Frontline Ibrutinib/Venetoclax Induces Higher MRD Clearance and Fewer Relapses in Elderly and Unfit CLL

Talha Munir, MBBS

Frontline fixed-duration treatment with ibrutinib (Imbruvica) plus venetoclax (Venclexta) led to deeper and prolonged rates of undetectable minimal residual disease (uMRD) in the bone marrow and peripheral blood, leading to fewer relapses in the first year post-treatment vs chlorambucil plus obinutuzumab (Gazyva) in elderly and unfit patients with chronic lymphocytic leukemia (CLL), according to findings from the phase 3 GLOW study (NCT03462719) that were presented at the 2021 ASH Annual Meeting and Exposition.¹

The results showed that the uMRD rate at 10^-4 was significantly higher 3 months after the end of treatment in the bone marrow and peripheral blood with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab.

In the bone marrow, the uMRD rate was 51.9% vs 17.1%, respectively (P < .0001); in the peripheral blood, these rates were 54.7% vs 39.0%, respectively (P = .0259). Moreover, the concordance of uMRD in the peripheral blood and bone marrow at 10^-4 was 92.9% with ibrutinib plus venetoclax vs 43.6% with chlorambucil plus obinutuzumab.

Similarly, the uMRD rate at 10^-5 was higher with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab 3 months after the end of treatment in the bone marrow and peripheral blood.

In the bone marrow, the uMRD rate was 40.6% vs 7.6%, respectively; in the peripheral blood, these rates were 43.4% vs 18.1%, respectively. Notably, most patients with uMRD at 10^-4 had deep responses of uMRD at 10^-5 in the ibrutinib plus venetoclax arm but not the chlorambucil plus obinutuzumab arm. Moreover, the concordance of uMRD in the peripheral blood and bone marrow at 10^-5 was 90.9% with ibrutinib plus venetoclax vs 36.8% with chlorambucil plus obinutuzumab.

“All-oral, once-daily, fixed-duration ibrutinib plus venetoclax achieved deeper and better sustained uMRD responses vs chlorambucil as assessed by next-generation sequencing [NGS],” lead author Talha Munir, MBBS, a consultant in clinical hematology at Leeds Teaching Hospitals NHS Trust in Leeds, England, said in a presentation of the data.

MRD status is an indicator of PFS in CLL following treatment with chemoimmunotherapy and time-limited treatment with venetoclax and an anti-CD20 antibody. However, its association with the combination of ibrutinib plus venetoclax had been unknown.

As such, investigators evaluated MRD outcomes and its relationship with PFS in patients in the GLOW study.

The study enrolled previously untreated patients with CLL at least 65 years of age or under the age of 65 years with a cumulative illness rating scale (CIRS) score of at least 6 or creatinine clearance of less than 70 mL/min without deletion 17p or known TP53 mutation and an ECOG performance status between 0 and 2.

Patients were randomized to 420 mg of ibrutinib daily for a 3-cycle lead-in followed by 12 cycles of ibrutinib plus venetoclax (n = 106) or 0.5 mg/kg of chlorambucil on days 1 and 15 for 5 cycles plus 1000 mg of obinutuzumab on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2 through 6 (n = 105).

Venetoclax was ramped-up from 20 mg to 400 mg over 5 weeks beginning in cycle 4.

Patients with independent review committee (IRC)–confirmed progressive disease and active disease requiring treatment were allowed to receive subsequent therapy with ibrutinib.

PFS by IRC served as the primary end point.

MRD was evaluated with NGS and reported with cutoffs of less than 10^-4 and 10^-5 as not all samples had adequate cell yield to be evaluated at 10^-6.

Peripheral blood and bone marrow concordance was calculated for patients with uMRD in the peripheral blood 3 months after the end of treatment who had a matching bone marrow sample.

Findings from the primary analysis, which were calculated with a median follow-up of 27.7 months, demonstrated superior PFS with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab (HR, 0.216; 95% CI, 0.131-0.357; P < .0001).²

At a median follow-up of 34.1 months, the median PFS was maintained in favor of ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab (HR, 0.212; 95% CI, 0.129-0.349; P < .0001). The 30-month PFS rates were 80.5% vs 35.8%, respectively.

Overall survival data also reflected favorably on ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab, with 11 deaths vs 16 deaths, respectively (HR, 0.76; 95% CI, 0.35-1.64).

Additional findings demonstrated that the uMRD rate at 10-4 was also higher in the bone marrow with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab across prespecified subgroups of age (<65 vs ≥65 years), baseline ECOG performance status (0 vs 1-2), CIRS total score (≤6 vs >6), Rai stage (0-II vs III-IV), bulky disease (yes vs no), elevated lactate dehydrogenase at baseline (no vs yes), IGHV status (mutated vs unmutated), and deletion 11q (no vs yes).

Additional analyses showed that uMRD rates were high in the bone marrow and the peripheral blood with ibrutinib plus venetoclax in patients with unmutated IGHV.

Among patients with unmutated IGHV, the collective uMRD rates were 58.2% (12.7%, 10-4; 45.5%, 10-5) in the bone marrow (n = 55) vs 61.8% (12.7%, 10-4, 49.1%, 10-5) in the peripheral blood (n = 55), showing a similar depth of MRD response in both compartments.

Among patients with mutated IGHV, the collective uMRD rates were 44.4% (14.8%, 10-4; 29.6%, 10-5) in the bone marrow (n = 27) vs 44.4% (7.4%, 10-4, 37.0%, 10-5) in the peripheral blood (n = 27).

Moreover, 5 of 7 patients with mutated TP53 achieved uMRD at 10^-5 in the bone marrow and the peripheral blood with ibrutinib plus venetoclax.

MRD dynamics post-treatment showed that uMRD was better sustained with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab from 3 months after the end of treatment to 12 months after the end of treatment.

Specifically, 84.5% (n = 49/58) of patients had sustained uMRD at 10^-4 and 80.4% (n = 37/46) had sustained uMRD at 10^-5 with ibrutinib plus venetoclax vs 29.3% (n = 12/41) and 26.3% (n = 5/19) of patients with chlorambucil plus obinutuzumab, respectively.

Moreover, the uMRD rate at 10^-4 decreased only 6% with ibrutinib plus venetoclax vs 27% with chlorambucil plus obinutuzumab.

Furthermore, detectable MRD of at least 10^-4 was less likely to worsen or lead to progression by 12 months after the end of treatment with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab.

In looking at PFS according to response, investigators found that the 30-month PFS rate was greater than 85% with ibrutinib plus venetoclax whether patients had a complete response (CR), CR with incomplete bone marrow recovery, or partial response (PR) vs with chlorambucil plus obinutuzumab where most patients with a PR had disease progression.

In patients with detectable MRD at 10^-4 in the bone marrow, the PFS rate greater than 90% was sustained during the first 12 months post-treatment with ibrutinib plus venetoclax vs with chlorambucil plus obinutuzumab where early relapse was common.

Moreover, the PFS rate during the first 12 months post-treatment was sustained with ibrutinib plus venetoclax, regardless of MRD status in the bone marrow or peripheral blood.

Finally, investigators showed that among patients with uMRD at 10^-4 in the bone marrow 3 months after the end of treatment, lymph node responses were generally maintained in both arms but were better maintained over time with ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab in patients with detectable MRD in the bone marrow.

“Additional follow-up is warranted to confirm the longer-term impact of MRD status on PFS,” concluded Munir.

References

1. 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: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 70.
2. Kater A, Owen C, Moreno C, et al. Fixed duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (CLB+O) for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract LB1902.