Editor's Note: The 18th International Conference on Malignant Lymphoma (ICML) was held, gathering top experts in the lymphoma field in Lugano. At the prestigious John Ultmann Memorial Lecture, Professor Emanuele Zucca, co-founder and Scientific Director of the International Extranodal Lymphoma Study Group (IELSG), delivered a keynote report titled "Extranodal Lymphomas: Improving Prognosis Through International Collaborative Research." This article, based on Professor Zucca's presentation, systematically reviews how investigator-initiated international collaborative studies over the past three decades have revolutionized the understanding and treatment paradigms of extranodal lymphomas, aiming to provide profound insights for clinical and research colleagues.Legacy and Tribute
Professor Emanuele Zucca. Since his graduation from the University of Milan in 1983, Professor Zucca has been dedicated to clinical research. With his profound expertise in clinical pharmacology and molecular pathology, along with his exceptional skills in international collaboration and clinical trial design, he has become a globally recognized leader in lymphoma research. He co-founded and leads the IELSG, transforming it from a loose coalition of young researchers into an international academic organization capable of conducting practice-changing clinical trials.
The Origin and Development of IELSG: Collaborative Research Driving Breakthroughs in Rare Diseases
Professor Zucca’s report began with the story of IELSG’s inception, profoundly illustrating the power of academic collaboration. He pointed out that the prognosis of extranodal lymphomas is not necessarily inferior to that of lymphomas originating in the lymph nodes; rather, the anatomical site and histological type are more critical prognostic factors. However, due to the limited number of cases at single centers, in-depth research on site-specific extranodal lymphomas once faced significant challenges.
The turning point occurred at a pre-ICML workshop in 1993, where Professor Isaacson’s pioneering data on inducing remission in gastric mucosa-associated lymphoid tissue (MALT) lymphoma by eradicating Helicobacter pylori (H. pylori) was first disclosed. This discovery ignited the research passion of Professor Zucca and his colleagues. They quickly followed up, not only becoming one of the first academic teams to validate this hypothesis but also confirming through molecular studies that the lymphoma cells originated from B cells selected by H. pylori infection. Based on these early results, a collaborative network of passionate young researchers was formed, with the selfless support of senior mentors like Cavalli, Coiffier, and Monserrat. The IELSG was founded precisely to pool global cases and expertise to answer clinical and biological questions that no single institution could resolve. Today, the IELSG brings together over 350 research institutions worldwide, has enrolled more than 8,500 patients, and its research findings have profoundly influenced global clinical practice.
Marginal Zone Lymphoma: A Paradigm Shift from Etiological Exploration to Precision Therapy
Marginal Zone Lymphoma (MZL) was one of the first areas of focus for the IELSG. Professor Zucca reviewed several landmark studies in this field.
A Chemotherapy-Sparing Strategy for Gastric MALT Lymphoma: The first clinical trial led by IELSG confirmed that for patients with early-stage gastric MALT lymphoma, subsequent chlorambucil chemotherapy provided no additional benefit after successful eradication of H. pylori. The study pioneered the use of Minimal Residual Disease (MRD) monitoring and demonstrated that transient molecular relapse does not affect long-term prognosis, providing a solid basis for the “watch and wait” strategy and successfully achieving treatment “de-escalation.”
A New Standard of Care for Systemic MZL: For MZL patients requiring systemic therapy, IELSG designed and completed the only randomized controlled trial in this field to date. The results clearly demonstrated the synergistic anti-tumor activity of Rituximab combined with Bendamustine. Concurrently, the MALT Lymphoma International Prognostic Index (MALT-IPI), developed from this study, has become the gold standard for risk stratification in this disease.
Molecular Subtyping of Splenic MZL: Through in-depth translational research, IELSG revealed two major clusters of gene mutations in splenic MZL: the “NNK” type, defined by mutations in NFKB, Notch, and KLF2 genes, and the “DMT” type, defined by mutations in DNA damage repair pathway genes. This discovery not only has significant clinical guidance value but also provided core evidence for the definitions of this disease in the latest World Health Organization (WHO) Classification of Lymphoid Neoplasms and the International Consensus Classification (ICC).
Mediastinal and Immune-Privileged Site Lymphomas: Landmark Studies Overcoming High-Risk Challenges
For aggressive lymphomas originating in specific sites like the mediastinum and testes, IELSG has completely transformed the treatment landscape through a series of studies.
Primary Mediastinal Large B-cell Lymphoma (PMBCL): IELSG’s early retrospective study was the first to challenge the “dogma” of the time that considered the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) as the standard of care for all diffuse large B-cell lymphomas, pointing out its suboptimal efficacy in PMBCL. Subsequently, through the prospective IELSG26 study, the team established the critical role of Positron Emission Tomography (PET) in assessing treatment response in PMBCL, contributing core data to the development of the Lugano Classification. Building on this, the pivotal IELSG37 randomized controlled trial proved that for patients achieving a Complete Metabolic Response (CMR) after chemoimmunotherapy, consolidation radiotherapy could be safely omitted. This successfully spared a large number of young patients from the long-term toxicity of radiotherapy, perfectly illustrating the concept of “precision de-escalation.”
Primary Testicular Lymphoma: This disease once had an extremely poor prognosis due to a very high rate of Central Nervous System (CNS) relapse and risk of contralateral testicular involvement. Through a large-scale real-world study, IELSG precisely identified a highly effective combined-modality treatment: an anthracycline-based systemic chemotherapy, intrathecal prophylaxis, and radiotherapy to the contralateral testis. The subsequent prospective IELSG10 study successfully validated this regimen, elevating the prognosis of the disease to a new level. Further research confirmed that a CNS prophylaxis strategy combining systemic Methotrexate with intrathecal injections could achieve a “zero incidence” of CNS relapse, providing the best evidence for clinical practice.
Central Nervous System Lymphoma: High-Intensity Combination Regimens Forging New Heights in Survival
Primary CNS Lymphoma (PCNSL) is another key area tackled by IELSG. Through a series of meticulously designed randomized controlled trials, IELSG has progressively established the global standard of care for PCNSL.
Laying the Foundation for Combination Chemotherapy: The IELSG20 study was the first randomized controlled trial to demonstrate that a regimen of high-dose Methotrexate combined with high-dose Cytarabine was significantly superior to high-dose Methotrexate alone, thus laying the cornerstone for combination chemotherapy.
Establishing the MATRIX Induction Regimen: Subsequently, the IELSG32 study added Rituximab and Thiotepa to the aforementioned two-drug combination, forming the globally recognized standard induction regimen today—the MATRIX regimen.
Optimizing Consolidation Therapy: The second part of the IELSG32 study randomized patients to compare Autologous Stem Cell Transplantation (ASCT) versus Whole-Brain Radiotherapy (WBRT) as consolidation therapy. The results showed that although survival data were similar, ASCT had an overwhelming advantage in preserving patients’ neurocognitive functions, thereby establishing ASCT as the standard consolidation modality for young, fit patients. Subsequent research has further confirmed that for elderly patients who cannot tolerate transplantation, no other chemotherapy regimen can currently replace the role of ASCT.
Future Outlook and Conclusion
At the end of his report, Professor Zucca introduced several important ongoing studies by IELSG, including the use of PET for MZL assessment, research on new drugs for lymphoma transformation, and exploration of primary nodal marginal zone lymphoma, showcasing the organization’s continuous innovative vitality.
Professor Emanuele Zucca’s report is not just a history of IELSG’s journey but also a tribute to international academic collaboration. It eloquently demonstrates that in the face of rare and complex extranodal lymphomas, investigator-initiated, patient-centered independent academic research is the irreplaceable core engine driving progress in clinical understanding and treatment practices. The success of IELSG not only brings hope of survival to lymphoma patients worldwide but also provides a valuable model for research in other rare cancers, allowing the world to share the wisdom and achievements born from academic collaboration.
Contributed by/Interview Source: Oncology Horizon – Oncology Times
