162 results on '"Kerry A. Rogers"'
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2. Consensus opinion from an international group of experts on measurable residual disease in hairy cell leukemia
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Farhad Ravandi, Robert J. Kreitman, Enrico Tiacci, Leslie Andritsos, Versha Banerji, Jacqueline C. Barrientos, Seema A. Bhat, James S. Blachly, Alessandro Broccoli, Timothy Call, Dai Chihara, Claire Dearden, Judit Demeter, Sasha Dietrich, Monica Else, Narendranath Epperla, Brunangelo Falini, Francesco Forconi, Douglas E. Gladstone, Alessandro Gozzetti, Sunil Iyengar, James B. Johnston, Jeffrey Jorgensen, Gunnar Juliusson, Francesco Lauria, Gerard Lozanski, Sameer A. Parikh, Jae H. Park, Aaron Polliack, Graeme Quest, Tadeusz Robak, Kerry A. Rogers, Alan Saven, John F. Seymour, Tamar Tadmor, Martin S. Tallman, Constantine S. Tam, Philip A. Thompson, Xavier Troussard, Clive S. Zent, Thorsten Zenz, Pier Luigi Zinzani, Bernhard Wörmann, Kanti Rai, and Michael Grever
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.
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- 2022
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3. Preclinical evaluation of combination nemtabrutinib and venetoclax in chronic lymphocytic leukemia
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Elizabeth M. Muhowski, Janani Ravikrishnan, Britten Gordon, Lianbo Yu, Shrilekha Misra, Brandi Walker, Sudharshan Eathiraj, Deepa Sampath, Kerry A. Rogers, John C. Byrd, and Jennifer A. Woyach
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CLL ,Nemtabrutinib ,Ibrutinib ,Venetoclax ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Inhibitors of B cell receptor (BCR) signaling such as the Bruton’s tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.
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- 2022
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4. Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia
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Janek S. Walker, Zachary A. Hing, Bonnie Harrington, Jordan Baumhardt, Hatice Gulcin Ozer, Amy Lehman, Brian Giacopelli, Larry Beaver, Katie Williams, Jordan N. Skinner, Casey B. Cempre, Qingxiang Sun, Sharon Shacham, Benjamin R. Stromberg, Matthew K. Summers, Lynne V. Abruzzo, Laura Rassenti, Thomas J. Kipps, Sameer Parikh, Neil E. Kay, Kerry A. Rogers, Jennifer A. Woyach, Vincenzo Coppola, Yuh Min Chook, Christopher Oakes, John C. Byrd, and Rosa Lapalombella
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XPO1 ,Chronic lymphocytic leukemia ,Mouse model ,Selinexor ,Sines ,Expression profiling ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Exportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood. Methods We performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor). Results We report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL. Conclusions These findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.
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- 2021
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5. Optimizing extracellular vesicles’ isolation from chronic lymphocytic leukemia patient plasma and cell line supernatant
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Sara Elgamal, Emanuele Cocucci, Ellen J. Sass, Xiaokui M. Mo, Angela R. Blissett, Edward P. Calomeni, Kerry A. Rogers, Jennifer A. Woyach, Seema A. Bhat, Natarajan Muthusamy, Amy J. Johnson, Karilyn T. Larkin, and John C. Byrd
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Hematology ,Oncology ,Medicine - Abstract
In chronic lymphocytic leukemia (CLL) and very likely all cancer types, extracellular vesicles (EVs) are a common mechanism by which intercellular messages are communicated between normal, diseased, and transformed cells. Studies of EVs in CLL and other cancers have great variability and often lack reproducibility. For CLL patient plasma and cell lines, we sought to characterize current approaches used in isolating EV products and understand whether cell culture–conditioned media or complex biological fluids confound results. Utilizing nanoparticle tracking analysis, protein quantification, and electron microscopy, we show that ultracentrifugation with an OptiPrep cushion can effectively minimize contaminants from starting materials including plasma and conditioned media of CLL cell lines grown in EV-depleted complete RPMI media but not grown in the serum-free media AIM V commonly used in CLL experimental work. Moreover, we confirm the benefit of including 25 mM trehalose in PBS during EV isolation steps to reduce EV aggregation, to preserve function for downstream applications and characterization. Furthermore, we report the highest particles/μg EVs were obtained from our CLL cell lines utilizing the CELLine bioreactor flask. Finally, we optimized a proliferation assay that offers a functional evaluation of our EVs with minimal sample requirements.
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- 2021
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6. Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia
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Kerry A. Rogers, Philip A. Thompson, John N. Allan, Morton Coleman, Jeff P. Sharman, Bruce D. Cheson, Daniel Jones, Raquel Izumi, Melanie M. Frigault, Cheng Quah, Rakesh K. Raman, Priti Patel, Min Hui Wang, and Thomas J. Kipps
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
B-cell receptor signalling inhibition by targeting Bruton tyrosine kinase (BTK) is effective in treating chronic lymphocytic leukemia (CLL). The BTK inhibitor ibrutinib may be intolerable for some patients. Acalabrutinib is a more selective BTK inhibitor that may be better tolerated by patients who are intolerant to ibrutinib. A phase 2 study of acalabrutinib was conducted in patients with relapsed/refractory CLL who were ibrutinib-intolerant and had continued disease activity. Intolerance was defined as having discontinued ibrutinib due to persistent grade 3/4 adverse events (AEs) or persistent/recurrent grade 2 AEs despite dose modification/interruption. Patients received oral acalabrutinib 100 mg twice daily until disease progression or intolerance. Sixty patients were treated. Overall response rate to acalabrutinib was 73% and three patients (5%) achieved complete remission. At median follow-up of 35 months, the median progressionfree and overall survival were not reached; 24-month estimates were 72% and 81%, respectively. The most frequent AEs with acalabrutinib were diarrhea (53%), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%). Most common reasons for acalabrutinib discontinuation were progressive disease (23%) and AEs (17%). Most patients with baseline samples (49/52; 94%) and all with on-treatment samples (3/3; 100%) had no detectable BTK and/or PLCG2 mutations. Acalabrutinib is effective and tolerable in most patients with relapsed/refractory CLL who are intolerant of ibrutinib. Acalabrutinib may be useful for patients who may benefit from BTK inhibitor therapy but are ibrutinib intolerant.
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- 2021
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7. Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib
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Cecelia R. Miller, Amy S. Ruppert, Nyla A. Heerema, Kami J. Maddocks, Jadwiga Labanowska, Heather Breidenbach, Gerard Lozanski, Weiqiang Zhao, Amber L. Gordon, Jeffrey A. Jones, Joseph M. Flynn, Samantha M. Jaglowski, Leslie A. Andritsos, Kristie A. Blum, Farrukh T. Awan, Kerry A. Rogers, Michael R. Grever, Amy J. Johnson, Lynne V. Abruzzo, Erin K. Hertlein, James S. Blachly, Jennifer A. Woyach, and John C. Byrd
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 (P = .03), deletion 17p (P = .03), and complex karyotype (P = .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation (P < .0001), but not due to progressive CLL (P = .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; P < .0001) and complex karyotype (HR, 4.77; 95% CI, 1.42-15.94; P = .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.
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- 2017
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8. Ventricular arrhythmias and sudden death events following acalabrutinib initiation
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Seema A. Bhat, John Gambril, Leylah Azali, Sunnia T. Chen, Lindsay Rosen, Marilly Palettas, Tracy E. Wiczer, Sujay Kalathoor, Qiuhong Zhao, Kerry A. Rogers, Adam Kittai, Michael Grever, Farrukh Awan, Patrick Ruz, John C. Byrd, Jennifer Woyach, and Daniel Addison
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Heart Failure ,Death, Sudden ,Pyrazines ,Benzamides ,Immunology ,Humans ,Arrhythmias, Cardiac ,Cell Biology ,Hematology ,Biochemistry ,Aged - Abstract
Acalabrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, unexplained ventricular arrhythmias (VAs) with next-generation BTKi-therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow-up is unknown. Leveraging a large-cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence of VAs. The primary-endpoint was incident VA development (ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular contractions). Probability-scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as function of time-on-therapy were calculated. Weighted average observed incidence rates were compared with expected population rates using relative-risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1063 person-years of follow-up, there were 8 cases of incident-VAs, including 6 in those without coronary disease (CAD) or heart failure (HF) and 1 sudden-death; median time-to-event 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100 000 person years compared with a reported incidence of 48.1 among similar-aged non–BTKi-treated subjects (relative risk, 8.2; P
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- 2022
9. Evaluation of allogeneic and autologous membrane-bound IL-21–expanded NK cells for chronic lymphocytic leukemia therapy
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Max Yano, Chia Sharpe, J. Rachel Lance, Janani Ravikrishnan, Kevan Zapolnik, Xiaokui Mo, Jennifer A. Woyach, Deepa Sampath, Adam S. Kittai, Sumithira Vasu, Seema Bhat, Kerry A. Rogers, Dean A. Lee, Natarajan Muthusamy, and John C. Byrd
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Killer Cells, Natural ,Mice ,immune system diseases ,hemic and lymphatic diseases ,Hematopoietic Stem Cell Transplantation ,Animals ,Humans ,Antineoplastic Agents ,Hematology ,Leukemia, Lymphocytic, Chronic, B-Cell - Abstract
Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with anti-CD20 antibodies significantly enhances NK recognition and killing of CLL targets. As any CLL immune therapy would likely be given in combination, we assess commonly used treatments and demonstrate that ibrutinib has mixed suppressive and protective effects on expanded NK cells, whereas expanded NKs are highly resistant to venetoclax. We demonstrate efficacy in vivo in 2 xenograft mouse models of human CLL that support building upon a regimen of venetoclax and obinutuzumab with mbIL-21–expanded NK cells. Collectively, these data support development of mbIL-21–expanded NKs combined with the CD20 antibody obinutuzumab and venetoclax in the treatment of CLL.
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- 2022
10. Differential regulation of CTLA4 expression through BTK-dependent and independent mechanisms in CLL
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Max Yano, Jessica Nunes, Xiaokui Mo, Kerry A. Rogers, Jennifer A. Woyach, John C. Byrd, and Natarajan Muthusamy
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Pyrimidines ,Agammaglobulinaemia Tyrosine Kinase ,Humans ,Pyrazoles ,CTLA-4 Antigen ,Hematology ,Protein-Tyrosine Kinases ,Leukemia, Lymphocytic, Chronic, B-Cell - Abstract
Cytotoxic T lymphocyte antigen 4 (CTLA4) is a major immune checkpoint and target for cancer immunotherapy. Although originally discovered and primarily studied on T cells, its role on other cell types has also been recognized in recent years. Here we describe an unexpected interaction between ibrutinib (a targeted inhibitor of Bruton tyrosine kinase [BTK]) and CTLA4 expression on malignant chronic lymphocytic leukemia (CLL) cells. Although BTK itself does play a role in CTLA4 expression in CLL, we demonstrate that ibrutinib’s main suppressive effect on CTLA4 protein expression and trafficking occurs through non-BTK targets influenced by this drug. This suppression is not seen in T cells, indicating a different mechanism of CTLA4 regulation in CLL vs T cells. Appreciating this distinct mechanism and the beneficial non-BTK effects of ibrutinib may contribute to understanding the immune benefits of ibrutinib treatment and lead to therapeutic approaches to improve immune function in patients with CLL by suppressing CTLA4 expression.
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- 2022
11. Correction: Evaluation of bleeding events in patients receiving acalabrutinib therapy
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Pooja S. Kumar, Tracy Wiczer, Lindsay Rosen, Arthur J. Pollauf, Amy Zheng, Marilly Palettas, Leylah Azali, Seema A. Bhat, John C. Byrd, Michael R. Grever, Kerry A. Rogers, Jennifer A. Woyach, and Adam S. Kittai
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Cancer Research ,Oncology ,Hematology - Published
- 2023
12. Abstract CT021: Assessing clinical and pharmacodynamic (PD) profiles of patients (pts) with chronic lymphocytic leukemia (CLL) on ianalumab (VAY736) + ibrutinib
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Kerry Anne Rogers, Pearlly Yan, Ian W. Flinn, Deborah M. Stephens, Thomas J. Kipps, Sarah M. Larson, Laura Martz, Xi Chen, Huabao Wang, Ethan Hopping, Ralf Bundschuh, Alexandra Acosta, Daniela Baldoni, Anwesha Chaudhury, Jeanne Whalen, Nadia B. Hassounah, Nina Orwitz, Janghee Woo, and John C. Byrd
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Cancer Research ,Orphan Drug ,Rare Diseases ,Oncology ,Lymphoma ,Clinical Research ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Hematology ,Oncology & Carcinogenesis ,Cancer - Abstract
Introduction VAY736 is an afucosylated, human monoclonal antibody engineered to enhance antibody-dependent cellular cytotoxicity that targets BAFF-R+ B cells for elimination. In preclinical CLL models, VAY736 showed antileukemic activity and, when combined with ibrutinib, significantly reduced disease burden, which may allow some pts to discontinue ibrutinib. Methods This Phase Ib dose-escalation (ESC)/-expansion (EXP) trial (NCT03400176) enrolled pts with CLL who did not achieve a complete response (CR) after >1 year of ibrutinib or had developed a resistance mutation to ibrutinib. Pts received IV VAY736 (ESC: 0.3-9 mg/kg; EXP: 3 mg/kg) once every 2 weeks and oral ibrutinib (420 mg) once daily for up to 8 28-day cycles. Pts achieving undetectable MRD (uMRD) at C9D1 could discontinue ibrutinib at investigator discretion. The study aimed to characterize the safety and tolerability of VAY736 + ibrutinib, assess antitumor activity, PK, and characterize PD profiles. Results By Jul 29, 2022, 39 pts were enrolled (ESC: n=15; EXP: n=24). Table 1 shows pt characteristics, safety, and efficacy data. The overall response at C9D1 for 37 evaluable pts was 40.5% CR + CRi and 16.2% PR (1L: 63.6% CR + CRi and 18.2% PR). At C9D1, 17 pts (45.9%) had uMRD in blood or bone marrow (BM). In the 2-year follow-up period, 16 pts discontinued ibrutinib and were off therapy for 4.9-19.8 months. Frequency of peripheral NKp46+ NK cells increased at least 50% after VAY736 in over 50% of pts. Preliminary coverage-based limiting-cell experiment analysis of RNAseq (CLEAR) data from 10 pts supports peripheral NK cell activation with VAY736. Conclusions VAY736 + ibrutinib appears highly active and has an acceptable safety profile. Multiple pts attained uMRD in blood or BM. Biomarker data suggest NK cell activation with VAY736. More pts will be included in the RNAseq analysis at presentation. Future development of VAY736 for CLL is strongly indicated based on these promising data. Table 1. Patient characteristics, safety, and efficacy results. All patients (N=39) Patient demographics and prior treatment Median age, years (range) 65.0 (39-82) ECOG performance status, n (%) 0 36 (92.3) 1 3 (7.7) No prior regimens excluding ibrutinib, n (%) 12 (30.8) Median number of prior regimens, n (range) 1.0 (0.0-14.0) Median duration of ibrutinib, years (range) 2.95 (0.2-8.3) Patient baseline characteristics Dohner risk by FISH,a n (%) 17p deletion 6 (15.4) 11q deletion 9 (23.1) Trisomy 12 3 (7.7) 13q deletion 10 (25.6) IGHV mutant status, n (%) Non-mutant 32 (82.1) Complex karyotype, n (%) Yes 20 (51.3) Safety Dose-limiting toxicities, n (%) 0 Patients with at least one AE, any grade, n (%) 38 (97.4) Patients with at least one Grade ≥3 AE, n (%) 13 (33.3) Most common (occurring in ≥2 patients) Grade ≥3 AEs, n (%) Neutrophil count decreased 5 (12.8) Lymphocyte count decreased 2 (5.1) Hypophosphatemia 2 (5.1) Lipase increased 2 (5.1) Efficacy 1Lb n=11 R/R n=26 Evaluable patients N=37 Overall response at C9D1 or before discontinuation,c n (%) Complete response 6 (54.5) 8 (30.8) 14 (37.8) Complete response with incomplete marrow recovery 1 (9.1) 0 1 (2.7) Partial response 2 (18.2) 4 (15.4) 6 (16.2) Stable disease 2 (18.2) 8 (30.8) 10 (27.0) Progressive disease 0 5 (19.2) 5 (13.5) uMRD response at C9D1 or before discontinuation,c n (%) Bone marrow uMRD 6 (54.5) 6 (23.1) 12 (32.4) Blood uMRD 7 (63.6) 10 (38.5) 17 (45.9) Blood or bone marrow uMRD 7 (63.6) 10 (38.5) 17 (45.9) Patients elected to discontinue ibrutinib after achieving CR or uMRD, n (%) 16 (43.2) aThe categories were: patients with a 17p deletion; patients with an 11q deletion without a 17p deletion; patients with trisomy 12 without a 17p deletion or an 11q deletion; and patients with a 13q deletion without a 17p deletion, trisomy 12, or an 11q deletion; bPatients with no prior therapies excluding ibrutinib; cFor evaluable patients (N=37). 1L, first line; AE, adverse event; CR, complete response; C, cycle; D, day; ECOG, Eastern Cooperative Oncology Group; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy chain variable region; R/R, relapsed/refractory; uMRD, undetectable minimal residual disease. Citation Format: Kerry Anne Rogers, Pearlly Yan, Ian W. Flinn, Deborah M. Stephens, Thomas J. Kipps, Sarah M. Larson, Laura Martz, Xi Chen, Huabao Wang, Ethan Hopping, Ralf Bundschuh, Alexandra Acosta, Daniela Baldoni, Anwesha Chaudhury, Jeanne Whalen, Nadia B. Hassounah, Nina Orwitz, Janghee Woo, John C. Byrd. Assessing clinical and pharmacodynamic (PD) profiles of patients (pts) with chronic lymphocytic leukemia (CLL) on ianalumab (VAY736) + ibrutinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT021.
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- 2023
13. Data from Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia
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John C. Byrd, Min-Hui Wang, Cheng Quah, Veerendra Munugalavadla, Raquel Izumi, Ahmed Hamdy, Melanie M. Frigault, Michael Gulrajani, Barbara L. Andersen, David M. Weiss, Gerard Lozanski, Mojgan Jianfar, Seema A. Bhat, Kerry A. Rogers, James S. Blachly, and Jennifer A. Woyach
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Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2–6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL.Significance:Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity–enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.This article is highlighted in the In This Issue feature, p. 327
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- 2023
14. Supplemental Methods from The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
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Jennifer A. Woyach, John C. Byrd, Amy J. Johnson, Brian Schwartz, Giovanni Abbadessa, Sudharshan Eathiraj, Rosa Lapalombella, Deepa Sampath, Amy M. Lehman, Leslie Andritsos, Kami Maddocks, Farrukh T. Awan, Kerry A. Rogers, Bonnie K. Harrington, Minh Tran, Virginia M. Goettl, Catherine A. Fabian, Elizabeth M. Muhowski, J.T. Greene, Lisa L. Smith, Rose Mantel, and Sean D. Reiff
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methods
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- 2023
15. Suppl Figure 2 from The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
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Jennifer A. Woyach, John C. Byrd, Amy J. Johnson, Brian Schwartz, Giovanni Abbadessa, Sudharshan Eathiraj, Rosa Lapalombella, Deepa Sampath, Amy M. Lehman, Leslie Andritsos, Kami Maddocks, Farrukh T. Awan, Kerry A. Rogers, Bonnie K. Harrington, Minh Tran, Virginia M. Goettl, Catherine A. Fabian, Elizabeth M. Muhowski, J.T. Greene, Lisa L. Smith, Rose Mantel, and Sean D. Reiff
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Suppl Figure 2 with legend
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- 2023
16. Suppl Table 2 from The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
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Jennifer A. Woyach, John C. Byrd, Amy J. Johnson, Brian Schwartz, Giovanni Abbadessa, Sudharshan Eathiraj, Rosa Lapalombella, Deepa Sampath, Amy M. Lehman, Leslie Andritsos, Kami Maddocks, Farrukh T. Awan, Kerry A. Rogers, Bonnie K. Harrington, Minh Tran, Virginia M. Goettl, Catherine A. Fabian, Elizabeth M. Muhowski, J.T. Greene, Lisa L. Smith, Rose Mantel, and Sean D. Reiff
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Suppl Table 2 with legend
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- 2023
17. Suppl Table 1 from The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
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Jennifer A. Woyach, John C. Byrd, Amy J. Johnson, Brian Schwartz, Giovanni Abbadessa, Sudharshan Eathiraj, Rosa Lapalombella, Deepa Sampath, Amy M. Lehman, Leslie Andritsos, Kami Maddocks, Farrukh T. Awan, Kerry A. Rogers, Bonnie K. Harrington, Minh Tran, Virginia M. Goettl, Catherine A. Fabian, Elizabeth M. Muhowski, J.T. Greene, Lisa L. Smith, Rose Mantel, and Sean D. Reiff
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Suppl Table 1 with legend
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- 2023
18. Suppl Figure 1 from The BTK Inhibitor ARQ 531 Targets Ibrutinib-Resistant CLL and Richter Transformation
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Jennifer A. Woyach, John C. Byrd, Amy J. Johnson, Brian Schwartz, Giovanni Abbadessa, Sudharshan Eathiraj, Rosa Lapalombella, Deepa Sampath, Amy M. Lehman, Leslie Andritsos, Kami Maddocks, Farrukh T. Awan, Kerry A. Rogers, Bonnie K. Harrington, Minh Tran, Virginia M. Goettl, Catherine A. Fabian, Elizabeth M. Muhowski, J.T. Greene, Lisa L. Smith, Rose Mantel, and Sean D. Reiff
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Suppl Figure 1 with legend
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- 2023
19. Refining prognosis in chronic lymphocytic leukemia with normal Fluorescence in situ hybridization results
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Matthew R. Avenarius, Ying Huang, Jonathan Hyak, John C. Byrd, Seema A. Bhat, Michael Grever, Adam S. Kittai, Kerry A. Rogers, Dan Jones, Weiqiang Zhao, Nyla A. Heerema, Lynne V. Abruzzo, Jennifer Woyach, and Cecelia R. Miller
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Cancer Research ,Oncology ,Hematology ,General Medicine - Published
- 2023
20. Supplementary Data from Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia
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John C. Byrd, Min-Hui Wang, Cheng Quah, Veerendra Munugalavadla, Raquel Izumi, Ahmed Hamdy, Melanie M. Frigault, Michael Gulrajani, Barbara L. Andersen, David M. Weiss, Gerard Lozanski, Mojgan Jianfar, Seema A. Bhat, Kerry A. Rogers, James S. Blachly, and Jennifer A. Woyach
- Abstract
Figure S1 shows immunoglobulin A, B, and M levels in treated patients over time Figure S2 shows investigator-assessed progression-free survival by CLL-IPI score and presence or absence of complex karyotype
- Published
- 2023
21. Enitociclib (VIP152/formerly BAY1251152) Is a Selective and Active CDK9 Inhibitor : Preliminary Safety and Early Signs of Efficacy in Patients with Non-Hodgkin Lymphoma (NHL) and Chronic Lymphocytic Leukemia (CLL)
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Mazyar Shadman, Anthony R. Mato, Connie Lee Batlevi, Ian W. Flinn, Martin Gutierrez, Marc Uemura, Don A. Stevens, Daniel Morillo, John C. Byrd, Melanie M. Frigault, George Clemens, Xin Huang, Raquel Izumi, Harvey Wong, Renee Breed, Hermes Garban, Amy J. Johnson, Beatrix Stelte-Ludwig, Arushi Mithal, Joseph Birkett, Ahmed Hamdy, and Kerry A. Rogers
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
22. Characterizing the Development of Secondary Myelodysplastic Syndrome (MDS) with Antecedent or Concurrent Chronic Lymphocytic Leukemia (CLL) in the Era of Small Molecule Inhibitors for the Treatment of CLL
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Kristin L Koenig, Prachi Jain, Ying Huang, Kerry A. Rogers, Seema A. Bhat, Jennifer A. Woyach, Michael R. Grever, Uma Borate, Alice S. Mims, Daniel Jones, Cecelia Miller, James S. Blachly, and Adam S Kittai
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
23. Treatment of CLL-Associated Autoimmune Cytopenias and Outcomes in a Single Institution Cohort Study
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Isaac Esplin, Ying Huang, Seema A. Bhat, Cara Grantier, Michael R. Grever, Corinne Hoffman, Adam S Kittai, Margaret S. Lucas, Mollie E. Moran, Mark Reid, Swetha Suresh, Jennifer A. Woyach, and Kerry A. Rogers
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study
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Deborah M. Stephens, Ying Huang, Amy S. Ruppert, Janek S. Walker, Daniel Canfield, Casey B. Cempre, Qiang Fu, Sharyn Baker, Boyu Hu, Harsh Shah, Renee Vadeboncoeur, Kerry A. Rogers, Seema Bhat, Samantha M. Jaglowski, Hank Lockman, Rosa Lapalombella, John C. Byrd, and Jennifer A. Woyach
- Subjects
Adult ,Cancer Research ,Adenine ,Lymphoma, Non-Hodgkin ,Triazoles ,Leukemia, Lymphocytic, Chronic, B-Cell ,Article ,Hydrazines ,Pyrimidines ,Piperidines ,Oncology ,Humans ,Pyrazoles ,Lymphoma, Large B-Cell, Diffuse - Abstract
Purpose: Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Patients and Methods: In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD. Results: Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1–14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9–16.1] and 2.7 (95% CI, 0.7–5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1–89.2) and 27.8% (95% CI, 10.1–48.9) for patients with CLL and NHL, respectively. Conclusions: The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.
- Published
- 2022
25. Data from Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study
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Jennifer A. Woyach, John C. Byrd, Rosa Lapalombella, Hank Lockman, Samantha M. Jaglowski, Seema Bhat, Kerry A. Rogers, Renee Vadeboncoeur, Harsh Shah, Boyu Hu, Sharyn Baker, Qiang Fu, Casey B. Cempre, Daniel Canfield, Janek S. Walker, Amy S. Ruppert, Ying Huang, and Deborah M. Stephens
- Abstract
Purpose:Dual blockade of Bruton's tyrosine kinase with ibrutinib and selinexor has potential to deepen responses for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).Patients and Methods:In this phase I study (clinicaltrials.gov: NCT02303392), adult patients with CLL/NHL, relapsed/refractory to ≥1 prior therapy were enrolled. Patients received weekly oral selinexor and daily oral ibrutinib in 28-day cycles until progression or intolerance. Primary objective was to determine MTD.Results:Included patients had CLL (n = 16) or NHL (n = 18; 9 Richter transformation, 6 diffuse large B-cell lymphoma, and 3 mantle cell lymphoma). Median prior therapies were 4 (range = 1–14) and 59% previously received ibrutinib. The established MTD was 40 mg of selinexor (days 1, 8, 15) and 420 mg daily ibrutinib. Common nonhematologic adverse events were fatigue (56%), nausea (53%), anorexia (41%), and diarrhea (41%) and were mostly low grade. Overall response rate was 32%. An additional 47% achieved stable disease (SD), some prolonged (up to 36 months). Median progression-free survival for patients with CLL and NHL was 8.9 [95% confidence interval (CI), 3.9–16.1] and 2.7 (95% CI, 0.7–5.4) months, respectively. For patients with CLL who did not receive prior ibrutinib, only 20% (1/5) progressed. Estimated 2-year overall survival was 73.7% (95% CI, 44.1–89.2) and 27.8% (95% CI, 10.1–48.9) for patients with CLL and NHL, respectively.Conclusions:The selinexor and ibrutinib combination has demonstrated tolerability in patients with relapsed/refractory CLL/NHL. Responses were durable. Notable responses were seen in patients with CLL with minimal prior therapy. Future study of this combination will focus on efforts to deepen remissions in patients with CLL receiving ibrutinib therapy.
- Published
- 2023
26. Supplementary Data from Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia
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Farrukh T. Awan, John C. Byrd, Jennifer A. Woyach, Jeffrey Jones, Kerry A. Rogers, Leslie A. Andritsos, Mitch A. Phelps, Darlene M. Bystry, Mohamed Badawi, Xiaokui Mo, Lindsey Rike, Narendranath Epperla, Qiuhong Zhao, and Shanmugapriya Thangavadivel
- Abstract
Supplementary file
- Published
- 2023
27. Data from Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma
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Jennifer A. Woyach, Rosa Lapalombella, John C. Byrd, Pearlly Yan, Danielle K. White, Ronni Wasmuth, Lisa L. Smith, Deepa Sampath, Rose Mantel, Parviz Kanga, Zachary A. Hing, Virginia M. Goettl, Ralf Bundschuh, Justin Breitbach, Lianbo Yu, Alexander Pan, Bonnie K. Harrington, Kerry A. Rogers, and Fabienne Lucas
- Abstract
Purpose:Aberrant Myc expression is a major factor in the pathogenesis of aggressive lymphoma, and these lymphomas, while clinically heterogeneous, often are resistant to currently available treatments and have poor survival. Myc expression can also be seen in aggressive lymphomas that are observed in the context of CLL, and we sought to develop a mouse model that could be used to study therapeutic strategies for aggressive lymphoma in the context of CLL.Experimental Design:We crossed the Eμ-TCL1 mouse model with the Eμ-Myc mouse model to investigate the clinical phenotype associated with B-cell–restricted expression of these oncogenes. The resulting malignancy was then extensively characterized, from both a clinical and biologic perspective.Results:Eμ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically, immunophenotypically, and molecularly distinct concurrent CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in the double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was, however, observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma.Conclusions:The Eμ-TCL1xMyc mouse is a new preclinical tool for testing experimental drugs for aggressive B-cell lymphoma, including in the context of CLL.
- Published
- 2023
28. Supplementary Data from Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study
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Jennifer A. Woyach, John C. Byrd, Rosa Lapalombella, Hank Lockman, Samantha M. Jaglowski, Seema Bhat, Kerry A. Rogers, Renee Vadeboncoeur, Harsh Shah, Boyu Hu, Sharyn Baker, Qiang Fu, Casey B. Cempre, Daniel Canfield, Janek S. Walker, Amy S. Ruppert, Ying Huang, and Deborah M. Stephens
- Abstract
Supplementary Data from Selinexor Combined with Ibrutinib Demonstrates Tolerability and Safety in Advanced B-Cell Malignancies: A Phase I Study
- Published
- 2023
29. Supplementary Tables 4 and 5 from Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma
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Jennifer A. Woyach, Rosa Lapalombella, John C. Byrd, Pearlly Yan, Danielle K. White, Ronni Wasmuth, Lisa L. Smith, Deepa Sampath, Rose Mantel, Parviz Kanga, Zachary A. Hing, Virginia M. Goettl, Ralf Bundschuh, Justin Breitbach, Lianbo Yu, Alexander Pan, Bonnie K. Harrington, Kerry A. Rogers, and Fabienne Lucas
- Abstract
Supplemental Table 4: Abundance information of top 20 CDR3 sequences and top 10 heavy chains and top 10 light chains (see supplemental Excel file) Supplemental Table 5: DESeq2 normalized counts, log2-fold change, and p-values and adjusted p-values for selected oncogenes, Myc and TCL1A (see supplemental Excel file)
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- 2023
30. Supplementary Data from Eμ-TCL1xMyc: A Novel Mouse Model for Concurrent CLL and B-Cell Lymphoma
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Jennifer A. Woyach, Rosa Lapalombella, John C. Byrd, Pearlly Yan, Danielle K. White, Ronni Wasmuth, Lisa L. Smith, Deepa Sampath, Rose Mantel, Parviz Kanga, Zachary A. Hing, Virginia M. Goettl, Ralf Bundschuh, Justin Breitbach, Lianbo Yu, Alexander Pan, Bonnie K. Harrington, Kerry A. Rogers, and Fabienne Lucas
- Abstract
Supplemental Figure 1: Commonly used murine cell surface markers of B-cell development Supplemental Figure 2: Multicolor flow cytometry gating strategy and representative flow plots from a WT spleen sample Supplemental Figure 3: Histopathological assessment of bone marrow aspirates Supplemental Figure 4: Relative changes of mature B-cell subsets in marrow and blood Supplemental Figure 5: Myc and TCL1 expression in CD21-IgM-, CD21-IgM+ and CD19+CD5+ populations Supplemental Figure 6: Characterization of BCR and V gene usage Supplemental Figure 7: B220low/+CD19+CD5+ CLL-like population in recipients of flow-sorted dTG malignancy components Supplemental Figure 8: Immunophenotype of B220+ non-CLL cells in recipients of flow-sorted dTG malignancy components Supplemental Table 1: Fluorophores, concentrations and suppliers of antibodies used to stain murine cells Supplemental Table 2: Low-input RNA-seq post-alignment quality control metrics Supplemental Table 3: Alignment statistics of heavy- and light chain- (lambda and kappa) B-cell receptor (BCR) reads Supplemental Table 6: Characteristics of recipient mice and engrafted diseases after injection of flow-sorted CLL, CD21-IgM- and CD21-IgM+ cells obtained from pooled diseased dTG donor mice (n=3)
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- 2023
31. Data from Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia
- Author
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Farrukh T. Awan, John C. Byrd, Jennifer A. Woyach, Jeffrey Jones, Kerry A. Rogers, Leslie A. Andritsos, Mitch A. Phelps, Darlene M. Bystry, Mohamed Badawi, Xiaokui Mo, Lindsey Rike, Narendranath Epperla, Qiuhong Zhao, and Shanmugapriya Thangavadivel
- Abstract
Purpose:Infectious complications constitute a leading cause of morbidity and mortality in chronic lymphocytic leukemia (CLL). Patients respond poorly to vaccines, particularly pneumococcal polysaccharide and influenza vaccines. In addition, patients with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated clinical activity in CLL, can potentially restore immune system dysfunction associated with CLL while improving disease outcomes.Patients and Methods:Phase II study randomized 49 patients with genetically high-risk CLL or small lymphocytic lymphoma [SLL; defined as unmutated Ig heavy chain variable region, deletion(17p) or (11q), and/or complex abnormal karyotype], to receive lenalidomide either concurrent (arm A) or sequential to (arm B) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13) administered 2 months apart, in patients not meeting International Workshop on Chronic Lymphocytic Leukemia treatment criteria.Results:Four serotypes (3, 4, 5, 6B) achieved the additional seroprotection definition of a fourfold increase in arm A, and six serotypes (3, 4, 5, 6B, 19A, 19F) in arm B. All patients achieved the defined concentration of 0.35 μg/mL for at least one serotype tested. No significant difference was observed with the addition of lenalidomide. At median time on treatment of 3.6 years, median progression-free survival (PFS) was 5.8 years [95% confidence interval (CI), 3.1—not reached]. PFS at 1, 2, and 3 years was 85% (95% CI, 72–93), 79% (95% CI, 64–88), and 72% (95% CI, 57–83), respectively.Conclusions:Lenalidomide is efficacious with manageable toxicities as an early intervention strategy in patients with high-risk CLL, but did not enhance humoral response to PCV13 vaccine.
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- 2023
32. Evaluation of bleeding events in patients receiving acalabrutinib therapy
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Pooja S. Kumar, Tracy Wiczer, Lindsay Rosen, Arthur J. Pollauf, Amy Zheng, Marilly Palettas, Leylah Azali, Seema A. Bhat, John C. Byrd, Michael R. Grever, Kerry A. Rogers, Jennifer A. Woyach, and Adam S. Kittai
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Cancer Research ,Oncology ,Hematology - Published
- 2023
33. Impact of sex on outcomes in patients with hairy cell leukemia. An <scp>HCL</scp> patient data registry analysis
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Narendranath Epperla, Qiuhong Zhao, Mirela Anghelina, Jasmine Neal, James S. Blachly, Kerry A. Rogers, Gerard Lozanski, Christopher C. Oakes, Seema A. Bhat, Clive S. Zent, Versha Banerji, Michael Grever, and Leslie A. Andritsos
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Hematology - Published
- 2023
34. Depth of response and progression-free survival in chronic lymphocytic leukemia patients treated with ibrutinib
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Audrey M. Sigmund, Ying Huang, Amy S. Ruppert, Kami Maddocks, Kerry A. Rogers, Samantha Jaglowski, Seema A. Bhat, Adam S. Kittai, Michael R. Grever, John C. Byrd, and Jennifer A. Woyach
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
35. HSR22-153: Real-World Time to Discontinuation of First-Line Venetoclax + Obinutuzumab in Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
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Xiaoxiao Lu, Qing Huang, Linda Wu, Bruno Emond, Shaun P. Forbes, Annalise Hilts, Stephanie Liu, Marie-Hélène Lafeuille, Patrick Lefebvre, and Kerry A. Rogers
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Oncology - Published
- 2022
36. The impact of increasing karyotypic complexity and evolution on survival in patients with CLL treated with ibrutinib
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Seema A. Bhat, Adam Kittai, Kyle A. Beckwith, Cecelia R. Miller, Ying Huang, Daniel Goldstein, Jennifer A. Woyach, Kerry A. Rogers, Lynne V. Abruzzo, Amy S. Ruppert, Michael R. Grever, John C. Byrd, David A. Bond, and Nyla A. Heerema
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Chronic lymphocytic leukemia ,Immunology ,Abnormal Karyotype ,Disease ,Biochemistry ,Somatic evolution in cancer ,Clonal Evolution ,chemistry.chemical_compound ,Piperidines ,Refractory ,Chemoimmunotherapy ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Venetoclax ,Adenine ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Analysis ,Progression-Free Survival ,chemistry ,Ibrutinib ,Female ,business ,IGHV@ - Abstract
Complex karyotype, defined as ≥3 cytogenetic abnormalities, is prognostic of survival in patients treated with ibrutinib or venetoclax in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL). Recent studies re-evaluating this dichotomous variable have shown that higher numbers of cytogenetic abnormalities (ie, ≥5) have a worse overall survival in patients treated with chemoimmunotherapy. We sought to determine if increasing karyotypic complexity, treated as a continuous variable, was prognostic of survival for patients treated with ibrutinib for CLL. We conducted a retrospective analysis of all patients with CLL treated with single-agent ibrutinib or in combination with an anti–CD20 antibody at our institution. We included 456 patients with both treatment-naive and RR disease. Median number of prior therapies was 2 (range, 0-13), 30% of patients had presence of del(17p), and 75% expressed unmutated IGHV. Fifty percent had ≥3 cytogenetic abnormalities, including 30% with ≥5. In a multivariable analysis, increasing karyotypic complexity was an independent predictor of shorter progression-free survival (hazard ratio, 1.07; 95% confidence interval, 1.04-1.10; P < .0001) and overall survival (hazard ratio, 1.09; 95% confidence interval, 1.05-1.12; P < .0001). Furthermore, we found that presence of clonal evolution determined by cytogenetic analysis at progression was prognostic of subsequent survival (P = .02). This solidifies karyotypic complexity as an important prognostic factor for patients with CLL treated with ibrutinib. Further research should consider sequential karyotypic analysis as a determination of risk of progression and death in patients with CLL.
- Published
- 2021
37. Recognizing Unmet Need in the Era of Targeted Therapy for CLL/SLL: 'What's Past Is Prologue' (Shakespeare)
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Meghan C. Thompson, Andre Goy, Chan Yoon Cheah, Matthew S. Davids, Neil E. Kay, Chadi Nabhan, Constantine S. Tam, Mazyar Shadman, Anthony R. Mato, Kerry A. Rogers, Lindsey E. Roeker, Arnon P. Kater, John F. Seymour, John M. Pagel, Joanna Rhodes, Clare Sun, Alan P Skarbnik, Catherine C. Coombs, Toby A. Eyre, Jennifer R. Brown, Jennifer A. Woyach, Chaitra Ujjani, Stephen J. Schuster, Susan O'Brien, Danielle M. Brander, Nicole Lamanna, Nitin Jain, Jeff P. Sharman, Hematology, CCA - Cancer biology and immunology, AII - Cancer immunology, Experimental Immunology, Clinical Haematology, and CCA - Cancer Treatment and Quality of Life
- Subjects
Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Context (language use) ,Article ,Targeted therapy ,Unmet needs ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,immune system diseases ,Chemoimmunotherapy ,hemic and lymphatic diseases ,medicine ,Humans ,Intensive care medicine ,Protein Kinase Inhibitors ,Btk inhibitors ,Venetoclax ,business.industry ,Leukemia, Lymphocytic, Chronic, B-Cell ,Clinical Practice ,Oncology ,chemistry ,Immunotherapy ,Previously treated ,business - Abstract
The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.
- Published
- 2021
38. COVID-19 in patients with CLL: improved survival outcomes and update on management strategies
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Lindsey E. Roeker, Toby A. Eyre, Meghan C. Thompson, Nicole Lamanna, Alexander R. Coltoff, Matthew S. Davids, Peter O. Baker, Lori Leslie, Kerry A. Rogers, John N. Allan, Raul Cordoba, Alberto Lopez-Garcia, Darko Antic, John M. Pagel, Nicolas Martinez-Calle, José Antonio García-Marco, Jose-Ángel Hernández-Rivas, Fatima Miras, Catherine C. Coombs, Anders Österborg, Lotta Hansson, Amanda N. Seddon, Javier López Jiménez, Matthew R. Wilson, Dima El-Sharkawi, Daniel Wojenski, Shuo Ma, Talha Munir, Susana Valenciano, Erlene Seymour, Paul M. Barr, Jeffrey Pu, Piers E. M. Patten, Guilherme F. Perini, Scott F. Huntington, Helen Parry, Suchitra Sundaram, Alan Skarbnik, Manali Kamdar, Ryan Jacobs, Harriet Walter, Renata Walewska, Angus Broom, Sonia Lebowitz, Krista M. Isaac, Craig A. Portell, Inhye E. Ahn, Chaitra S. Ujjani, Mazyar Shadman, Sigrid S. Skånland, Elise A. Chong, and Anthony R. Mato
- Subjects
Adult ,Male ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunology ,MEDLINE ,Improved survival ,Antiviral Agents ,Biochemistry ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Aged ,Retrospective Studies ,Aged, 80 and over ,Lymphoid Neoplasia ,SARS-CoV-2 ,business.industry ,COVID-19 ,Disease Management ,Cell Biology ,Hematology ,Middle Aged ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,United States ,Survival Rate ,Drug Therapy, Combination ,Female ,business ,Follow-Up Studies - Published
- 2021
39. Patient characteristics that predict Richter's transformation in patients with chronic lymphocytic leukemia treated with ibrutinib
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Adam S. Kittai, Ying Huang, Kyle A. Beckwith, Seema A. Bhat, David A. Bond, John C. Byrd, Daniel Goldstein, Michael R. Grever, Cecelia Miller, Kerry A. Rogers, Max Yano, and Jennifer A. Woyach
- Subjects
Hematology - Abstract
Chronic lymphocytic leukemia (CLL) transformation to aggressive lymphoma, known as Richter's Transformation (RT), has a dismal prognosis. There are limited data evaluating risk of RT in patients treated with ibrutinib. We performed a retrospective analysis to determine prognostic variables associated with development of RT and overall survival (OS) at progression after treatment with ibrutinib. We identified 559 patients with CLL treated with ibrutinib from 2010-2019. After a median follow-up of 44.5 months from ibrutinib start, 179 patients progressed and were included in our analysis. After a median follow-up of 20.8 months from progression, 54 out of 179 patients developed RT. Progression on treatment (hazard ratio [HR] 4.01 [1.60-10.00], p = .003), higher LDH (HR 1.80 for 2-fold increase [1.33-2.43], p = .0001), and lymphadenopathy without lymphocytosis (HR 2.88 [1.15-7.20], p = .02) were independent prognostic variables for the development of RT at progression. Progression with lymphadenopathy without lymphocytosis continued to be an independent prognostic variable of worse OS post-progression. In a subset analysis of 50 patients who obtained a PET-CT at progression, the median SUV
- Published
- 2022
40. Racial and socioeconomic disparities in CLL/SLL: Analysis of SEER data from 2006-2019
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Adam S Kittai, Ying Huang, Seema A Bhat, Electra D Paskett, Kerry A. Rogers, Jacqueline Barrientos, James L Fisher, and Jennifer A. Woyach
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Hematology - Published
- 2022
41. Clinical and economic burden of tumor lysis syndrome among patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: A real-world US retrospective study
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Kerry A Rogers, Xiaoxiao Lu, Bruno Emond, Aurélie Côté-Sergent, Frédéric Kinkead, Marie-Hélène Lafeuille, Patrick Lefebvre, and Qing Huang
- Subjects
Adult ,Health Policy ,Quality of Life ,Pharmaceutical Science ,Humans ,Antineoplastic Agents ,Financial Stress ,Pharmacy ,Health Care Costs ,Tumor Lysis Syndrome ,Lenalidomide ,Leukemia, Lymphocytic, Chronic, B-Cell ,Retrospective Studies - Published
- 2022
42. Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity
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Benjamin Buck, Aaron P. Chum, Mitkumar Patel, Rebecca Carter, Haseeb Nawaz, Vedat Yildiz, Patrick Ruz, Tracy Wiczer, Kerry A. Rogers, Farrukh T. Awan, Seema Bhat, Avirup Guha, Adam S. Kittai, Orlando P. Simonetti, Subha V. Raman, Grant Wallace, Reynaldo Sanchez, Janice M. Bonsu, John Gambril, Devin Haddad, James Mann, Lai Wei, Onaopepo Kola-Kehinde, John C. Byrd, Jennifer A. Woyach, and Daniel Addison
- Subjects
Cancer Research ,Oncology - Abstract
ImportanceIbrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown.ObjectiveTo assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity.Design, Setting, and ParticipantsThis cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry.ExposuresIbrutinib treatment for cancer control.Main Outcomes and MeasuresThe primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk–matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE.ResultsOverall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P P = .01, and P 2SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE.Conclusions and RelevanceIn this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.
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- 2023
43. Hairy cell leukemia and COVID-19 adaptation of treatment guidelines
- Author
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Francesco Forconi, Jae H. Park, Martin S. Tallman, Brunangelo Falini, Robert J. Kreitman, James B. Johnston, Sameer A. Parikh, Timothy G. Call, Xavier Troussard, Seema A. Bhat, James S. Blachly, Sasha Dietrich, Gerard Lozanski, Matthew Cross, Jacqueline C. Barrientos, Thorsten Zenz, Claire Dearden, Sunil Iyengar, Alan Saven, Francesco Lauria, Judit Demeter, Gunnar Juliusson, Tadeusz Robak, Douglas E. Gladstone, Versha Banerji, Kerry A. Rogers, Enrico Tiacci, Tamar Tadmor, Pier Luigi Zinzani, John F. Seymour, Farhad Ravandi, Bernhard Wörmann, Constantine S. Tam, Michael R. Grever, Aaron Polliack, Alessandro Gozzetti, Clive S. Zent, Eric H. Kraut, Leslie A. Andritsos, Grever M., Andritsos L., Banerji V., Barrientos J.C., Bhat S., Blachly J.S., Call T., Cross M., Dearden C., Demeter J., Dietrich S., Falini B., Forconi F., Gladstone D.E., Gozzetti A., Iyengar S., Johnston J.B., Juliusson G., Kraut E., Kreitman R.J., Lauria F., Lozanski G., Parikh S.A., Park J., Polliack A., Ravandi F., Robak T., Rogers K.A., Saven A., Seymour J.F., Tadmor T., Tallman M.S., Tam C.S., Tiacci E., Troussard X., Zent C., Zenz T., Zinzani P.L., and Wormann B.
- Subjects
Cancer Research ,medicine.medical_specialty ,Consensus ,Hairy Cell ,medicine.medical_treatment ,Diseases ,Consensu ,Review Article ,Disease ,Severity of Illness Index ,Internal medicine ,medicine ,Leukaemia ,Humans ,Hairy cell leukemia ,Intensive care medicine ,Cladribine ,Pandemics ,Leukemia, Hairy Cell ,Leukemia ,Hematology ,Pandemic ,SARS-CoV-2 ,business.industry ,Standard treatment ,COVID-19 ,Immunosuppression ,Practice Guidelines as Topic ,medicine.disease ,Oncology ,business ,Human ,medicine.drug - Abstract
Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.
- Published
- 2021
44. Incidence, Description, and Timing of Serious or Opportunistic Infections in Patients with Hairy Cell Leukemia Treated with Purine Nucleoside Analogues
- Author
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Nilesh Kapoor, Qiuhong Zhao, Andrew Stiff, Seema A. Bhat, Mirela Iulia Anghelina, Jasmine Neal, Leslie A. Andritsos, James S. Blachly, Narendranath Epperla, Zeinab El Boghdadly, Michael R. Grever, and Kerry A. Rogers
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
45. Retrospective Analysis of Residual Hairy Cell Leukemia Measured By IHC or Flow Cytometry and Frontline Treatment with Pentostatin on Time to Next Treatment
- Author
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Andrew Stiff, Qiuhong Zhao, Nilesh Kapoor, Kerry A. Rogers, Mirela Iulia Anghelina, Jasmine Neal, Leslie A. Andritsos, James S. Blachly, Gerard Lozanski, Michael R. Grever, and Seema A. Bhat
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
46. Extended Follow up of a Phase 2 Study of Ibrutinib in Hairy Cell Leukemia
- Author
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Kerry A. Rogers, Eric McLaughlin, Lai Wei, Mirela Iulia Anghelina, Mir Khader Ali, Leslie A. Andritsos, Evgeny Arons, James S. Blachly, Timothy G. Call, S. Percy Ivy, Lacey James-Echenique, Jeffrey A. Jones, Robert J. Kreitman, Gerard Lozanski, Farhad Ravandi, Charles A. Schiffer, William E. Carson, and Michael R. Grever
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
47. FISH Analysis of CDKN2A/B Deletion in Chronic Lymphocytic Leukemia
- Author
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Samantha M Teierle, Ying Huang, Adam S Kittai, Seema A. Bhat, Michael R. Grever, Kerry A. Rogers, Weiqiang Zhao, Daniel Jones, John C. Byrd, Matthew R Avenarius, Nyla A. Heerema, Jennifer A. Woyach, and Cecelia Miller
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
48. Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia
- Author
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Kerry A. Rogers, David M. Weiss, Ying Huang, Jennifer A. Woyach, Lynne V. Abruzzo, Nyla A. Heerema, Christin Banks, Allison Dean, Cara Grantier, Barbara L. Andersen, Margaret S. Lucas, Jeffrey A. Jones, Gerard Lozanski, Seema A. Bhat, John C. Byrd, Farrukh T. Awan, Kami J. Maddocks, Amy S. Ruppert, and Thomas R. Valentine
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Neutropenia ,Chronic lymphocytic leukemia ,Phases of clinical research ,Antibodies, Monoclonal, Humanized ,Young Adult ,chemistry.chemical_compound ,Cognition ,Piperidines ,Obinutuzumab ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Aged ,Sulfonamides ,business.industry ,Venetoclax ,Adenine ,Remission Induction ,ORIGINAL REPORTS ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Thrombocytopenia ,Progression-Free Survival ,CD4 Lymphocyte Count ,Killer Cells, Natural ,Survival Rate ,Leukemia ,chemistry ,Ibrutinib ,Hypertension ,Retreatment ,Quality of Life ,Female ,Refractory Chronic Lymphocytic Leukemia ,business ,Follow-Up Studies ,Hyponatremia - Abstract
PURPOSE The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy. PATIENTS AND METHODS This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety. RESULTS The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed. CONCLUSION The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.
- Published
- 2020
49. Combined BCL2 and BTK inhibition in CLL demonstrates efficacy after monotherapy with both classes
- Author
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Jonathan M. Hyak, Ying Huang, Kerry A. Rogers, Seema A. Bhat, Michael R. Grever, John C. Byrd, Adam S. Kittai, Dan Jones, Cecelia R. Miller, and Jennifer A. Woyach
- Subjects
Pyrimidines ,Proto-Oncogene Proteins c-bcl-2 ,Agammaglobulinaemia Tyrosine Kinase ,Humans ,Hematology ,Leukemia, Lymphocytic, Chronic, B-Cell - Published
- 2022
50. A CAPTIVATE-ing new regimen for CLL
- Author
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Kerry A. Rogers and Jennifer A. Woyach
- Subjects
Sulfonamides ,Piperidines ,Adenine ,Immunology ,Humans ,Cell Biology ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,Biochemistry ,Leukemia, Lymphocytic, Chronic, B-Cell - Published
- 2022
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