Editor's Note: The 66th Annual Meeting of the American Society of Hematology (ASH) successfully concluded in 2024, bringing together over 30,000 experts and scholars from around the world. With over a hundred meticulously planned sessions, the meeting delivered valuable insights and profound inspiration across various dimensions, including basic research, innovative therapies, and disease management in hematology. To delve deeper into the core takeaways from the ASH meeting and capture the latest dynamics in the field of hematology, Hematology Frontier invited Dr. David John Lewis from the University Hospitals Plymouth NHS Trust in the UK to share his unique insights and research findings in mantle cell lymphoma (MCL). Additionally, we have curated groundbreaking advancements in follicular lymphoma (FL) and MCL as presented by ASH, aiming to bring our readers a comprehensive overview of the latest progress and major discoveries in these areas.Dr. David John Lewis: I am a hematology consultant based in Plymouth, UK, with a primary clinical and research focus on lymphoma. I work at a center specializing in early-phase and first-in-human clinical trials, as well as large randomized studies. At this year’s ASH meeting, I served as the principal investigator of the ENRICH study, a landmark Phase III randomized trial, and the UK co-lead investigator of the OASIS2 study, both of which were featured during the conference. I also practice at a major transplant and CAR-T center.
At the ASH meeting, I presented the latest data from the ENRICH study, a milestone Phase III randomized trial that provides a detailed comparison of ibrutinib combined with rituximab versus chemotherapy regimens in previously untreated MCL patients. Excitingly, our research revealed for the first time that non-chemotherapy approaches demonstrate significant advantages over traditional chemotherapy in this patient population. Specifically, the combination of ibrutinib and rituximab showed remarkable superiority, particularly in progression-free survival.
The progress in MCL presented at this year’s ASH meeting underscores the growing trend of BTK inhibitors advancing into frontline treatment. I believe we are on the verge of entering a chemotherapy-free era for MCL. The ENRICH study data clearly illustrate the notable advantages of ibrutinib and rituximab over chemotherapy. Simultaneously, the interim analysis results of the OASIS2 trial, presented by Steven Le Gouill, offer invaluable insights. This study compares a triple-agent non-chemotherapy regimen (ibrutinib, venetoclax, and a CD20 monoclonal antibody) with a dual-agent regimen of ibrutinib and a CD20 monoclonal antibody. These findings have sparked great enthusiasm among researchers for clinical trials investigating chemotherapy-free regimens, making it reasonable to anticipate that such regimens will soon become the standard frontline therapy for MCL.
However, as we work towards setting new treatment standards in MCL, it is crucial to confront existing challenges. A pressing issue lies in treating high-risk blastoid MCL patients, where current efforts remain inadequate. We urgently need novel therapies and clinical trials targeting this high-risk group, as the existing treatment options fall short. Additionally, a critical question for the future is how to plan second- and third-line therapies once frontline BTK inhibitors become the standard for MCL. This is a key area requiring further exploration.
Addressing the Challenges of Treatment Choices in Follicular Lymphoma and Mantle Cell Lymphoma
By Andrés Gómez-De León and Michelle Morcos-Sandino
Advancements in research and technology play a vital role in improving patient care and treatment outcomes. However, these advancements also bring new challenges, particularly in decision-making for complex diseases like MCL. For newly diagnosed MCL patients, treatment options now include immunochemotherapy regimens with proteasome inhibitors, immunomodulators, and BTK inhibitors. The growing number of choices increases the complexity of decision-making, presenting uncertainties for clinicians managing lymphoma patients. Fortunately, the oral abstract sessions at ASH helped demystify the complexity of treating MCL and FL.
A key highlight of the meeting was the new chapter of the TRIANGLE Phase III randomized trial conducted by the European MCL Network. This trial investigates the efficacy of ibrutinib combined with immunochemotherapy as frontline therapy. Following the plenary session and publication at ASH 2022, questions about the role of autologous transplant as consolidation therapy remain unresolved. Dr. Martin Dreyling, the study’s lead investigator, addressed two critical questions: How do patients treated with ibrutinib and immunochemotherapy fare long-term without undergoing transplantation compared to those on standard regimens? And what additional benefit does transplantation offer to patients in the ibrutinib-containing arm? “The data are robust,” Dr. Dreyling stated. “With a median follow-up of five years, we now provide definitive answers” (Abstract 240). Meanwhile, Dr. Marco Ladetto presented a retrospective analysis of rituximab maintenance therapy, revealing its safety and efficacy across treatment groups in the trial (Abstract 237).
Oral abstracts also featured trials exploring MCL therapies of varying intensities. Dr. Nina D. Wagner-Johnston shared results from the ECOG-ACRIN EA4181 study, examining the efficacy of acalabrutinib combined with bendamustine-rituximab and cytarabine-rituximab regimens (Abstract 236). Additionally, Dr. David John Lewis discussed the ENRICH Phase III trial results comparing ibrutinib and rituximab with rituximab monotherapy in elderly patients (Abstract 235). “This study defines the standard control arm for future MCL trials,” Dr. Lewis remarked. “I believe the audience will find the results surprising.”
Several factors influence shared decision-making processes. What are the patient’s preferences and goals? How can clinicians balance the appeal of novel “all-oral, non-chemotherapy” regimens against the reality that they may not always be the best option? Clinicians must help patients weigh their fear of toxicity, long-term risks, short-term benefits, and the potential pros and cons of each treatment, while instilling confidence in their recommendations. This detailed decision-making process is particularly crucial in FL, where treatment plans depend on disease burden. For patients with minimal disease burden, the “watch and wait” strategy is considered viable. However, this approach may also negatively impact quality of life due to patient anxiety, earning it the nickname “watch and worry.”
Dr. Noriko Fukuhara presented results from the JOCG1411/Flora trial (Abstract 338), a randomized study investigating whether early rituximab monotherapy for low-tumor-burden FL could delay disease progression and reduce the need for cytotoxic chemotherapy. Incorporating more modern elements into FL frontline therapy, Dr. Lorenzo Falchi introduced the initial analysis of the Mithic-FL1 Phase II trial (Abstract 340), evaluating the CD20xCD3 bispecific antibody mosunetuzumab in FL patients with treatment indications.
The oral abstracts also highlighted novel therapies for relapsed and refractory diseases, including analyses of loncastuximab tesirine, epcoritamab, unnamed bispecific antibodies, and CAR-T therapies. By the end of these sessions, the “paradox of choice” in MCL and FL treatments had been clarified, presenting more actionable strategies. These findings equip hematologists with critical insights necessary to provide the highest level of care for their patients.
