Editor's Note: The conference focused on the latest diagnostic and therapeutic advances in lymphoid system tumors, providing a cutting-edge academic exchange platform for the global oncology community. At this prestigious event, internationally renowned lymphoma research expert Professor Bruce D. Cheson (currently Chairman of the Division of Hematology and Oncology at Georgetown University Hospital, and former Head of the Medical Section, Drug Evaluation Program at the National Cancer Institute, NCI, USA) delivered a keynote speech titled "Dreams, Luck, and a Little Bit of Crazy: Creating a New Future for Lymphoma Treatment." Professor Cheson reviewed the forty-year journey of transformation in lymphoma treatment, from early drug development to the practice of "chemotherapy-free" concepts, and the evolution of precise assessment techniques, painting an exciting blueprint for the future of lymphoma therapy.Dreams, Luck, and a Little Bit of Crazy – The Transformative Journey of Lymphoma Treatment
Professor Cheson began his speech by emphasizing that to foresee the future, one must first understand the present, and the present evolves from the past. He likened his career to a journey filled with “dreams, luck, and a little bit of crazy,” dedicated to creating a better future for lymphoma patients. He deeply thanked the International Conference on Malignant Lymphoma (ICML) for the honor bestowed upon him, stating that it is his profound concern for patients and infinite passion for scientific research that continuously drive him to explore new directions in lymphoma treatment.
Early Explorations and the Cornerstone of Drug Development
Professor Cheson reviewed his early contributions to new drug development. In 1984, he had the privilege of joining the National Cancer Institute (NCI), participating in the development of new drugs for hematologic malignancies. Among them, deoxycoformycin (pentostatin) demonstrated excellent efficacy in the treatment of hairy cell leukemia, proven superior to interferon, the standard therapy at the time, and ultimately received approval from the U.S. Food and Drug Administration (FDA). Subsequently, Fludarabine also showed broad activity and was proven superior to chlorambucil in a study led by Kanti Rai, also receiving FDA approval. However, 25 years ago, a trip to a cancer conference in Berlin, Germany, became a turning point in his career. He met Dr. Angelika Pieper and was first introduced to a drug called bendamustine. Although at the time the drug only had German literature and its efficacy was “too good to be true,” Professor Cheson, after in-depth discussions with Professor Volker Diehl, believed the data was full of potential. By facilitating a collaboration between bendamustine and an American company, Professor Cheson’s team conducted the first three clinical trials in the U.S., including monotherapy and combination therapy with rituximab. The results showed that the drug exhibited similar efficacy to the German data in rituximab-refractory indolent lymphoma patients, with nearly three-quarters of patients achieving remission and a quarter achieving complete remission, ultimately leading to bendamustine’s FDA approval. Subsequently, the GADOLIN trial further confirmed the superiority of bendamustine combined with obinutuzumab (BG) in rituximab-refractory indolent lymphoma. Although objective response rates and complete response rates were similar between the two groups, the progression-free survival (PFS) and overall survival (OS) were significantly better in the BG group. Research led by Christiane Pott revealed the mechanism: patients in the BG treatment group were more likely to achieve minimal residual disease (MRD) negativity, and their progression-free survival curve showed a plateau. At the same time, studies by Matthias Rummel team also established bendamustine combined with rituximab (BR) as the standard first-line treatment for follicular lymphoma and chronic lymphocytic leukemia (CLL).
The Germination and Practice of the “Chemotherapy-Free” Dream
Professor Cheson pointed out that while the BR regimen is effective, the acute and long-term toxicities of chemotherapeutic drugs (such as secondary malignancies) cannot be ignored. Therefore, in 2004, when he chaired the CALGB (now Alliance) Lymphoma Committee, he proposed a bold “chemotherapy-free” dream: to completely transform lymphoma treatment through dual biological agent regimens. Although the submitted proposal was initially dismissed as “crazy,” Professor Cheson’s team persevered. They first attempted the anti-CD20 monoclonal antibody GA101 (obinutuzumab) combined with rituximab, with encouraging results. Subsequently, the combination of anti-CD22 monoclonal antibody epratuzumab with rituximab led to 90% of patients achieving remission, half of whom achieved complete remission, and many patients remained in remission years later. In the search for new partners for rituximab, Professor Cheson’s team turned to the immunomodulatory agent lenalidomide (brand name Revlimid®) and proposed the innovative “R2” regimen. Although NCI initially showed little interest in the regimen, Professor Cheson, after two and a half years of effort, finally convinced NCI to approve a study of R2 as first-line treatment. Initial results were very optimistic, but the timing was a bit late. Subsequently, MD Anderson Cancer Center advanced the research on the R2 regimen , especially the RELEVANCE trial, which showed that the efficacy of R2 was comparable to rituximab combined with chemotherapy (R-chemo), but with lower toxicity. Today, according to John Leonard’s Augment trial, R2 has become the standard therapy for relapsed follicular lymphoma. Although not yet approved for first-line treatment, it has become the control regimen for research in relapsed/refractory lymphoma and serves as a cornerstone for novel combination therapies, fundamentally changing the landscape of lymphoma treatment.
Challenging “Incurable” – Reappraising the Curative Potential of Lymphoma
For a long time, follicular lymphoma has often been described as “highly treatable but incurable.” However, Professor Cheson, drawing on decades of clinical experience and observations of patients with long-term remission, firmly believes that follicular lymphoma is curable. His colleague Ayushi Shah (currently a researcher at MD Anderson Cancer Center) supported this view with a study: analyzing follicular lymphoma patients who had not relapsed within two years after completing treatment and had sufficient material for next-generation sequencing (NGS) to detect MRD. The results showed that most patients were MRD-negative at the 10-6 level, while 3 out of 5 MRD-positive patients experienced relapse, strongly supporting the theory that follicular lymphoma is curable. Professor Cheson further extended the “chemotherapy-free” concept to Hodgkin lymphoma. In a study led by Anas Younes, he demonstrated the efficacy of Brentuximab vedotin(BV) in relapsed Hodgkin lymphoma. Years later, he heard Steven Ansell report exciting data on Nivolumab at an ASH meeting. He immediately contacted two relevant companies, promoting the use of BV combined with Nivolumab (BV-Nivo) in first-line Hodgkin lymphoma patients unsuitable for chemotherapy. Although the study was initially limited to only six cycles of Nivolumab treatment, five-year follow-up data showed that 41% of patients remained progression-free and likely achieved a cure. For patients requiring subsequent treatment, 85% remained in remission. This heralds the potential for chemotherapy-free treatment in Hodgkin lymphoma in the future.
Precise Assessment: Evolution from Experience to Science
Accurate staging and efficacy assessment are cornerstones of successful lymphoma treatment, and Professor Cheson’s work in this field spans nearly forty years. He recalled that early in AML and MDS research, due to the lack of unified remission criteria, he had to “invent” his own standards. But realizing this was not sustainable, he and his colleagues jointly developed standardized remission criteria for AML and MDS, which were updated as biological data accumulated. More monumentally, in 1988, Professor Cheson and colleagues such as Kanti Rai drafted the first remission criteria for chronic lymphocytic leukemia (CLL) in a trailer at Long Island Jewish Hospital. During discussions about the boundary between normal and abnormal lymphocytes, Professor Cheson, without any scientific basis, proposed “How about 5000?” — a number that is still used today. Subsequently, these standards were continuously updated to differentiate between clinical trials and clinical practice, incorporating cytogenetics, immunophenotyping, new features of the Fludarabine era, later prognostic markers (such as FISH, mutation status), and new entities like complete remission incomplete (CR incomplete). The most recent updates integrated a better understanding of genomic profiling and the clinical relevance of genetic testing, as well as the potential of MRD testing. However, with the advent of targeted drugs, assessment criteria also faced new challenges. For example, lenalidomide can cause a “flare reaction” of rapidly progressing lymphadenopathy and fever, which was initially often misdiagnosed as disease progression. BTK and PI3k inhibitors can lead to transient lymphocytosis, for which a new remission category, “partial remission with lymphocytosis,” was introduced. In the field of lymphoma, early treatment was limited to radiotherapy, and the staging process was “pure torture” – including laparotomy for splenectomy, liver biopsy, bone marrow aspiration, and painful lymphangiography. It wasn’t until 1989, when Andrew Lister introduced CT scans at the Cotswold meeting, that the staging system was revolutionized, eliminating these invasive procedures. For non-Hodgkin lymphoma, Professor Cheson’s team established the first unified remission criteria in 1999, which were then adopted for Hodgkin lymphoma. Subsequently, the advent of positron emission tomography (PET), which Professor Cheson vividly called “man’s best friend,” completely transformed the way lymphoma is assessed. In 2005, researchers such as Juweid ME demonstrated that in large cell lymphoma, patients with partial remission by CT but complete remission by PET had the same prognosis as those with complete remission by CT, indicating that PET scans could effectively differentiate between scar tissue, fibrotic tissue, and active lymphoma. The application of PET led to the 2007 update of remission criteria, and formulate the Deauville 5-point scale, simplifying PET scan interpretation. Subsequent studies confirmed the utility of PET in other histological types such as follicular lymphoma. After multiple Lugano meetings, the “bible” of the lymphoma field – the Lugano staging classification – was finally formed. A significant outcome of this classification was that PET scans were superior to bone marrow biopsy in identifying bone marrow involvement in large cell lymphoma and Hodgkin lymphoma, thus eliminating routine bone marrow biopsy for patients with these pathological types. Furthermore, Rutherford’s research also suggested that most follicular lymphoma patients might not require bone marrow biopsy. The first major revision of the Lugano classification stemmed from tumor “flare reactions” caused by checkpoint inhibitors in Hodgkin lymphoma. Experts collaboratively developed the LYRIC criteria to interpret potential inflammatory reactions and guide subsequent management.
Future Outlook: A New Chapter in Genomics and Precision Medicine
Despite many advances, Professor Cheson pointed out that science and technology continue to progress. At the recent Lugano meeting, experts discussed whether the Lugano classification needed revision, including whether to shift from anatomical staging to prognostic staging, whether to further refine PET scan assessment, and whether to integrate new biomarker technologies such as radiomics. After surveying 80 attendees, experts concluded that it was not yet time for a comprehensive revision of the Lugano classification. To effectively integrate these new technologies, the optimal platform needs to be identified, sufficient validation performed, and their clinical relevance, global accessibility, and economic feasibility demonstrated. Professor Cheson revealed that ICML will establish a steering committee to define the development direction of next-generation scientific technologies (such as NGS) and determine when to launch “Lugano Classification 2.0.” Papers related to this series of discussions have recently been published. Professor Cheson concluded his speech with a steadfast commitment, “I’m going to keep on rocking.” He sincerely thanked his wife, daughter, his golden retrievers who are like family, the countless young researchers he has mentored over the years, CALGB members, and numerous colleagues and patients, whose support and trust have made this journey truly meaningful.
Contribution/Interview Source: Oncology Outlook – Oncology News
