SEQUOIA Trial Shows Long-Term Benefits for People With Chronic Lymphocytic Leukemia

If you or someone you love has just been diagnosed with chronic lymphocytic leukemia (CLL), you're suddenly faced with unfamiliar medical terms and treatment decisions. New long-term research may help you have a more informed conversation with your hematologist about today's treatment options.

So what is Chronic Lymphocytic Leukemia? CLL is a slow-growing blood cancer that starts when abnormal white blood cells called B lymphocytes multiply out of control. Those cells build up in the bone marrow, then spread into the blood, lymph nodes, spleen and liver, crowding out the healthy cells your body needs.

CLL is the most common form of leukemia in adults. The American Cancer Society estimates about 22,760 new cases will be diagnosed in the U.S. in 2026, and most people are diagnosed at age 65 or older, with an average age at diagnosis around 70.

Although leukemia is often thought of as a rapidly progressing cancer, CLL is different. Many people live for years before needing treatment, and some never require therapy at all. During this period, often called "watch and wait," doctors closely monitor the disease through regular blood tests and physical exams, typically every three to six months, according to Mazie Tsang, MD, a hematologist and CLL specialist at Mayo Clinic in Arizona, until treatment becomes medically necessary.

Early Symptoms and Diagnosis

CLL is often silent at first. About 7 in 10 people have no symptoms when they're diagnosed, and the disease is frequently caught by accident, through a routine blood test that turns up an elevated white blood cell count.

When symptoms do appear, they tend to be easy to dismiss as something else. The most common early signs include:

• Swollen, usually painless lymph nodes in the neck, underarms, or groin
• Fatigue that doesn't improve with rest
• Low-grade fevers or frequent infections
• Night sweats and unintentional weight loss
• A feeling of fullness or discomfort in the abdomen, from an enlarged spleen or liver

Some people notice swollen lymph nodes on their own, often while bathing, shaving, or getting dressed, before any other symptom appears.

Doctors confirm CLL with blood tests, including a complete blood count and flow cytometry, which identifies the abnormal lymphocytes. From there, doctors use staging systems, most often the Rai system (stages 0 through IV) or the Binet system (stages A through C), to gauge how advanced the disease is and decide whether treatment is needed right away or if watchful waiting makes more sense.

Why CLL Hits Older Adults Hardest

Because most people are diagnosed later in life, CLL often arrives alongside other age-related health conditions, from heart disease to reduced kidney function, which can complicate treatment choices. The disease itself also wears on the immune system over time. As abnormal lymphocytes crowd out healthy blood cells, older adults can become more vulnerable to infections, fatigue, and reduced stamina, all of which affect independence and day-to-day functioning.

How CLL Is Treated Today

People with early-stage, symptom-free disease are usually monitored closely under a watch-and-wait approach, since starting treatment early hasn't been shown to improve outcomes. Doctors typically start treatment once the disease progresses, causes significant symptoms, or leads to anemia or low platelet counts.

Care has shifted substantially away from standard chemotherapy in recent years. Targeted therapies, including BTK inhibitors and BCL-2 inhibitors, are now common first-line options, often used instead of or alongside immunotherapy.

The Phase III SEQUOIA trial (NCT03336333) tested one of these newer options, zanubrutinib, a next-generation Bruton's tyrosine kinase (BTK) inhibitor, as a first treatment for adults with untreated CLL or small lymphocytic lymphoma (SLL), a closely related form of the disease. BTK is an enzyme leukemia cells rely on to survive and multiply, and BTK inhibitors interfere with this pathway, helping slow the growth and survival of leukemia cells.

The trial specifically studied outcomes for patients with deletion 17p, or del(17p), a genetic abnormality that has historically predicted a more aggressive disease course and weaker response to older treatments.

What the 6-Year Data Show

Researchers presented six-year follow-up data from SEQUOIA at the American Society of Hematology's (ASH) annual meeting, held December 6-9, 2025, in Orlando, Florida, with a median follow-up of 72.8 months. According to the investigators, this represents the longest follow-up reported to date for zanubrutinib as first-line therapy in CLL.

• Zanubrutinib reduced the risk of disease progression or death by 72 percent compared with bendamustine plus rituximab, a standard chemoimmunotherapy combination, in patients without del(17p). Progression-free survival measures how long patients live without their cancer worsening, one of the most important ways researchers evaluate cancer treatments.
• At six years, 74 percent of patients on zanubrutinib had no disease progression, compared with 32 percent on chemoimmunotherapy.
• The overall response rate with zanubrutinib was 98 percent.
• Among patients with del(17p), the six-year progression-free survival rate was 64 percent.

A separate analysis of five-year follow-up data in the del(17p) group, presented earlier at the 2025 American Society of Clinical Oncology (ASCO) meeting, reached a similar conclusion.

"The results are confirmatory and reassuring of the current practice to use BTKis in patients with 17p-deleted CLL." — Dr. Constantine Tam, a hematologist at Alfred Health and Monash University in Australia, told ASH Clinical News.

Sources: Tam CS, Munir T, Robak T, et al. "Sustained efficacy of zanubrutinib vs bendamustine + rituximab in treatment-naive CLL/SLL and continued favorable survival in non-randomized patients with del(17p): 6-year follow-up in the phase 3 SEQUOIA study." Blood. 2025;146(suppl 1):2129, presented at ASH 2025. OncLive, "SEQUOIA Long-Term Data Continue to Support Zanubrutinib in Treatment-Naive CLL/SLL," April 2026. ASH Clinical News, "Five-Year Results of SEQUOIA Trial Show Maintenance of Benefit for Patients With Del(17p) Treatment-Naïve CLL," July 2025.

The sequoia zanubrutinib trial reported long-term safety outcomes during extended follow-up. Compared with first-generation BTK inhibitors, zanubrutinib has demonstrated a distinct safety profile in clinical studies, with ongoing research evaluating the potential impact of its greater BTK selectivity on adverse event rates, including cardiovascular events.

What Happens If CLL Progresses

As CLL advances, it increasingly interferes with the bone marrow's ability to make healthy blood cells. That can lead to anemia, low platelet counts and a drop in infection-fighting white blood cells, leaving people more prone to bleeding, bruising and serious infections. Up to two-thirds of patients eventually develop low antibody levels, a condition that further raises infection risk.

CLL can also trigger the immune system to attack the body's own blood cells, leading to autoimmune complications such as autoimmune hemolytic anemia or immune thrombocytopenia. People with CLL also face a higher lifetime risk of second cancers, driven by a combination of immune suppression, prior chemotherapy exposure and genetics, though newer chemotherapy-free treatment approaches may help lower that risk over time.

So, when we talk about other cancers or second cancers, there is an increased risk for second cancers in patients with CLL. We've reported on that from our data set and others have. We think that it's because the immune system doesn't function normally. So, this surveillance and protection against developing cancers that usually occurs because of a normal immune system is deficient." — Dr. William Wierda, President & CEO of CLL Global Research Foundation and a CLL specialist at MD Anderson Cancer Center, quoted in CLL Global Research Foundation town hall transcript.

Richter Transformation

In a small share of cases, roughly 2 percent to 10 percent, CLL transforms into a fast-growing lymphoma called Richter transformation. It's usually signaled by rapidly swelling lymph nodes, new fevers or sudden weight loss, and it requires more intensive treatment, often chemotherapy combined with immunotherapy. This transformation is far more aggressive than typical CLL and carries a significantly shorter life expectancy than the underlying disease. Fortunately, Richter transformation remains uncommon, affecting only a small minority of people with CLL.

Life Expectancy and Disability Considerations

Life expectancy with CLL varies enormously from person to person, depending on stage, genetic risk factors, and how the disease responds to treatment. People diagnosed at an early, low-risk stage often live well over a decade, and many never need treatment at all. Historically, patients with high-risk, advanced-stage disease faced a median survival closer to five years, though that outlook was shaped largely by older chemotherapy-based treatments and predates the targeted-therapy era.

Newer targeted therapies, including the BTK inhibitor data outlined above, have meaningfully changed that picture for many patients, extending the time people live without disease progression even in higher-risk groups like del(17p). CLL still isn't considered curable, but doctors increasingly describe it as a manageable, chronic condition for many patients rather than an immediate threat to life.

That said, the cumulative effects of CLL, including chronic fatigue, weakened immunity and treatment side effects, can gradually limit physical stamina and independence, especially in older adults managing other health conditions at the same time. That's why long-term planning matters alongside medical treatment.

What This Means for Treatment Planning

Because many people stay on BTK inhibitors for years, safety and quality of life matter as much as disease control. Zanubrutinib was designed to be more selective than earlier BTK inhibitors, and researchers continue to study whether that translates into fewer side effects, including certain cardiovascular complications. Researchers reported no new safety concerns during the six-year follow-up, per the ASH 2025 presentation cited above.

Your doctor will weigh several factors before recommending zanubrutinib or another therapy, including:

• Age and overall health
• Cardiovascular history
• Kidney and liver function
• Genetic risk factors like del(17p)
• How long you're likely to stay on treatment
• Your own goals for daily life and independence

Medicare and Treatment Costs

Zanubrutinib and other oral BTK inhibitors are typically covered under Medicare Part D rather than Part B, since they're taken as pills at home instead of infused in a clinic. These drugs usually sit on a plan's highest "specialty" tier, which historically meant coinsurance of 25 percent to 33 percent of the cost.

That changed substantially in 2026. Medicare Part D now caps annual out-of-pocket drug costs at $2,100. Once you hit that cap, your plan covers 100 percent of your covered drug costs for the rest of the calendar year, a major shift from years when specialty cancer drugs could cost patients thousands of dollars out of pocket annually.

A few things to keep in mind when planning for treatment costs:

• Not every Part D plan covers every oral cancer drug, and some require prior authorization, so confirm your specific medication is on your plan's formulary before starting treatment.
• Specialty pharmacies, rather than your local retail pharmacy, typically fill these prescriptions and coordinate with your insurance.
• If you have limited income and resources, the Medicare Extra Help program can cover some or all of your Part D premiums, deductibles, and cost-sharing.
• Drug manufacturers often run patient assistance programs that can reduce or eliminate out-of-pocket costs for eligible patients, so ask your care team or pharmacist about options.
• The Medicare Prescription Payment Plan lets you spread your out-of-pocket drug costs into smaller monthly payments across the year instead of paying large amounts up front, which can help with cash flow even though it doesn't lower your total costs.

Long-Term Care and Quality of Life

Most people diagnosed with CLL are older adults, so long-term independence is part of the conversation from day one. The disease's toll on the immune system means fatigue and infection risk aren't just side effects to track during active treatment; they're ongoing factors that can lead to hospitalizations and gradually increase the need for help with daily tasks.

Families should plan ahead rather than wait for a crisis, thinking through future caregiving needs, the cost of care, and legal or financial planning alongside cancer treatment. Planning early gives families more choices before a health crisis limits options. Caregiver burden is real too: supporting someone over years of monitoring, treatment and recovery from infections can be a long-term commitment for family caregivers, not a short-term one.

If you have a CLL history and are considering Long-Term Care Insurance, coverage isn't automatically off the table. LTC Insurance underwriting varies significantly by insurer and changes over time, but as one example of how this can play out, some carriers may consider applicants with early-stage, low-risk CLL that isn't currently being treated and has been stable for a defined period, sometimes at a substandard rate class with reduced benefit limits.

CLL that's in remission after treatment may also be considered after a waiting period, again often at a higher rate class. Other companies decline CLL outright, or route it to individual consideration, where an underwriter reviews the specific case rather than applying a standard rule. Because these rules differ by insurance carrier and change as underwriting guidelines are updated, the only reliable way to know where you stand is to work with a Long-Term Care Insurance specialist who can shop your specific health history across multiple companies.

Our Cost of Long-Term Care Services Calculator can help you estimate what future care might cost in your area, and the Caregiver Directory can help you find vetted local providers when the time comes. Our Learning Center has more resources on caregiving, advance directives, Long-Term Care Insurance, and Medicare planning for aging and long-term care.

Talk to Your Care Team

New data like this is expanding options that weren’t available even a year or two ago. Ask your hematologist how the latest SEQUOIA results relate to your diagnosis, genetic profile and overall health. As CLL care becomes more personalized, knowing your individual risk factors matters just as much as keeping up with emerging research.

What questions should I ask my hematologist about the SEQUOIA trial?

Consider asking:

• Am I a candidate for zanubrutinib or another BTK inhibitor?
• Do I have any high-risk genetic abnormalities, such as del(17p)?
• What are the potential benefits and risks of long-term BTK inhibitor therapy?
• How often will my disease be monitored?
• What side effects should I watch for?
• How will treatment affect my daily activities and quality of life?
• Will Medicare cover my medication, and what costs should I expect?
• Should I also begin planning for future caregiving or long-term care needs?

This article is for informational purposes only and isn't medical advice. Talk with your hematologist about which treatment approach fits your diagnosis, health history, and goals.

Sources

• American Cancer Society, Detection, Diagnosis and Staging for Chronic Lymphocytic Leukemia
• American Cancer Society, Key Statistics for Chronic Lymphocytic Leukemia
• American Society of Hematology, 67th ASH Annual Meeting and Exposition, December 6-9, 2025
• ASH Clinical News, "Five-Year Results of SEQUOIA Trial Show Maintenance of Benefit for Patients With Del(17p) Treatment-Naïve CLL," July 2025
• Cleveland Clinic, Chronic Lymphocytic Leukemia and Richter Transformation
• Medicare.gov and Triage Cancer, Medicare Part D Quick Guide, 2026
• Merck Manual Professional Edition, Chronic Lymphocytic Leukemia
• National Cancer Institute, Chronic Lymphocytic Leukemia
• NCCN Clinical Practice Guidelines in Oncology, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• OncLive, "SEQUOIA Long-Term Data Continue to Support Zanubrutinib in Treatment-Naive CLL/SLL," April 2026
• Tam CS, Munir T, Robak T, et al. Blood. 2025;146(suppl 1):2129