Chronic Lymphocytic Leukemia (CLL): What to Know

Chronic lymphocytic leukemia is defined by a count and a marker pattern. NCI states that the blood lymphocyte count is usually 5,000/mm3 or higher, with a characteristic immunophenotype: B cells that carry both CD5 and CD23.

That pattern comes from flow cytometry, a test that sorts cells by the proteins on their surface. Bone marrow aspiration and biopsy are usually not required at diagnosis. Neither is a CT scan, unless you have enlarged nodes you can feel.

The initial workup NCI lists is mostly blood work: a complete blood count, a chemistry panel, LDH, beta-2-microglobulin, immunoglobulin levels, and tests for hepatitis B, hepatitis C, and HIV. Those infection tests are not routine paperwork. Some CLL treatments can wake up a dormant hepatitis B infection.

CLL has no single staging system. NCI presents two.

The Rai system runs 0 through IV. Stage III is defined by hemoglobin under 11 g/dL. Stage IV is defined by a platelet count under 100,000/mm3. Stage 0 is written as absolute lymphocytosis above 15,000/mm3 with no enlarged nodes, no enlarged liver or spleen, no anemia, and no low platelets.

Notice the mismatch. Rai's original 1975 threshold was 15,000/mm3, while the modern diagnostic cutoff NCI cites is 5,000/mm3. Both numbers appear on the same NCI page. If your count sits between the two, you can meet the definition of CLL without meeting Rai's original stage 0 wording. Ask which figure your team is using.

The Binet system uses letters instead. Stage A means no anemia or low platelets and fewer than three areas of lymphoid involvement. Stage B means the same blood picture with three or more areas. Stage C means anemia or low platelets regardless of node count. CLL staging walks through both.

Many people with CLL are not treated at diagnosis. NCI is direct: chemotherapy is not indicated for people who are asymptomatic or minimally affected, and observation is the generally accepted approach.

This is not vague. The International Workshop on CLL sets numeric triggers for starting treatment. NCI lists them.

• Hemoglobin below 10 g/dL, or platelets below 50,000 per microliter.
• A spleen that reaches 6 cm or more below the left rib margin, or that is growing or causing symptoms.
• A lymph node 10 cm or larger in its longest dimension, or nodes that are growing or causing symptoms.
• A rise in lymphocyte count of 50% or more over two months, or a lymphocyte doubling time under 6 months.
• Autoimmune anemia or low platelets that respond poorly to steroids.
• Disease affecting the skin, kidney, lung, or spine.

That last line about doubling time comes with a caveat NCI states: infections and steroid use can push the count up on their own, so those must be ruled out first. Watchful waiting versus active surveillance covers what monitoring looks like in practice.

IGHV mutation status splits CLL almost in two. NCI reports that finding significant numbers of variants in this region carries a median survival over 20 to 25 years. Absence of those variants carries a median survival of 8 to 10 years. The counterintuitive part is that mutated is the good result here.

FISH looks for missing or extra pieces of chromosome. NCI gives median overall survival by finding, from one prospective study. A del(13q) is favorable at 17 years. Trisomy 12 and del(11q) sit at 9 to 11 years. A del(17p) is the most unfavorable at 7 years, and it usually travels with a TP53 mutation, which predicts poor and short-lived responses to older drugs.

Those survival figures come from the era before BTK and BCL2 inhibitors. NCI notes that in older trials from the 1970s through the 1990s, median survival for all patients ran 8 to 12 years, but that since these newer drugs arrived, median survival has not been reached with more than 10 years of follow-up. NCI adds that even the widely used CLL-IPI prognostic model may now be outdated for the same reason.

NCI notes FDA approval of ibrutinib, acalabrutinib, and venetoclax for first-line use in newly diagnosed CLL that requires therapy. For del(17p) or TP53 mutation, those agents specifically should be considered.

A trial of 533 previously untreated patients compared acalabrutinib with ibrutinib head to head. At 41 months median follow-up, progression-free survival was identical at 38.4 months in both arms. The difference was in side effects: atrial fibrillation of any grade occurred in 9.4% on acalabrutinib versus 16.0% on ibrutinib.

Another trial in patients 65 or older, or with reduced kidney function, gave 24-month progression-free survival rates of 93% for acalabrutinib plus obinutuzumab, 87% for acalabrutinib alone, and 47% for chlorambucil plus obinutuzumab.

NCI frames the strategy shift bluntly. Older chemotherapy drugs such as fludarabine, bendamustine, cyclophosphamide, and chlorambucil damage DNA, which can produce more aggressive disease at relapse and can cause second cancers. Avoiding chemotherapy up front is described as a new paradigm. Venetoclax explains the BCL2 side of that approach, including its ramp-up schedule.

In 2% to 10% of people, CLL transforms into an aggressive lymphoma, usually diffuse large B-cell lymphoma. This is called Richter transformation.

NCI restricts PET-CT to a specific situation: recurring fever, drenching night sweats, weight loss over 10% of body weight in 6 months, or lymph nodes growing quickly. In a review of 432 patients, 209 had a maximum standardized uptake value of 5 or higher, and 80% of those had aggressive CLL or Richter syndrome. When the value reached 10 or higher, 5-year overall survival was 30%.

If transformation follows prior CLL treatment, NCI puts median survival at 6 to 14 months. If the CLL was never treated, outcomes resemble a new DLBCL diagnosis.

• Your temperature reaches 100.4 degrees F (38 C). MedlinePlus, reviewed October 2024, uses 100.4 F; NCI's infection page, reviewed January 2020, uses 100.5 F. Use the lower, newer number. CLL weakens antibody defenses even before treatment starts.
• Drenching night sweats return, or you lose more than 10% of your body weight over 6 months.
• A single lymph node grows noticeably faster than the rest, over weeks rather than months.
• You become breathless climbing stairs, or your skin looks pale and yellow-tinged, which can signal autoimmune destruction of red cells.
• You bruise without injury or bleed from the gums, which can mean platelets have fallen.

• https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq
• https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq
• https://www.cancer.gov/about-cancer/treatment/side-effects/infection
• https://medlineplus.gov/ency/patientinstructions/000913.htm