Ibrutinib/Venetoclax Bests Chlorambucil/Obinutuzumab for Treating CLL

Two levels of minimal residual disease (MRD) activity evaluated among elderly or unfit patients with chronic lymphocytic leukemia (CLL)—MRD at 10^–­4 and 10^–5—in the GLOW¹ study demonstrate ibrutinib plus venetoclax (Ibr+Ven) capable of producing superior outcomes compared withchlorambucil plus obinutuzumab (Clb+O).

The kinase inhibitor/B-cell lymphoma-2 inhibitor pair vs the alkylating agent/monoclonal antibody combination, both as first-line treatment, led to a deeper and more sustained treatment response, according to the phase 3 GLOW data analysis presented on December 11 at the 63rd American Society of Hematology Annual Meeting & Exposition, “First Prospective Data on Minimal Residual Disease (MRD) Outcomes After Fixed-Duration Ibrutinib Plus Venetoclax (Ibr+Ven) Versus Chlorambucil Plus Obinutuzumab (Clb+O) for First-Line Treatment of CLL in Elderly or Unfit Patients: The Glow Study.”²

“MRD status is an established predictive marker for progression-free survival (PFS) in CLL following chemoimmunotherapy, as well as for fixed-duration treatment with venetoclax and an anti-CD20 antibody,” the authors wrote. “To date, this relationship has not been explored for the combination of Ibr+Ven, a treatment with complementary mechanisms of action that work synergistically to eliminate CLL subpopulations in distinct tumor compartments.”

MRD status was evaluated via peripheral blood (PB) and bone marrow (BM) samples, with concordance between the two calculated 3 months after treatment’s end (EOT+3) among those with undetectable MRD (uMRD) in their PB. PFS analysis occurred among those “with known MRD status at EOT+3 and no prior progression, death, or withdrawal.”

With a primary end point of PFS and a secondary end point of rate of uMRD (<10^–4), 106 and 105 patients (median age, 71 years) were randomized to Ibr+Ven and Clb+O, respectively; potential participants were excluded if they had del(17p) or TP53 mutations. Those in the treatment cohort first received 3 ibrutinib cycles as lead-in treatment, and that was followed by 12 cycles of Ibr+Ven; the comparator group received 6 Clb+O cycles. Median follow-up was 27.7 months.

For MRD at 10^–4, the following results were seen:

• uMRD in BM: 51.9% with Ibr+Ven vs 17.1% with Clb+O
• uMRD in PB: 54.7% vs 39.0%, respectively
• uMRD following complete response (CR) or CR with incomplete marrow recovery (CRi): 65.9% vs 33.3%
• uMRD following partial response in BM: 54.9% vs 16.9%
• uMRD in BM following Ibr+Ven was higher in those of unmutated vs mutated IGHV status: 58.2% vs 44.4%
• From 3 to 12 months after treatment, PB showed more patients on Ibr+Ven remained at uMRD vs Clb+O: 84.5% vs 29.3%
• PB/BM concordance in those with uMRD who received Ibr+Ven: 92.9%

For MRD at 10^–5, the following results were seen:

• uMRD in BM: 40.6% with Ibr+Ven vs 7.6% with Clb+O
• uMRD in patients with uIGHV status: 45.5% vs 5.6%, respectively
• Most patients starting at uMRD < 10^–4 in the Ibr+Ven arm achieved uMRD < 10^–5 in their PB (79.3%) and BM (78.2%)
• From 3 to 12 months after treatment, 80.4% of those in the Ibr+Ven arm vs 26.3% of those in the Clb+O arms remained at uMRD < 10^–5
• uMRD in BM: 40.6% with Ibr+Ven vs 7.6% with Clb+O
• PB/BM concordance in those with uMRD who received Ibr+Ven: 90.9%

Overall, whereas more than 90% of the Ibr+Ven arm was able to maintain PFS in the year following treatment, participants who received Clb+O relapsed faster, according to PB data. These results were seen in both cohorts among those with uMRD and detectable MRD, and PFS trends evaluated via BM were similar.

Superior results were seen in the treatment arm compared with the comparator arm, with the authors noting that among those who received Ibr+Ven, BM clearance of disease mirrored results seen in PB.

“In the Ibr+Ven arm, clinical relapse was infrequent during the first year off treatment for patients with known MRD status 3 months after treatment ended, supported by largely sustained uMRD/MRD levels over the same period,” they wrote. “All-oral, once-daily, fixed-duration Ibr+Ven demonstrated superior uMRD responses that were deeper and better sustained post treatment vs Clb+O in elderly or unfit [patients] with previously untreated CLL.”

However, follow-up studies are recommended in order to confirm their results, the authors concluded.

References

1. A study of the combination of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab for the first-line treatment of participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). ClinicalTrials.gov. Updated December 3, 2021. Accessed December 18, 2021. https://clinicaltrials.gov/ct2/show/NCT03462719

2. Munir T, Moreno C, Owen C, et al. First prospective data on minimal residual disease (MRD) outcomes after fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O) for first-line treatment of CLL in elderly or unfit patients: the Glow study. Presented at: 63rd American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 70. Accessed December 17, 2021. https://ash.confex.com/ash/2021/webprogram/Paper148666.html