Novel Agents Reshape Sequencing Across Different Lymphoma Populations

At the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting, “Meet-the-Professor” (MTP) Session XIV brought together 3 presentations spanning uncommon but biologically distinct non-Hodgkin lymphoma subtypes. Won Seog Kim, MD, PhD, hematologic oncologist of the Samsung Medical Center, opened with an overview of evolving induction and immunotherapy strategies in extranodal NK/T-cell lymphoma (ENKTL). Narendranath Epperla, MD, MS, FACP, an associate professor in the Division of Hematology and Hematologic Malignancies in the Department of Medicine at the Huntsman Cancer Institute at the University of Utah, followed with a survey of bispecific antibody data in marginal zone lymphoma (MZL). Jorge J. Castillo, MD, clinical director of the Bing Center for Waldenström Macroglobulinemia at the Dana-Farber Cancer Institute and an associate professor of Medicine at Harvard Medical School, closed the session with a comparative review of Bruton’s tyrosine kinase (BTK) inhibitor data in lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) and MZL.

Chemotherapy-Free and Immune-Directed Strategies Advance in Extranodal NK/T-Cell Lymphoma

Kim opened by noting that ENKTL outcomes have historically diverged sharply by disease site and stage. Data from the International Peripheral T-Cell Lymphoma Project showed markedly worse survival with extranasal vs nasal disease, and the International T-Cell Project confirmed inferior progression-free survival (PFS) and overall survival (OS) with advanced- vs limited-stage disease.^1,2 He outlined 5 shifts that have defined the field over the past 2 decades: abandonment of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy, integration of radiotherapy (RT) with chemotherapy in early-stage disease, adoption of L-asparaginase–containing regimens, use of immune checkpoint inhibitors (ICIs) in relapsed/refractory disease, and development of the PINK and PINK-E prognostic models.

For localized disease, long-term follow-up of 40-Gy concurrent chemoradiotherapy (CCRT) with weekly cisplatin and systemic chemotherapy showed a 5-year PFS rate of 68% and 5-year OS rate of 82.2%, with CCRT plus systemic chemotherapy significantly outperforming CCRT alone (P = .004).³ Kim also previewed an ongoing trial combining tislelizumab (Tevimbra) with RT (40 Gy/20 fractions) followed by 2 years of maintenance tislelizumab in low-risk, stage IE/IIE nasal ENKTL, which has thus far produced high complete response (CR) rates and strong local control with a manageable safety profile.

In advanced-stage disease, a randomized comparison of SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide) and DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) chemotherapy (NCT01501149) showed that DDGP produced a higher objective response rate (ORR; 90% vs 60%), improved the 3-year PFS rate (56.6% vs 41.8%), and improved the 5-year OS rate (74.3% vs 51.7%), with less treatment-related mortality than SMILE.⁴ A large real-world series similarly showed superior PFS with SMILE relative to DeVIC or non-anthracycline regimens, with hematopoietic stem cell transplant consolidation further improving outcomes.⁵

Turning to immunotherapy, Kim highlighted that pembrolizumab (Keytruda) activity in relapsed/refractory ENKTL appears to track with 4 immune subtypes defined by FoxP3, PD-L1, and CD68 staining—immune tolerance, immune evasion-A, immune evasion-B, and immune silenced—consistent with earlier case series demonstrating durable Epstein-Barr virus (EBV) DNA clearance with pembrolizumab.^6,7

CD38-directed approaches were also discussed. Daratumumab (Darzalex) monotherapy produced a 25% ORR, while combined CD38/PD-1 blockade with isatuximab (Sarclisa) plus cemiplimab (Libtayo) produced an ORR of 65% and a CR rate of 51%.^8,9 Kim closed with first-line immunochemotherapy data, including the single-arm SPIRIT trial (NCT04127227) of sintilimab (Tyvyt) with peg-asparaginase, gemcitabine, and oxaliplatin (P-GEMOX), which achieved an 85% CR rate, and a large retrospective comparison showing that adding a PD-1 inhibitor to P-GEMOX improved the 3-year PFS (64.1% vs 40.7%) and OS rate (79.5% vs 60.8%) over chemotherapy alone.¹⁰ Kim noted that single-cell sequencing has begun to define 4 tumor microenvironment programs—immune exhausted, immune desert, immune excluded, and tertiary lymphoid structure-enriched—that may eventually guide rational pairing of checkpoint blockade with histone deacetylase (HDAC) inhibitors, JAK inhibitors, or asparagine-targeted therapy.

Kim concluded that despite substantial progress over the past 2 decades, several questions remain unanswered: the optimal induction regimen, management of central nervous system (CNS) relapse, the positioning of ICIs, and a validated molecular classification for ENKTL.

Can CD20/CD3 Bispecific Antibodies Deliver Durable Remissions in Marginal Zone Lymphoma?

Epperla’s talk, “Bispecific Antibodies in Marginal Zone Lymphoma: Game Changer or Hype?,” opened with the epidemiology and pathogenesis of MZL’s 3 recognized subtypes—extranodal MZL of mucosa-associated lymphoid tissue (EMZL), nodal MZL (NMZL), and splenic MZL (SMZL)—and the distinct microenvironmental niches that appear to shape sensitivity to T-cell–engaging bispecific antibodies (BsAbs): chronic antigenic stimulation in EMZL, NOTCH2/KLF2-driven follicular and interfollicular niches in NMZL, and high circulating tumor burden in SMZL. He noted that baseline CD8-positive T-cell infiltration appears predictive of BsAb response in NMZL, with CR rates of 95% in tumors with high infiltration vs 12% in those with low infiltration, while chronic antigenic exposure and T-cell exhaustion in EMZL and high circulating tumor cell burden with cytokine release risk in SMZL represent distinct mechanisms of potential BsAb failure or toxicity.

Turning to clinical data, Epperla reviewed the MorningSun trial’s (NCT05207670) first-line MZL cohort, in which subcutaneous mosunetuzumab (Lunsumio) produced a 78% ORR and 64% CR rate in a population enriched for elevated lactate dehydrogenase (LDH) and advanced-stage disease, with cytokine release syndrome (CRS) largely grade 1 to 2 and confined to cycle 1.¹¹ The phase 2 BrUOG-401 trial (NCT04792502) combining mosunetuzumab with response-adapted lenalidomide (Revlimid) augmentation in untreated follicular lymphoma and MZL showed CR rates of 88% by PET criteria in the MZL cohort, with a 2-year PFS estimate of 93.3%.¹² In the relapsed/refractory setting, the ELM-2 study (NCT03888105) of odronextamab (Ordspono) monotherapy enrolled a heavily pretreated population—64.3% refractory to last therapy, 50% with progression of disease within 24 months—and reported an ORR of 77.1% (95% CI, 59.9%-89.6%), with all responses being complete and neither median PFS nor OS reached at data cutoff; CRS was predominantly low grade, and no immune effector cell-associated neurotoxicity syndrome events were observed.¹³

Epperla closed by outlining several ongoing studies designed to further define BsAb positioning, including the phase 2 EZR triplet trial (NCT06563596) of epcoritamab (Epkinly), zanubrutinib (Brukinsa), and rituximab (Rituxan) in relapsed/refractory follicular lymphoma and MZL; the phase 3 MARSUN trial (NCT06006117) of mosunetuzumab/lenalidomide vs investigator’s choice in relapsed/refractory MZL; and the randomized phase 2 MOZART MZL/S2506 trial (NCT07638722) comparing mosunetuzumab alone against mosunetuzumab plus zanubrutinib or polatuzumab vedotin-piiq (Polivy).^14-16

Epperla concluded that CD20/CD3 bispecific antibodies offer off-the-shelf availability, targeted cytolysis, and durable CR rates in heavily pretreated MZL, positioning the class as a potential practice-changer as data mature from the relapsed into the first-line setting.

How Do BTK Inhibitors Compare Across LPL/WM and Marginal Zone Lymphoma?

Castillo’s presentation, “BTK Inhibitors in LPL and MZL: What Does the Data Tell Us?” opened with WM diagnostic criteria—immunoglobulin M (IgM) monoclonal protein, lymphoplasmacytic bone marrow infiltration, and MYD88 L265P mutation—and clinical manifestations including hyperviscosity syndrome, IgM neuropathy, and Bing-Neel syndrome. After reviewing established rituximab combination regimens, he turned to BTK inhibitor data, beginning with long-term follow-up of ibrutinib (Imbruvica) monotherapy in previously treated patients, in which response rates and PFS varied by MYD88/CXCR4 genotype: ORR was 100% in MYD88-mutated/CXCR4 wild-type disease vs 60% in double–wild-type disease, with a similar genotype-dependent pattern observed in patients who were treatment naive.

The phase 3 iNNOVATE trial (NCT02165397) final analysis showed that adding ibrutinib (Imbruvica) to rituximab improved PFS over rituximab plus placebo across all 3 genotype subgroups, and the phase 3 ASPEN trial (NCT03053440) demonstrated numerically longer PFS with zanubrutinib vs ibrutinib alongside a more favorable safety profile, particularly less atrial fibrillation and hypertension.^17,18 A subsequent ASPEN biomarker analysis showed that CXCR4 and TP53 mutations were each associated with inferior PFS, with the effect of TP53 mutation most pronounced among ibrutinib-treated patients.

Castillo also reviewed long-term venetoclax (Venclexta) monotherapy data, which showed a median PFS of 36 months and demonstrated feasibility of venetoclax retreatment after progression, and presented 5-year follow-up of the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) from the phase 3 BRUIN trial (NCT03740529), which showed an 82.5% best response rate in WM (72.5% major response) and a median PFS of 35.9 months (95% CI, 19.3-not evaluable), with continued responses regardless of prior BTK inhibitor exposure.^19,20

Shifting to MZL, Castillo reviewed differential diagnostic features distinguishing LPL/WM from MZL—including a MYD88 L265P prevalence of 90% vs 10%, respectively—before summarizing chemoimmunotherapy data showing bendamustine/rituximab as a noninferior, less toxic alternative to R-CHOP (rituximab plus CHOP) across indolent histologies, including MZL. Single-agent ibrutinib in relapsed/refractory MZL produced an ORR of 48% and a median PFS of 14 months, with a 2-year OS of 80%, and long-term follow-up with biomarker analysis showed more durable responses with single-agent rituximab retreatment than with rituximab-based chemoimmunotherapy in this population.

Acalabrutinib (Calquence) in the phase 3 ACE-LY-003 trial (NCT02180711) showed more modest durability, with PFS declining below 50% by approximately 28 months, while the MAGNOLIA trial (NCT03846427) final analysis of zanubrutinib reported a 24-month PFS rate of 70.9% (95% CI, 57.2%-81.0%) and OS rate of 85.9% (95% CI, 74.7%-92.4%) with a favorable cardiac safety profile.^21,22 Pirtobrutinib in the BRUIN R/R MZL cohort (NCT03740529) showed an ORR of 55.6% (95% CI, 38.1%-72.1%), with higher response rates among patients who were BTK inhibitor naive and those without elevated LDH.²³ Castillo also referenced 3-year follow-up of axicabtagene ciloleucel (Yescarta; axi-cel) in the indolent lymphoma ZUMA-5 study (NCT03105336), which showed a 77% ORR and 65% CR rate in MZL, with an estimated 64% (95% CI, 40%-80%) of responses maintained at 36 months.²⁴

Castillo concluded that while both covalent and noncovalent BTK inhibitors are safe and effective across LPL/WM and MZL, response depth and survival outcomes appear consistently superior in WM, underscoring the importance of accurate differential diagnosis between the 2 entities before treatment selection.

References

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