PEOPLE WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) who received two targeted therapies achieved long-lasting remissions that allowed some to stop treatment, according to a study published June 15, 2025, in the New England Journal of Medicine.
This study looked at treatments that are already approved for CLL: a BTK inhibitor called Imbruvica (ibrutinib), which patients typically take for as long as the cancer is responding, and a BCL2 inhibitor called Venclexta (venetoclax), which is usually given along with antibodies for a fixed period of 12 to 24 months depending on the regimen.
The phase III clinical trial enrolled 786 people with CLL who received either Imbruvica plus Venclexta, Imbruvica alone, or chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab, known as the FCR regimen. Researchers used highly sensitive tests that detect the presence of cancer cells that remain after treatment—called measurable residual disease (MRD)—to gauge whether patients should stop or continue treatment with the targeted therapy combination.
“We do know that when we treat our CLL patients, the response could be very diverse, and I think so should the treatment paradigm for our CLL patients,” says Talha Munir, a hematologist at Leeds Teaching Hospitals NHS Trust in England and the trial’s primary investigator.
In the study, 66.2% of people who took Imbruvica and Venclexta achieved undetectable MRD (uMRD), which meant researchers found no cancer cells in their bone marrow samples, within two years. All the patients in the Imbruvica-only group still had MRD, while 48.3% of the FCR group achieved uMRD.
Learn how doctors are tracking measurable residual disease to predict remission and transform treatment for blood cancers.
Measurable residual disease (MRD), which is also called minimal residual disease, refers to a very small number of cancer cells that remain in the body after treatment.
Doctors are able to check for MRD using sensitive assays that can detect cancer cells in blood or other samples. In a sample of 100,000 blood cells, the test can identify even a single chronic lymphocytic leukemia (CLL) cell, says Talha Munir, a hematologist at Leeds Teaching Hospitals NHS Trust in England. MRD remains a valuable marker that can help to personalize care in CLL. “If you go down to that depth of remission, it’s a very good surrogate marker to tell us how long the patient will stay disease-free,” Munir says.
In 2024, a Food and Drug Administration (FDA) panel unanimously approved using MRD to evaluate drugs for multiple myeloma, which is a blood cancer. However, the FDA did not formally include MRD as a surrogate endpoint—which is a substitute marker that the agency recognizes as likely to provide a real clinical benefit—that can be used when evaluating drugs for multiple myeloma or CLL.
For people taking the targeted therapy combination, Munir and colleagues used uMRD—also called MRD negativity—as a marker to determine how long to continue treatment with Imbruvica and Venclexta. For example, if a patient had no MRD after one year, that patient continued treatment for another year. “If we use our modeling system and give some extra treatment, we hopefully are taking patients down to a very low level of disease and possibly cure in some patients,” Munir says.
After five years, 93.9% of the people who took Imbruvica and Venclexta were alive without cancer progression. Among those who took Imbruvica alone, 79% were alive without cancer progression, compared with 58.1% of the FCR group.
Some people with CLL had a quick response to the combination, especially those whose cancer had unmutated IGHV, a genetic marker found in about 40% of CLL cases. Unmutated IGHV is a marker that signals faster disease progression and a poor response to immunotherapy. “Those with unmutated IGHV are the patients who will become MRD-negative quickly and will need a shorter duration of Imbruvica plus Venclexta,” Munir says.
The most common severe side effect from the combination was neutropenia, a low count of white blood cells called neutrophils, which can make a person susceptible to infection. Munir notes that 1 in 4 people experienced neutropenia. Other side effects included heart issues like high blood pressure and irregular heartbeat, as well as diarrhea.
Alvaro J. Alencar, a hematologist-oncologist at the University of Miami Health System who was not involved in the study, notes that treatments for CLL are evolving and that many oncologists will decide to use second-generation BTK inhibitors like Brukinsa (zanubrutinib) or Calquence (acalabrutinib), which are better tolerated. However, doctors can still use these findings to guide their decision to use the combination treatment with the newer BTK inhibitors, says Alencar.
“It’s the typical oncology world where we’re in a constant flux, always trying to look for what is next, but it’s very nice to see that there’s clearly a way forward with very effective and well-tolerated combinations,” Alencar says.
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