Response in patients with BIRC3-mutated relapsed/refractory chronic lymphocytic leukemia treated with fixed-duration venetoclax and rituximab

BIRC3 is a negative regulator of the non-canonical NF-kB signaling pathway.1 BIRC3 gene mutation occurs in ~3–5% of patients with chronic lymphocytic leukemia (CLL) and is considered one of the disease-driver events.52 In a recent issue of Haematologica, Diop et al. reported that BIRC3-mutated primary CLL cells exhibited active non-canonical NF-kB signaling and resistance to fludarabine in vitro.6 Furthermore, this study also demonstrated that BIRC3 mutation increased the risk of clinical progression after treatment with fludarabine-based chemoimmunotherapy. However, the impact of BIRC3 mutation on the clinical outcome of patients treated with novel targeted therapies is largely unknown. Recently, Tausch et al. reported that BIRC3 mutation was not associated with shorter progression-free survival (PFS) in front-line CLL patients treated with venetoclax, a highly selective BCL2 inhibitor, in combination with obinutuzumab.4 In this letter, we report minimal residual disease (MRD) and clinical responses and PFS in patients with relapsed/refractory (R/R) CLL with BIRC3 mutations who were treated with fixed-duration venetoclax plus rituximab (VenR).

The combination of VenR is approved for the treatment of patients with R/R CLL based on results of the MURANO Phase III study (NCT02005471), which demonstrated improved PFS and overall survival (OS) with fixed-duration VenR (2 years of 400 mg venetoclax once daily, plus monthly rituximab for the first six months) versus bendamustine plus rituximab (BR).7 MURANO also showed early and durable undetectable MRD (uMRD) status with VenR, which is associated with improved survival in CLL.8

In MURANO, non-silent, deleterious BIRC3 mutations were found in 8 of 160 (5.0%) patients in the BR arm and 9 of 153 (5.9%) in the VenR arm by whole-exome sequencing with DNA specimens from CD19-enriched baseline samples (313 of 389 enrolled patients). The prevalence of BIRC3 mutation in the MURANO study is therefore comparable to what was reported in the front-line setting. All patients with BIRC3 mutations and a known immunoglobulin variable heavy chain gene (IGVH) mutation status (n=15) were unmutated for IGVH. Forty-seven per cent of patients with BIRC3 mutations had concomitant TP53 disruption by deletion of chromosome 17p (del[17p]) and/or mutations in the TP53 gene: 3 of 8 in the BR arm and 5 of 9 in the VenR arm.

In MURANO, PFS was based on investigator assessment, and Kaplan-Meier estimates were used to analyze time-to-event data. With a median follow-up of 48 months, within the BR arm, PFS was shorter in patients with BIRC3 mutations (Hazard ratio [HR] 2.2, 95% confidence interval [CI]: 0.92–5.1, P=0.077, adjusted for TP53, del(17p) and IGVH status; Figure 1A). Whereas, in the VenR arm, there was no statistically significant impact on PFS seen with BIRC3 mutations (HR 1.5, 95% CI: 0.5–4.3, P=0.44, same adjustments as BR; Figure 1B). While noting the small number of cases involved, for those with BIRC3-mutated disease, PFS was superior with VenR compared with BR (HR 0.15, 95% CI: 0.04–0.63, P=0.0089).

Figure 1.Progression-free survival in the MURANO study according to BIRC3 mutation status. PFS: progression-free survival; BR: bendamustine plus rituximab; VenR: venetoclax plus rituximab; HR: hazard ratio; ^MUT: mutated.

Previously, we reported that a higher rate of peripheral blood (PB) uMRD (uMRD defined as <1 CLL cell/10,000 leukocytes [<10], assessed centrally by either allele-specific oligonucleotide PCR or multi-color flow cytometry according to the European Research Initiative on CLL guidance) was achieved at the end of combination treatment (EOCT) in the VenR arm (62.4%) versus the BR arm (13.3%).8 Furthermore, achieving uMRD status at EOCT is associated with prolonged PFS regardless of the clinical response status.8 Looking specifically into the BIRC3-mutated subgroup, two patients failed to reach EOCT (one treatment-unrelated death in the VenR arm, one disease progression [PD] in the BR arm). Of the remaining patients, at EOCT, in the BR arm (n=7), three patients with BIRC3 mutations had partial response (PR), one stable disease (SD), one PD, and two had no available response status due to missing computerized tomography scan or physical examination. Only one patient with BIRC3 mutation in the BR arm achieved uMRD with treatment but became MRD-positive three months after treatment cessation. At EOCT, in the VenR arm (n=8), three patients with BIRC3 mutations achieved PR and uMRD in PB at EOCT; three had PR and low-MRD (≥10–<10) status, one of whom subsequently attained uMRD during venetoclax monotherapy; one had SD with high-MRD (≥10) status, one was withdrawn for non-compliance and had no clinical response assessment at this visit but was low-MRD. Notably, all four patients with BIRC3 mutations who achieved uMRD in the VenR arm maintained their uMRD status after cessation of the treatment and remain progression free at this follow-up (43–50 months); among these, one had concomitant TP53 disruption.

These data from the MURANO study suggest that, similar to the setting of fludarabine, cyclophosphamide and rituximab (FCR), PFS was reduced in patients with BIRC3-mutated relapsed/refractory CLL treated with BR, indicating BIRC3 mutation is an independent adverse risk factor with a range of chemoimmunotherapy. Within the limitations of the small numbers of patients involved, there was no significant PFS reduction observed in patients with BIRC3 mutations treated with VenR overall with the current follow-up; nearly half of these patients were able to achieve and maintain uMRD, supporting the use of time-limited, chemotherapy-free VenR in R/R CLL patients with BIRC3 mutations.