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 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 ASH 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 del(11q) status, to receive either:

  • ibrutinib + venetoclax (3 cycles of ibrutinib lead-in, followed by 12 cycles of ibrutinib + venetoclax, n = 106)
  • 6 cycles of chlorambucil + 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 nine 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 + venetoclax arm than the chlorambucil + obinutuzumab arm, both in BM (51.9% vs. 17.1%; p < 0.0001) and in PB (54.7% vs. 39.0%; p = 0.0259).

In the ibrutinib + 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 + 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 + venetoclax versus chlorambucil + obinutuzumab across prespecified subgroups, including patients with bulky disease, del11q, and unmutated IGHV. For the 30 patients with detectable MRD after ibrutinib + venetoclax, MRD levels remained stable for most patients from three months to 12 months after the end of treatment.

The ibrutinib + 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 + obinutuzumab arm, patients with detectable MRD in PB relapsed more quickly than those with undetectable MRD.