Ibrutinib (IBR), a Bruton’s tyrosine kinase inhibitor, is approved for patients with chronic lymphocytic leukemia (CLL). Venetoclax (VEN), a BCL2 inhibitor, is approved for patients with CLL who have received prior therapy and have del(17p). The rationale for combining IBR and VEN includes preclinical models that show synergism with combined IBR and VEN; their nonoverlapping toxicity profiles and nonoverlapping mechanisms of action; and the agents’ complementary activity in treating disease compartment.1 At ASH 2017, the authors reported on the preliminary results of an investigator-initiated phase 2 trial of combined IBR and VEN for patients with CLL.2
Two patient cohorts were enrolled. Cohort 1 enrolled patients with relapsed/refractory (R/R) CLL; cohort 2, untreated patients with ≥1 high-risk features: del(17p), mutated TP53, del(11q), unmutated IGHV, aged ≥65 years. Treatment consisted of IBR monotherapy 420 mg daily for the first 3 months, followed by the addition of VEN (weekly dose escalation to the target dose of 400 mg daily). IBR could be continued indefinitely; VEN for a total of 2 years. The primary end point was complete remission (CR)/CR with incomplete blood count recovery (CRi).
A total of 77 patients initiated treatment (cohort 1, n = 37; cohort 2, n = 40), with a median follow-up of 11.8 months. Of the 7 patients who discontinued IBR during the monotherapy dosing phase, 4 had side effects, including rash and infection.
In cohort 1, 34 patients with R/R CLL received IBR monotherapy then initiated VEN dose escalation. All 26 patients who completed at least 3 months of IBR combined with VEN had a response (42% CR/CRi; 58% partial response [PR]). There was a significant decrease in bone marrow infiltrate with the addition of VEN, including minimal residual disease (MRD) negativity or MRD <0.1% in 2 R/R patients with high-risk cytogenetics.
In cohort 2, 36 first-line CLL patients received IBR monotherapy then initiated VEN dose escalation. All patients who completed at least 3 months of the combination therapy had a response (61% CR/CRi; 39% PR). After 3 months, 21% of these patients achieved undetectable bone marrow MRD status with the addition of VEN. The MRD rate increased to 45% at 3 months, 80% at 6 months, and 100% at 12 months.
Overall, 36% of patients required a dose reduction of IBR and 26% required a dose reduction of VEN. The most common reason for dose reduction was neutropenia. Ten (13%) patients developed atrial fibrillation, likely secondary to IBR. A total of 15 patients have discontinued therapy (7 during IBR monotherapy; 8 after the addition of VEN).
The authors concluded that the combination of IBR and VEN is safe and active in patients with CLL. Significant improvement in bone marrow CLL infiltrate was noted with patients achieving undetectable MRD status as early as 3 months into the combination therapy.
References
- Cervantes-Gomez F, et al. Clin Cancer Res. 2015;21:3705-3715.
- Jain N, et al. ASH 2017. Abstract 429.