Venetoclax and Ibrutinib for Relapsed and Refractory CLL: Interim Analysis of MRD Testing

Whether results of minimal residual disease (MRD) testing can help oncologists decide to stop targeted treatments for CLL is being studied in an ongoing clinical trial known as VISION or HOVON 141. Specifically, the study is testing patients with relapsed and refractory CLL who are receiving venetoclax plus ibrutinib to learn if MRD-guided breaks in treatment are acceptable.

In the VISION study, patients receive ibrutinib for 2 months followed by venetoclax using ramp-up dosing. The full dosage of venetoclax combined with ibrutinib is given after 3 cycles for a total of 15 cycles (or 14 months). Patients who reach at least a partial remission (PR) and undetectable MRD in blood and bone marrow at cycle 15 then either receive maintenance ibrutinib or they stop both drugs. Patients who become MRD-positive after stopping both drugs can restart treatment using the combination regimen. Patients who are MRD-positive at cycle 15 remain on ibrutinib alone until disease progression.

Enrollment of 230 patients for the VISION study is now complete. This interim analysis included data from the first 51 patients who finished 15 cycles of treatment. Among these 51 patients, 24 patients had undetectable MRD after 15 cycles of treatment and then received either ibrutinib maintenance or received no treatment.

This group of 51 patients is similar to previously-published clinical trials in relapsed and refractory CLL. Their median age is 67 years. Most are male (71%) and have higher-stage CLL (85%). Most (71%) had received standard chemoimmunotherapy in the past. More than half (57%) are IGHV unmutated, while 18% have deletions or other mutations in TP53.

Of the 51 patients, 43 patients completed all 15 cycles of treatment with ibrutinib and venetoclax. Eight patients have discontinued therapy due to refusal (2), intolerance (2), second malignancy (2), and death (2).

Side effects are consistent with the safety profiles of each individual drug. Moderate side effects were experienced by 16% of patients, while 50% and 26% experienced severe side effects and very severe side effects, respectively. Twenty percent of patients experienced atrial fibrillation and 14% reported bleeding.

Investigators have evaluated responses in 45 of the 51 patients using scans and bone marrow findings. All but 1 of these 45 patients responded to treatment with ibrutinib and venetoclax at cycle 15: 29 patients achieved complete response and 13 achieved partial responses in their lymph nodes or spleen.

In addition to response rates, depth of response was measured. More than half (55%) of patients reached undetectable MRD at cycle 15. This rate of undetectable MRD is similar to what was reported in 2018 with the combination of venetoclax and obinutuzumab for relapsed and refractory CLL.¹

Researchers concluded that treatment with ibrutinib combined with venetoclax in the setting of relapsed and refractory CLL is effective and safe with a high CR rate. Similarities in MRD based on measures in blood and bone marrow suggest that patients’ responses can be followed using blood testing rather than biopsies. This ongoing trial will continue to assess the feasibility and effectiveness of MRD-guided therapy with ibrutinib plus venetoclax in patients with relapsed and refractory CLL.

1. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378:1107-1120.

Abstract 4292. ASH 2019.