The usual approach with most venetoclax based therapies is a “one size fits all” with all patients stopping treatment after a fixed duration, such as after one or two years of venetoclax.
This trial had a more personalized approach. It assessed MRD status after 15 months of treatment to determine the next best step.
Here are the details.
It was a phase II trial that compared progression-free survival (PFS) for two groups of patients with
R/R CLL. All patients received ibrutinib + venetoclax (I+V) with delayed start and ramp-up of venetoclax from cycle 3 for the 15 cycles of 28 days each.
Patients who did not achieve uMRD continued on ibrutinib maintenance (non-randomized group).
Patients who achieved uMRD after cycle 15 were randomized 1:2 between either ibrutinib maintenance or stopping treatment.
This trial evaluated the risks and benefits of MRD guided, time-limited I+V treatment and whether continuing ibrutinib after reaching uMRD improved outcomes.
- 225 patients who had never received ibrutinib or similar drugs were enrolled. 88% of patients had high-risk disease defined as unmutated IgHV or positiveTP53 aberrations.
- 194 patients were able to complete the 15 treatment cycles before randomization.
- 86% showed at least a partial response (PR) to I+V.
- 81 patients (36%) reached uMRD (fewer than one per 10,000 malignant cells) in blood and bone marrow.
- 125 patients (56%) did not achieve uMRD at cycle 15 and continued on ibrutinib.
- 24 patients who were uMRD at 15 months were randomized to the ibrutinib maintenance. The other 48 patients ceased treatment and were just observed.
- None of the patients in the observation group had disease progression, and only one did not maintain uMRD.
- The most frequent adverse event was an infection which occurred in 58% of patients during V+I treatment or ibrutinib maintenance. In addition, 12% of patients off treatment developed infections. Other adverse events, including heart rhythm disturbance, hypertension, and bleeding, occurred only in patients during treatment.
- At the end of 27 cycles from the start of treatment, 75% of patients on ibrutinib maintenance remained uMRD in the blood vs 71% of patients off treatment. This was statistically the same result.
- The 48 patients who discontinued treatment experienced far fewer adverse events than the 24 who continued on ibrutinib maintenance for the next 12 months, yet they remained in uMRD as frequently as those who continued ibrutinib.
- Treatment efficacy was the same regardless of mutation or TP53 aberration status.
This trial supports the option in those with R/R CLL of using the achievement of uMRD after 15 months of I+V treatment as a signal to stop all therapy safely. Maintaining treatment with ibrutinib increased side effects and did not improve outcomes.
To read the original ASH 2021 abstract, which goes into greater detail and includes some excellent graphics, please click on Time-Limited Venetetoclax and Ibrutinib for Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Who Have Undetectable Minimal Residual Disease (uMRD) – Primary Analysis from the Randomized Phase II Vision HO141 Trial.
Thanks for reading.
Robert Hander, MD
Eye and Medical consultant, CLL patient