Venetoclax Combo May Help Achieve MRD Negativity in High-Risk CLL

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The combination of venetoclax and ibrutinib may yield long-lasting treatment-free remission among patients with high-risk chronic lymphocytic leukemia.

"Thus, in high-risk patients, therapy with combined ibrutinib and venetoclax may reduce, but does not eliminate, the risk of selecting treatment-resistant cells. The mechanisms of MRD persistence and resistance to combined BTK and BCL2 inhibition remain to be elucidated," according to the study authors.

"Thus, in high-risk patients, therapy with combined ibrutinib and venetoclax may reduce, but does not eliminate, the risk of selecting treatment-resistant cells. The mechanisms of MRD persistence and resistance to combined BTK and BCL2 inhibition remain to be elucidated," according to the study authors.

Use of venetoclax (Venclexta) consolidation following 12 months of treatment with ibrutinib (Imbruvica) or more improved survival and produced higher rates of bone marrow undetectable measurable residual disease (MRD) in a cohort of patients with high-risk chronic lymphocytic leukemia (CLL), according to findings from a phase 2 trial (NCT03128879) published in the journal Leukemia.

The addition of venetoclax to ibrutinib achieved undetectable MRD in 57% of patients at 12 months and in 71% of patients following the completion of treatment. The best cumulative rate of undetectable MRD was 73%. Moreover, following treatment with the combination, 55% of patients improved their response to a complete remission (CR). Prior to treatment, 5% of patients had experienced a CR.

All patients experienced a reduction in lymph node size, with a median change of −70% in the sum of the product diameters of 6 measurable lymph nodes. The estimated rate of progression-free survival (PFS) at 3 years was 95%.

Regarding patients with high-risk disease characteristics, there were no statistically significant differences in rates of undetectable MRD among patients with (65.4%) vs without a TP53 abnormality (78.9%; P = .32), those with (72.7%) vs without a complex karyotype (66.7%; P = .61), and those who were treatment naïve (81.8%) vs those who had relapsed/refractory disease at the time of ibrutinib initiation (60.9%; P = .12).

Venetoclax dose reductions also did not significantly reduce the likelihood of undetectable MRD in patients (60%) compared with that of those who did not require a dose reduction (76%; P = .25. The same was true of patients who had ibrutinib dose reductions (74%) vs those who did not (67%; P = .64), regardless of whether the latter occurred before or during the study period. There was also no difference in outcomes associated with length of ibrutinib treatment; 80% of patients treated with ibrutinib for less than 2.5 years achieved undetectable MRD compared with 64% of those treated for more than 2.5 years (P = .24).

“Given the distinct mechanisms of action of ibrutinib and venetoclax, we hypothesized that the likelihood of simultaneous selection of resistance mutations to both agents would be low. Importantly, in our study, only 1 of 45 patients developed progressive disease during combined therapy,” the investigators wrote. “Thus, in high-risk patients, therapy with combined ibrutinib and venetoclax may reduce, but does not eliminate, the risk of selecting treatment-resistant cells. The mechanisms of MRD persistence and resistance to combined BTK and BCL2 inhibition remain to be elucidated.”

This investigator-initiated, response-adapted trial included 45 patients with CLL who had at least 1 high-risk feature for disease progression and who’d undergone at least 1 year of ibrutinib monotherapy. The median patient age was 68.5 years (range, 51-80), and the median number of prior therapies was 1 (range, 0-3).

For 22 of these patients, ibrutinib was the initial therapy. The median duration of ibrutinib therapy prior to receipt of venetoclax was 32 months (range, 12-73) across the overall population.

TP53 mutations or 17p deletions were present in 63% of patients. Of those with stimulated karyotype results available (n = 36), 31% had a complex karyotype. The median MRD percentage prior to venetoclax therapy was 7.3% (range, 0.03%-70.1%).

The primary end point was the rate of undectable MRD at 10-4 sensitivity in the bone marrow following 12 cycles of treatment. Secondary end points included CR, PFS, and safety.

During the study, patients continued receiving their tolerated dose of ibrutinib, ranging from 140 mg to 420 mg once daily. They also received venetoclax at escalating doses, up to the target dose of 400 mg once daily. Patients received this regimen for a maximum of 24 cycles of 28 days each, amounting to approximately 2 years of therapy.

The most frequent adverse effect (AE) was diarrhea in 47% of patients, with a severity of grade 1/2 in all but one of this group. Anemia was the most frequent grade 3/4 AE, affecting 20% of patients. There were no instances of clinical or biochemical tumor lysis syndrome, nor any of febrile neutropenia.

In total, 25 serious AEs occurred across 18 patients. These included non-melanoma skin cancers in 9 patients, myelodysplastic syndrome in 2, other solid tumors in 6, and grade 3 infections in 3.

“An MRD-directed treatment approach allowed early treatment discontinuation in patients with rapid achievement of undetectable MRD status and continuation of [Bruton tyrosine kinase] inhibitor maintenance in those with persistently detectable MRD,” the investigators concluded. “This approach may benefit patients by limiting duration of exposure to [the] drug and risk of [AEs] in rapid responders, and [by] improving remission durability in sub-optimal responders who remain MRD positive.”

The investigators also noted that the heterogeneity of the study population was both an intentional part of the design and a potential limitation to these findings.

Reference

Thompson PA, Keating MJ, Ferrajoli A, et al. Venetoclax consolidation in high-risk CLL treated with ibrutinib for ≥1 year achieves a high rate of undetectable MRD. Leukemia. Published online May 3, 2023. doi:10.1038/s41375-023-01901-4

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