Advances in R/R CLL management with venetoclax
Venetoclax: A potent BCL-2–specific inhibitor
The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of venetoclax, with or without an anti-CD20 monoclonal antibody (eg, rituximab), in the management of R/R CLL patients with or without chromosome 17p deletion (a marker of p53 deletion). [NCCN Clinical Practice Guidelines in Oncology, Chronic Lymphocytic Leukaemia/ Small Lymphocytic Lymphoma, version 4.2020]
High expression of pro-survival proteins or inactivation of p53 is observed in many cancers, especially those refractory to therapy. Venetoclax is a BCL-2-homology (BH) domain 3-only mimetic protein, which acts by specifically engaging the surface grove of anti-apoptotic BCL-2 family proteins, thereby releasing BAX and BAK from sequestration, triggering mitochondrial permeabilization and thus tumour cell apoptosis. BAX and BAK are also activated by pro-apoptotic BH3-only proteins, such as BIM, upon exposure of tumour cells to venetoclax. [Trends Cancer 2016;2:443-460]
MURANO trial: Sustained PFS and OS benefits with VenR
In the randomized, open-label, phase III MURANO trial, 389 patients (men, 73.8 percent; median age, 65 years; Eastern Cooperative Oncology Group Performance Status [ECOG PS] 0–1) with R/R CLL who had received 1–3 previous treatments (including ≥1 chemotherapy-containing regimen) were randomized (1:1) to receive venetoclax plus rituximab (VenR; n=194) after completion of venetoclax ramp-up (R dosage, 375 mg/m2 intravenously [IV] for the first dose [day 1 of cycle 1] and 500 mg/m2 IV thereafter [day 1 of cycle 2 through 6]), or bendamustine (70 mg/m2 IV on days 1 and 2 of each 28-day cycle for 6 cycles) plus rituximab (BR; n=195). Venetoxclax was administered according to a 5-week dose ramp-up schedule (from 20 mg/day to the recommended daily dose of 400 mg/day) and continued for 2 years unless disease progression or unacceptable toxicity occurred sooner. [N Engl J Med 2018;378:1107-1120]
In this population of R/R CLL, adverse prognostic factors were prevalent. For example, 92 of 342 patients (26.9 percent) evaluated for chromosome 17p status had 17p deletion, and 99 of 376 patients (26.3 percent) tested for TP53 mutation had TP53 mutations. Among 360 patients tested for immunoglobulin heavy-chain variable (IGHV) gene mutation status, 246 (68.3 percent) had unmutated IGHV gene.
The primary endpoint was investigator-assessed PFS. At a median follow-up of 23.8 months, significantly improved PFS was seen in the VenR vs BR group (2-year PFS rate, 84.9 percent vs 36.3 percent; hazard ratio [HR], 0.17; 95 percent CI, 0.11 to 0.25; p<0.001). Similar results were seen in the analysis by independent review committee. In prespecified subgroup analyses, consistent benefit was observed in the VenR vs BR group, including those with chromosome 17p deletion, mutated TP53 and unmutated IGHV.
In an extended analysis with a median follow-up of 48 months, the PFS benefit of VenR was maintained (4- year PFS estimate, 57.3 percent vs 4.6 percent; HR, 0.19; 95 percent CI, 0.14 to 0.25; p<0.0001). (Figure 1) A sustained OS benefit was also seen with VenR vs BR (4-year OS rate, 85.3 percent vs 66.8 percent; HR, 0.41; 95 percent CI, 0.26 to 0.65; p<0.0001). [Blood 2019;134(suppl 1):355]
The advantage of VenR over BR is also reflected by the depth of response, as a significantly higher rate of peripheral blood (PB) uMRD was observed in the VenR vs BR group at the end of combination therapy (EOCT) (62.4 percent vs 13.3 percent; p<0.001), with superiority sustained through month 24 (end of therapy). “Importantly, patients with uMRD in each treatment arm had a longer duration of PFS than those with detectable MRD at EOCT,” noted Chan. (Figure 2) [J Clin Oncol 2019;37:269-277]
This association between PB uMRD at EOCT and improved PFS in both treatment arms was maintained with extended 48-month follow-up. [Blood 2019;134(suppl 1):355]
Toxicities associated with VenR were generally manageable. Neutropenia was the most common adverse event (AE) of any grade (60.8 percent for VenR vs 44.1 percent for BR) or grade 3/4 (57.7 percent vs 38.8 percent). Neutropenia (of any grade) also accounted for most AEs that led to dose interruption in the VenR group, with growth factor treatment required in 47.9 percent vs 43.1 percent of patients. The rate of grade 3/4 tumour lysis syndrome (TLS) was 3.1 percent vs 1.1 percent. [N Engl J Med 2018;378:1107-1120]
R/R CLL management in clinical practice
“The MURANO study was practice-changing and VenR has proved itself as an effective regimen in R/R CLL. Compared with other novel agents such as Bruton’s tyrosine kinase [BTK] inhibitors, a fixed duration of VenR treatment also offers greater convenience and represents a lower financial burden to patients,” commented Chan.
According to Chan, treatment selection for R/R CLL should be a shared decision-making process, taking patients’ preferences into account. “Patients should be informed of the benefits and risks of time-limited therapy vs continuous therapy,” he advised.
“Patient-specific risk factors, such as age, comorbidities and genetic profile, should be considered when deciding on an appropriate treatment option. For example, some BTK inhibitors are associated with increased risks of atrial fibrillation and bleeding, and may therefore be unsuitable for elderly patients with pre-existing cardiovascular comorbidities or those on anticoagulants,” he continued. “On the other hand, sufficient renal clearance and willingness to adhere to a dose-escalation regimen are crucial in patients receiving VenR.”
“Excellent ORR and PFS with venetoclax have been observed in some of our patients, with only one patient failing single-agent venetoclax for compassionate use after 2 years,” noted Chan. “AEs such as TLS predominately occur in the first month of treatment. In the long run, venetoclax’s AE profile remains favourable.”
“Overall, VenR combination therapy is very effective for treatment of CLL. The AE of TLS can be well managed with a dose ramping schedule and conservative measures. The fixed-duration regimen should be incorporated into the treatment algorithm of R/R CLL,” concluded Chan.