GLOW trial: A 4-year update on fixed-duration ibrutinib + venetoclax in previously untreated CLL

Bruton kinase inhibitors such as ibrutinib have significantly improved the treatment landscape of chronic lymphocytic leukemia (CLL). Ibrutinib and venetoclax, a B-cell lymphoma 2 inhibitor, are complementary in their mode of action; phase II studies have shown deep, durable responses, and improvements in progression-free survival (PFS), including in patients with high-risk CLL disease.

The Lymphoma Hub has previously reported findings from the GLOW trial. Here, we summarize a recently published article by Niemann et al.¹ in The Lancet Oncology on the 4-year follow-up of the phase III GLOW trial (NCT03462719) investigating fixed duration ibrutinib + venetoclax vs chlorambucil + obinutuzumab in patients with previously untreated CLL.

Study design¹

GLOW is a randomized, multicenter study conducted across 14 countries in patients with previously untreated CLL. Eligible patients were aged ≥65 years or 18–64 years with comorbidities (cumulative illness rating scale score of >6/creatinine clearance of <70 mL/min), or both and had an Eastern Cooperative Oncology Group performance status of ≤2. Patients were randomized as shown in Figure 1.

The primary endpoint was PFS assessed by an independent review committee, defined as the time from randomization until disease progression or death from any cause.

Secondary endpoints included:

• Measurable residual disease (MRD) negativity rate: the proportion of patients who had undetectable MRD in bone marrow
• Complete response (CR) rate: number of patients who achieved CR or CR with incomplete bone marrow recovery (CRi)
• Overall response rate: number of patients who achieved CR, CRi, or partial response
• Overall survival (OS): time from randomization to death from any cause
• Duration of CR: time from initial CR or CRi until disease progression or death from any cause
• Time to next treatment: time from randomization until the start of any subsequent anticancer therapy and safety

OD, once daily.
*Adapted from Niemann, et al.¹

Results¹

A total of 211 patients received ibrutinib + venetoclax (n = 106) and chlorambucil + obinutuzumab (n = 105). The baseline characteristics are summarized in Table 1.

Table 1. Baseline characteristics*

Characteristic, % (unless otherwise stated)		Ibrutinib +  venetoclax arm (n = 106)	Chlorambucil + obinutuzumab arm (n = 105)
CIRS, cumulative illness rating scale; CrCL, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; IGHV, immunoglobulin heavy chain variable region gene; IQR, interquartile range; LDH, lactate dehydrogenase. *Data from Niemann, et al.1 †Denotes >10% numerical difference between arms. ‡IGHV status of baseline samples were updated since primary analysis based on post hoc reclassification using clonoSEQ. 35 out of 48 patient samples that were classified as unknown by Sanger sequencing during the primary analysis were reclassified using clonoSEQ and in the remaining 13, reclassification was not possible.
Median age, years		71	71
Sex
Male		55.7	60.0
ECOG PS 1−2		67.0	62.9
Median CIRS score, n		9	8
>6†		69.8	58.1
Median CrCL, mL/min		66.5	63.2
Rai stage III–IV		57.3	52.5
Bulky disease ≥5 cm		39.0	36.2
Elevated LDH†	33.0		48.6
IGHV status‡
Mutated	30.2		33.3
Unmutated	63.2		54.3
Unknown	6.6		12.4
Del(11q)	18.9		17.1
TP53 mutation	6.6		1.9

Efficacy

At a median follow-up of 46 months:

• The PFS remained significantly higher in the ibrutinib + venetoclax arm vs chlorambucil + obinutuzumab arm, with 29 vs 78 events (p < 0·0001) reported in each arm, respectively (Figure 2).
  • The median PFS was not reached in the ibrutinib + venetoclax arm and was 21.7 months in the chlorambucil + obinutuzumab arm.
• Univariate and multivariate analyses revealed a significant association between immunoglobulin heavy chain variable gene (IGHV) mutational status (mutated vs unmutated) and PFS in both treatment arms (p < 0.05).
• In the ibrutinib + venetoclax arm, the 2-year PFS for patients with undetectable (n = 58) and detectable MRD (n = 31), 3 months posttreatment was 93% and 79.6%, respectively.
  • In patients with mutated IGHV, the 2-year PFS for those with detectable (n = 14) and undetectable MRD (n = 13), 3 months posttreatment was 92.3% and 100%, respectively.
  • In patients with unmutated IGHV, the 2-year PFS for those with detectable (n = 16) and undetectable MRD (n = 40), 3 months posttreatment was 67% and 89.9%, respectively.
• In the chlorambucil + obinutuzumab arm, the 2-year PFS for patients with undetectable (n = 41) and detectable MRD (n = 47), 3 months posttreatment was 66.6% and 18%, respectively.
• Post hoc analysis investigating MRD levels in the ibrutinib + venetoclax group by IGHV mutation status revealed that:
  • Undetectable MRD rates were higher in the unmutated IGHV subgroup (52% of 67 participants) vs the mutated IGHV subgroup (31% of 32 participants)
  • The MRD kinetics varied in different subgroups, with undetectable MRD rates declining in patients with unmutated IGHV from 60% at 3 months to 36% at 27 months after the end of treatment. Whereas, in patients with mutated IGHV, undetectable MRD rates remained stable in this period (changing from 41% to 44% over this period)
• CR/CRi was 43% vs 12% in the ibrutinib + venetoclax arm and chlorambucil-obinutuzumab arm, respectively.
  • CR/CRi at 36 months was 93% in the ibrutinib + venetoclax arm vs 60% in the chlorambucil-obinutuzumab arm.
• Patients in the ibrutinib + venetoclax arm, maintained lymph node clearance, regardless of IGHV mutation or MRD status.
• 8 vs 41 patients (p < 0.0001) required second-line treatment in the ibrutinib + venetoclax arm and chlorambucil + obinutuzumab arm, respectively.
• OS was significantly higher for patients in the ibrutinib + venetoclax vs chlorambucil + obinutuzumab arm (hazard ratio of 0.487; p = 0.021).
  • The estimated 42-month OS was 87.5% vs 77.6%, respectively.

PFS, progression-free survival.

*Adapted from Niemann et al.¹ 

Safety

• There were a greater number of deaths reported in the chlorambucil + obinutuzumab arm vs ibrutinib + venetoclax arm, 30 deaths vs 15 deaths, respectively.
• In the ibrutinib + venetoclax arm, deaths were due to progression (n = 1); treatment-emergent adverse events including cardiac failure, pneumonia, and sinus node dysfunction (n = 7); occurred in remission (n = 6); and occurred during subsequent therapy (n = 1)
• In the chlorambucil + obinutuzumab arm, deaths were due to progressive disease (n = 1); treatment-emergent adverse events including pneumonia (n = 2); occurred in remission (n = 6); occurred after disease progression but prior to subsequent therapy (n = 13); and occurred during subsequent therapy (n = 8).
• There were more infection-related deaths reported in the chlorambucil + obinutuzumab arm compared with ibrutinib + venetoclax arm, 11 vs 4 deaths, respectively.
• A total of 11 patients in the ibrutinib + venetoclax arm and 14 patients in the chlorambucil + obinutuzumab arm experienced a secondary malignancy at longer follow-up.
• In the chlorambucil + obinutuzumab arm, one patient experienced a serious adverse event of myelodysplastic syndrome.

Conclusion

The 4-year follow-up data of the GLOW trial demonstrated that fixed-duration ibrutinib + venetoclax continues to significantly improve PFS and achieve an OS advantage compared with chlorambucil + obinutuzumab in patients with previously untreated CLL. The findings support the clinical use of this combination regimen as a first-line treatment option in patients with CLL.

Supported by an educational grant from Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. All content is developed by SES in collaboration with an expert steering committee; funders are allowed no influence on the content of this resource.