Venetoclax for del(17p) chronic lymphocytic leukemia: Long-term follow-up data from the M13-982 trial

The phase II M13-982 trial (NCT01889186) assessed venetoclax monotherapy in patients aged ≥18 years with relapsed/refractory (R/R) or previously untreated chronic lymphocytic leukemia (CLL) with a 17p deletion (del[17p]).¹ The study design and primary results have previously been reported by the Lymphoma Hub. Briefly, venetoclax was associated with an overall response rate (ORR) of 77% and was well tolerated.¹ Here, we summarize the 6-year follow-up and subgroup analyses from the M13-982 trial, published by Stilgenbauer, et al.¹ in Blood Advances.

Study design and patient population

• This was an open-label, multicenter, phase II trial of patients with R/R CLL.
• Following dose ramp-up, patients received 400 mg venetoclax once daily continuously.
• Post hoc subgroup analyses of outcomes were conducted in genetically defined subgroups.
• To assess continuous single-agent venetoclax for ≥2 years vs time-limited venetoclax plus rituximab in patients with R/R CLL with del(17p)/TP53 mutations, outcomes were compared with the phase III MURANO trial (NCT02005471).
• Study endpoints included complete remission (CR) rate, partial remission (PR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Key findings

• Overall, 158 patients with R/R CLL (n = 153) and previously untreated CLL (n = 5) were included.

Efficacy

• At a median follow-up of 70 months, the ORR was 77% (Table 1).

Table 1. Response rates in the M13-982 trial*

• Among responders, the median duration of response was 39.3 months (95% confidence interval [CI]: 31.1–50.5).
• Median progression-free survival (PFS) and overall survival (OS) are shown in Figure 1.
  • The actuarial 5-year PFS and OS rates were 24% and 52%, respectively.

Figure 1. Long-term survival outcomes in M13-982 trial*

CR, complete remission; CRi, CR with incomplete hematological recovery; nPR, nodular partial remission; NR, not reached; OS, overall survival; PFS, progression-free survival; PR, partial remission.
^*Data from Stilgenbauer et al.^1
†Response at Week 36 (±4 weeks)

Safety

• No new safety signals were observed in this analysis.
• 98% and 89% of patients experienced any-grade and Grade ≥3 treatment-emergent adverse events, respectively.
  • The most common Grade ≥3 treatment-emergent adverse events were neutropenia (42%), infections (33%), anemia (16%), and thrombocytopenia (16%).
• Adverse events resulting in a dose reduction occurred in 18% of patients.

Post hoc genetic subgroup analysis

• In the univariate analysis, the median PFS was higher in patients with unmutated SF3B1 vs mutated SF3B1 (30.2 vs 16.4 months; p = 0.0071).

• Multivariable analysis showed that ≥2 prior therapies, unmutated IGHV, nodal size ≥5 cm, SF3B1 mutated, and ≥2 TP53 mutations did not significantly impact ORR and PFS.

Post hoc comparative analysis of M13-982 and MURANO

• Median PFS from treatment initiation was 27.6 months (95% CI: 22.8–37.1) in the M13-982 cohort, while the median PFS from randomization was 37.4 months (95% CI: 29.4–52.3) in the MURANO cohort.
• The estimated 60-month OS rates were 50.6% and 70.2% in the M13-982 and MURANO cohorts, respectively.
• Median PFS by MRD status in patients who received ≥2 years of venetoclax in both trials is shown in Figure 2.

Figure 2. Median PFS from month 24 by MRD status in the M13-982 and MURANO trials*

MRD, measurable residual disease; NR, not reached; PFS, progression-free survival.
*Data from Stilgenbauer et al.^1
†MRD status was classified as undetectable (<10⁻⁴), low MRD positive (MRD+, 10⁻⁴ to 10^–2), and high MRD+ (>10⁻²).