B-Cell Lymphomas in Veterans: 
Expanding the Role of  
Next-Generation BTK Inhibition
	
	
2 0 2 6  C O M P E N D I U M  O F  F E D E R A L  M E D I C I N E  
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By Annette M. Boyle
WASHINGTON, DC—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-con-
nected conditions for veterans who served in qualify-
ing 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 ion-
izing 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 lym-
phomas across a wide diagnostic spectrum, from the indo-
lent to the aggressive. Many of these patients are younger 
than the typical community oncology population for lym-
phoma, having developed disease in their 40s or 50s fol-
lowing service-related exposure.1
For clinicians caring for this population, the treatment 
landscape for B-cell malignancies has changed dra-
matically in recent years, with next-generation Bruton’s 
tyrosine kinase inhibitors offering new options across mul-
tiple 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, 

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