Patients with chronic lymphocytic leukemia (CLL) who received frontline ibrutinib plus venetoclax had a four-year progression-free survival (PFS) rate of 94.5%, according to follow-up data from a phase II trial.
Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center and colleagues conducted the trial to evaluate first-line ibrutinib plus venetoclax in patients with high-risk CLL. They previously reported data on 80 patients and provided updated data for a total of 120 patients with a median follow-up of 48.8 months.
The study included patients with previously untreated CLL who had at least one high-risk feature, which were defined as being at least 65 years old, or having del(17p), mutated TP53, del(11q), or unmutated IGHV. The patients received ibrutinib 420 mg daily for three cycles, followed by the addition of venetoclax with a weekly dose-escalation to 400 mg daily. Patients received combined therapy for 24 cycles.
Those who had undetectable minimal residual disease (MRD) in bone marrow after 24 cycles of the combination therapy discontinued ibrutinib and venetoclax. Patients who remained MRD positive continued with ibrutinib. However, a trial amendment allowed an additional 12 cycles of ibrutinib and venetoclax for those who remained MRD positive after cycle 24.
Of the 120 patients enrolled, six patients did not continue with the study during the first three cycles of ibrutinib monotherapy, and the remaining 114 patients started treatment with venetoclax.
After 12 cycles of the combination therapy, 52% (62/120) of patients achieved remission with undetectable MRD in bone marrow. However, 36% (43/120) of patients were MRD-positive in bone marrow at that time point.
After 24 cycles of ibrutinib plus venetoclax, 64% (77/120) of patients achieved remission with undetectable MRD in bone marrow, while 20% (24/120) had MRD-positive bone marrow. Overall, 72% achieved undetectable MRD in bone marrow as their best response.
Of the 77 patients who achieved remission with undetectable MRD in bone marrow, 73 discontinued all therapy, while four continued with ibrutinib “per treating physician discretion,” Dr. Jain and colleagues wrote. At a median follow-up of 23.9 months after cycle 24, 11 of those 77 patients had recurrence of blood MRD.
Of the 24 patients who had MRD-positive bone marrow at the end of cycle 24, one had high levels of MRD and the remaining 23 had low levels of MRD. The patient who had high levels of MRD at the end of cycle 24 was “noted to have Richter transformation at that time,” the study’s authors wrote.
The remaining 23 patients continued ibrutinib monotherapy, and with the trial amendment, those who remained MRD positive after cycle 24 could receive 12 additional cycles of venetoclax. Most of the patients (18/23) resumed venetoclax, with 11 of those 18 patients achieved undetectable-MRD remission during the third year of combined therapy.
After six months of the combination therapy, the TP53 mutation was associated with a lower rate of undetectable MRD in bone marrow (P=.03).
However, none of the baseline patient and disease characteristics—including age, gender, IGHV mutation status, CLL fluorescence in situ hybridization panel, complex karyotype, TP53 mutation, del(17p)/TP53 mutation—were associated with bone marrow MRD responses at 12 months or with best MRD response at any time during the combination therapy.
The four-year PFS rate was 94.5%, with a four-year OS rate of 96.6%. The four-year PFS for those with del(17p)/TP53 mutation (n=27) was 90.9%, while it was 95.5% for those without del(17p)/TP53 mutation (n=93). However, none of the patient or disease characteristics were associated with PFS.
“MRD responses and PFS were independent of baseline [patient]/disease characteristics,” Dr. Jain and colleagues concluded. “Continuation of combined therapy among marrow MRD-positive [patients] during the second and the third year led to achievement of [undetectable] MRD in a subset of patients.”
Reference
Jain N, Keating MJ, Thompson PA, et al. Combined ibrutinib and venetoclax for first-line treatment of patients with chronic Lymphocytic leukemia (CLL): 4-year follow-up data. Blood. 2022;140(Supplement 1):234-237. doi:10.1182/blood-2022-170850
