Chronic lymphocytic leukemia (CLL) is the most common form of adult chronic leukemia in the western hemisphere. Leukemia is a cancer of the blood cells, which are formed in the bone marrow—the soft, spongy center of bones. Normally, blood cells are produced in an orderly way as the body needs them, but when leukemia develops, the body produces large numbers of abnormal blood cells that do not function properly.
CLL is a currently incurable blood and bone marrow disease in which the marrow makes too many lymphocytes (a type of white blood cell). These abnormal lymphocytes do not become normal, healthy white blood cells and are not able to properly perform the primary white blood cell function of fighting infection. As the number of abnormal lymphocytes increases, there is less room for healthy blood cells, and this may cause infection, anemia and easy bleeding. CLL often occurs during or after middle age, and it usually worsens slowly.
At the OSUCCC – James, research for CLL and other forms of leukemia occurs within the Leukemia Research Program, a program that comprises many disciplines and the collaboration of many scientists — including 42 investigators from four colleges and 11 academic departments at Ohio State.
Program researchers are supported by several large, ongoing, collaborative or network research grants totaling millions of dollars. Some of these grants support a CLL Experimental Therapeutics Laboratory that conducts translational research and collaborations across the university and nation to improve understanding of CLL and to develop new therapies. The leukemia treatment team at the OSUCCC – James contains 11 physician-researchers who specialize in the various forms of this disease, including CLL.
More information about CLL is available from the CLL Research Consortium (CRC), a multi-institutional program sponsored by the National Cancer Institute. At Ohio State, cancer investigators Michael Grever, MD, and John C. Byrd, MD, are involved with a CRC project examining pharmacologic agents in CLL.
- Examine all molecular aspects of CLL cells—genetic, epigenetic, RNA/protein, non-coding RNAs and biochemical—and integrate these features to improve CLL risk stratification and more effectively direct targeted therapies toward each person’s unique cancer
- Develop preclinical and clinical immunotherapeutic approaches that bolster the human immune system’s innate ability to combat CLL
- Devise targeted therapies designed to thwart CLL-relevant kinase-signaling pathways
Experimental Therapeutics of Leukemia (P50 CA140158 05)
Specialized Program of Research Excellence (SPORE) funded by the National Cancer Institute
PI: John C. Byrd, MD
- Conduct highly translational research that improves understanding of leukemia development, risk stratification and therapy. This SPORE will work to develop prognostic factors and therapies to benefit leukemia patients via five individual projects.
- Project 1 (led by Albert de la Chapelle, MD, PhD, and John C. Byrd, MD) – “Early Predisposing Genes and Risk Stratification for Chronic Lmphocytic Leukemia (CLL).” This project will examine biology of DAPK1 and the prognostic significance of early events in risk stratification of CLL.
- Project 2 (led by Clara D. Bloomfield, MD, and Guido Marcucci, MD) – “Molecular Characterization and Risk Stratification of Acute Myeloid Leukemia (AML).” This project will study the impact of select prognostic gene (FLT3 ITD, MLL PTD, NPM1, WT-1, CEBPA, KIT) mutations, aberrant gene (BAALC, ERG, FLT3, MN1 and EVI1) expression, and mRNA/miRNA expression profiles on predicting treatment outcome of newly diagnosed AML patients.
- Project 3 (John C. Byrd, MD) –“Lenalidomide as an Immune Modulating Agent for CLL.” This work will focus on the mechanism of lenalidomide-induced CLL cell activation and its contribution both to efficacy and to tumor flare, and will examine strategies to reduce morbidity and improve efficacy.
- Project 4 (led by Michael A. Caligiuri, MD, Guido Marcucci, MD and William Blum, MD) – “Preclinical and Clinical Investigation of MLL-PTD AML.” This project will focus on utilizing a novel MLL PTD mouse model to characterize events in leukemic transformation and to preclinically study novel therapeutic approaches for this subset of patients. It will also initiate a clinical trial of epigenetic therapy to improve the outcome of patients with MLL PTD[+] AML.
Pharmacologic Inhibitors of Cellular Kinases and Signal Transduction (5 P01 CA081534 13)
This grant was awarded by the National Cancer Institute to the Chronic Lymphocytic Leukemia Research Consortium. Thomas Kipps, MD, PhD, of the University of California at San Diego, is overall principal investigator. Ohio State is part of the consortium and is leading one of the projects funded by the grant.
Project 6 PI: Michael Grever, MD
Objectives for Project 6:
- Perform mechanistic studies of flavopiridol and SCH727965 to study: a) the contribution of ER stress to cell death promoted by these agents; b) the contribution of autophagy to CDK inhibitor drug resistance; c) the influence of microenvironment on promoting resistance to CDK inhibitors in CLL cells, and strategies to overcome these with novel targeted agents. Researchers also will perform pharmacodynamic studies with completed and planned CDK inhibitor clinical trials within the research consortium
- Interrogate the PI3K-delta pathway with a focus on: a) identifying the mechanism by which CAL-101 promotes cytotoxicity toward CLL cells b) the relevance of external signals antagonized by CAL-101 in the microenvironment to the survival of CLL cells c) preclinical testing of PI3K-delta inhibitors in the TCLI mouse model of CLL to validate optimal combination studies with this agent and d) performance of pharmacodynamic studies in concert with CAL-101 clinical trials in the research consortium
Targeted Therapy for Lymphoid Malignancies (5 R01 CA177292 02)
PI: John C. Byrd, MD
- Perform a phase II clinical trial of ibrutinib to determine the response and two-year progression-free survival (PFS) among patients having, versus lacking, del(17p13.1), and to determine the long-term toxicity of this agent administered as a continuous therapy
- Perform baseline and serial pharmacodynamic studies to determine if traditional genomic features, select BCR activation markers and changes in miR marker expression are predictive for response and two-year PFS
- Perform studies derived from samples from patients participating in both this and the earlier completed single agent ibrutinib trial to determine the biologic features of tumor cells not cleared from the blood by 12 months, and to devise pharmacologic strategies to eliminate these
- At the end of this study, investigators will have determined the effectiveness of ibrutinib in relapsed del(17p13.1) CLL and identified features predictive of single-agent activity of this agent and also of tumor cells not eliminated by ibrutinib. These will guide future combination studies with ibrutinib that could change the treatment paradigm of CLL.
(OSU-13031) A Phase II Study of MOR00208 in Combination With Lenalidomide for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia(CLL)/Small Lymphocytic Lymphoma (SLL)/Prolymphocytic Leukemia (PLL) or Patients With Untreated CLL/SLL/PLL
PI: Jennifer Woyach, MD
- Determine the overall response rate (ORR) at six months for patients with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)/prolymphocytic leukemia (PLL) treated with the combination of MOR00208 plus lenalidomide
- Determine the ORR at six months for patients with treatment-naive CLL/SLL/PLL treated with the combination of MOR00208 plus lenalidomide
- Determine the ORR at 12 months for patients with untreated CLL/SLL/PLL or relapsed/refractory disease treated with the combination of MOR00208 plus lenalidomide
- Determine the complete response (CR) rate, nodular partial response (nPR) rate, partial response (PR) rate and stable disease (SD) rate for patients with untreated CLL/SLL/PLL or relapsed or refractory disease treated with the combination of MOR00208 plus lenalidomide
- Summarize the progression-free survival (PFS), time to next treatment and overall survival (OS) for each of two cohorts of patients treated with this regimen
- Evaluate toxicity with this regimen, including frequency and severity of toxicities, dose-reduction requirements and adverse events requiring drug discontinuation
PI: John C. Byrd, MD
- Evaluate the safety and efficacy of a new Bruton tyrosine kinase (Btk) inhibitor, ACP-196, for treating patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
(OSU-12095) A Phase 1b Open-Label Study to Evaluate the Safety and Efficacy of TRU-016 in Combination With Rituximab or in Combination With Obinutuzumab in Patients With Chronic Lymphocytic Leukemia
PI: Kami Maddocks, MD
- Evaluate the safety and efficacy of TRU-016 when administered in combination with rituximab or obinutuzumab in patients with chronic lymphocytic leukemia (CLL).
Recent Clinical Research Accomplishments
OSUCCC – James Researchers Develop and Test Drug for Treating CLL. OSUCCC – James researchers John C. Byrd, MD, and Ching-Shih Chen, PhD, initiated the development of AR-42, a type of compound called histone deacetylase (HDAC) inhibitors that are designed to reactivate genes that normally protect against cancer but are turned off by the cancer process. AR-42 is designed to treat relapsed or treatment-resistant CLL, multiple myeloma or lymphoma. A phase I/IIa clinical trial is assessing the agent’s safety and initial evidence of therapeutic activity. AR-42 is licensed to the biopharmaceutical company Arno Therapeutics, Inc., for clinical development
OSUCCC – James Plays Major Role in FDA Approval of CLL Drug. In February 2014, the U.S. Food and Drug Administration (FDA) expanded the approved use of the drug ibrutinib (Imbruvica®) for certain patients with CLL. Ibrutinib is the first drug designed to target a protein essential for CLL-cell survival and proliferation. Much of the clinical and basic-science research that led to FDA approval was conducted at the OSUCCC – James. The Ohio State work was co-led by John C. Byrd, MD, and by Amy Johnson, PhD. Byrd says his team’s clinical studies consistently suggested that ibrutinib is a highly active oral therapeutic that produces a high rate of lasting remissions with acceptable side effects in CLL patients who have relapsed or whose cancer has resisted standard treatment.
Phase III Study Strengthens Use of Ibrutinib as Second-Line Therapy for CLL. In a head-to-head comparison of two U.S. Food and Drug Administration (FDA)-approved drugs for the treatment of relapsed CLL, ibrutinib significantly outperformed ofatumumab as a second-line therapy, according to a multicenter, interim study published in the “OnLine First” edition of the New England Journal of Medicine. Ibrutinib (Imbruvica®) is the first drug designed to target a protein essential for CLL-cell survival and proliferation. In this study, patients were randomized to receive once-a-day oral ibrutinib or the anti-CD20 antibody ofatumumab, a drug considered part of the current standard of care for CLL.
Translational Research Accomplishments
Laboratory Study Confirms Target of Potent CLL Drug. A study led by OSUCCC – James researchers helped confirm that a molecule targeted by the experimental drug ibrutinib is critical for the development of CLL. The drug incapacitates a molecule called Bruton’s tyrosine kinase (BTK), stopping the transmission of a signal that promotes cell growth and proliferation. But researchers also found that ibrutinib inhibits other molecules in CLL cells as well. Like BTK, these molecules are proteins called kinases, and they might be important for CLL-cell survival. “Ibrutinib’s lack of selectivity might mean that BTK is not the critical target in CLL, and that future drugs developed for CLL should focus on other molecules,” says principal investigator Amy Johnson, PhD. Jennifer Woyach, MD, was first author for the study, whose findings were published in the journal Blood.
Mechanisms of Ibrutinib Resistance Identified in Chronic Leukemia. A study led by researchers at the OSUCCC – James and published in the New England Journal of Medicine discovered how resistance develops in patients taking ibrutinib, a new and highly effective drug for treating patients with CLL. The study identified gene mutations that cause ibrutinib resistance in CLL patients. "Knowledge of these mutations is the first step in the development of drugs or drug combinations that might prevent or treat ibrutinib-resistant CLL," says co-principal investigator (PI) John C. Byrd, MD. Co-PI Amy Johnson, PhD, notes that researchers saw none of these mutations in patients before they used ibrutinib.
Novel Export-Inhibitor Shows Promise in Treating CLL. An experimental drug that blocks the export of key control molecules from the nucleus of cancer cells shows promise as a treatment for CLL and other B-cell malignancies, a study at the OSUCCC – James showed. The agent, KPT-SINE, is in a class of drugs called selectiveinhibitors of nuclear export (SINE). Developed by Karyopharm Therapeutics Inc., the agent kills cancer cells by restoring biochemical pathways that normally cause unhealthy cells to self-destruct through apoptosis (programmed cell death). The agent targets the CRM1 protein, which had not been adequately explored in CLL, researchers say. “We believe KPT-SINE and other nuclear-export inhibitors may represent a new therapeutic strategy for treating cancer by simultaneously restoring multiple cell-death pathways,” says OSUCCC – James researcher Rosa Lapalombella, MD, co-investigator on the study with John C. Byrd, MD.