Survival Similar in CLL Without Undetectable MRD Regardless of Continued Therapy Type

Patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib plus venetoclax who did not initially show confirmed undetectable minimal residual disease (MRD) had similar survival outcomes regardless of whether they continued treatment with ibrutinib alone or in combination with venetoclax, according to new results from the phase 2 CAPTIVATE study (Abstract CT166/28) presented at the American Association for Cancer Research (AACR) Annual Meeting 2023. However, patients treated with the combination did have improved undetectable MRD rates compared with ibrutinib alone.

“With combination ibrutinib plus venetoclax therapy there seems to be excellent deep and durable remissions, regardless of MRD status,” said author and presenter Tanya Siddiqi, MD, director of the CLL program at the Toni Stephenson Lymphoma Center in Duarte, California. “Undetectable MRD may be more important for durability of responses in other treatments, such as venetoclax plus obinutuzumab.”

That said, the improved undetectable MRD rates in patients receiving ibrutinib plus venetoclax suggests this additional treatment may further delay relapses with the deepest remissions, Dr. Siddiqi said.

In CAPTIVATE, 164 patients with previously untreated CLL, and aged younger than 70 years, received three cycles of ibrutinib, followed by 12 cycles of ibrutinib plus venetoclax. Patients received a 13th cycle of the combination concurrent with MRD assessment.

Those patients who did not meet the criteria for confirmed undetectable MRD were then randomly assigned to open-label ibrutinib (31 patients) or ibrutinib plus venetoclax (32 patients). Dr. Siddiqi presented results for these patients, with a median follow-up of 33 months post-randomization.

Compared with pre-randomization, patients assigned to ibrutinib plus venetoclax had improved undetectable MRD rates in both the peripheral blood and the bone marrow. In peripheral blood, ibrutinib alone was associated with +3% improved rates (to 48%), whereas ibrutinib plus venetoclax was associated with +25% improved rates (to 72%). In the bone marrow, ibrutinib alone was associated with +10% improved rates (to 42%), whereas ibrutinib plus venetoclax was associated with +38% improved rates (to 69%).

However, response and survival outcomes were similar between the two arms. The improvement in complete response was +29% for ibrutinib alone and +28% for the combination. Four-year progression-free survival was 93% for patients in both arms, and the 4-year overall survival rates were 97% for ibrutinib alone and 100% for ibrutinib plus venetoclax.

The outcomes achieved were not affected by pre-randomization confirmed undetectable MRD status, as patients without confirmed undetectable MRD had similar outcomes to those with confirmed undetectable MRD status.

“Indefinite therapy [was given] in this cohort until the study stops or a patient has to stop for other reasons,” Dr. Siddiqi said. “In another cohort – fixed duration – everyone stopped treatment after 1.5 years of ibrutinib plus venetoclax regardless of MRD status. It seems, in the first few years, all patients seem to do just as well whether they got maintenance, continued therapy, or observation of the combination therapy.”

No adverse events led to treatment discontinuation. According to the researchers, adverse events decreased over time, with the exception of hypertension. Atrial fibrillation was rare, with only one case per treatment arm.

“In community practice, MRD testing is not done routinely. And what this shows us is that patients with unconfirmed MRD at end of treatment tend to do just as well as those with confirmed MRD,” says Tara Graff, DO, MS, a medical oncologist at Mission Cancer + Blood in Des Moines, Iowa.

“We know CLL is a chronic disease, but to be able to give our patients a break from therapy is nice with fixed-duration therapy options,” Graff added. “It is also refreshing to see that, if undetectable MRD is truly the goal, maintaining them on a BTKi [Bruton tyrosine kinase inhibitor] can deepen this response.”

Dr. Siddiqi disclosed relationships with various industry entities including Juno Therapeutics, Celgene, Bristol Myers Squib, Kite Pharma, AstraZeneca, BeiGene, Ascentage Pharma, Pharmacyclics, LLC, Oncternal, TG Therapeutics, and Jannsen.

Dr. Graff reported financial relationships with multiple companies, including AbbVie, Bristol Myers Squibb, and Kite.