Biomedical Informatics Commons^™

Clinical Insights Into Small Cell Lung Cancer: Tumor Heterogeneity, Diagnosis, Therapy, And Future Directions, Zsolt Megyesfalvi, Carl M Gay, Helmut Popper, Robert Pirker, Gyula Ostoros, Simon Heeke, Christian Lang, Konrad Hoetzenecker, Anna Schwendenwein, Kristiina Boettiger, Paul A Bunn, Ferenc Renyi-Vamos, Karin Schelch, Helmut Prosch, Lauren A Byers, Fred R Hirsch, Balazs Dome

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or …

Outcomes In Patients With Poor-Risk Cytogenetics With Or Without Tp53 Mutations Treated With Venetoclax And Azacitidine, Daniel A Pollyea, Keith W Pratz, Andrew H Wei, Vinod Pullarkat, Brian A Jonas, Christian Recher, Sunil Babu, Andre C Schuh, Monique Dail, Yan Sun, Jalaja Potluri, Brenda Chyla, Courtney D Dinardo

Faculty, Staff and Student Publications

PURPOSE: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt.

PATIENTS AND METHODS: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.

RESULTS: Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared …

Inclusion Of Premenopausal Women In Breast Cancer Clinical Trials, Kelsey L Corrigan, Ramez Kouzy, Joseph Abi Jaoude, Roshal R Patel, Rachel M Layman, Sharon H Giordano, Wendy A Woodward, Benjamin D Smith, Simona F Shaitelman, Ethan B Ludmir

Faculty, Staff and Student Publications

BACKGROUND: Patients with premenopausal breast cancer (PMBC) have been historically excluded from some clinical trials because of the limitations of using endocrine therapy (ET) in this population. We analyzed breast cancer randomized clinical trials (RCTs) to determine the rates of and factors associated with inclusion of PMBC patients to provide a benchmark for PMBC inclusion in RCTs moving forward.

METHODS: Using ClinicalTrials.Gov, we identified breast cancer phase III RCTs and extracted inclusion criteria and patient enrollment information. Multiple binary logistic regression modeling was used to assess trial-related factors that were associated with PMBC patient inclusion.

RESULTS: Of 170 breast …

Neoadjuvant Chemotherapy Is Associated With Altered Immune Cell Infiltration And An Anti-Tumorigenic Microenvironment In Resected Pancreatic Cancer, Andressa Dias Costa, Sara A Väyrynen, Akhil Chawla, Jinming Zhang, Juha P Väyrynen, Mai Chan Lau, Hannah L Williams, Chen Yuan, Vicente Morales-Oyarvide, Dalia Elganainy, Harshabad Singh, James M Cleary, Kimberly Perez, Kimmie Ng, William Freed-Pastor, Joseph D Mancias, Stephanie K Dougan, Jiping Wang, Douglas A Rubinson, Richard F Dunne, Margaret M Kozak, Lauren Brais, Emma Reilly, Thomas Clancy, David C Linehan, Daniel T Chang, Aram F Hezel, Albert C Koong, Andrew J Aguirre, Brian M Wolpin, Jonathan A Nowak

Faculty, Staff and Student Publications

PURPOSE: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood.

DESIGN: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient …

Phase Ii Study Of Venetoclax Added To Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine In Older Patients With Newly Diagnosed Acute Myeloid Leukemia, Tapan M Kadia, Patrick K Reville, Xuemei Wang, Caitlin R Rausch, Gautam Borthakur, Naveen Pemmaraju, Naval G Daver, Courtney D Dinardo, Koji Sasaki, Ghayas C Issa, Maro Ohanian, Guillermo Montalban-Bravo, Nicholas J Short, Nitin Jain, Alessandra Ferrajoli, Kapil N Bhalla, Elias Jabbour, Koichi Takahashi, Rashmi Malla, Kelly Quagliato, Rashmi Kanagal-Shamanna, Uday R Popat, Michael Andreeff, Guillermo Garcia-Manero, Marina Y Konopleva, Farhad Ravandi, Hagop M Kantarjian

Faculty, Staff and Student Publications

PURPOSE: The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML.

METHODS: This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with …

Epacadostat Plus Pembrolizumab And Chemotherapy For Advanced Solid Tumors: Results From The Phase I/Ii Echo-207/Keynote-723 Study, John D Powderly, Samuel J Klempner, Aung Naing, Johanna Bendell, Ignacio Garrido-Laguna, Daniel V T Catenacci, Matthew H Taylor, James J Lee, Fred Zheng, Feng Zhou, Xiaohua Gong, Hema Gowda, Gregory L Beatty

Faculty, Staff and Student Publications

Background: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy.

Methods: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab …

Lenalidomide-Based Maintenance After Autologous Hematopoietic Stem Cell Transplantation For Patients With High-Risk Multiple Myeloma, Oren Pasvolsky, Denái R Milton, Mikael Rauf, Mark R Tanner, Qaiser Bashir, Samer Srour, Guilin Tang, Neeraj Saini, Jeremy Ramdial, Adeel Masood, Yago Nieto, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Maintenance therapy with single-agent lenalidomide (Len) after autologous hematopoietic stem cell transplantation (autoHCT) for multiple myeloma (MM) is associated with improved progression-free survival (PFS). However, MM patients with high-risk chromosomal abnormalities (HRMMs) may need a more intense regimen. We hypothesized that adding another antimyeloma drug to Len maintenance would lead to improved outcomes. We conducted this retrospective single-center chart review analysis of adult HRMM patients who underwent autoHCT between 2008 and 2018, followed by Len-based maintenance therapy. High-risk cytogenetics were defined as del(17p), t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization. We divided patients into those who …

Surgical Outcomes After Neoadjuvant Nivolumab Or Nivolumab With Ipilimumab In Patients With Non-Small Cell Lung Cancer, Boris Sepesi, Nicolas Zhou, William N William, Heather Y Lin, Cheuk H Leung, Annikka Weissferdt, Kyle G Mitchell, Apar Pataer, Garrett L Walsh, David C Rice, Jack A Roth, Reza J Mehran, Wayne L Hofstetter, Mara B Antonoff, Ravi Rajaram, Marcelo V Negrao, Anne S Tsao, Don L Gibbons, J Jack Lee, John V Heymach, Ara A Vaporciyan, Stephen G Swisher, Tina Cascone

Faculty, Staff and Student Publications

BACKGROUND: Surgical outcomes for non-small cell lung cancer after neoadjuvant immune checkpoint inhibitors continue to be debated. We assessed perioperative outcomes of patients treated with Nivolumab or Nivolumab plus Ipilimumab (NEOSTAR) and compared them with patients treated with chemotherapy or previously untreated patients with stage I-IIIA non-small cell lung cancer.

METHODS: Forty-four patients with stage I to IIIA non-small cell lung cancer (American Joint Committee on Cancer Staging Manual, seventh edition) were randomized to nivolumab (N; 3 mg/kg intravenously on days 1, 15, and 29; n = 23) or nivolumab with ipilimumab (NI; I, 1 mg/kg intravenously on day 1; …

Nab-Paclitaxel, Capecitabine, And Radiation Therapy After Induction Chemotherapy In Treating Patients With Locally Advanced And Borderline Resectable Pancreatic Cancer: Phase 1 Trial And Imaging-Based Biomarker Validation, Eugene J Koay, Mohamed Zaid, Maureen Aliru, Polycarpe Bagereka, Arie Van Wieren, Maria Jovie Rodriguez, Galia Jacobson, Robert A Wolff, Michael Overman, Gauri Varadhachary, Shubham Pant, Huamin Wang, Ching-Wei Tzeng, Naruhiko Ikoma, Michael Kim, Jeffrey E Lee, Matthew Hg Katz, Eric Tamm, Priya Bhosale, Cullen M Taniguchi, Emma B Holliday, Grace L Smith, Ethan B Ludmir, Bruce D Minsky, Christopher H Crane, Albert C Koong, Prajnan Das, Xuemei Wang, Milind Javle, Sunil Krishnan

Faculty, Staff and Student Publications

PURPOSE: Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.

METHODS AND MATERIALS: Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m

RESULTS: Twenty-three patients started and finished …

Neoadjuvant Toripalimab Combined With Gemcitabine And Cisplatin In Resectable Locally Advanced Head And Neck Squamous Cell Carcinoma (Neotgp01): An Open Label, Single-Arm, Phase Ib Clinical Trial, Xiaotao Huang, Qiaodan Liu, Guihua Zhong, Yingpeng Peng, Ye Liu, Lizhong Liang, Haiyu Hong, Weineng Feng, Shuang Yang, Yaqin Zhang, Shiping Xian, Zhanyu Li, Yuling Zhou, Zhaoyuan Zhang, Wen Jiang, Jun Liang, Zhi-Gang Liu

Faculty, Staff and Student Publications

BACKGROUND: Neoadjuvant programmed death receptor-1 (PD-1) inhibitors have drawn increasing attention in locally advanced head and neck squamous cell carcinoma (HNSCC). In this study, we investigated the safety and efficacy of gemcitabine and cisplatin (GP), combined with a PD-1 inhibitor, in patients with locally advanced HNSCC.

MATERIALS AND METHODS: A total of 23 eligible patients were administered two cycles of toripalimab and GP followed by surgical resection. The primary endpoints were safety, treatment-related adverse events (TRAEs), and non-operation delay rates. The secondary endpoints consisted of pathological complete response (pCR) rate, major pathological response (MPR) rate, objective response rate (ORR), and …

Lenvatinib Plus Pembrolizumab In Japanese Patients With Endometrial Cancer: Results From Study 309/Keynote-775, Kan Yonemori, Mayu Yunokawa, Kimio Ushijima, Jun Sakata, Ayumi Shikama, Shinichiro Minobe, Tomoka Usami, Takayuki Enomoto, Kazuhiro Takehara, Kosei Hasegawa, Wataru Yamagami, Keiko Yamamoto, Shirong Han, Lea Dutta, Robert Orlowski, Takuma Miura, Vicky Makker, Keiichi Fujiwara

Faculty, Staff and Student Publications

Study 309/KEYNOTE-775 is a phase 3 open-label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum-based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression-free survival (PFS) and overall survival (OS) in all-comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m

First-In-Human Study Of An Ox40 (Ivuxolimab) And 4-1bb (Utomilumab) Agonistic Antibody Combination In Patients With Advanced Solid Tumors, Omid Hamid, Alberto A Chiappori, John A Thompson, Toshihiko Doi, Siwen Hu-Lieskovan, Ferry A L M Eskens, Willeke Ros, Adi Diab, Jean-Philippe Spano, Naiyer A Rizvi, Jeffrey S Wasser, Eric Angevin, Patrick A Ott, Alison Forgie, Wenjing Yang, Cen Guo, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

Background: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.

Methods: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every …

Mri-Based Digital Models Forecast Patient-Specific Treatment Responses To Neoadjuvant Chemotherapy In Triple-Negative Breast Cancer, Chengyue Wu, Angela M Jarrett, Zijian Zhou, Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Rania M M Mohamed, Medine Boge, Lei Huo, Jason B White, Debu Tripathy, Vicente Valero, Jennifer K Litton, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is persistently refractory to therapy, and methods to improve targeting and evaluation of responses to therapy in this disease are needed. Here, we integrate quantitative MRI data with biologically based mathematical modeling to accurately predict the response of TNBC to neoadjuvant systemic therapy (NAST) on an individual basis. Specifically, 56 patients with TNBC enrolled in the ARTEMIS trial (NCT02276443) underwent standard-of-care doxorubicin/cyclophosphamide (A/C) and then paclitaxel for NAST, where dynamic contrast-enhanced MRI and diffusion-weighted MRI were acquired before treatment and after two and four cycles of A/C. A biologically based model was established to …

Venetoclax Combined With Flag-Ida Induction And Consolidation In Newly Diagnosed Acute Myeloid Leukemia, Courtney D Dinardo, Curtis A Lachowiez, Koichi Takahashi, Sanam Loghavi, Tapan Kadia, Naval Daver, Lianchun Xiao, Maria Adeoti, Nicholas J Short, Koji Sasaki, Sa A Wang, Gautam Borthakur, Ghayas Issa, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Guillermo Montalban Bravo, Lucia Masarova, Musa Yilmaz, Nitin Jain, Michael Andreeff, Guillermo Garcia-Manero, Steven Kornblau, Farhad Ravandi, Elias Jabbour, Marina Y Konopleva, Hagop M Kantarjian

Faculty, Staff and Student Publications

Multi-agent induction chemotherapy (IC) improves response rates in younger patients with acute myeloid leukemia (AML); however, relapse remains the principal cause of treatment failure. Improved induction regimens are needed. A prospective single-center phase Ib/II study evaluating fludarabine, cytarabine, G-CSF, and idarubicin combined with venetoclax (FLAG-IDA + VEN) in patients with newly diagnosed (ND) or relapsed/refractory AML. The primary efficacy endpoint was assessment of overall activity (overall response rate [ORR]: complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi] + morphologic leukemia free state + partial response). Secondary objectives included additional assessments of …

Treatment-Free Remission After Ceasing Venetoclax-Based Therapy In Patients With Acute Myeloid Leukemia, Chong Chyn Chua, Danielle Hammond, Andrew Kent, Ing Soo Tiong, Marina Y Konopleva, Daniel A Pollyea, Courtney D Dinardo, Andrew H Wei

Faculty, Staff and Student Publications

The clinical benefit of adding venetoclax (VEN) to hypomethylating agents or low-dose cytarabine in older and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) has been confirmed in phase 3 studies. With the increased uptake of VEN-based therapies for patients with AML, a pertinent question is whether treatment can be safely ceased among patients who have achieved sustained remission. We hypothesized that a proportion of patients opting to cease therapy may benefit from a treatment-free remission (TFR) period without indefinite treatment. We report the retrospective outcomes of 29 patients in remission for a minimum of 12 months on VEN-based …

Rationale And Design Of The Phase 3 Keylynk-013 Study Of Pembrolizumab With Concurrent Chemoradiotherapy Followed By Pembrolizumab With Or Without Olaparib For Limited-Stage Small-Cell Lung Cancer, Andreas Rimner, Wei-Chu Victoria Lai, Raffaele Califano, Salma K Jabbour, Charles M Rudin, Corinne Faivre-Finn, Byoung Chul Cho, Terufumi Kato, Jinming Yu, Wyatt Chafin, Li Yu, Bin Zhao, Lauren Byers

Faculty, Staff and Student Publications

Background: The current standard of care for patients with newly diagnosed limited-stage small-cell lung cancer (SCLC) is concurrent chemoradiotherapy (CCRT). The prognosis remains poor due to the aggressiveness and high risk of progression or relapse of SCLC even if an initial response is achieved. Therefore, there is an urgent unmet clinical need in this population. The multicenter, phase 3, randomized, placebo-controlled, double-blind KEYLYNK-013 study evaluates the addition of pembrolizumab to CCRT followed by pembrolizumab with or without olaparib in participants with previously untreated limited-stage SCLC. (ClinicalTrials.gov: NCT04624204).

Methods: Eligible participants aged ≥18 years with newly diagnosed, pathologically confirmed, limited-stage …

Urgent Cytoreduction For Newly Diagnosed Acute Myeloid Leukemia Patients Allows Acquisition Of Pretreatment Genomic Data And Enrollment On Investigational Clinical Trials, Kunhwa Kim, Marina Konopleva, Courtney D Dinardo, Gautam Borthakur, Sanam Loghavi, Guilin Tang, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Caitlin R Rausch, Musa Yilmaz, Koji Sasaki, Nicholas J Short, Nitin Jain, Mark Brandt, Sherry Pierce, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did …

Molecular Characterization And Prospective Evaluation Of Pathologic Response And Outcomes With Neoadjuvant Therapy In Metaplastic Triple-Negative Breast Cancer, Clinton Yam, Nour Abuhadra, Ryan Sun, Beatriz E Adrada, Qing-Qing Ding, Jason B White, Elizabeth E Ravenberg, Alyson R Clayborn, Vicente Valero, Debu Tripathy, Senthilkumar Damodaran, Banu K Arun, Jennifer K Litton, Naoto T Ueno, Rashmi K Murthy, Bora Lim, Luis Baez, Xiaoxian Li, Aman U Buzdar, Gabriel N Hortobagyi, Alistair M Thompson, Elizabeth A Mittendorf, Gaiane M Rauch, Rosalind P Candelaria, Lei Huo, Stacy L Moulder, Jeffrey T Chang

Faculty, Staff and Student Publications

PURPOSE: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies.

EXPERIMENTAL DESIGN: To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide-based neoadjuvant therapy.

RESULTS: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience …

Impact Of Venetoclax And Azacitidine In Treatment-Naïve Patients With Acute Myeloid Leukemia And Idh1/2 Mutations, Daniel A Pollyea, Courtney D Dinardo, Martha L Arellano, Arnaud Pigneux, Walter Fiedler, Marina Konopleva, David A Rizzieri, B Douglas Smith, Atsushi Shinagawa, Roberto M Lemoli, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L Miller, Hagop M Kantarjian

Faculty, Staff and Student Publications

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML).

Patients and methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle).

Results: …

A Win Consortium Phase I Study Exploring Avelumab, Palbociclib, And Axitinib In Advanced Non-Small Cell Lung Cancer, Benjamin Solomon, Ana Callejo, Jair Bar, Guy Berchem, Lyudmila Bazhenova, Pierre Saintigny, Fanny Wunder, Jacques Raynaud, Nicolas Girard, J Jack Lee, Raed Sulaiman, Bruce Prouse, Catherine Bresson, Hila Ventura, Shai Magidi, Eitan Rubin, Brandon Young, Amir Onn, Brian Leyland-Jones, Richard L Schilsky, Vladimir Lazar, Enriqueta Felip, Razelle Kurzrock

Faculty, Staff and Student Publications

Background: The Worldwide Innovative Network (WIN) Consortium has developed the Simplified Interventional Mapping System (SIMS) to better define the cancer molecular milieu based on genomics/transcriptomics from tumor and analogous normal tissue biopsies. SPRING is the first trial to assess a SIMS-based tri-therapy regimen in advanced non-small cell lung cancer (NSCLC).

Methods: Patients with advanced NSCLC (no EGFR, ALK, or ROS1 alterations; PD-L1 unrestricted; ≤2 prior therapy lines) received avelumab, axitinib, and palbociclib (3 + 3 dose escalation design).

Results: Fifteen patients were treated (five centers, four countries): six at each of dose levels 1 (DL1) and DL2; three at DL3. …

Statins Enhance The Chemosensitivity Of R-Chop In Diffuse Large B-Cell Lymphoma, Sushanth Gouni, Paolo Strati, Gokce Toruner, Akanksha Aradhya, Ralf Landgraf, Daniel Bilbao, Francisco Vega, Nitin Kumar Agarwal

Faculty, Staff and Student Publications

The beneficial effect of statins on the anti-lymphoma activity of the rituximab-based chemotherapy regimen is controversial. Here, we retrospectively reviewed patients with naïve-treated advanced diffuse large B-cell lymphoma (DLBCL) receiving frontline R-CHOP, and for whom data regarding differential statins use was available at the time of initiation of treatment. We observe that patients treated with statins and R-CHOP experienced a significantly higher CR rate as compared to those who received R-CHOP only. We further show that patients receiving medium or high intensity statins and R-CHOP experienced a significantly higher CR as compared to those treated with R-CHOP. Six-year progression free …

Assessment Of Clinical Response Following Atezolizumab And Bevacizumab Treatment In Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial, Daniel M Halperin, Suyu Liu, Arvind Dasari, David Fogelman, Priya Bhosale, Armeen Mahvash, Jeannelyn S Estrella, Laura Rubin, Ajaykumar C Morani, Mark Knafl, Tim A Overeem, Szu-Chin Fu, Luisa M Solis, Edwin Parra Cuentas, Anuj Verma, Hong-Lei Chen, Swati Gite, Priya Subashchandrabose, Shannon Dervin, Katja Schulze, Walter C Darbonne, Cindy Yun, Ignacio I Wistuba, P Andrew Futreal, Scott E Woodman, James C Yao

Faculty, Staff and Student Publications

Importance: Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing.

Objective: To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs.

Design, setting, and participants: This single-arm, open-label …

Androgen Receptor Blockade Promotes Response To Braf/Mek-Targeted Therapy, Christopher P Vellano, Michael G White, Miles C Andrews, Manoj Chelvanambi, Russell G Witt, Joseph R Daniele, Mark Titus, Jennifer L Mcquade, Fabio Conforti, Elizabeth M Burton, Matthew J Lastrapes, Gabriel Ologun, Alexandria P Cogdill, Golnaz Morad, Peter Prieto, Alexander J Lazar, Yanshuo Chu, Guangchun Han, M A Wadud Khan, Beth Helmink, Michael A Davies, Rodabe N Amaria, Jeffrey J Kovacs, Scott E Woodman, Sapna Patel, Patrick Hwu, Michael Peoples, Jeffrey E Lee, Zachary A Cooper, Haifeng Zhu, Guang Gao, Hiya Banerjee, Mike Lau, Jeffrey E Gershenwald, Anthony Lucci, Emily Z Keung, Merrick I Ross, Laura Pala, Eleonora Pagan, Rossana Lazcano Segura, Qian Liu, Mikayla S Borthwick, Eric Lau, Melinda S Yates, Shannon N Westin, Khalida Wani, Michael T Tetzlaff, Lauren E Haydu, Mikhila Mahendra, Xiaoyan Ma, Christopher Logothetis, Zachary Kulstad, Sarah Johnson, Courtney W Hudgens, Ningping Feng, Lorenzo Federico, Georgina V Long, P Andrew Futreal, Swathi Arur, Hussein A Tawbi, Amy E Moran, Linghua Wang, Timothy P Heffernan, Joseph R Marszalek, Jennifer A Wargo

Faculty, Staff and Student Publications

Treatment with BRAF/MEK-targeted therapy has revolutionized care in melanoma and other cancers, however therapeutic resistance is common and innovative treatment strategies are needed1,2. We studied a group of melanoma patients treated with neoadjuvant BRAF/MEK-targeted therapy (NCT02231775, n=51), and observed significantly higher rates of major pathologic response (MPR= <10% viable tumor at resection) and improved recurrence-free survival (RFS) in females versus males (MPR-66% versus 14%, p=0.001; RFS-64% versus 32% at 2 years, p=0.021). Findings were validated in a several additional cohorts2–4 patients with unresectable metastatic melanoma treated with BRAF and/or MEK-targeted therapy (n=664 patients in total), demonstrating improved progression-free survival (PFS) and overall survival (OS) in females versus males in several of these studies. Studies in pre-clinical models demonstrated significantly impaired anti-tumor activity in male …

Venetoclax Combined With Induction Chemotherapy In Patients With Newly Diagnosed Acute Myeloid Leukaemia: A Post-Hoc, Propensity Score-Matched, Cohort Study, Curtis A Lachowiez, Patrick K Reville, Hagop Kantarjian, Elias Jabbour, Gautam Borthakur, Naval Daver, Sanam Loghavi, Ken Furudate, Lianchun Xiao, Sherry Pierce, Nicholas J Short, Abhishek Maiti, Musa Yilmaz, Koji Sasaki, Koichi Takahashi, Marina Konopleva, Naveen Pemmaraju, Uday Popat, Elizabeth Shpall, Guillermo Garcia-Manero, Farhad Ravandi, Courtney D Dinardo, Tapan M Kadia

Faculty, Staff and Student Publications

Background: Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone.

Methods: This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia …

Genetic Correlates In Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated With Hyper-Cvad Plus Dasatinib Or Ponatinib, Yuya Sasaki, Hagop M Kantarjian, Nicholas J Short, Feng Wang, Ken Furudate, Hidetaka Uryu, Rebecca Garris, Nitin Jain, Koji Sasaki, Farhad Ravandi, Marina Konopleva, Guillermo Garcia-Manero, Latasha Little, Curtis Gumbs, Li Zhao, P Andrew Futreal, Koichi Takahashi, Elias Jabbour

Faculty, Staff and Student Publications

Recurring genetic abnormalities have been identified in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Among them, IKZF1 deletion was associated with poor prognosis in patients treated with imatinib-based or dasatinib-based regimens. However, the molecular determinants for clinical outcomes in ponatinib-treated patients remain unknown. We systematically analyzed genetic alterations in adults with Ph-positive ALL uniformly treated in clinical trials with dasatinib-based regimens or a ponatinib-based regimen and investigated the molecular determinants for treatment outcomes using pretreatment specimens collected from adults with Ph-positive ALL treated with Hyper-CVAD plus dasatinib or ponatinib. DNA sequencing and SNP microarray were performed and recurrent genetic abnormalities …

Activity Of Decitabine As Maintenance Therapy In Core Binding Factor Acute Myeloid Leukemia, Jayastu Senapati, Mahran Shoukier, Guillermo Garcia-Manero, Xuemei Wang, Keyur Patel, Tapan Kadia, Farhad Ravandi, Naveen Pemmaraju, Maro Ohanian, Naval Daver, Courtney Dinardo, Yesid Alvarado, Jeffrey Aldrich, Gautam Borthakur

Faculty, Staff and Student Publications

Background: Posttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML.

Methods: We prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%.

Results: Thirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received …

Venetoclax Combinations Delay The Time To Deterioration Of Hrqol In Unfit Patients With Acute Myeloid Leukemia, Keith W Pratz, Panayiotis Panayiotidis, Christian Recher, Xudong Wei, Brian A Jonas, Pau Montesinos, Vladimir Ivanov, Andre C Schuh, Courtney D Dinardo, Jan Novak, Vlatko Pejsa, Don Stevens, Su-Peng Yeh, Inho Kim, Mehmet Turgut, Nicola Fracchiolla, Kazuhito Yamamoto, Yishai Ofran, Andrew H Wei, Cat N Bui, Katy Benjamin, Rajesh Kamalakar, Jalaja Potluri, Wellington Mendes, Jacob Devine, Walter Fiedler

Faculty, Staff and Student Publications

Phase 3 trials Viale-A and Viale-C evaluated health-related quality of life (HRQoL) in patients with AML unfit for intensive chemotherapy who received venetoclax (VEN) + (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C) or placebo (PBO) + AZA or LDAC. Patient-reported outcomes included: EORTC QLQ-C30 global health status (GHS/QoL) and physical functioning (PF), PROMIS Cancer Fatigue Short Form 7a (Fatigue), and EQ-5D-5L health status visual analog scale (HS-VAS). Time to deterioration (TTD), defined as worsening from baseline in meaningful change thresholds (MCT) of ≥10, 5, or 7 points for GHS/QoL or PF, fatigue, and HS-VAS, respectively, was assessed; differences between groups …

Autologous Stem Cell Transplantation For Large B-Cell Lymphoma With Secondary Central Nervous System Involvement, Serkan Akin, Chitra Hosing, Issa Khouri, Sairah Ahmed, Amin Alousi, Nathan Fowler, Jacinth Joseph, Jonathan Truxillo, Jeremy L Ramdial, Farzaneh Maadani, Gabriela Rondon, May Daher, Jin S Im, Raphael Steiner, Jason Westin, Swaminathan P Iyer, Bouthaina Dabaja, Paolo Anderlini, Uday R Popat, Muzaffar H Qazilbash, Christopher R Flowers, Elizabeth Shpall, Richard E Champlin, Yago Nieto, Samer A Srour

Faculty, Staff and Student Publications

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare, with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression-free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 …

Interleukin-6 Blockade Abrogates Immunotherapy Toxicity And Promotes Tumor Immunity, Ahmed Omar Kaseb, Elshad Hasanov, Hop Sanderson Tran Cao, Lianchun Xiao, Jean-Nicolas Vauthey, Sunyoung S Lee, Betul Gok Yavuz, Yehia I Mohamed, Aliya Qayyum, Sonali Jindal, Fei Duan, Sreyashi Basu, Shalini S Yadav, Courtney Nicholas, Jing Jing Sun, Kanwal Pratap Singh Raghav, Asif Rashid, Kristen Carter, Yun Shin Chun, Ching-Wei David Tzeng, Divya Sakamuri, Li Xu, Ryan Sun, Vittorio Cristini, Laura Beretta, James C Yao, Robert A Wolff, James Patrick Allison, Padmanee Sharma

Faculty, Staff and Student Publications

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma.

METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 …

Perioperative Nivolumab Monotherapy Versus Nivolumab Plus Ipilimumab In Resectable Hepatocellular Carcinoma: A Randomised, Open-Label, Phase 2 Trial, Ahmed Omar Kaseb, Elshad Hasanov, Hop Sanderson Tran Cao, Lianchun Xiao, Jean-Nicolas Vauthey, Sunyoung S Lee, Betul Gok Yavuz, Yehia I Mohamed, Aliya Qayyum, Sonali Jindal, Fei Duan, Sreyashi Basu, Shalini S Yadav, Courtney Nicholas, Jing Jing Sun, Kanwal Pratap Singh Raghav, Asif Rashid, Kristen Carter, Yun Shin Chun, Ching-Wei David Tzeng, Divya Sakamuri, Li Xu, Ryan Sun, Vittorio Cristini, Laura Beretta, James C Yao, Robert A Wolff, James Patrick Allison, Padmanee Sharma

Faculty, Staff and Student Publications

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma.

METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 …