B-Cell Lymphomas in Veterans: Expanding the Role of Next-Generation BTK Inhibition

The PACT Act marked the largest single expansion of veterans’ benefits for toxic exposure in the history of the VA. Among its most consequential provisions for hematology-oncology care, the legislation established lymphomas of any type as presumptive service-connected conditions for veterans who served in qualifying locations during the Gulf War era or in the post-September 11, 2001, conflicts. Lymphomas were already presumptive conditions for veterans exposed to Agent Orange and “atomic veterans” exposed to ionizing radiation.

The practical effect of these provisions is that VA hematology-oncology services are now evaluating and treating a growing population of veterans with B-cell lymphomas across a wide diagnostic spectrum, from the indolent to the aggressive. Many of these patients are younger than the typical community oncology population for lymphoma, having developed disease in their 40s or 50s following service-related exposure.¹

For clinicians caring for this population, the treatment landscape for B-cell malignancies has changed dramatically in recent years, with next-generation Bruton’s tyrosine kinase inhibitors offering new options across multiple indications.

Second-Generation BTK Inhibitors: A Broader Platform

Bruton’s tyrosine kinase (BTK) serves as an essential component of B-cell receptor signaling and is necessary for proliferation of B-cell malignancies. The first-generation BTK inhibitor ibrutinib demonstrated transformative efficacy across CLL, mantle cell lymphoma, and Waldenström’s macroglobulinemia, but its off-target inhibition of related kinases contributed to atrial fibrillation, major bleeding, arthralgias, and other adverse effects that led to treatment discontinuation in a meaningful proportion of patients.

Second-generation BTK inhibitors were engineered to achieve more complete and sustained BTK occupancy while minimizing off-target kinase activity. The resulting class of agents, which includes acalabrutinib, zanubrutinib, and the investigative tirabrutinib and orelabrutinib, offered comparable or superior efficacy and substantially improved cardiovascular and tolerability profiles compared to ibrutinib. For several B-cell lymphomas, zanubrutinib has emerged as a preferred agent based on prospective trial data, making it an important tool for clinicians in the VA.

Waldenström’s Macroglobulinemia: A Preferred Monotherapy

Waldenström’s macroglobulinemia is a rare, indolent B-cell lymphoplasmacytic lymphoma characterized by the infiltration of bone marrow with malignant lymphoplasmacytic cells and the overproduction of monoclonal immunoglobulin M paraprotein. Median age at diagnosis exceeds 70 years, placing it squarely within the population of older veterans who are most commonly treated at VAMCs.

The disease’s clinical manifestations arise from the direct infiltration of bone marrow, lymph nodes, and the spleen by malignant cells, which causes cytopenias, organomegaly, and constitutional symptoms, and the physical properties of the IgM paraprotein itself, which can produce hyperviscosity syndrome, cryoglobulinemia, peripheral neuropathy, and the rare but serious Bing-Neel syndrome. Treatment is initiated based on symptom burden, paraprotein levels, and evidence of organ compromise rather than disease stage alone; asymptomatic patients may be observed indefinitely.

Whole-genome sequencing identified the MYD88 L265P somatic mutation in more than 90% of patients with the disease. A second recurrent mutation, in the CXCR4 gene, is present in approximately 30% to 40% of patients and historically predicted attenuated responses to BTK inhibition. These molecular features have shaped both treatment selection and the comparative performance of BTK inhibitors in clinical trials.

The pivotal data supporting zanubrutinib in Waldenström’s macroglobulinemia (WM) came from the phase III ASPEN trial, which randomized 201 patients with MYD88-mutated symptomatic WM to zanubrutinib or ibrutinib. The primary endpoint was the combined rate of complete response and very good partial response assessed by independent review. Although the trial did not meet its primary endpoint at the initial analysis, zanubrutinib demonstrated a numerically higher combined response rate of 28% vs. 19% for ibrutinib.²

At the long-term follow-up analysis at a median of 44.4 months, the very good partial response or complete response rate was 36.3% with zanubrutinib vs. 25.3% with ibrutinib, and the 42-month progression-free survival rate was 78% for zanubrutinib compared with 70% for ibrutinib.³

The cardiovascular tolerability advantage was pronounced and consistent throughout follow-up. Atrial fibrillation occurred in 2% of zanubrutinib-treated patients vs. 15.3% of ibrutinib-treated patients at the primary analysis, a difference that persisted and widened at longer follow-up. Diarrhea, muscle spasms, hypertension, and adverse events leading to treatment discontinuation were all more common with ibrutinib. While neutropenia was more common with zanubrutinib, rates of grade 3 or higher infections were similar between arms.

In patients with the CXCR4 mutation, zanubrutinib demonstrated a more favorable major response rate of 85.7% vs. 53.8% with ibrutinib, and progression-free survival was substantially better in the zanubrutinib arm.⁴ That finding is clinically significant as a drug that performs well regardless of CXCR4 status offers a practical advantage in settings where molecular profiling may be incomplete.

The National Comprehensive Cancer Network responded to the ASPEN data by designating zanubrutinib as a category 1 preferred regimen for both primary therapy and previously treated Waldenström’s macroglobulinemia, making it the only agent to hold category 1 preferred status as a monotherapy across both treatment.⁵

Mantle Cell Lymphoma With TP53 Mutation: A Chemotherapy-Free Induction Platform

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma driven by the t(11;14) chromosomal translocation and defined by the overexpression of cyclin D1. It represents 6% to 7% of all non-Hodgkin lymphoma diagnoses in the U.S., but it carries a disproportionate burden among older men, the demographic that constitutes the core VA oncology patient population. Among the molecular features that stratify MCL outcomes, TP53 mutation stands out as particularly adverse: patients with TP53-mutated disease historically have had a median progression-free survival under one year with standard chemoimmunotherapy and poor long-term outcomes regardless of regimen intensity.

A multicenter, phase 2 study evaluated the chemotherapy-free combination of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in 25 previously untreated patients with MCL carrying a TP53 mutation with stage II bulky and noncontiguous disease or at stage III or IV. Patients achieving complete remission with undetectable minimal residual disease (MRD) at cycle 24 were eligible for treatment discontinuation, introducing the possibility of fixed-duration therapy in a disease where continuous treatment has been the norm.⁶

The BOVen regimen produced an overall response rate (ORR) of 96%, with 88% of patients achieving complete response (CR). Undetectable minimal residual disease was documented in 95% of evaluable patients at cycle 13.

With a median follow-up of 28.2 months, the two-year progression-free survival (PFS) was 72%, compared with the roughly 12-month median progression-free survival historically reported for chemoimmunotherapy in TP53-mutated MCL. Two-year overall survival was 76%, and disease-specific survival at two years was 91%, suggesting that the mortality signal in the short follow-up period was driven substantially by non-lymphoma causes, consistent with the older, multimorbid population enrolled.

The NCCN has incorporated BOVen into its B-Cell lymphomas guidelines as a suitable option for all patients with TP53-mutated MCL, acknowledging the clinical rationale for a chemotherapy-sparing approach in a disease subset that responds poorly to conventional therapy.⁷ For VA oncologists managing older veterans with TP53-mutated MCL, the BOVen regimen offers a fully outpatient, orally anchored treatment platform with response rates and overall survival that represent a meaningful advance over historical benchmarks.

Follicular Lymphoma: A Category 2A Option in the Third Line and Beyond

The most prevalent indolent B-cell lymphoma, follicular lymphoma,has a characteristic relapsing-remitting course, which means that many patients accumulate multiple prior lines of therapy over years of disease management. After progression through two or more prior systemic therapies that have included an anti-CD20 antibody and an alkylating agent, treatment options narrow considerably, and the disease may exhibit increasing resistance to prior agents.

The ROSEWOOD trial addressed this unmet need in a randomized, open-label, phase 2 study that enrolled 217 patients with relapsed or refractory grade 1 to 3A follicular lymphoma (FL) who had received at least two prior lines of therapy. Researchers randomized patients 2:1 to zanubrutinib plus the anti-CD20 monoclonal antibody obinutuzumab or obinutuzumab alone. The zanubrutinib-containing arm achieved an overall response rate of 69% compared with 46% in the control arm. The complete response rate was 39% vs. 19%. With a median follow-up of approximately 20 months, the median PFS was 28 months in the zanubrutinib plus obinutuzumab arm vs. 10.4 months in the control arm. Median time to next treatment was not reached in the combination arm vs. 12.2 months in the obinutuzumab alone arm.⁸

On the basis of ROSEWOOD, the FDA granted accelerated approval to zanubrutinib plus obinutuzumab for patients with relapsed or refractory FL who had received at least two prior lines of systemic therapy in March 2024, making zanubrutinib the first and only BTK inhibitor approved in follicular lymphoma.⁹ The NCCN subsequently incorporated the combination into its B-Cell Lymphomas guidelines as a category 2A recommended option for third-line and subsequent therapy in follicular lymphoma, reflecting the randomized data and the absence of a clear single standard of care in this heavily pretreated setting.

ROSEWOOD found cardiovascular events were consistent with other trials of zanubrutinib. The most common adverse events were hematologic, primarily neutropenia and thrombocytopenia, and infusion-related reactions associated with obinutuzumab. For VA patients who have already progressed through standard chemoimmunotherapy in the first and second lines, the zanubrutinib-obinutuzumab doublet offers a chemotherapy-free, outpatient regimen with favorable response rates and PFS duration.

 

1. Sgrignoli R, Rendo M, Fenderson JL, et al. Impact of military deployment on non-Hodgkin lymphoma subtype. Meeting Abstract: 2024 ASCO Annual Meeting I. JCO. 2024 May 29;42(16 Suppl). E19070.
2. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood.  2020 Oct 29;136(18):2038-2050. doi: 10.1182/blood.2020006844. PMID: 32731259; PMCID: PMC7596850.
3. Dimopoulos MA, Opat S, D’Sa S, et al. Zanubrutinib vs. ibrutinib in symptomatic Waldenström macroglobulinemia: final analysis from the randomized phase III ASPEN study. J Clin Oncol. 2023 Nov 20;41(33):5099-5106. doi: 10.1200/JCO.22.02830. Epub 2023 Jul 21. PMID: 37478390; PMCID: PMC10666987.
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5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma. Version 3.2025. https://www.nccn.org.
6. Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood. 2025 Jan 30;145(5):497-507.
7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: B-Cell Lymphomas. Version 2.2025. https://www.nccn.org.
8. Zinzani PL, Mayer J, Flowers CR, et al. ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzumab vs. obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2023 Nov 20;41(35):5107-5117.
9. U.S. Food and Drug Administration. FDA grants accelerated approval to zanubrutinib plus obinutuzumab for relapsed or refractory follicular lymphoma. March 7, 2024.