Personalized CLL Therapy With MRD Guidance Improves Survival Outcomes

Tailoring chronic lymphocytic leukemia (CLL) treatment based on measurable residual disease (MRD) can significantly improve patient outcomes, according to a study published in The New England Journal of Medicine.¹

The phase 3 FLAIR trial found that MRD-guided therapy with ibrutinib and venetoclax not only extended progression-free survival (PFS) compared with standard chemoimmunotherapy with fludarabine–cyclophosphamide–rituximab (FCR), but also allowed most patients to discontinue therapy early.

The study enrolled 523 patients with untreated CLL, randomly assigning them to receive either MRD-driven ibrutinib-venetoclax therapy or standard FCR. After a median follow-up of 43.7 months, disease progression or death occurred in 4.6% of patients in the ibrutinib-venetoclax group compared with 28.5% in the FCR group.

At 3 years, PFS was markedly higher in the MRD-driven ibrutinib–venetoclax group (97.2%) compared with the FCR group (76.8%). Similarly, overall survival at 3 years was 98.0% in the ibrutinib–venetoclax group, slightly higher than the 93.0% for FCR.

“The positive outcome of the FLAIR trial appeared most marked in patients with IGHV-unmutated CLL, with substantial improvements in progression-free and overall survival,” the researchers said. However, they noted that the benefit was not as pronounced for patients with mutated IGHV.

One of the most notable findings was that MRD-based monitoring allowed many patients to stop treatment early. At 2 years, 28.9% of patients in the ibrutinib-venetoclax group had stopped treatment due to achieving undetectable MRD, doubling to 58% of patients by year 3. Additionally, by 5 years, 65.9% of patients had undetectable MRD in the bone marrow, and 92.7% had undetectable MRD in peripheral blood.

“No plateau was seen in achievement of undetectable MRD in peripheral blood, which suggests that continued therapy informed by MRD is justified,” the authors said.

While the study confirmed the effectiveness of MRD-based treatment, safety concerns remain. The risk of infection was similar between both treatment groups. However, the rate of cardiac serious adverse events was higher in the ibrutinib-venetoclax group (10.7%) than the FCR group (0.4%). The ibrutinib-venetoclax group was also more likely to experience tumor lysis syndrome, though this was only 1 case, while severe infections were reported more in the FCR group.

“In the current trial, more cases of atrial fibrillation and hypertension were reported in the ibrutinib-venetoclax group than in the FCR group (findings that were consistent with previous findings), but these results did not translate into an increased risk of sudden death,” the authors added. “Whether these findings illustrate the effect of changes in the management of hypertension and cardiac side effects cannot be ascertained.”

On the other hand, patients receiving FCR had higher rates of hematologic toxicities, including neutropenia (47.3% vs 10.3%) and secondary cancers. Notably, the incidence of secondary cancers per 100 patient-years was lower with ibrutinib-venetoclax (2.6%) compared with FCR (5.4%).

Ibrutinib was first approved to treat CLL in 2014, and other recent studies have supported the drug's efficacy in the space.² Earlier this year, a Japanese study confirmed that ibrutinib improved survival rates in both newly diagnosed and relapsed/refractory (R/R) CLL, with an overall survival rate of 90.8% for first-line treatment and 83.7% for patients with R/R CLL at 3 years.³ However, the study also highlighted the need for managing adverse events like bleeding, infections, and atrial fibrillation, which often led to treatment discontinuations and were mentioned in the FLAIR trial.

Similarly, a large Italian study with more than 3300 patients demonstrated that ibrutinib provided prolonged disease control in R/R CLL.⁴ While older age, prior therapies, and TP53 mutations were linked to shorter survival and faster treatment discontinuation, the study supported ibrutinib’s role as an effective salvage therapy.

References

1. Munir T, Cairns DA, Bloor A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063
2. Dangi-Garimella S. FDA Grants Accelerated Approval for Ibrutinib for CLL. AJMC^®. February 13, 2014. Accessed February 6, 2025. https://www.ajmc.com/view/fda-grants-accelerated-approval-for-ibrutinib-for-cll
3. Jacobsen-Sive K. Ibrutinib safe and effective in patients with CLL/SLL, real-world data show. AJMC. January 10, 2025. Accessed February 6, 2025. https://www.ajmc.com/view/ibrutinib-safe-and-effective-in-patients-with-cll-sll-real-world-data-show
4. Turim Dickstein G. Real-world data confirm ibrutinib's role in relapsed CLL. AJMC. November 26, 2024. Accessed February 6, 2025. https://www.ajmc.com/view/real-world-data-confirm-ibrutinib-s-role-in-relapsed-cll