by Annette M. Boyle
WASHINGTON, DC–Chronic lymphocytic leukemia 
and small lymphocytic lymphoma (CLL/SLL) remain the 
most common hematologic malignancies in the United 
States, accounting for roughly 40% of all leukemias. At 
the VA, service-related exposures create a disproportion-
ate burden associated with the blood cancers. 
The VA recognizes exposure to ionizing radiation for 
“atomic” veterans, Agent Orange during Vietnam-era 
service, contaminated drinking water at Camp Lejeune, 
and burn pits during the Gulf War and post-9/11 conflicts 
as contributing factors to CLL/SLL risk, qualifying the 
disease as a presumptive service-connected condition 
for eligible veterans. With a median age at diagnosis of 
approximately 70 years and up to twice the incidence in 
males, CLL/SLL strikes precisely the population the VA 
most often serves, making treatment selection a matter of 
significant importance.
Over the last several years, acalabrutinib, both as a 
monotherapy and in combination with venetoclax, has 
emerged as a first-line treatment option for CLL/SLL 
with a growing body of evidence to support its preferential 
use over older Bruton’s tyrosine kinase (BTK) inhibitors 
and traditional chemoimmunotherapy. The drug’s favor-
able tolerability profile, its demonstrated efficacy across 
Acalabrutinib Gains Ground 
As Preferred BTK Inhibitor for 
CLL/SLL in Veterans Likely to 
Have Co-Morbidities
Veterans with chronic lymphocytic leukemia and 
small lymphocytic leukemia tend to be very different 
than typical clinical trial populations, presenting with 
diagnoses of hypertension, type 2 diabetes, chronic 
kidney disease, obstructive sleep apnea, and post-
traumatic stress disorder, among other conditions.  
That is why VA’s oncology clinical pathways now prefer 
a first-line therapy that has demonstrated efficacy 
across high-risk genomic subgroups, has a lower rate 
of adverse effects and is compatible with the complex 
comorbidity profile common among older veterans.
	
	
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  
1 5
Oncology Clinical Pathways Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) 
Source: VA
a General Supportive Care for CLL/SLL includes IVIG for hypogammaglobulinemia and frequent infections, 
vaccinations (e. g.  COVID, influenza, pneumococcus, and varicella-zoster virus); do not administer live 
attenuated vaccines; screen for secondary malignancies, particularly non-melanoma skin cancers
b Monitor consider hepatitis B and C and HIV testing at baseline; monitoring frequency dependent on current 
symptoms, patient preference, absolute lymphocyte doubling time
c Risk Assessment using CLL/SLL IPI score which includes CLL/SLL FISH panel, TP53 mutation status, 
serum beta-2-microglobulin, IGHV mutation status, Rai or Binet staging, and age; also consider checking 
FISH t(11;14) to rule out mantle cell lymphoma, and CpG-stimulated karyotype; CLL FISH panel should 
include probes for: 13q, 17p, 11q, and 12 d Indications for Treatment include anemia (Hgb <10 g/dL) , 
platelets < 100,000/mm3, thrombocytopenia/anemia must be non-immune and not related to alternate 
causes, B-symptoms, and symptomatic adenopathy; consider cross-sectional imaging prior to initiation 
of therapy
e Supportive Care and Pre-Treatment Evaluation During Therapy Includes: 1) Hepatitis B serologies if not 
already checked, particularly with anti-CD20 antibodies (rituximab, obinutuzumab, ofatumumab), 2) TLS 
risk stratification prior to Venetoclax initiation, with prevention strategies as recommended by manufacturer, 
3) provide COVID prophylaxis dependent on availability, and 4) consider HSV/VZV prophylaxis
f BTK Inhibitor in pre-existing severe hepatic impairment, use dose-reduced Zanubrutinib; monitor for 
adverse events; if hepatic impairment during therapy, rule out drug-induced liver injury
g Progression BTK or PLC-gamma-2 mutation testing can identify causes for progression on BTKi therapy 
but is not recommended
h Patient Preference After Shared Decision Making shared decision includes discussion about time-limited 
therapy and complex dose ramp up with venetoclax; it also should include discussion about cardiac and 
infectious toxicities
i Monitor after completion of therapy for indication for therapy (footnote d); undetectable MRD by flow 
cytometry or targeted sequencing assay following venetoclax + obinutuzumab is associated with 
favorable prognosis 
Follow Relapsed
CLL/SLL pathway
Continue to monitor
Yes
No
Yes
No
Follow Relapsed
CLL/SLL pathway
Continue therapy
Acalabrutinib (indefinite)
Acalabrutinib + venetoclax 
(fixed duration)
Monitor after completion 
of therapy i
Progression or  
intolerance? g
Patient  
preference after  
shared decision 
making h
Del17p or  
TP53 mutation  
present?
Indication for 
treatment? d
Yes
No
Risk assessment if  
not previously performed c
Monitor every 3-6 months and 
consider risk assessment a b c
Chronic Lymphocytic Leukemia (CLL) and 
Small Lymphocytic Lymphoma (SLL)  
First Line
Yes
No
Acalabrutinib e f
Progression  
meeting criteria for 
therapy?

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