Blood Podcast: Review Series on Marginal Zone Lymphoma

Podcast Host: American Society of Hematology
Published: January 8, 2026
Episode Theme: In-depth review and discussion of the latest advances and challenges in the understanding and treatment of marginal zone lymphoma (MZL), led by Associate Editor Dr. Philippe Armand with authors Dr. Ariela Noy and Dr. Juan Pablo Alderuccio.

Episode Overview

This bonus episode centers on the recently published review series on marginal zone lymphoma (MZL) in Blood, the leading peer-reviewed journal in hematology. Dr. Philippe Armand moderates a discussion with Dr. Ariela Noy and Dr. Juan Pablo Alderuccio, both contributing authors, focusing on the distinct nature of MZL, nuances across its subtypes, current treatment paradigms, the complexity of clinical trials in this population, and the pressing need for tailored research and drug development.

Key Discussion Points & Insights

1. Marginal Zone Lymphoma: A Distinct and Underappreciated Entity

• Not as rare as perceived:
  • MZL is the third most common non-CLL B-cell non-Hodgkin lymphoma ([00:52]).
• Distinct from other indolent lymphomas:
  • "People assume it's a rare lymphoma and we don't need to know much about it because we can just treat it like other indolent lymphomas, particularly like follicular lymphoma. And I think those statements are both incorrect." – Dr. Philippe Armand [00:52].
• Diversity within MZL:
  • The disease encompasses three biologically and clinically distinct subtypes:
    • Extranodal MZL (EMZL)
    • Splenic MZL (SMZL)
    • Nodal MZL (NMZL)

2. Clinical Approach to MZL Subtypes

Subtype Differentiation & Influence on Treatment

• Extranodal MZL:
  • Usually localized at diagnosis (stage I)
  • Rare bone marrow involvement
  • Frequently managed with localized radiation, often achieving durable remission ([03:00]).
• Splenic MZL:
  • Usually disseminated, with bone marrow and blood involvement.
  • Systemic agents (e.g., rituximab monotherapy) preferred, especially for patients requiring therapy ([03:00]).
• Nodal MZL:
  • Primarily involves lymph nodes.
  • Treatment paradigms often extrapolated from follicular lymphoma ([03:00]).

Relapsed/Refractory Setting

• The disease's biology and site of relapse inform decisions:
  • Ocular EMZL typically relapses only on the contralateral side.
  • SMZL can evolve into nodal patterns; "it becomes more fluid as the disease progresses."
  • Nodal relapses may mimic follicular lymphoma management, but splenectomy can remain an option in SMZL ([04:30]).
  • "It's a marathon, not a sprint... we're not treating an aggressive lymphoma for cure. We only have palliative therapy." – Dr. Ariela Noy [06:35].

3. Systemic Therapy Preferences and Sequences

Frontline Systemic Therapy

• Bendamustine-Rituximab (BR):
  • Preferred for NMZL and disseminated EMZL.
  • In SMZL, higher risk of infections/treatment-related mortality; thus, rituximab monotherapy is often favored ([08:41]).

Second-Line and Beyond

• Lenalidomide-Rituximab (R2):
  • Reasonable across subtypes if not previously used.
  • Not all tolerate it well; some data limitations noted ([09:43], [11:05]).
• Bruton Tyrosine Kinase Inhibitors (BTKi) [e.g., Zanubrutinib]:
  • Strong option in relapsed settings with favorable toxicity (especially Zanubrutinib for cardiac safety in elderly).
  • "It is very reasonable. It is NCCN and FDA approved. Patients can enjoy very prolonged disease control and progression-free survival on a BTKi." – Dr. Ariela Noy [10:28].
• Insurance approval and lack of FDA label for some agents (e.g., acalabrutinib, pirtobrutinib) create access challenges ([12:32]).
• Lack of standardized sequencing:
  • "Even we're just in second line... already there is a small difference of opinion between two experts, which reflects how little definitive standard of care exists." – Dr. Philippe Armand [13:04].

Beyond Second Line:

• Bispecific Antibodies (e.g., Mosunetuzumab):
  • Early results are promising, particularly in relapsed EMZL.
  • Caution advised in SMZL with circulating disease due to CRS risk.
  • Pre-phase therapy (e.g., dexamethasone) may reduce disease burden and lower CRS risk ([13:56]).
• Logistical considerations regarding antigen competition and selection of bispecifics highlighted ([15:10]).

CAR T-Cell Therapy

• Still in its infancy for MZL.
• Emerging data could mark a paradigm shift if curability is proven, but significant commitment and immunosuppression risks must be considered.
• Real-world use is rare; most patients opt for other therapies or trials ([15:55]).

4. Key Differences from Follicular Lymphoma

• Toxicity profiles and unique clinical features:
  • Higher infection risk in particular settings (e.g., SMZL with BR).
• Challenges in clinical trial accrual:
  • Current Lugano criteria can exclude typical MZL presentations (small lesions, extranodal sites, moderate splenomegaly without lymphadenopathy).
  • Need for disease measurement criteria adaptation ([18:21], [19:27]).
  • "By Lugano criteria, that patient has no disease. That is absurd." – Dr. Ariela Noy [19:27].

5. Challenges in Clinical Trial Design and Research for MZL

• Barriers:

  • Lack of suitable measurement criteria for disease burden limits eligibility ([19:27]).
  • Overall survival is impractical as a primary endpoint; many patients require lengthy follow-up.
  • Surrogate endpoints like CR24 and CR30 (complete remission at 24/30 months) are not yet FDA-accepted for approval ([23:00]).
  • Economic disincentives for industry to invest in drug development ([24:31]).
  • Difficulty in establishing "standard of care" due to lack of RCTs and variable eligibility.

• Quotes Highlighting Issues:

  • "You can't run a clinical trial for 10 years." – Dr. Juan Pablo Alderuccio [24:13]
  • "Not having a uniform way to evaluate 100 patients on a trial is not a way to move drug development." – Dr. Ariela Noy [20:43]
  • "Any one of us here could come up with a great trial design... [but] our company is not aligned with this, we can't prioritize that." – Dr. Ariela Noy [24:31]

• Suggested Solutions:

  • Modify trial eligibility criteria for MZL.
  • Push for regulatory acceptance of surrogate endpoints.
  • Increase advocacy for research prioritization and better industry incentives.

Notable Quotes & Memorable Moments

• "People assume it's a rare lymphoma...I think those statements are both incorrect."
  – Dr. Philippe Armand [00:52]

• "It's a marathon, not a sprint... we're not treating an aggressive lymphoma for cure. We only have... palliative therapy."
  – Dr. Ariela Noy [06:35]

• "Even we're just in second line and already there is a...small difference of opinion between two experts, which reflects how little...definitive standard of care exists."
  – Dr. Philippe Armand [13:04]

• "By Lugano criteria, that patient has no disease. That is absurd."
  – Dr. Ariela Noy [19:27]

• "You can't run a clinical trial for 10 years."
  – Dr. Juan Pablo Alderuccio [24:13]

• "Any one of us here could come up with a great trial design... but our company is not aligned with this, we can't prioritize that."
  – Dr. Ariela Noy [24:31]

Key Timestamps

• 00:52: Introduction of MZL as distinct and underestimated in frequency and complexity.
• 03:00: Overview of MZL subtypes and how they influence diagnosis and initial treatment.
• 04:30: Clinical approach and changing patterns at relapse.
• 06:35: Philosophy behind therapy selection—tailoring to palliative goals.
• 08:41: Current treatment sequences for frontline and beyond.
• 10:28: BTK inhibitors' role and their tolerability.
• 13:04: Discussion of off-label and investigational therapies, highlighting research gaps.
• 15:55: Reflections on CAR T-cell therapy and real-world considerations.
• 18:21–24:31: Challenges in trial design, measurement criteria, surrogate endpoints, and industry engagement.

Conclusion

This episode provides a comprehensive and candid assessment of marginal zone lymphoma as a unique, diverse, and under-recognized set of diseases. The experts emphasize the need for nuanced, subtype-specific approaches, highlight the lack of robust evidence guiding therapy sequencing, underscore the challenges faced in clinical research and drug development, and advocate for urgent systemic changes in how MZL research is prioritized and conducted.

For further details or to read the full review articles, listeners are encouraged to visit bloodjournal.org.