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*

*Data from Stilgenbauer et al.1
Response rate, %	Venetoclax monotherapy
Overall response rate	77
Complete remission	21
Complete remission with incomplete hematological recovery	3
Partial remission	49
Nodular partial remission	4
Stable disease	19
Progressive disease	2
Not evaluable	2

• 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.

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.

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).

 

Key learnings
Long-term survival outcomes from the M13-982 trial show the benefit of continuous venetoclax monotherapy in patients with del(17p) CLL. Efficacy of venetoclax for patients with del(17p) CLL was not remarkably impacted by the presence of individual adverse biological features.