GLOW: MRD Outcomes After Fixed-Duration Ibrutinib Combinations in Older CLL Patients

The all-oral, once-daily, fixed-duration combination of ibrutinib and venetoclax demonstrated superior undetectable measurable residual disease (MRD) responses in older or unfit patients with previously untreated chronic lymphocytic leukemia (CLL), according to findings from the GLOW trial presented at the 2021 American Society of Hematology Annual Meeting.

The GLOW trial enrolled 211 patients aged 65 years or older (or 18-64 years with cumulative illness rating scale score >6 or creatinine clearance <70 mL/min). Patients with del17p or known TP53 mutations were excluded. Participants were randomized 1:1, stratified by IGHV mutational and del11q status, to receive either:

• ibrutinib plus venetoclax (3 cycles of ibrutinib lead-in, followed by 12 cycles of ibrutinib plus venetoclax; n, 106)
• 6 cycles of chlorambucil plus obinutuzumab (n, 105)

Participants’ median age was 71 years, and 51.7% had confirmed unmutated IGHV, 18.0% had del11q, and 4.3% had a TP53 mutation.

MRD samples were collected for responders every 3-4 months in peripheral blood (PB) and at months 9 and 18 in bone marrow (BM). MRD was evaluated using next-generation sequencing (NGS; clonoSEQ) and 8-color flow cytometry.

After a median follow-up of 27.7 months (range, 1.7-33.8) months, the rate of undetectable MRD was significantly higher in the ibrutinib plus venetoclax arm than the chlorambucil plus obinutuzumab arm, both in BM (51.9% vs. 17.1%; P < .0001) and in PB (54.7% vs. 39.0%; P = .0259).

In the ibrutinib plus venetoclax arm, two-thirds of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi) and 54.9% of patients with a partial response (PR) achieved undetectable MRD in BM. For those treated with chlorambucil plus obinutuzumab, rates of CR/CRi and PR were 33.3% and 16.9%, respectively.

Researchers reported that BM undetectable MRD rates were higher for ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab across prespecified subgroups, including patients with bulky disease, del11q, and unmutated IGHV. For the 30 patients with detectable MRD after ibrutinib plus venetoclax, MRD levels remained stable for most patients from three months to 12 months after the end of treatment.

The ibrutinib plus venetoclax combination also was associated with PFS rates of greater than 90% in patients with undetectable MRD, as well as patients with detectable MRD. In contrast, in the chlorambucil plus obinutuzumab arm, patients with detectable MRD in PB relapsed more quickly than those with undetectable MRD.

Disclosures: This research was supported by Pharmacyclics LLC and Janssen Research & Development. Study authors report financial relationships with Janssen Research & Development, the manufacturer of ibrutinib.         

Reference

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. Abstract #70. Presented at the 2021 American Society of Hematology Annual Meeting, December 11-14, 2021.