JL1013E: 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

Background:
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. To date, this relationship has not been explored for the combination of Ibr+Ven, an all-oral, once-daily, fixed-duration treatment with complementary mechanisms of action that work synergistically to eliminate CLL subpopulations in distinct tumor compartments. In the primary analysis of the phase 3 international GLOW trial, independent review committee (IRC)-assessed PFS for Ibr+Ven was superior to Clb+O (hazard ratio, 0.216; P< 0.0001). Herein we further investigate MRD outcomes at the time of the GLOW primary analysis.

Methods:
GLOW (NCT03462719) enrolled patients aged ≥65 years or 18-64 years with cumulative illness rating scale score >6 or creatinine clearance < 70 mL/min. Patients with del(17p) or known TP53 mutations were excluded. Patients were randomized 1:1, stratified by IGHV mutational and del(11q) status, to Ibr+Ven (3 cycles of ibrutinib lead-in, followed by 12 cycles of Ibr+Ven) or 6 cycles of Clb+O. The primary end point was PFS assessed by IRC and rate of undetectable MRD (uMRD; < 10-4) was a secondary end point; additional MRD analyses reported here are exploratory. 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. PB/BM concordance was calculated for pts with uMRD in PB at end of treatment plus 3 months (EOT+3) who had a paired BM sample. Analysis of PFS by MRD status includes patients with known MRD status at EOT+3 and no prior progression, death, or withdrawal.

Results:
106 patients were randomized to Ibr+Ven and 105 to Clb+O. Median age was 71.0 years, 51.7% had confirmed unmutated (u)IGHV, 18.0% had del(11q), and 4.3% had a TP53 mutation. Median follow-up was 27.7 (range, 1.7-33.8) months. MRD results are all via NGS and reported for EOT+3 unless otherwise noted.

MRD Results at 10-4: Rate of uMRD was significantly higher for Ibr+Ven vs Clb+O in BM (51.9% vs 17.1%; P< 0.0001) (Fig A) and in PB (54.7% vs 39.0%; P=0.0259). PB/BM uMRD concordance with Ibr+Ven was 92.9%. In the Ibr+Ven arm, 65.9% (27/41) of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi) and 54.9% (28/51) with a partial response achieved uMRD in BM; rates for Clb+O were 33.3% (4/12) and 16.9% (13/77), respectively. BM uMRD rates were higher for Ibr+Ven vs Clb+O across prespecified subgroups, including bulky disease (≥5 cm), del(11q), and uIGHV. In the Ibr+Ven arm, BM uMRD was higher for uIGHV (58.2%) vs mutated IGHV (44.4%). With Ibr+Ven, 84.5% (49/58) of patients maintained PB uMRD from EOT+3 to EOT+12 vs 29.3% (12/41) with Clb+O. For patients with detectable MRD after Ibr+Ven (n = 30), MRD levels remained stable for most patients from EOT+3 to EOT+12 (Fig B).

MRD Results at 10-5: Rate of uMRD < 10-5 was higher for Ibr+Ven vs Clb+O in BM (40.6% vs 7.6%) (Fig A), including patients with uIGHV (45.5% vs 5.6%). With Ibr+Ven, PB/BM uMRD concordance at < 10-5 was 90.9% (40/44). Among patients with uMRD < 10-4 in the Ibr+Ven arm, the majority achieved < 10-5 in PB (79.3%) and BM (78.2%), including patients with uIGHV. uMRD < 10-5 in PB was largely sustained from EOT+3 to EOT+12 with Ibr+Ven (80.4% [37/46] of patients) but not Clb+O (26.3% [5/19] of patients) (Fig B).

PFS by MRD Status at 10-4: In the Ibr+Ven arm, PFS rate during the first 12 months after EOT was >90% for patients with uMRD as well as patients with detectable MRD. In contrast, patients in the Clb+O arm with detectable MRD in PB relapsed more quickly than those with uMRD (Fig C). PFS trends were similar according to MRD status in BM (Fig D). Note that not all patients in the Ibr+Ven arm had 12 months’ follow-up post-EOT.

Conclusion:
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. Most patients with uMRD in the Ibr+Ven arm, including those with uIGHV, achieved clearance below 10-5, and deeper clearance in PB was mirrored in BM. In the Ibr+Ven arm, clinical relapse was infrequent during the first year off treatment for patients with known MRD status at EOT+3 (whether uMRD or detectable MRD), supported by largely sustained uMRD/MRD levels over the same period. Additional follow-up will be important to confirm these early results.

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