Medicine and Health Sciences Commons^™

Targeted Therapy With Nanatinostat And Valganciclovir In Recurrent Ebv-Positive Lymphoid Malignancies: A Phase 1b/2 Study, Bradley Haverkos, Onder Alpdogan, Robert Baiocchi, Jonathan E. Brammer, Tatyana A. Feldman, Marcelo Capra, Elizabeth A. Brem, Santosh Nair, Phillip Scheinberg, Juliana Pereira, Leyla Shune, Erel Joffe, Patricia Young, Susan Spruill, Afton Katkov, Robert Mcrae, Ivor Royston, Douglas V. Faller, Lisa Rojkjaer, Pierluigi Porcu

Department of Medical Oncology Faculty Papers

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine …

Impact Of Second Primary Malignancy Post–Autologous Transplantation On Outcomes Of Multiple Myeloma: A Cibmtr Analysis, Brittany Knick Ragon, Mithun Vinod Shah, Anita D'Souza, Noel Estrada-Merly, Lohith Gowda, Gemlyn George, Marcos De Lima, Shahrukh Hashmi, Mohamed A. Kharfan-Dabaja, Navneet S. Majhail, Rahul Banerjee, Ayman Saad, Gerhard C. Hildebrandt, Hira Mian, Muhammad Bilal Abid, Minoo Battiwalla, Lazaros J. Lekakis, Sagar S. Patel, Hemant S. Murthy, Yago Nieto, Christopher Strouse, Sherif M. Badawy, Samer Al Hadidi, Bhagirathbhai Dholaria, Mahmoud Aljurf, David H. Vesole, Cindy H. Lee, Attaphol Pawarode, Usama Gergis, Kevin C. Miller, Leona A. Holmberg, Aimaz Afrough, Melhem Solh, Pashna N. Munshi, Taiga Nishihori, Larry D. Anderson, Baldeep Wirk, Gurbakhash Kaur, Muzaffar H. Qazilbash, Nina Shah, Shaji K. Kumar, Saad Z. Usmani

Department of Medical Oncology Faculty Papers

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first …

Effect Of A Muc5ac Antibody (Npc-1c) Administered With Second-Line Gemcitabine And Nab-Paclitaxel On The Survival Of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial, Brandon M Huffman, Atrayee Basu Mallick, Nora K Horick, Andrea Wang-Gillam, Peter Joel Hosein, Michael A Morse, Muhammad Shaalan Beg, Janet E Murphy, Sharon Mavroukakis, Anjum Zaki, Benjamin L Schlechter, Hanna Sanoff, Christopher Manz, Brian M Wolpin, Philip Arlen, Jill Lacy, James M Cleary

Department of Medical Oncology Faculty Papers

Importance: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel.

Objective: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC.

Design, setting, and participants: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis …

The Mutational Landscape In Chronic Myelomonocytic Leukemia And Its Impact On Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center For Blood And Marrow Transplantation Research (Cibmtr) Analysis, Matthew Mei, Raju Pillai, Soyoung Kim, Noel Estrada-Merly, Michelle Afkhami, Lixin Yang, Zhuo Meng, Muhammad Bilal Abid, Mahmoud Aljurf, Ulrike Bacher, Amer Beitinjaneh, Christopher Bredeson, Jean-Yves Cahn, Jan Cerny, Edward Copelan, Corey Cutler, Zachariah Defilipp, Miguel Angel Diaz Perez, Nosha Farhadfar, César O Freytes, Shahinaz M Gadalla, Siddhartha Ganguly, Robert Peter Gale, Usama Gergis, Michael R Grunwald, Betty K Hamilton, Shahrukh Hashmi, Gerhard C Hildebrandt, Hillard M Lazarus, Mark Litzow, Reinhold Munker, Hemant S Murthy, Sunita Nathan, Taiga Nishihori, Sagar S Patel, David Rizzieri, Sachiko Seo, Mithun Vinod Shah, Melhem Solh, Leo F Verdonck, Ravi Vij, Ronald M Sobecks, Betul Oran, Bart L Scott, Wael Saber, Ryotaro Nakamura

Department of Medical Oncology Faculty Papers

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of …

Establishing A Primary Care Alliance For Conducting Cancer Prevention Clinical Research At Community Sites, Bernard W Parker, Barbara L Mcaneny, Edith P. Mitchell, Ana Maria Lopez, Sandra A Russo, Pamela Maxwell, Leslie G Ford, Worta Mccaskill-Stevens

Department of Medical Oncology Faculty Papers

In September 2020, the National Cancer Institute convened the first PARTNRS Workshop as an initiative to forge partnerships between oncologists, primary care professionals, and non-oncology specialists for promoting patient accrual into cancer prevention trials. This effort is aimed at bringing about more effective accrual methods to generate decisive outcomes in cancer prevention research. The workshop convened to inspire solutions to challenges encountered during the development and implementation of cancer prevention trials. Ultimately, strategies suggested for protocol development might enhance integration of these trials into community settings where a diversity of patients might be accrued. Research Bases (cancer research organizations that …

Standardizing Definitions Of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, And Donor Chimerism In Allogeneic Hematopoietic Cell Transplantation: A Report On Behalf Of The American Society For Transplantation And Cellular Therapy., Mohamed A. Kharfan-Dabaja, Ambuj Kumar, Ernesto Ayala, Mahmoud Aljurf, Taiga Nishihori, Rebecca Marsh, Lauri M. Burroughs, Navneet Majhail, A. Samer Al-Homsi, Zaid S. Al-Kadhimi, Merav Bar, Alice Bertaina, Jaap J. Boelens, Richard Champlin, Sonali Chaudhury, Zachariah Defilipp, Bhagirathbhai Dholaria, Areej El-Jawahri, Suzanne Fanning, Ellen Fraint, Usama Gergis, Sergio Giralt, Betty K. Hamilton, Shahrukh K. Hashmi, Biljana Horn, Yoshihiro Inamoto, David A. Jacobsohn, Tania Jain, Laura Johnston, Abraham S. Kanate, Ankit Kansagra, Adetola Kassim, Leslie S. Kean, Carrie L. Kitko, Jessica Knight-Perry, Joanne Kurtzberg, Hien Liu, Margaret L. Macmillan, Zahra Mahmoudjafari, Marco Mielcarek, Mohamad Mohty, Arnon Nagler, Eneida Nemecek, Timothy S. Olson, Betul Oran, Miguel-Angel Perales, Susan E. Prockop, Michael A. Pulsipher, Iskra Pusic, Marcie L. Riches, Cesar Rodriguez, Rizwan Romee, Gabriela Rondon, Ayman Saad, Nina Shah, Peter J. Shaw, Shalini Shenoy, Jorge Sierra, Julie Talano, Michael R. Verneris, Paul Veys, John E. Wagner, Bipin N. Savani, Mehdi Hamadani, Paul A. Carpenter

Department of Medical Oncology Faculty Papers

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and …

The Effect Of Neighborhood Social Environment On Prostate Cancer Development In Black And White Men At High Risk For Prostate Cancer, Shannon M Lynch, Elizabeth Handorf, Kristen A Sorice, Elizabeth Blackman, Lisa Bealin, Veda N. Giri, Elias Obeid, Camille Ragin, Mary Daly

Department of Medical Oncology Faculty Papers

INTRODUCTION: Neighborhood socioeconomic (nSES) factors have been implicated in prostate cancer (PCa) disparities. In line with the Precision Medicine Initiative that suggests clinical and socioenvironmental factors can impact PCa outcomes, we determined whether nSES variables are associated with time to PCa diagnosis and could inform PCa clinical risk assessment.

MATERIALS AND METHODS: The study sample included 358 high risk men (PCa family history and/or Black race), aged 35-69 years, enrolled in an early detection program. Patient variables were linked to 78 nSES variables (employment, income, etc.) from previous literature via geocoding. Patient-level models, including baseline age, prostate specific antigen (PSA), …

Gilteritinib Or Chemotherapy For Relapsed Or Refractory Flt3-Mutated Aml, Alexander E. Perl, Giovanni Martinelli, Jorge E. Cortes, Andreas Neubauer, Ellin Berman, Stefania Paolini, Pau Montesinos, Maria R. Baer, Richard A. Larson, Celalettin Ustun, Francesco Fabbiano, Harry P. Erba, Antonio Di Stasi, Robert Stuart, Rebecca Olin, Margaret Kasner, Fabio Ciceri, Wen-Chien Chou, Nikolai Podoltsev, Christian Recher, Hisayuki Yokoyama, Naoko Hosono, Sung-Soo Yoon, Je-Hwan Lee, Timothy Pardee, Amir T. Fathi, Chaofeng Liu, Nahla Hasabou, Xuan Liu, Erkut Bahceci, Mark J. Levis

Department of Medical Oncology Faculty Papers

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML.

METHODS: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission …

Determination Of An Optimal Response Cut-Off Able To Predict Progression-Free Survival In Patients With Well-Differentiated Advanced Pancreatic Neuroendocrine Tumours Treated With Sunitinib: An Alternative To The Current Recist-Defined Response., Angela Lamarca, Jorge Barriuso, Matthew Kulke, Ivan Borbath, Heinz-Josef Lenz, Jean Luc Raoul, Neal J. Meropol, Catherine Lombard-Bohas, James Posey, Sandrine Faivre, Eric Raymond, Juan W. Valle

Department of Medical Oncology Faculty Papers

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent.

METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) …

Phase Ib/Ii Study Of The Safety And Efficacy Of Combination Therapy With Multikinase Vegf Inhibitor Pazopanib And Mek Inhibitor Trametinib In Advanced Soft Tissue Sarcoma., Vivek Subbiah, Christian Meyer, Ralph G. Zinner, Funda Meric-Bernstam, Marianna L. Zahurak, Ashley O'Connor, Jason Roszik, Kenna Shaw, Joseph A. Ludwig, Razelle Kurzrock, Nilofe A. Azad

Department of Medical Oncology Faculty Papers

Purpose: Pazopanib, a multireceptor tyrosine kinase inhibitor targeting primarily VEGFRs1–3, is approved for advanced soft tissue sarcoma (STS) and renal cell cancer. Downstream of VEGFR, trametinib is an FDA-approved MEK inhibitor used for melanoma. We hypothesized that vertical pathway inhibition using trametinib would synergize with pazopanib in advanced STS. Experimental Design: In an open-label, multicenter, investigator-initiated National Comprehensive Cancer Network (NCCN)-sponsored trial, patients with metastatic or advanced STS received pazopanib 800 mg and 2 mg of trametinib continuously for 28-day cycles. The primary endpoint was 4-month progression-free survival (PFS). Secondary endpoints were overall survival, response rate, and disease control rate. …

Post-Transplant Outcomes In High-Risk Compared With Non-High-Risk Multiple Myeloma: A Cibmtr Analysis., Emma C. Scott, Parameswaran Hari, Manish Sharma, Jennifer Le-Rademacher, Jiaxing Huang, Dan Vogl, Muneer Abidi, Amer Beitinjaneh, Henry Fung, Siddhartha Ganguly, Gerhard Hildebrandt, Leona Holmberg, Matt Kalaycio, Shaji Kumar, Robert Kyle, Hillard Lazarus, Cindy Lee, Richard T. Maziarz, Kenneth Meehan, Joseph Mikhael, Taiga Nishihori, Muthalagu Ramanathan, Saad Usmani, Jason Tay, David Vesole, Baldeep Wirk, Jean Yared, Bipin N. Savani, Cristina Gasparetto, Amrita Krishnan, Tomer Mark, Yago Nieto, Anita D'Souza

Department of Medical Oncology Faculty Papers

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (-Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher …

Risk Analysis Of Prostate Cancer In Practical, A Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci., Ali Amin Al Olama, Sara Benlloch, Antonis C Antoniou, Graham G Giles, Gianluca Severi, David E Neal, Freddie C Hamdy, Jenny L Donovan, Kenneth Muir, Johanna Schleutker, Brian E Henderson, Christopher Haiman, Fredrick R Schumacher, Nora Pashayan, Paul D P Pharoah, Elaine A Ostrander, Janet L Stanford, Jyotsna Batra, Judith A Clements, Suzanne K Chambers, Maren Weischer, Børge G Nordestgaard, Sue A Ingles, Karina D Sorensen, Torben F Orntoft, Jong Y Park, Cezary Cybulski, Christiane Maier, Thilo Doerk, Joanne L Dickinson, Lisa Cannon-Albright, Hermann Brenner, Timothy R Rebbeck, Charnita Zeigler-Johnson, Tomonori Habuchi, Stephen N Thibodeau, Kathleen A Cooney, Pierre O Chappuis, Pierre Hutter, Radka P Kaneva, William D Foulkes, Maurice P Zeegers, Yong-Jie Lu, Hong-Wei Zhang, Robert Stephenson, Angela Cox, Melissa C Southey, Amanda B Spurdle, Liesel Fitzgerald, Daniel Leongamornlert, Edward Saunders, Malgorzata Tymrakiewicz, Michelle Guy, Tokhir Dadaev, Sarah J Little, Koveela Govindasami, Emma Sawyer, Rosemary Wilkinson, Kathleen Herkommer, John L Hopper, Aritaya Lophatonanon, Antje E Rinckleb, Zsofia Kote-Jarai, Rosalind A Eeles, Douglas F Easton

Department of Medical Oncology Faculty Papers

BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.

METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.

RESULTS: The prostate cancer risk for men in the top 1% of the …

E5501: Phase Ii Study Of Topotecan Sequenced With Etoposide/Cisplatin, And Irinotecan/Cisplatin Sequenced With Etoposide For Extensive-Stage Small-Cell Lung Cancer., Taofeek K. Owonikoko, Joseph Aisner, Xin Victoria Wang, Suzanne E. Dahlberg, Eric H. Rubin, Suresh S. Ramalingam, Murugesan Gounder, Paul Gregory Rausch, Rita S. Axelrod, Md, Joan H. Schiller

Department of Medical Oncology Faculty Papers

PURPOSE: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC).

METHODS: Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m(2)) on days 1, 2 and 3, etoposide (70 mg/m(2)) and cisplatin (20 mg/m(2)) (PET) on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m(2)) and cisplatin (20 mg/m(2)) on days 1 and 8 followed by etoposide (85 mg/m(2) PO …

Recommendations For High-Priority Research On Cancer-Related Fatigue In Children And Adults., Andrea M. Barsevick, Michael R. Irwin, Pamela Hinds, Andrew Miller, Ann Berger, Paul Jacobsen, Sonia Ancoli-Israel, Bryce B Reeve, Karen Mustian, Ann O'Mara, Jin-Shei Lai, Michael Fisch, David Cella

Department of Medical Oncology Faculty Papers

Over the past decades, some scientific progress has been made in understanding and treating cancer-related fatigue (CRF). However, three major problems have limited further progress: lack of agreement about measurement, inadequate understanding of the underlying biology, and problems in the conduct of clinical trials for CRF. This commentary reports the recommendations of a National Cancer Institute Clinical Trials Planning Meeting and an ongoing National Cancer Institute working group to address these problems so that high-priority research and clinical trials can be conducted to advance the science of CRF and its treatment. Recommendations to address measurement issues included revising the current …

Is There A Role For The Quantification Of Rrm1 And Ercc1 Expression In Pancreatic Ductal Adenocarcinoma?, Matias E Valsecchi, Thomas Holdbrook, Benjamin E Leiby, Edward Pequignot, Susan J Littman, Charles Yeo, Jonathan Brody, Angieszka Witkiewicz

Department of Medical Oncology Faculty Papers

BACKGROUND: RRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce.

METHODS: We investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS).

RESULTS: A total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data …

A 2-Step Approach To Myeloablative Haploidentical Stem Cell Transplantation: A Phase 1/2 Trial Performed With Optimized T-Cell Dosing., Dolores Gross, Matthew Carabasi, Joanne Filicko-O'Hara, Margaret Kasner, John L Wagner, Beth Colombe, Patricia Cornett Farley, William O'Hara, Phyllis Flomenberg, Maria Werner-Wasik, Janet Brunner, Bijoyesh Mookerjee, Terry Hyslop, Mark Weiss, Neal Flomenberg

Department of Medical Oncology Faculty Papers

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg …

Tumor-Derived Interleukin-10 As A Prognostic Factor In Stage Iii Patients Undergoing Adjuvant Treatment With An Autologous Melanoma Cell Vaccine., Amit Mahipal, Mizue Terai, David Berd, Inna Chervoneva, Kashyap Patel, Michael Mastrangelo, Takami Sato

Department of Medical Oncology Faculty Papers

OBJECTIVES: Interleukin-10 (IL-10) downregulates T-cell-mediated immune responses. We studied the association between IL-10 production by freshly isolated melanoma cell suspensions in vitro and overall survival in patients undergoing adjuvant treatment with a vaccine prepared from the same autologous melanoma cells modified with a hapten, dinitrophenyl (DNP).

METHODS: Forty-four patients with cutaneous melanoma (29 stage III and 15 stage IV) were prospectively evaluated. Tumor cells were extracted from metastatic deposits for production of DNP-modified autologous melanoma cell vaccine. Small aliquots of the melanoma cell suspensions were separated prior to vaccine processing and cultured overnight for IL-10 production. Based on a blind …