Advances in Malignant Lymphoma: Discoveries from Precursors to Progression
From June 23-26, researchers from around the world will gather in Boston for the Third AACR International Meeting on Advances in Malignant Lymphoma. A collaboration between the American Association for Cancer Research (AACR), the International Conference on Malignant Lymphoma (ICML), and Blood Cancer Discovery, a journal of the AACR, the meeting will feature presentations about the latest lymphoma discoveries from prominent blood cancer researchers.
Lymphoma is a blood cancer characterized by the production of malignant lymphocytes, a type of immune cell. The disease is often categorized into two types: Hodgkin lymphoma, marked by inflammation and the presence of giant Reed-Sternberg cells, and non-Hodgkin lymphoma, the more common type, which can be further classified as B-cell or T-cell lymphoma. According to federal statistics, an estimated 8,500 cases of Hodgkin lymphoma and 80,500 cases of non-Hodgkin lymphoma will be diagnosed in the U.S. in 2022.
The theme of this year’s meeting is “Maximizing the Basic-Translational Interface for Clinical Application,” which refers to the pipeline of knowledge from the laboratory to a patient’s bedside. The importance of discoveries at all steps of this pipeline is exemplified by several cutting-edge topics featured at the meeting and in recent Blood Cancer Discovery publications.
Genetic Underpinnings of Lymphoma
Accurate cancer subtyping is important for determining the best options for treatment. However, when different subtypes have similar morphological characteristics, telling them apart can become tricky.
Understanding the genetic differences between subtypes of B-cell lymphoma using high-throughput sequencing can facilitate this process, according to Ryan Morin, PhD, a senior scientist at Simon Fraser University. In late 2020, Morin and colleagues published a paper in Blood Cancer Discovery describing a machine learning algorithm that uses RNA sequencing data to differentiate between similar subtypes of the same disease. During the meeting, Morin will discuss how methods such as these can improve lymphoma classification and provide unique insights into how lymphomas form and evolve.
Using genetics to understand lymphomagenesis is a primary research interest of Riccardo Dalla-Favera, MD, FAACR, co-chair of the meeting and co-Editor-in-Chief of Blood Cancer Discovery.
Dalla-Favera, who is director of the Institute for Cancer Genetics at Columbia University Irving Medical Center, uses genomic methods to study how normal B cells undergo malignant transformation and explores how researchers can target these processes.
Dalla-Favera will chair a plenary session on the genetics of diffuse large B-cell lymphoma (DLBCL) and ways in which scientists can use genomic knowledge to drive advances in precision medicine. His colleague Elodie Bal, PhD, will also present a poster on a unique aspect of this topic—the contribution of mutations in noncoding areas of the genome to DLBCL development.
Tracing Progression Using Liquid Biopsies
In recent years, researchers have discovered how to elicit more information about cancer from molecules, such as DNA fragments, found in patients’ blood. Because the genetic underpinnings of lymphoma are diverse and can affect the optimal course of treatment, sequencing of circulating tumor DNA (ctDNA) can provide a noninvasive way to assess the characteristics of lymphoma and to predict and monitor progression.
In a review article published in January 2022, Davide Rossi, MD, PhD, a scientific editor of Blood Cancer Discovery, head of the experimental hematology research program at the Institute of Oncology Research, and co-chair of the Clinical Lymphoid Tumors Investigation Program at the Oncology Institute of Southern Switzerland; David Kurtz, MD, PhD, an assistant professor of medicine at Stanford University; and colleagues established that ctDNA analysis has several advantages over current standards of lymphoma assessment. The genomic profiles observed in ctDNA more accurately capture the heterogeneity of the cancer cells, can sensitively detect disease emergence and recurrence, and have a high predictive value for treatment response and prognosis.
At the meeting, Rossi will discuss how he and his colleagues are leveraging data from ctDNA analyses to better understand the basic biology of Hodgkin lymphoma. Traditional bone marrow biopsies, while informative, may cause discomfort and capture relatively few cancer cells. By contrast, liquid biopsies can be noninvasively performed multiple times throughout the disease course, which may provide crucial information about lymphoma evolution and progression. Rossi and colleagues have used this information to identify potential driver mutations of Hodgkin lymphoma, which may pave the way for new therapies.
Such information may also be used to improve the way clinicians classify lymphoma into subtypes. Kurtz will discuss this application of ctDNA in his presentation, and he will also describe how ctDNA monitoring may predict relapse and forecast patient prognosis.
Progression From Precancer to Aggressive Lymphoma
Some blood cancers grow so slowly that they don’t pose an immediate or severe risk to the patient, often requiring minor treatment or none at all. However, these cancers can occasionally evolve into different, more aggressive cancer types.
Many researchers, including Catherine Wu, MD, a scientific editor of Blood Cancer Discovery, chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber Cancer Institute, and an institute member at the Broad Institute of MIT and Harvard, have sought to understand one such transformation—the switch from chronic lymphocytic leukemia (CLL) to aggressive lymphoma.
Although CLL grows slowly, the transformation—called Richter’s syndrome—usually results in a high-grade lymphoma that is difficult to treat. At the meeting, Wu will chair a plenary session about lymphoma evolution and will review what is known about the genetic underpinnings of Richter syndrome. In the same plenary, a member of her lab, Elisa ten Hacken, PhD, an instructor of medicine at Dana-Farber Cancer Institute, will speak about mouse models of Richter syndrome that she and her colleagues have designed.
Another of Wu’s colleagues, Erin Parry, MD, PhD, also an instructor of medicine at Dana-Farber Cancer Institute, will present a poster on the topic. Perry will describe an analysis of the genomic and transcriptomic differences between CLL and aggressive lymphoma in a cohort of matched samples from patients who experienced disease evolution.
Follicular lymphoma, like CLL, is a slow-growing blood cancer that patients may live with for years without intervention. It can also progress rapidly in rare cases, and the mechanisms underlying that transformation are not completely understood.
Jessica Okosun, MBBCh, MRCP, FRCPath, a clinical senior lecturer and group leader at the Queen Mary University of London, will deliver a plenary presentation about the transformation of follicular lymphoma into more aggressive forms of lymphoma. In a poster presentation, Jeffrey Craig, MD, PhD, a clinical assistant professor at the University of British Columbia, will also provide insights on this topic. Using single-cell sequencing techniques, he and his colleagues have profiled matched samples of follicular lymphoma and transformed DLBCL from a cohort of patients.
CAR T-Cell Therapy for Lymphoma
Since the advent of CAR T-cell therapy, some patients with advanced blood cancers have seen their disease vanish after a single round of the treatment. Approved forms of CAR T-cell therapy—which involve harvesting a patient’s T cells, reprogramming them to fight cancer, and infusing them back into the patient—target B cells, the source of many types of lymphoma. Around one third of lymphoma patients who receive CAR T-cell therapy never need another cancer treatment.
Predicting which patients will respond, however, is a complex topic and the subject of many ongoing research efforts. The first plenary session of the meeting, chaired by Sattva Neelapu, MD, deputy chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, will address recent advances in the use of CAR T-cell therapy to treat lymphoma.
Neelapu will open the session with a presentation about how lymphoma subtypes and lines of prior treatment may influence the outcomes of CAR T-cell therapy. Neelapu and colleagues recently published an article in Blood Cancer Discovery, in which they examined the relationship between clonal hematopoiesis—a benign condition marked by mutations in cancer-associated genes in the blood—and adverse events following CAR T-cell therapy.
In this study, the researchers found that lymphoma patients with evidence of clonal hematopoiesis prior to CAR T-cell therapy had an increased risk of immune effector cell-associated neurotoxicity syndrome. Clonal hematopoiesis was also associated with an increased risk of therapy-related secondary blood cancers. The researchers suggested that these findings highlight the importance of identifying biomarkers of CAR T outcomes and evaluating the mechanisms that link those biomarkers to their effects.