6-year follow-up results of the CLL14 study of venetoclax-obinutuzumab in previously untreated CLL

The CLL14 trial (NCT02242942), comparing the safety and efficacy of fixed-duration venetoclax plus obinutuzumab (Ven-Obi) against chlorambucil plus obinutuzumab (Clb-Obi) treatment in patients with treatment-naïve chronic lymphocytic leukemia (CLL) and comorbidities, is ongoing. This is the first trial to compare a novel, chemotherapy-free, fixed-duration regimen with chemoimmunotherapy for patients with treatment-naïve CLL, including those with del17p or TP53 mutations.¹

The Lymphoma Hub previously reported on the long-term safety outcomes of Ven-Obi vs Clb-Obi in patients with CLL at a median follow-up of 39.6 months. Below, we summarize the 6-year efficacy and safety results of the CLL14 trial in previously untreated CLL, presented by Al-Sawaf at the European Hematology Association (EHA) 2023 Congress.²

Study design^1,2

CLL14 is an ongoing multicentre, randomized, open-label phase III trial that included patients aged ≥18 years with previously untreated CLL and comorbidities (cumulative illness rate of ≥6 or creatinine clearance of 30–69 mL/min). Patients were randomized 1:1 to receive either 12 cycles of venetoclax with six cycles of obinutuzumab (Ven-Obi arm), or 12 cycles of chlorambucil with six cycles of obinutuzumab (Clb-Obi arm).

The primary endpoint was investigator-assessed progression-free survival (PFS). Key secondary endpoints included response, minimal residual disease (MRD), and overall survival (OS).

Results

In total, 432 patients were treated, 216 with fixed-duration Ven-Obi and 216 with Clb-Obi. Baseline characteristics were summarized in Table 1.

Table 1. Baseline characteristics*

Clb-Obi, chlorambucil plus obinutuzumab; CIRS, cumulative illness rating score; del, deletion; IGHV, immunoglobulin heavy chain variable region; TLS, tumor lysis syndrome; Ven-Obi, venetoclax plus obinutuzumab. *Data from Al-Sawaf, et al.1
Characteristic, % (unless otherwise stated)	Ven-Obi (n = 216)	Clb-Obi (n = 216)
Median age, years	72	71
Binet stage
A	21	20
B	35	37
C	44	43
Median total CIRS score (range)	9 (0−23)	8 (1−28)
TLS risk category
Low	13	12
Intermediate	64	68
High	22	20
IGHV mutational status
Unmutated	61	59
Mutated	38	40
Not evaluable	1	1
Del (17p) and/or TP53 mutation	12	12
Cytogenetic subgroups
Deletion in 17p	8	7
Deletion in 11q	17	18
Trisomy in 12	17	19
No abnormalities	24	20
Deletion in 13q alone	34	36

Efficacy²

The median PFS overall and across high-risk subgroups are reported in Figure 1. At a median follow-up of 76.4 months, the 6-year PFS rate was significantly higher in the Ven-Obi vs Clb-Obi arm. Patients without TP53^WT had significantly longer PFS than those with TP53 deletions/mutations across both arms. Multivariate analyses showed that a high lymph node size of ≥5 cm, an unmutated IGHV and TP53 deletions/mutations were independently prognostic of the worse PFS outcomes in the Ven-Obi arm.

Clb-Obi, chlorambucil plus obinutuzumab; del, deletion; IGHV, immunoglobulin heavy chain variable region; mut, mutation; NR, not reached; PFS, progression-free survival; Ven-Obi, venetoclax plus Obinutuzumab; WT, wild type.
*Data from Al-Sawaf, et al.¹

• The median time to the next treatment was not reached in the Ven-Obi arm but was 52.9 months in the Clb-Obi arm.
• A total of 39 patients in the Ven-Obi arm and 103 patients in the Clb-Obi required second-line treatment; most patients received targeted therapies, with 53–59% receiving Bruton’s kinase inhibitors and 15–18% receiving BCL2 inhibitors, although 23–30% of patients received chemotherapy/chemoimmunotherapy.
• The median OS was not reached in both arms and the 6-year OS was slightly higher in the Ven-Obi vs Clb-Obi arm, but this difference was not significantly different.
• The 6-year PFS, time to next treatment, and OS rates are summarized in Figure 2.

Clb-Obi, chlorambucil plus obinutuzumab; OS, overall survival; PFS, progression-free survival; TTNT, time to next treatment; Ven-Obi, venetoclax plus obinutuzumab.
*Data from Al-Sawaf, et al.¹

After 5 years of treatment, 1.9% and 7.9% of patients had sustained MRD at <10⁻⁴ by next-generation sequencing in the Clb-Obi and Ven-Obi arm, respectively. In the Ven-Obi arm, the end of treatment MRD status in peripheral blood by next-generation sequencing significantly correlated with both PFS and OS, with a shorter PFS observed in patients with MRD ≥10⁻⁴ than those with <10⁻⁴.

Safety

The most common Grade ≥3 adverse events (AEs) during treatment were neutropenia, thrombocytopenia, and infusion-related reactions (Figure 3); there was a very low incidence of these Grade 3 events posttreatment. There were a higher number of overall secondary malignancy events in the Ven-Obi compared with the Clb-Obi arm, with 31 events versus 20 events, respectively, though this difference was not statistically significant.

Clb-Obi, chlorambucil plus obinutuzumab; Ven-Obi, venetoclax plus obinutuzumab.
*Data from Al-Sawaf, et al.¹

Conclusion

The 6-year follow-up results of CLL14 demonstrated the significant long-term PFS benefit of fixed-duration Ven-Obi across all subgroups of patients with previously untreated CLL and comorbidities. These benefits were maintained across high-risk groups, such as those harboring the TP53 deletions/mutations or IGHV unmutated, and over 60% of patients did not require a second-line treatment. This study also showed the prognostic value of end of treatment MRD status on PFS and OS, highlighting the need for MRD-guided approaches. Overall, treatment was manageable with no new safety signals reported at longer follow-up. The ongoing study continues to monitor the secondary malignancy rate with anticipated further follow-up results later this year.