Title of the Research Project:
“Optimizing Glofitamab Combination Therapy in Richter’s Transformation”
Research Project Summary:
Over the last decade, patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) have experienced significant improvements in outcomes thanks to targeted therapies like BTK and BCL2 inhibitors (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, and venetoclax). However, a small subset of those with CLL will experience a rare, but serious complication known as Richter’s transformation (RT). This occurs when the disease transforms into a more aggressive type of Hodgkin lymphoma called diffuse large B-cell lymphoma (DLBCL).
Treating these individuals with traditional chemotherapy has led to complete remissions in about 20% of RT patients, and more recently, combining chemotherapy with venetoclax has increased that number to about 50%. Still, the side effects of chemotherapy, especially in older or medically complex patients, make this a less-than-ideal solution. The goal of this research project is aimed at finding more effective and less toxic treatment options for RT by exploring the use of glofitamab, a promising non-chemotherapy treatment that is FDA approved for DLBCL, either alone or in combination with other drugs, to improve outcomes for patients with RT.
About the Award Recipient, Dr. Matthew Davids:
Matthew Davids, MD, MMSc, is a CLL and lymphoma expert at Dana-Farber Cancer Institute in Boston, Massachusetts where he serves as Director of Clinical Research in the Lymphoma Division. He is also an Associate Professor of Medicine at Harvard Medical School and cares for hospitalized patients with blood cancers at Brigham and Women’s Hospital. Dr. Davids received his undergraduate degree in chemistry from Harvard College and earned his medical degree from Yale School of Medicine. He completed his residency training in internal medicine and served as assistant chief resident at New York-Presbyterian/Weill Cornell Medical Center and Memorial Sloan Kettering Cancer Center. He went on to complete a fellowship in hematology and oncology at the combined Dana-Farber / Massachusetts General Hospital program, and he later earned a master’s degree in medical science from Harvard Medical School. In addition to caring for patients, Dr. Davids leads a translational research lab at Dana-Farber Cancer Institute that is focused on developing better treatments for CLL. He leads many clinical trials, and his work has led to cutting edge therapies becoming FDA approved to treat CLL. Through both his research lab and the patients he cares for, Dr. Davids is dedicated to improving outcomes for those living with CLL / SLL and related blood cancers.
Why Is Research on Glofitimab Needed for CLL / SLL?
While DLBCL that develops independently from CLL is often curable, DLBCL that transforms from CLL is notoriously more difficult to treat. Despite advances in CLL therapies, patients with RT continue to face major treatment challenges. The disease still carries a poor prognosis, and chemotherapy (which has been largely ineffective) has been used as the primary treatment. As a result, RT remains an unmet need, and has become a critical area of research scientific investigators working to improve survival and quality of life for those living with CLL and SLL.
What Kind of Drug is Glofitamab and How Does It Work?
Glofitamab is a bispecific antibody, which differs from traditional monoclonal antibodies like rituximab that target only one cancer marker (such as CD20) on the surface of B-cells. Bispecific antibodies target two cancer markers. In this case, CD20 is located on the surface of the cancerous CLL cells and CD3 which is located on immune T cells. By binding to both cancer markers, glofitamab effectively “recruits” a patient’s own T cells to recognize the cancerous cells and attack them. So glofitamab harnesses the body’s own immune system to fight the disease. This immune-based approach has already shown encouraging results in other aggressive lymphomas and has early signs of promise in RT. Based on these findings, Dr. Davids and his team will be investigating glofitamab further as a possible treatment option for RT.
Who is Eligible for This Study?
The trial is specifically designed with broad eligibility criteria to ensure maximum participation. Any patient with a confirmed diagnosis of RT may be eligible, regardless of whether they’ve previously received treatment for RT or not. While prior therapies and individual patient characteristics may influence which treatment arm (cohort) individuals are assigned to, they will generally not affect eligibility overall. This inclusive clinical trial design ensures that the findings can apply to a wide range of RT patients. More information about the trial can be accessed on clinicaltrials.gov here.
What Interventions Will Be Used?
While glofitamab may be effective on its own for some patients, Dr. Davids believes combination therapies may offer broader benefits. The study is structured to first evaluate RT patients who receive glofitamab alone with no other drug combination. Then the study will expand into three additional “cohorts” or treatment arms, each exploring a different drug combination. In addition to examining the data for those given the drug alone, Dr. Davids and his team will also examine and compare outcomes when patients are given one of the following combination treatments:
- Glofitamab combined with Pirtobrutinib: Pirtobrutinib is a next-generation, non-covalent BTK inhibitor that can work even after patients develop a drug resistance to one of the earlier BTK inhibitors. It is expected not only to enhance cancer control but may also help reduce immune-related side effects such as cytokine release syndrome (CRS), a key safety concern when the immune system is activated by drugs like glofitamab.
- Glofitamab combined with Polatuzumab: Polatuzumab is a type of treatment called an antibody-drug conjugate (ADC) that is already approved for use as a combination therapy for DLBCL. It combines a targeted antibody with a small dose of chemotherapy. The antibody helps to ‘guide’ the chemotherapy medication directly to the cancer cells to destroy them instead of killing off non-cancerous cells as well. This may potentially reduce side effects and reduce the occurrence of CRS.
- Glofitamab combined with Atezolizumab: Atezolizumab is a type of treatment called a checkpoint inhibitor. It works by helping the immune system recognize cancer cells that might otherwise hide and go undetected. When used together with glofitamab this combination may make it easier for the immune system to find and attack the cancerous RT cells.
A unique aspect of this study is the use of advanced lab techniques to study how the immune system and cancer cells respond to treatment. Researchers will use Cytometry by Time of Flight (CyTOF) testing, a state-of-the-art tool that allows scientists to analyze up to 30–40 proteins on each cell, far beyond what traditional flow cytometry testing can offer. This will provide a deeper look into the immune environment in those with RT. In addition, the study will incorporate RNA and DNA genetic sequencing from patient samples to better understand genetic and molecular changes that occur during the various treatment regimens. By linking these laboratory findings to treatment outcomes, Dr. Davids’ team hopes to uncover patterns that could predict which RT patients respond best to each unique treatment approach.
How Will the Findings Be Used?
This study is expected to lay the foundation for more personalized approaches to treating RT. The goal is to move away from a one-size-fits-all treatment approach and instead match patients with a therapy that is most likely to benefit them. Whether that’s receiving glofitamab alone, receiving a specific combination of drugs, or utilizing other CLL targeted therapies. This work represents a major step forward in addressing one of the toughest challenges in CLL / SLL, and the research brings hope for patients facing RT who currently have limited treatment options.
Please watch the interview between CLL Society’s Senior Director of Scientific Affairs, Robyn Brumble, RN, MSN, and Matthew Davids, MD, MMSc.
