine, Maintenance therapy, immune system diseases, hemic and lymphatic diseases, Biopsy, Rare case, medicine, Classical Hodgkin lymphoma, Diseases of the blood and blood-forming organs, medicine.diagnostic_test, business.industry, General Medicine, medicine.disease, Lymphoma, Lymphatic system, 030220 oncology & carcinogenesis, Rituximab, RC633-647.5, business, 030215 immunology, medicine.drug
Abstract

A 60-year-old woman was diagnosed with isolated mucosa-associated lymphoid tissue (MALT) lymphoma of the ocular adnexa and treated with two years of weekly rituximab for eight doses followed by rituximab maintenance. After nearly two years of maintenance therapy, she developed a tender, indurated mass on the left neck. Biopsy results were consistent with primary cutaneous classical Hodgkin lymphoma (PCCHL).

Published
2020

34. Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells

Author

Leo I. Gordon, Vineela Chukkapalli, Parameswaran Venugopal, Jeffrey A. Borgia, and Reem Karmali

Subjects
0301 basic medicine, CDK9 inhibitor, Venetoclax, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cyclin-dependent kinase, hemic and lymphatic diseases, medicine, Protein kinase A, biology, Kinase, double hit lymphoma, Bcl-2 inhibitor, Metformin, 030104 developmental biology, Oncology, chemistry, P110δ, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Cancer research, metformin, Idelalisib, Research Paper, medicine.drug
Abstract

Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines. We demonstrated that metformin as a single agent, especially at high concentrations produced significant reductions in viability and proliferation only in Daudi and SUDHL-4 cell lines with associated alterations in mitochondrial oxidative and glycolytic metabolism. As bcl-2 proteins, cyclin dependent kinases (CDK) and phosphoinositol-3- kinase (PI3K) also influence mitochondrial physiology and metabolism with clear relevance to the pathogenesis of lymphoma, we investigated the potentiating effects of metformin when combined with novel agents Venetoclax (bcl-2 inhibitor), BAY-1143572 (CDK9 inhibitor) and Idelalisib (p110δ- PI3K inhibitor). Co-treating KPUM-UH1 and SUDHL-4 cells with 10 mM of metformin resulted in 1.4 fold and 8.8 fold decreases, respectively, in IC-50 values of Venetoclax. By contrast, 3-fold and 10 fold reduction in IC-50 values of BAY-1143572 in Daudi and Jeko-1 cells respectively was seen in the presence of 10 mM of metformin. No change in IC-50 value for Idelalisib was observed across cell lines. These data suggest that although metformin is not a potent single agent, targeting cancer metabolism with similar but more effective drugs in novel combination with either bcl-2 or CDK9 inhibitors warrants further exploration.

Published
2018
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35. Olaparib-Induced Severe Folate Deficiency in a Patient With Advanced Ovarian Cancer

Author

Parameswaran Venugopal, Lydia Usha, Jamile M. Shammo, Timothy M. Kuzel, Elizabeth Elliott, Kristin Richardson, Melody A. Cobleigh, and Summer B. Dewdney

Subjects
Ovarian Neoplasms, Oncology, Advanced ovarian cancer, medicine.medical_specialty, Oncology (nursing), business.industry, Health Policy, MEDLINE, Antineoplastic Agents, Folic Acid Deficiency, Middle Aged, Piperazines, Olaparib, chemistry.chemical_compound, Folic Acid, chemistry, Internal medicine, medicine, Humans, Phthalazines, Female, business
Published
2019
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36. Impact of Crizanlizumab on Acute Medical Care Utilization in the Height of the COVID-19 Pandemic

Author

Jerome J Martin, Shivi Jain, Sean O'Mahony, Katherine Barnett, Peter Wu, Sefer Gezer, Parameswaran Venugopal, Teresa O'Brien, Ramandeep Kaur, Christopher Bruti, Nicole K. Yun, Celine Goetz, James Coggan, and Shivani Rao

Subjects
Coronavirus disease 2019 (COVID-19), business.industry, Immunology, Pandemic, medicine, 114.Hemoglobinopathies, Excluding Thalassemia: Clinical and Epidemiological, Cell Biology, Hematology, Medical emergency, medicine.disease, business, Biochemistry, Medical care
Abstract

Background Sickle cell disease (SCD) is a hemoglobinopathy which manifests clinically as hemolytic anemia and recurrent episodes of pain caused by vaso-occlusion, among other symptoms. Vaso-occlusive crises (VOCs) account for an overwhelming majority of visits to the emergency room (ER) and hospitalizations for patients with SCD (Shah et al. PLoS One 2019). Upregulation of P-selectin, a cellular adhesion protein expressed on activated platelets and endothelial cells, contributes to the pathophysiology of VOCs. Crizanlizumab is a monoclonal antibody administered intravenously that inhibits the interaction of P-selectin with its ligand; it was approved by the Food and Drug Administration (FDA) as a treatment for SCD patients in 2019. In the Phase II SUSTAIN trial, crizanlizumab therapy resulted in a significantly lower rate of sickle cell-related pain crises than placebo (Ataga et al. N Engl J Med 2017). Due to their high-risk status for COVID-19, the pandemic has posed significant challenges for SCD patients to readily access healthcare, including novel therapies such as crizanlizumab. This study aimed to investigate the utility of telemedicine in facilitating access to crizanlizumab as well as compare acute medical care utilization for patients on crizanlizumab six months before initiating therapy and up to six months after their final dose in 2020. Methods All patients (≥18 years of age as of January 1, 2020) with SCD who received crizanlizumab between January 1, 2020 and December 31, 2020 at Rush University Medical Center (RUMC) were included in the final analysis. Demographic features as well as the type of visit when the patient and healthcare provider discussed crizanlizumab treatment was documented. Paired t-tests and Wilcoxon matched-pairs signed rank tests were utilized to compare acute medical care utilization - defined by the number of ER visits, urgent care visits, and hospitalizations - six months prior to initiating therapy and six months after completing the specified therapy regimen for 2020. Simple linear regression models and multiple regression models were conducted to control for sex, BMI, age, insurance, duration of treatment, and type of visit. Results A total of ten patients were included in the final analysis. Five (50%) patients first agreed to proceed with crizanlizumab therapy during a telehealth video visit with their provider, one (10%) made the decision during a telehealth phone visit, and the other four (40%) did so during a traditional office visit. 9 (90%) patients were still on crizanlizumab after June 1, 2020, the date that RUMC urgent care started seeing patients with SCD. The mean number of visits to the ER in the period before initiating therapy was 2.8 (SD=4.26) compared to 2.5 (SD=2.76) after last dose in 2020, however this finding did not achieve statistical significance (p>0.9999). Visits to the urgent care clinic, on average, increased significantly from 1.7 (SD=2.87) in the six months before initiating therapy to 8.2 (SD=11.02) in the six months after ending therapy for 2020 (p=0.0234). The mean number of hospitalizations in the period before initiating therapy was 6.6 (SD=5.19) compared to 4.6 (SD=3.44) in the period after last dose in 2020, however this was also not statistically significant (p=0.2309). None of the covariates had a significant effect on differences in acute care utilization in the period before and after therapy in 2020. Conclusion This study suggests that administration of crizanlizumab therapy did reduce hospitalization and ED visits, but the results could not achieve statistical significance due to our small sample size and short study duration. The number of urgent care visits for these patients, however, did differ significantly from the period before initiating therapy to the six months after the last dose in 2020. This finding can be attributed to the fact that due to the COVID-19 pandemic, urgent care services were made increasingly available to SCD patients beginning on June 1, 2020 to avoid admissions to the ER and hospital. Additionally, our study suggests that during the COVID-19 pandemic, telemedicine played an important role in providing health services to patients with SCD, and it could continue to improve care accessibility for SCD patients after the pandemic. Continued collection and analysis of real-world data is needed to further understand the effect of crizanlizumab therapy on utilization of acute medical care. Figure 1 Figure 1. Disclosures Jain: DOVA: Other: advisory board; Sanofi: Other: advisory board; Argenx: Other: advisory board; Novartis: Speakers Bureau; GBT: Speakers Bureau.

Published
2021

37. Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor: Primary Analysis from a Phase 2 Study (CITADEL-205)

Author

Pier Luigi Zinzani, Wei Jiang, Fred Zheng, Fabrizio Pane, Caroline Dartigeas, Michał Taszner, Vittorio Ruggero Zilioli, Guillermo Rodriguez, Parameswaran Venugopal, Jan Walewski, Vincent Ribrag, Marek Trněný, Douglas J DeMarini, Jacob Haaber Christensen, and Amitkumar Mehta

Subjects
biology, business.industry, Immunology, Phases of clinical research, Cell Biology, Hematology, Biochemistry, Refractory Mantle Cell Lymphoma, biology.protein, Cancer research, Bruton's tyrosine kinase, Medicine, In patient, Previously treated, business
Abstract

Background: Mantle cell lymphoma (MCL) is an aggressive type of non-Hodgkin lymphoma (NHL) and accounts for 6% of all NHL cases in Western countries (Thandra KC. Med Sci. 2021;9:5). First-line treatment options are not curative and most patients (pts) experience relapse (Wu H. Front Oncol. 2020:10:588314; Kumar A. Blood Cancer J. 2019;9:50). Targeted therapies, including Bruton's tyrosine kinase (BTK) inhibitors, are used as second- and later-lines; however, treatment intolerance and failure are common with poor survival outcomes (Epperla N. Hematol Oncol. 2017;35:528-35; Jain P. Br J Haematol. 2018;182:404-11). Thus, novel therapies are needed for pts with relapsed or refractory (R/R) MCL. Parsaclisib is a potent, highly selective, next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) δ. Here, we report results of the primary analysis of the cohort of BTK inhibitor-naive pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544, EudraCT 2017-003148-19). Methods: Eligible pts were ≥18 years old, had pathologically confirmed MCL with documented cyclin D1 overexpression or t(11;14) translocation, and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Pts must have received 1-3 prior systemic therapies and not had any prior treatment with a BTK and/or PI3K inhibitor. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia was required. The primary endpoint was objective response rate (ORR) as determined by an independent review committee (IRC); secondary endpoints included complete response rate (CRR), duration of response (DOR), overall survival (OS), progression-free survival (PFS), and safety and tolerability. All radiology-based endpoints were confirmed by an IRC. Results: At data cutoff for the primary analysis (Jan 15, 2021), 108 pts naive to prior BTK inhibitor had been treated (WG, n=31; DG, n=77). Median (range) age was 72.0 (43-90) years, 79.6% of pts were male, 92.6% had ECOG PS ≤1, and median (range) time since initial diagnosis was 3.6 (0.1-20.9) years. Among all pts, 63.9% had received 1 line and 25.9% had received 2 lines of prior systemic therapy (median [range], 1 [1-3]); 31.5% of pts had prior hematopoietic stem cell transplant, and 50.0% had relapsed and 43.5% were refractory to their most recent prior therapy. 78 pts (72.2%) had discontinued treatment; primary reasons were progressive disease in 49 (45.4%) and adverse events in 25 (23.1%) pts. Median (range) treatment duration and follow-up from first dose to data cutoff were 8.3 (0.1-30.0) and 22.9 (11.6-35.9) months for all pts, and 7.9 (1.7-27.4) and 18.2 (11.6-35.9) months for DG, respectively. The ORR (95% CI) was 68.5% (58.9-77.1) for all pts and 70.1% (58.6-80.0) for the DG (Table 1); CRR (95% CI) was 17.6% (10.9-26.1) for all pts and 15.6% (8.3-25.6) for the DG. Among all treated pts with complete or partial response, 89.2% of responses occurred at the first disease assessment. Median (95% CI) DOR was 13.7 (9.0-19.9) months for all pts and 12.1 (9.0-not estimable) months for the DG. Median (95% CI) PFS was 11.99 (8.3-16.9) months for all pts and 13.6 (10.0-16.9) months for the DG. Median OS was not reached. Among 108 treated pts, treatment-emergent adverse events (TEAEs) occurred in 90.7% (n=98) pts (grade ≥3 in 62.0% [n=67]). The most common TEAEs were diarrhea (34.3%), pyrexia (17.6%), and constipation (13.0%); most common grade ≥3 TEAEs were diarrhea (13.9%) and neutropenia (8.3%). TEAEs leading to dose interruption or dose reduction occurred in 47.2% and 8.3% of all pts, respectively. TEAEs led to treatment discontinuation in 25.0% of all pts; the most common were diarrhea (11.1%), colitis (4.6%), and hypokalemia (2.8%). Serious TEAEs occurred in 42.6% (n=46) of all pts; the most common were diarrhea (9.3%) and colitis (4.6%). Six pts (5.6%) overall experienced fatal TEAEs. Conclusion: Parsaclisib monotherapy demonstrated a rapid and durable response, had an acceptable safety profile, and was generally well tolerated in BTK inhibitor-naive pts with R/R MCL. These data suggest that parsaclisib could be a potential treatment option for pts with R/R MCL. Figure 1 Figure 1. Disclosures Mehta: Seattle Genetics; Incyte; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics; Incyte; TG Therapeutics: Consultancy; 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. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Walewski: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Ribrag: Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, ; Janssen: Other: Travel, Accommodations, ; Jazz Pharmaceuticals: Consultancy, Other: Travel, Accommodations, Speakers Bureau. Rodriguez: Bristol-Myers Squibb; Celgene; EUSA Pharma; Janssen; Roche; Takeda: Consultancy; Bristol-Myers Squibb; Celgene; Janssen; Roche; Takeda: Speakers Bureau. Taszner: Roche, Takeda: Consultancy, Other: Travel. Zilioli: Takeda: Other: travel expenses, accommodation; Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Zheng: Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. DeMarini: Incyte: Current Employment, Current equity holder in publicly-traded company. Jiang: Incyte: Current Employment, Current equity holder in publicly-traded company. Zinzani: Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Investigational PI3Kdelta inhibitor (parsaclisib) for patients with MCL

Published
2021
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38. Efficacy and Safety of Umbralisib, Ublituximab (U2), and U2 Plus Bendamustine in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Author

James A. Reeves, Jerome H. Goldschmidt, Don A. Stevens, Tomasz Wróbel, Peter Sportelli, John M. Burke, Hari P. Miskin, Nilanjan Ghosh, John M. Pagel, Jason M. Melear, Owen A. O'Connor, Miguel Islas-Ohlmayer, Parameswaran Venugopal, Wojciech Jurczak, and Gustavo Fonseca

Subjects
Oncology, Bendamustine, medicine.medical_specialty, business.industry, Immunology, Cell Biology, Hematology, Biochemistry, Internal medicine, medicine, Refractory Diffuse Large B-Cell Lymphoma, In patient, business, medicine.drug
Abstract

Background: Patients with relapsed or refractory (R/R) DLBCL generally have a poor prognosis, particularly if they are not candidates for autologous stem cell transplantation (ASCT) or experience relapse following approved CAR-T therapies. The UNITY-NHL study systematically explored the efficacy and tolerability of the PI3K-d/CK1-e inhibitor, umbralisib, alone (umbra), and in combination with the glycoengineered anti-CD20 monoclonal antibody ublituximab (U2), followed by a cohort treated with U2 plus bendamustine (U2+benda). Herein we report on the experience in a large cohort of patients with R/R DLBCL. Methods: This study explored a sequential combination design as described above. Eligible patients had histologically confirmed R/R DLBCL and were ineligible for ASCT, with no limit on number or type of prior treatment. Umbra was given orally at 800 mg once daily in 28-day cycles (C) until disease progression or unacceptable tolerability. Ublituximab was administered intravenously (IV) on Days 1, 8, and 15 of C1, on Day 1 of C2-6, and on Day 1 every 3C through C24. Benda was administered IV (90 mg/m 2) on Days 1/2 of C1-6. Cell of origin, NGS, and c-myc (FISH) were analyzed centrally. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee. Secondary endpoints included duration of response, progression-free survival, time to response, and safety. Results: 226 patients with DLBCL were enrolled as follows: umbra monotherapy (n=30), U2 (n=66), and U2+benda (n=130). The population demographics included the following features: median age was 72 years (range 32-95); 59% were male; 64% of patients had stage III or IV disease; 58% were refractory to their immediate prior therapy; and the median number of prior therapies was 2 (range 1-8). There were no substantive differences in these characteristics across cohorts. Median follow-up for the umbra, U2, and U2+benda arms was 51 months (range 47-61), 46 months (range 41-57), and 40 months (range 35-47), respectively. Overall and complete response rates for the umbra mono, U2, and U2+benda arms were 13.3% (CR 3.3%), 31.8% (CR 10.6%), and 43.1% (CR 16.9%), respectively. Results pertaining to secondary endpoints are listed in Table 1. Correlation of response to cell of origin and mutation/c-myc status is ongoing and will be available at the time of presentation. Adverse events (AEs) were similar across the cohorts, with the exception of hematologic AEs which were increased in patients receiving benda. The most common all-grade AEs by treatment arm (umbra, U2, and U2+benda, respectively) were diarrhea (47%; 41%; and 48%), nausea (40%; 45%; and 45%), fatigue (33%; 30%; and 41%) and neutropenia (3.3%; 18%; and 32%). All-grade AEs of special interest included non-infectious colitis (3.3%, 1.5%, and 2.3%) and pneumonitis (3%, 1.5%, and 1.5%) in umbra, U2 and U2+benda treated patients respectively. Grade 3/4 AEs were uncommon, with the only events >10% being limited to neutropenia (11% for U2; 27% for U2+benda), and anemia (17% for U2+benda). Conclusions: In the DLBCL cohort of UNITY-NHL, the U2+benda triplet regimen was active and well tolerated in patients with R/R DLBCL who were unsuitable for transplant or who had relapsed following ASCT. Umbra monotherapy and U2 were also well tolerated but resulted in lower ORR than in the U2+benda cohort. Figure 1 Figure 1. Disclosures Burke: X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Kura: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Kymera: Consultancy; AbbVie: Consultancy; Verastem: Consultancy. Fonseca: Amgen: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; Dava Oncology: Honoraria; Epizyme: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Islas-Ohlmayer: Seagen Inc.: Research Funding. Reeves: Apollomics, Inc.: Research Funding; Tarveda Therapeutics: Research Funding; Ascentage Pharmaceuticals: Research Funding; Clovis Oncology: Research Funding; Arvinas: Research Funding; Pfizer: Research Funding; Ellipses: Research Funding; ImmunoGen: Research Funding; Karyopharm Therapeutics: Honoraria, Research Funding; Moderna: Research Funding; Thrive: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Astellas Pharma: Research Funding; IDEAYA Biosciences: Research Funding; Pharmacyclics: Research Funding; Loxo Oncology: Research Funding; AbbVie Inc.: Research Funding; Celgene: Research Funding; GSK: Research Funding; Jiangsu Hengrui Medicine Co.: Research Funding; Arcus Biosciences: Research Funding; Calithera: Research Funding; Amgen: Research Funding; Mirati Therapeutics, Inc.: Research Funding; Array BioPharma Inc.: Research Funding; Taiho Pharmaceutical: Research Funding; Boehringer Ingelheim: Research Funding; GI Therapeutics Inc.: Research Funding; Hutchison: Research Funding; MacroGenics: Research Funding; Ipsen: Research Funding; MedImmune, LLC.: Research Funding; BeiGene: Research Funding; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; Verastem: Research Funding; Janssen Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Co.: Research Funding, Speakers Bureau; Roche Pharma: Research Funding; Novartis Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Arvinas: Research Funding; CytomX: Research Funding; Sermonix Pharmaceutical: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Evelo Biosciences: Research Funding. Wróbel: Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria; Janssen: Honoraria, Speakers Bureau. Pagel: Incyte/MorphoSys: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Nomocan: Consultancy; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Kymera: Consultancy, Current equity holder in publicly-traded company; Mundipharma: Consultancy. Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Genentech: Research Funding; Karyopharma: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau.

Published
2021
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39. The Impact of Non-Clinical Factors in Clinical Trial Enrollments of Patients with Hematologic Malignancies

Author

Deborah A. Katz, Parameswaran Venugopal, Agne Paner, Sunita Nathan, Irene Dehghan-Paz, Celalettin Ustun, Anne Timmermann, Seo-Hyun Kim, Jamile M. Shammo, Melissa L. Larson, and Ankur Varma

Subjects
Clinical trial, medicine.medical_specialty, Non clinical, business.industry, Internal medicine, Immunology, Medicine, Cell Biology, Hematology, business, Biochemistry
Abstract

Introduction The improvement of care and advancement of treatment options is heavily reliant on the success and diversity of clinical trials (CTs), yet data suggests that only 3-9% of patients with a cancer diagnosis participate in CTs. We sought to evaluate reasons for declining participation in CTs among patients with hematologic malignancies within our medical center. Our primary objective was to assess the prevalence of non-clinical factors in patients contributing to the lack of participation compared to those who agreed to participate. The secondary objective was to identify the reasons noted by patients for declining trials. Methods We conducted a retrospective chart review of adult patients with hematologic malignancies who were offered a clinical trial from 2016-2020. Eligible patients were identified through review of Cancer Center Clinical Trials Office screening logs. We collected data relative to: disease, sex, age, race and ethnicity, English as a first language, marital status, caregiver support, level of education, type of insurance, trial phase, and trial indication. The data was compared between patients who refused participation versus those who agreed to participate. Descriptive statistics, chi-square analysis, and multivariate logistic regression were used to interpret the data with IBM SPSS Statistics. Results Of patients diagnosed with hematologic malignancies and offered a CT from 2016 to 2020 at our center, 136 signed consent and 125 declined participation. The sample was predominantly older with a mean patient age of 60.9 in those who signed ICF and 61.9 in those who declined participation (Table 1). Males and non-Hispanic white patients encompassed over half of the sample in each group. Multiple myeloma was the most common diagnosis among either group. Trials offered were predominantly phase 2 or 3 and for varying disease states. We found that patients who were divorced (P = 0.024), did not have caregiver support (P = 0.005), and did not speak English as their first language (P = 0.004) were more likely to decline CT participation (Table 2). The most common reasons that patients cited for declining participation were: preference for another treatment option, distance for travel, and concerns for transportation (Table 3). Conclusion In this retrospective analysis evaluating reasons behind CT refusal in patients with hematologic malignancies at our center, we found that being divorced, not having defined caregiver support, and not speaking English as the first language made patients more likely to decline a CT. Our sample displayed greater diversity in comparison to the national averages for cancer CT participation despite the predominance of male and non-Hispanic white patients within our sample. This may be representative of the population our center serves. The significance of marital status and caregiver support suggests that support systems are integral in the decision-making process for CTs. Furthermore, the role of divorce in declining trials may be indicative of familial motivation or spousal influence. The significance of English as a first language is notable as our center utilizes an oral translation for informed consent with a short form signature. This suggests that a full translation of CT documents may be beneficial to enrollment. Logistical concerns were frequently cited as a reason for declining, which should be considered by sponsors in the design of CTs as alleviating this burden on patients may help overall recruitment. Limitations of this study include its retrospective nature, manual data extraction, and consistency of research team documentation. The results suggest that introducing support groups and interventions to provide transportation services for trial patients may be beneficial to enrollment and retention. Figure 1 Figure 1. Disclosures Shammo: Abbvie: Current holder of individual stocks in a privately-held company, Research Funding; Astra zeneca: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI pharma: Research Funding; Stemline therapeutics: Research Funding; Kartos Pharma: Research Funding; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; sanofi: Consultancy, Honoraria, Speakers Bureau; Baxter: Current holder of stock options in a privately-held company; Takeda: Consultancy, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; NS Pharma: Membership on an entity's Board of Directors or advisory committees. Paner: Adaptive Biotechnologies: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Oncopeptides: Consultancy; Rush University Medical Center: Consultancy, Current Employment; Sanofi: Consultancy; BMS: Consultancy. Ustun: novartis: Honoraria; Blueprint: Honoraria.

Published
2021
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40. Impact of Blood Group Type on Severity of Disease in COVID-19 Patients

Author

Surbhi Warrior, Shivani Rao, Shivi Jain, Sefer Gezer, and Parameswaran Venugopal

Subjects
Blood type, medicine.medical_specialty, business.industry, Mortality rate, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Gastroenterology, Thrombosis, Pulmonary embolism, Sepsis, Internal medicine, ABO blood group system, medicine, 401.Basic Science and Clinical Practice in Blood Transfusion, business, Stroke, Rh blood group system
Abstract

Background The virus SARS-CoV-2, which causes COVID-19 has rapidly spread into a global pandemic. In critically ill patients with the disease, common symptoms include sepsis, severe pneumonia with acute respiratory distress syndrome (ARDS), and complications such as coagulopathy and thrombosis. Many patients with COVID-19 have sequelae such as venous thromboembolism (VTE) including pulmonary embolism (PE) and deep vein thrombosis (DVT) as well as arterial thromboembolism (ATE) including stroke. COVID-19 induced inflammation can induce a prothrombotic state by activating the coagulation cascade; coupled with the immobility of severe and critically ill patients in ICU, making thrombosis common in this patient population. Different blood types in patients include A, B, AB, and O. ABO carbohydrate moieties are genetically inherited and have been linked to predisposing patients to cardiovascular diseases, cancers, and even susceptibility of COVID-19. Blood type positivity and negativity are determined by the Rhesus (Rh) factor, which is a protein found on the surface of red blood cells and is also genetically inherited and linked to higher incidence of certain diseases such as diabetes. Studies have shown a relationship between blood types and increased severity of infection from COVID-19 including increased risk of thrombosis. Blood type A has been shown to have higher severity of disease with O blood type having a lower risk of infection or mortality. This study was done to evaluate if patients with different blood types have increased risk for thrombosis or higher mortality rates with COVID-19 infection. Methods A retrospective analysis was performed on COVID-19 positive hospitalized patients between March 1, 2020 and June 26, 2020 at our institution with reported blood typing. Patients who had a thromboembolism (VTE, DVT, PE, ATE, or stroke) verified by imaging were extracted from this cohort and included in the analysis. The prevalence of different blood types in COVID-19 patients was compared to the general population without COVID-19. The incidence of thrombosis and mortality rate based on blood type was analyzed to understand severity of COVID-19 disease. Statistical analysis was performed using chi-squared testing. Results Among 1265 COVID-19 positive patients during our time frame, 138 patients were identified to have a thrombosis. Of those, 102 patients with thrombosis and 402 without thrombosis had reported blood types that were used for analysis. There was no significant difference in prevalence of blood types in COVID-19 patients (A 34.3%, AB 2.9%, B 16.7%, O 46.1%) to the general nonCOVID-19 population (A32.7%, AB 4.2%, B 14.9%, O 48.1%) (p=0.8572). There was no significant difference in incidence of thrombosis between blood types: A (23.3%), AB (15%), B (20.7%), and O (18.7%) (p=0.6513). When stratifying by Rh factor, there was also no significant difference in incidence of thrombosis by blood types: A- (11.1%), A+ (24.1%), AB- (0%), AB+ (15.8%), B- (25%), B+ (20.3%), O- (18.2%), O+ (18.7%) (p=0.9054). There was also no significant difference in mortality rate between COVID-19 patients based on blood types in our cohort: A (20.7%), AB (15%), B (13.4%), and O (21.8%) (p=0.3747). Conclusion Our study demonstrates that there is no increased prevalence of one blood type over another between COVID-19 patients compared to the general population, showing that patients are not at higher risk for COVID-19 infection based on blood type. There was also no difference between blood types based on incidence of thrombosis. When further stratifying with Rh factor, there was also no difference in incidence of thrombosis based on blood types. This shows that regardless of Rh positivity or negativity, there is no increased risk for thrombosis in COVID-19 patients based on blood type. There is also no difference in mortality in COVID-19 patients based on blood type. Since COVID-19 patients who are critically ill and have more severe disease have higher incidence of thrombosis and higher mortality rates, our study suggests that patients are not at higher risk for severe COVID-19 disease based on blood type. However, this study is also limited due to small sample size, and prospective studies are needed to better understand the relationship between blood type and severity of disease in COVID-19+ patients. Disclosures No relevant conflicts of interest to declare.

Published
2021

41. Randomized Phase II Study of R-CHOP With or Without Bortezomib in Previously Untreated Patients With Non–Germinal Center B-Cell–Like Diffuse Large B-Cell Lymphoma

Author

Parameswaran Venugopal, Ian W. Flinn, Sven de Vos, Nicholas J. DiBella, Julio Hajdenberg, Dixie Lee Esseltine, James A. Reeves, Rachel Neuwirth, Christopher R. Flowers, Kathryn S. Kolibaba, Steven W. Papish, John P. Leonard, Jaehong Park, Anil Tulpule, Tatjana Kolevska, Robert H. Collins, Amir Tabatabai, Robert Robles, George Mulligan, Kaveri Suryanarayan, and Andrew Horodner

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Vincristine, Population, Phases of clinical research, Neutropenia, Gastroenterology, Disease-Free Survival, Bortezomib, Antibodies, Monoclonal, Murine-Derived, Young Adult, 03 medical and health sciences, 0302 clinical medicine, International Prognostic Index, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, education, Cyclophosphamide, Aged, Aged, 80 and over, education.field_of_study, business.industry, Hazard ratio, Middle Aged, medicine.disease, Surgery, 030104 developmental biology, Oncology, Doxorubicin, 030220 oncology & carcinogenesis, Prednisone, Female, Lymphoma, Large B-Cell, Diffuse, Germinal center B-cell like diffuse large B-cell lymphoma, Rituximab, business, medicine.drug
Abstract

PurposeTo evaluate the impact of the addition of bortezomib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on outcomes in previously untreated patients with non–germinal center B-cell–like (non-GCB) diffuse large B-cell lymphoma (DLBCL).Patients and MethodsAfter real-time determination of non-GCB DLBCL using the Hans immunohistochemistry algorithm, 206 patients were randomly assigned (1:1; stratified by International Prognostic Index [IPI] score) to six 21-day cycles of standard R-CHOP alone or R-CHOP plus bortezomib 1.3 mg/m2intravenously on days 1 and 4 (VR-CHOP). The primary end point, progression-free survival (PFS), was evaluated in 183 patients with centrally confirmed non-GCB DLBCL who received one or more doses of study drug (91 R-CHOP, 92 VR-CHOP).ResultsAfter a median follow-up of 34 months, with 25% (R-CHOP) and 18% (VR-CHOP) of patients having had PFS events, the hazard ratio (HR) for PFS was 0.73 (90% CI, 0.43 to 1.24) with VR-CHOP ( P = .611). Two-year PFS rates were 77.6% with R-CHOP and 82.0% with VR-CHOP; they were 65.1% versus 72.4% in patients with high-intermediate/high IPI (HR, 0.67; 90% CI, 0.34 to 1.29), and 90.0% versus 88.9% (HR, 0.85; 90% CI, 0.35 to 2.10) in patients with low/low-intermediate IPI. Overall response rate with R-CHOP and VR-CHOP was 98% and 96%, respectively. The overall survival HR was 0.75 (90% CI, 0.38 to 1.45); 2-year survival rates were 88.4% and 93.0%, respectively. In the safety population (100 R-CHOP and 101 VR-CHOP patients), grade ≥ 3 adverse events included neutropenia (53% v 49%), thrombocytopenia (13% v 29%), anemia (7% v 15%), leukopenia (26% v 25%), and neuropathy (1% v 5%).ConclusionOutcomes for newly diagnosed, prospectively enrolled patients with non-GCB DLBCL were more favorable than expected with R-CHOP and were not significantly improved by adding bortezomib.

Published
2017
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42. Impact of cachexia on outcomes in aggressive lymphomas

Author

Ibtihaj Fughhi, Palmi Shah, Sunita Nathan, Sanjib Basu, Frank J. Penedo, Jeffrey A. Borgia, Taha Alrifai, Kelly Szymanski-Grant, Reem Karmali, Ronald Ng, Vineela Chukkapalli, Leo I. Gordon, and Parameswaran Venugopal

Subjects
Male, Oncology, medicine.medical_specialty, Cachexia, Population, Muscle mass, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Outcome Assessment, Health Care, Weight Loss, Cox proportional hazards regression, Humans, Medicine, education, Proportional Hazards Models, Retrospective Studies, education.field_of_study, Hematology, business.industry, Lymphoma, Non-Hodgkin, digestive, oral, and skin physiology, General Medicine, Middle Aged, Prognosis, medicine.disease, Pathophysiology, Novel agents, 030220 oncology & carcinogenesis, Immunology, Female, Lymphoma, Large B-Cell, Diffuse, Involuntary weight loss, business, hormones, hormone substitutes, and hormone antagonists, 030215 immunology
Abstract

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87–93, 15). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into “non-cachectic” (CXI ≥49.8, n = 41) and “cachectic” (CXI

Published
2017
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43. Breast implant-associated anaplastic large-cell lymphoma and the role of brentuximab vedotin (SGN-35) therapy: A case report and review of the literature

Author

Reem Karmali, Brett Mahon, Kelly Grant‐ Szymanski, Taha Alrifai, George J. Kouris, Kristin Richardson, and Parameswaran Venugopal

Subjects
Oncology, Cancer Research, Vincristine, medicine.medical_specialty, Cyclophosphamide, 030230 surgery, law.invention, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, law, hemic and lymphatic diseases, Internal medicine, Medicine, Brentuximab vedotin, Anaplastic large-cell lymphoma, business.industry, Combination chemotherapy, Articles, medicine.disease, 030220 oncology & carcinogenesis, Breast implant, business, Breast reconstruction, medicine.drug
Abstract

Breast implant-associated (BIA) anaplastic large-cell lymphoma (ALCL) is a rare disease, comprising a small percentage of all non-Hodgkin lymphomas (NHLs), reportedly 2–3%. There is currently no established standard approach to the treatment of BIA ALCL. The first case on the development of ALCL in the presence of a breast implant was reported in 1997 and the association was first identified by the Food and Drug Administration in 2011. We herein describe a case of BIA ALCL in a patient with a previous history of breast cancer and breast reconstruction who presented with hardening of her breast implant. The patient underwent capsulectomy and the findings of the pathological examination were consistent with ALCL. The patient completed three cycles of combination chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP regimen) followed by radiation consolidation therapy, and has maintained a complete remission ever since. The aim of the present study was to review the treatment options for BIA ALCL and suggest an investigation of the CD30-directed antibody-drug conjugate, brentuximab vedotin, as a potential treatment option for BIA ALCL.

Published
2017
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44. Phase 2 study of CHOP-R-14 followed by 90Y-ibritumomab tiuxetan in patients with previously untreated diffuse large B-cell lymphoma

Author

Reem Karmali, Jamile M. Shammo, Melissa L. Larson, Teresa O'Brien, Parameswaran Venugopal, and Stephanie A. Gregory

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Vincristine, Dose-dense chemotherapy, medicine.medical_treatment, Phases of clinical research, CHOP, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, business.industry, medicine.disease, Regimen, 030104 developmental biology, 030220 oncology & carcinogenesis, Radioimmunotherapy, Rituximab, business, Diffuse large B-cell lymphoma, medicine.drug
Abstract

The aim of this open-label, single-center, phase 2 study was to assess the efficacy and safety of dose-dense CHOP-R-14 followed by 90Y-ibritumomab radioimmunotherapy (RIT) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). A total of 20 patients, the majority presenting with high-risk characteristics, were enrolled to receive dose-dense cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab every 14 days (CHOP-R-14), followed by 90Y-ibritumomab tiuxetan consolidation. Sixteen patients completed RIT consolidation (rituximab 250 mg/m2 on day 1 and day 7, 8, or 9, followed by a single injection of 90Y-ibritumomab). Complete response (CR) rates of 75 and 95% were observed after treatment with CHOP-R-14 and RIT, respectively; 4 of the 5 patients who achieved a partial response after CHOP-R-14 converted to CR following treatment with RIT. With a median follow-up of 89.7 months, the progression-free and overall survival rates for the cohort were 75 and 85%, respectively. Hematological adverse events were common following CHOP-R-14 and RIT, but they were manageable with treatment interruption. Therefore, this regimen achieved promising survival outcomes in high-risk DLBCL on long term follow-up, with manageable toxicity.

Published
2017
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45. Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis

Author

Parameswaran Venugopal, Graham P. Collins, Yun Kyong Choi, Suchitra Sundaram, Frank A. Post, Peter Martin, Victor M. Orellana-Noia, Juan Pablo Alderuccio, Umar Farooq, Andrew M. Evens, Ayushi Chauhan, Vaishalee P. Kenkre, Catherine Diefenbach, Kirsten M Boughan, Andrzej Stadnik, Albert Ren, Tatyana Feldman, Allandria Straker-Edwards, Stephen D. Smith, Madelyn Burkart, Alexey V. Danilov, Scott E. Smith, Emma Rabinovich, Reem Karmali, Catherine Zhu, Adam Zayac, Bradley M. Haverkos, Silvia Montoto, Amy Sperling, Narendranath Epperla, Adam J. Olszewski, Yong Lin, Manali Kamdar, Seth M. Maliske, Nadia Khan, Izidore S. Lossos, Catherine Wei, Maryam Sarraf Yazdy, Stephanie Berg, Paolo Caimi, Amandeep Godara, David A. Bond, Craig A. Portell, Seo-Hyun Kim, Gaurav Varma, Shireen Kassam, Michael C. Churnetski, Mark Bower, Andreas K. Klein, Deepa Jagadeesh, Kate Cwynarski, Ryan Vaca, Daniel Rector, Alessia Dalla Pria, Agrima Mian, Nishitha Reddy, Seema Naik, Kristie A. Blum, and Christopher D'Angelo

Subjects
Oncology, medicine.medical_specialty, business.industry, Immunology, Human immunodeficiency virus (HIV), Cell Biology, Hematology, medicine.disease, medicine.disease_cause, Biochemistry, Lymphoma, Internal medicine, medicine, business
Abstract

Introduction: There are few data about prognostication and outcomes in patients (pts) with HIV-BL treated in the cART era. Optimal treatment strategies to minimize treatment-related mortality (TRM) remain unclear and current recommendations are based on small studies. We conducted a multicenter international analysis to identify prognostic factors and outcomes in pts with HIV-BL treated in the cART era. Methods: This retrospective analysis included a subcohort from a recent study across 30 US sites (Evens et al. Blood 2020) augmented by data from 5 UK centers treated 2009-2018. Progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier & differences assessed by log-rank test. Univariate (UVA) associations were derived via Cox model and multivariable (MVA) models were constructed by forward selection of significant variables with P Results: 249 (US: 140 & UK: 109) pts with newly diagnosed HIV-BL were included. Clinical features included median age 43 (IQR 35-50 years [yrs]); male sex: 84%; ECOG PS: 2-4: 48%; elevated LDH: 85% (> 3x upper limit of normal (ULN) 49% & >5xULN 39%); >1 extranodal (EN) site: 60%; any CNS involvement (CNSinv) 25%; and +bone marrow (BM) 46%. MYC rearrangement was reported in 93% of pts with t(8;14) in 49%, break-apart probe in 41% and MYC-light chain in 3%; the rest had classical BL with negative MYC testing (4%) or missing result (3%) (otherwise classical BL). Median CD4 count was 217 (IQR 90-392 cells/µL) with 68% pts having CD4>100 cells/µL. At BL diagnosis, HIV viral load was detectable in 55%; 39% of pts were on cART. Baseline features were similar between the US & UK cohorts with significant differences only in ECOG PS 2-4 (32% vs 65%; P Tx regimens included: CODOX-M/IVAC (Magrath) 60%, DA-EPOCH 25%, HyperCVAD/MA 13%, & other 1%; most pts (87%) received rituximab (R). Similar regimens were used in pts with baseline CNSinv: Magrath 64%, DA-EPOCH 24% & HyperCVAD 12%. In the US, pts most frequently received DA-EPOCH (42%) followed by Magrath (32%) & HyperCVAD/MA (24%), whereas in the UK, 96% received Magrath. R was more frequently given in the US (94% vs 79%, P With median follow-up of 4.5 yrs, 3-yr PFS & OS were 61% & 66%, respectively, and nearly identical in both countries (Fig A). Pts with CD4>100 cells/µL had better 3-yr PFS (Fig B) & OS (68% vs 57% P=0.03). We observed significantly worse outcomes in pts with baseline CNSinv (3-yr PFS 36% vs 69%, P The incidence of CNS recurrence at 3 yr across all Tx was 11%. Higher incidence was observed with DA-EPOCH (P=0.032 vs other regimens; Fig F) with no difference according to CD4 count. Variables associated with PFS & OS on UVA included: ECOG PS 2-4, >1 EN, +BM, baseline CNSinv, LDH>ULN, CD4 5xULN (HR 2.09, P1 EN sites (HR 1.58 P=0.043). The same variables were significant on MVA for OS. Adjusting for all of the prognostic variables, Tx with Magrath was associated with longer PFS (adjusted HR, 0.45, P=0.005). Conclusions: These data represent the largest analysis of HIV-BL to date. There were favorable tolerance and outcomes with intensive R-containing regimens with Magrath being associated with lower TRM and the highest PFS. In addition, prognostic factors for pt outcomes were associated with lymphoma characteristics rather than with HIV-related features. Pts with baseline CNSinv represent a high-risk group with unmet therapeutic needs. Disclosures Alderuccio: Oncinfo: Honoraria; Puma Biotechnology: Other: Family member; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member. Olszewski:Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Evens:Epizyme: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Collins:Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; BeiGene: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Celleron: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Research Funding; Amgen: Research Funding; Pfizer: Honoraria. Danilov:Astra Zeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Aptose Biosciences: Research Funding; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; BeiGene: Consultancy; Abbvie: Consultancy. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding. Reddy:Genentech: Research Funding; Abbvie: Consultancy; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy. Farooq:Kite, a Gilead Company: Honoraria. Bond:Seattle Genetics: Honoraria. Khan:Celgene: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding. Yazdy:Bayer: Honoraria; Genentech: Research Funding; Octapharma: Consultancy; Abbvie: Consultancy. Karmali:Karyopharm: Honoraria; Takeda: Research Funding; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Martin:Janssen: Consultancy; Regeneron: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy, Research Funding. Diefenbach:Bristol-Myers Squibb: Consultancy, Research Funding; Denovo: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; MEI: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Trillium: Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Haverkos:Viracta THerapeutics: Consultancy. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Verastem: Other: Advisory Board. Kamdar:Roche: Research Funding. Feldman:Eisai: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Viracta: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau. Smith:AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Seattle Genetics: Research Funding; Ayala: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Bristol Meyers Squibb: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Ignyta: Research Funding; Genentech: Research Funding; De Novo Biopharma: Research Funding. Portell:Amgen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; Janssen: Consultancy; TG Therapeutics: Research Funding; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Xencor: Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Lossos:Janssen Biotech: Honoraria; Verastem: Consultancy, Honoraria; Stanford University: Patents & Royalties; NCI: Research Funding; Seattle Genetics: Consultancy, Other; Janssen Scientific: Consultancy, Other. Cwynarski:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau.

Published
2020
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46. Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor (CITADEL-205)

Author

Vittorio Ruggero Zilioli, Guillermo Rodriguez, Michał Taszner, Vincent Ribrag, Jacob Haaber Christensen, Parameswaran Venugopal, Pier Luigi Zinzani, Fabrizio Pane, Caroline Dartigeas, Douglas J DeMarini, Jan Walewski, Fred Zheng, Wei Jiang, Marek Trněný, and Amitkumar Mehta

Subjects
biology, business.industry, Immunology, Phases of clinical research, Cell Biology, Hematology, Biochemistry, Cancer research, Refractory Mantle Cell Lymphoma, biology.protein, Medicine, Bruton's tyrosine kinase, In patient, business, Previously treated
Abstract

Background: Mantle cell lymphoma (MCL) accounts for approximately 5-7% of non-Hodgkin lymphomas (NHL). A number of therapies are used for second- and later-line treatment including Bruton's tyrosine kinase inhibitors (BTKi). However, treatment failure and intolerance are common and alternative therapies are needed. Parsaclisib is a potent, highly-selective, next-generation PI3Kδ inhibitor that demonstrated clinical activity in patients (pts) with relapsed or refractory (R/R) NHL. We report preliminary results for a cohort of BTK inhibitor-naïve pts with R/R MCL treated with parsaclisib monotherapy in the open-label, phase 2 study CITADEL-205 (NCT03235544). Methods: Pts must be ≥18 years of age with pathologically confirmed MCL, R/R to the most recent treatment, documented cyclin D1 overexpression or t(11;14) translocation, have Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2, and received 1 to 3 prior systemic treatments. Prior treatment with BTKi and PI3Ki were prohibited. Pts were allocated to receive parsaclisib 20 mg once daily (QD) for 8 weeks followed by either 20 mg once weekly (weekly-dosing group [WG]) or 2.5 mg QD (daily-dosing group [DG]). Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) was required. Objective response rate (ORR) was the primary endpoint; complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability were secondary endpoints. All radiology-based endpoints were based on independent review. Results: From October 2017 to January 17, 2020 (data cut-off), 104 pts were treated (WG, n = 31; DG, n = 73). Enrollment was ongoing (target:100 pts). At cut-off, a total of 50 (48%) pts had discontinued treatment, including 31 (30%) pts for disease progression. The median exposure (range) was 4.0 months (0.1-19.1). The median age was 72 years and 80% of pts were men. The median time since initial diagnosis was 3.6 years. The majority of pts (92%) had ECOG PS ≤1, and 57% had high-risk MCL International Prognostic Index. The median number of previous systemic therapies was 1; 31% of pts had prior hematopoietic stem cell transplant, and 44% were refractory to their most recent systemic therapy. At the data cut-off, 92 pts were evaluable for efficacy including 31 in WG and 61 in DG (Table). The median follow-up duration (range) for this population was 11.8 months (1.9-24.0) overall and 9.1 (1.9-24.0) for DG. The ORR (95% confidence interval CI) and CRR were 66.3% (55.7-75.8) and 15.2%, respectively in all evaluable pts, and were 65.6% (52.3-77.3) and 11.5% for DG. The median time to response for pts with a complete or partial response was 7.9 weeks. The median DOR (95% CI) was 11.0 months (6.6-14.7) for all responders and 9.0 months (7.7-14.7) for DG. The median PFS (95% CI) was 11.1 (5.8-16.6) months overall, and 11.1 (5.6-16.6) months for DG. Among 104 safety-evaluable pts, most common treatment-emergent AEs (TEAEs) occurring in >10% of pts were diarrhea (25.0%), pyrexia (16.3%), constipation (11.5%), and neutropenia (10.6%). Most common grade ≥3 TEAEs reported in ≥5% of pts were neutropenia (8.7%) and diarrhea (7.7%). TEAEs leading to dose interruption or dose reduction occurred in 31.7% and 1.9% of pts, respectively. TEAEs leading to discontinuation occurred in 16.3% of pts including diarrhea (5.8%) and colitis (2.9%). Serious TEAEs reported in ≥2 pts included diarrhea (5.8%), colitis (2.9%), pyrexia (2.9%) and cytomegalovirus infection (1.9%). Four pts experienced fatal TEAEs. The fatal TEAEs in one pt (monocytic acute myeloid leukemia, leukocytosis, and acute kidney injury) were considered related to treatment. TEAEs of clinical interest included neutropenia (10.6%), rash (8.7%), colitis (4.8%), pneumonia (1.9%), PJP and pneumonitis (1% each). New or worsening grade ≥3 laboratory test values of clinical interest included decreased neutrophils (8.7%), platelets (7.7%), and hemoglobin (1.9%), and increases in alanine/aspartate aminotransferase (2.9%/1.9%). Conclusion: Parsaclisib demonstrated a high rate of rapid and durable response, and had an acceptable safely profile and was generally well tolerated. These preliminary results suggest that parsaclisib represents a potentially new drug class and treatment option for BTKi-naïve, R/R MCL. Updated study results will be presented. Disclosures Mehta: Takeda: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; Merck: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Research Funding; Roche-Genentech: Research Funding; Affimed: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Innate Pharmaceuticals: Research Funding; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding. Trněný:AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Amgen: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Walewski:Servier: Consultancy, Honoraria; GSK: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Ribrag:Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Institut Gustave Roussy: Current Employment; argenX: Current equity holder in publicly-traded company, Research Funding. Dartigeas:Janssen: Honoraria; Roche: Honoraria; Gilead: Other: non-financial support. Pane:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Rodríguez:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy. Zheng:Incyte: Current Employment, Current equity holder in publicly-traded company. DeMarini:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Jiang:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Zinzani:TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Published
2020
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47. Bendamustine and Rituximab: Complete Response in a 62-Year-Old Female with an Aggressive Lymphoma and an Ejection Fraction of 20%

Author

Taha Alrifai, Reem Karmali, Brett Mahon, Kelly Grant‐ Szymanski, Tochukwu M. Okwuosa, and Parameswaran Venugopal

Subjects
Bendamustine, Oncology, Vincristine, medicine.medical_specialty, Anthracycline, Aggressive lymphoma, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Prednisone, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Drug Discovery, medicine, Bendamustine Hydrochloride, Humans, Pharmacology (medical), Pharmacology, business.industry, Lymphoma, Non-Hodgkin, Standard treatment, Stroke Volume, General Medicine, Middle Aged, Regimen, Treatment Outcome, Infectious Diseases, 030220 oncology & carcinogenesis, Female, Rituximab, business, medicine.drug
Abstract

The treatment of diffuse large B-cell lymphoma in the presence of cardiac comorbidities can be challenging considering that the standard treatment regimen used for this aggressive subtype of non-Hodgkin lymphoma (NHL) consists of a combination of rituximab, cyclophosphamide, doxorubicin hydrochloride, Oncovin (vincristine), and prednisone (R-CHOP). The use of the anthracycline doxorubicin has been associated with arrhythmias and cardiomyopathy, making patients with cardiac dysfunction poor candidates for R-CHOP. As such, it is imperative to find alternative regimens that omit cardiac toxicity without compromising efficacy for this patient population. We report a case of composite NHL in a patient who received frontline bendamustine with rituximab with encouraging results. Our patient had a left ventricular ejection fraction of 20%, making her a poor candidate for anthracycline-based therapy. We opted to administer bendamustine with rituximab for a total of 6 cycles. She remains disease free 18 months after the completion of therapy.

Published
2016
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48. Phase 1 study of lenalidomide plus dose-adjusted EPOCH-R in patients with aggressive B-cell lymphomas with deregulated MYC and BCL2

Author

Michael R. Bishop, Parameswaran Venugopal, Aaron P. Rapoport, James Godfrey, Walter M. Stadler, Reem Karmali, Kenneth S. Cohen, Chadi Nabhan, Justin Kline, Theodore Karrison, and Sonali M. Smith

Subjects
Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Cyclophosphamide, Maximum Tolerated Dose, medicine.medical_treatment, Aggressive lymphoma, Drug Administration Schedule, Translocation, Genetic, Maintenance Chemotherapy, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, 0302 clinical medicine, Chemoimmunotherapy, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, 030212 general & internal medicine, EPOCH (chemotherapy), Lenalidomide, Aged, Etoposide, Aged, 80 and over, Chemotherapy, business.industry, Common Terminology Criteria for Adverse Events, Middle Aged, Treatment Outcome, Proto-Oncogene Proteins c-bcl-2, Doxorubicin, Vincristine, 030220 oncology & carcinogenesis, Feasibility Studies, Prednisone, Rituximab, Female, Lymphoma, Large B-Cell, Diffuse, business, medicine.drug
Abstract

Background Dual translocation of MYC and BCL2 or the dual overexpression of these proteins in patients with aggressive B-cell lymphomas (termed double-hit lymphoma [DHL] and double-expressor lymphoma [DEL], respectively) have poor outcomes after chemoimmunotherapy with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Retrospective reports have suggested improved outcomes with dose-intensified regimens. In the current study, the authors conducted a phase 1 study to evaluate the feasibility, toxicity, and preliminary efficacy of adding lenalidomide to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab (DA-EPOCH-R) in patients with DHL and DEL. Methods The primary objective of the current study was to determine the maximum tolerated dose of lenalidomide in combination with DA-EPOCH-R. A standard 3+3 design was used with lenalidomide administered on days 1 to 14 of each 21-day cycle (dose levels of 10 mg, 15 mg, and 20 mg). Patients attaining a complete response after 6 cycles of induction therapy proceeded to maintenance lenalidomide (10 mg daily for 14 days every 21 days) for 12 additional cycles. Results A total of 15 patients were enrolled, 10 of whom had DEL and 5 of whom had DHL. Two patients experienced dose-limiting toxicities at a lenalidomide dose of 20 mg, consisting of grade 4 sepsis. The maximum tolerated dose of lenalidomide was determined to be 15 mg. The most common nonhematologic grade ≥3 adverse events included thromboembolism (4 patients; 27%) and hypokalemia (2 patients; 13%) (toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The preliminary efficacy of the regimen was encouraging, especially in the DEL cohort, in which all 10 patients achieved durable and complete metabolic responses with a median follow-up of 24 months. Conclusions The combination of lenalidomide with DA-EPOCH-R appears to be safe and feasible in patients with DHL and DEL. These encouraging results have prompted an ongoing phase 2 multicenter study.

Published
2018

50. POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) AFTER SOLID ORGAN TRANSPLANT (SOT): SURVIVAL AND PROGNOSTICATION AMONG 570 PATIENTS (PTS) TREATED IN THE MODERN ERA

Author

Scott E. Smith, Andrew M. Evens, Wei Wei, Timothy S. Fenske, Parameswaran Venugopal, S. Barot, D. Hwang, Kevin A. David, Vikas R. Dharnidharka, Stephanie Berg, Jean L. Koff, D. Sriram, E. Xie, Nishitha Reddy, Donald E. Tsai, Nina D. Wagner-Johnston, Deepa Jagadeesh, Seo-Hyun Kim, and P. Santapuram

Subjects
Cancer Research, medicine.medical_specialty, Oncology, business.industry, Internal medicine, medicine, Hematology, General Medicine, medicine.disease, business, Solid organ transplantation, Gastroenterology, Post-transplant lymphoproliferative disorder
Published
2019
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