The Bottom Line:
Fixed-duration ibrutinib plus venetoclax provides an overall survival advantage and better sustained progression-free survival regardless of measurable residual disease (MRD) status compared with chlorambucil plus obinutuzumab as a first-line treatment for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
Who Performed the Research and Where Was it Presented:
Dr. Carsten Niemann from Rigshospitalet Copenhagen University Hospital and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in December 2022.
The GLOW study was designed to look at a new fixed-duration treatment combination specifically in older patients with untreated CLL and other concurrent diseases or conditions. The Bruton tyrosine kinase inhibitor ibrutinib was combined with the BCL2 inhibitor venetoclax in the hopes that combining two potent therapies would result in better outcomes for patients and limit the amount of time patients need to spend on treatment.
In this interview, our own Dr. Brian Koffman interviewed Dr. Carsten Niemann, a hematologist at Rigshospitalet Copenhagen University Hospital in Copenhagen, Denmark, about the latest results from this study.
Methods and Participants:
The GLOW study is a phase 3 clinical trial which compared fixed-duration ibrutinib plus venetoclax with chemoimmunotherapy as a first-line treatment for patients with untreated CLL and other concurrent diseases or conditions. One hundred and six patients received ibrutinib plus venetoclax for 12 cycles (~1 year), and 105 patients received chlorambucil plus obinutuzumab for 6 cycles.
- Previous results from the GLOW study demonstrated treatment with ibrutinib + venetoclax resulted in longer progression-free survival and higher rates of undetectable measureable residual disease (uMRD) compared with chlorambucil + obinutuzumab.
- New results presented at ASH 2022 showed that ibrutinib + venetoclax treatment improved overall survival vs. chlorambucil + obinutuzumab.
- At 3.5 years, 75% of patients in the ibrutinib + venetoclax arm were alive and progression-free compared with 25% of patients in the chlorambucil + obinutuzumab arm.
- Only about 40-60% of patients achieve uMRD, but it appears to be very stable. Two years after stopping treatment, 40% of patients still have uMRD.
- Even patients who have intermediate MRD (some measurable CLL cells) seem to have a sustained response after treatment, where the amount of CLL in the blood stays at the same level and the lymph nodes remain in remission.
- Among patients with detectable MRD 3 months after the end of treatment, 2 out of 31 patients (7%) in the ibrutinib + venetoclax arm progressed vs. 32 out of 47 patients (68%) in the chlorambucil + obinutuzumab arm 18 months after stopping treatment.
- The difference in overall survival between the two groups was mainly due to an increase in deaths from infection in the chlorambucil + obinutuzumab group after treatment had stopped, which is perhaps a signal of immune dysfunction.
Fixed-duration ibrutinib plus venetoclax provides an overall survival advantage and better sustained progression-free survival regardless of MRD status compared with chlorambucil plus obinutuzumab as a first-line treatment. These results are not surprising given that in the time since the GLOW study was designed, it has become quite clear that targeted therapies like ibrutinib and venetoclax are much more effective than chemoimmunotherapy. While this and other studies show that fixed-duration ibrutinib plus venetoclax is an effective therapy, it remains to be seen whether it is better than other targeted therapy combinations.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Residual Disease Kinetics Among Patients with High-Risk Factors Treated with First-Line Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O): The Glow Study
Some of the new data presented at the meeting but not included in the abstract can be found here: New Results from the Phase 3 GLOW Study of Fixed-Duration Treatment with IMBRUVICA® (ibrutinib) Plus Venetoclax Demonstrate Robust Efficacy and Sustained Response in Older, Unfit Patients with Previously Untreated Chronic Lymphocytic Leukemia
Take care of yourself first.
Ann Liu, PhD