Venetoclax Treatment Strategies in Patients with CLL

Introduction

Chronic lymphocytic leukemia is one of the most common hematologic-oncological diseases, with a current prevalence in the Czech Republic reaching approximately 5,000 patients. A significant revolution in the treatment of this disease was the advent of targeted therapy using small molecules a few years ago. The first and so far the only representative of Bcl-2 inhibitors that has found significant use not only in the treatment of CLL is venetoclax. This oral drug can currently be used in 1st-line patients with a fixed duration of 12 months (in combination with obinutuzumab) or for 24 months in relapses (in combination with rituximab), or as continuous monotherapy after previous failure of a B-cell receptor pathway inhibitor (BCRi).

Clinical Trial Results

Venetoclax is an oral selective Bcl-2 inhibitor that has already demonstrated significant and rapid antitumor activity in early clinical trials, although this was accompanied by an increased risk of tumor lysis syndrome (TLS). After the introduction of gradual dose escalation at the beginning of treatment (weekly increments: 20 mg, 50 mg, 100 mg, 200 mg, and a final dose of 400 mg once daily orally), clinically significant TLS was almost not observed. The overall safety profile of this drug is favorable, with neutropenia occurring more frequently, which is generally well-managed by administering granulocyte colony-stimulating factor (G-CSF) or dose reduction, and does not significantly increase the risk of serious infections.

Compared to BCRi, which typically achieve partial remission (or PR with lymphocytosis) and therefore need to be administered continuously, a significant proportion of patients on venetoclax achieve complete remission and negativity for minimal residual disease. This high efficacy became the basis for the concept of time-limited therapy, as was the case in the registration studies CLL14 and MURANO.

The first data from the phase III MURANO randomized study were published in 2018 (Seymour et al., 2018). Patients with relapsed CLL were treated with venetoclax + rituximab (VenR) for 2 years (along with 6 applications of rituximab every 4 weeks) or with 6 cycles of bendamustine + rituximab (BR) chemoimmunotherapy. Subsequent 4-year follow-up data were presented (Kater et al., 2020). Progression-free survival (PFS) in the VenR arm was 57.3% vs. 4.6% at 4 years (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.14–0.25).

The results of using venetoclax in the 1st line for patients with significant comorbidities were presented in the CLL14 study (Fischer et al., 2019). Patients were randomized to the obinutuzumab + venetoclax arm (with venetoclax for 12 months) or the obinutuzumab + chlorambucil arm. The venetoclax regimen (VenG) significantly increased the representation of complete remissions (50%), including undetectable MRD (76% in peripheral blood).

In the published longer follow-up (Al-Sawaf et al., 2020), the VenG regimen demonstrated significant PFS prolongation – at 3 years, 82% vs. 50% of patients were progression-free (HR 0.31; 95% CI 0.22–0.44; p < 0.0001).

Targeted Treatment Sequence

An important question regarding targeted therapy is the sequence of individual preparations. Currently, it is not possible to universally recommend fixed-duration therapy (venetoclax) or continuous therapy (mainly Bruton’s tyrosine kinase inhibitors – BTK). We do not yet have direct comparison results of individual drugs, but it seems that patients with the TP53 gene aberration due to poorer prognosis may benefit more from continuous treatment. On the other hand, time-limited therapy offers several advantages. Firstly, there are “therapeutic holidays,” where a patient after 1–2 years of venetoclax treatment can remain in remission for many years without any treatment or frequent check-ups. This also reduces cumulative toxicity, drug interaction risks, and non-compliance issues. There is also a lower risk of developing mutations and selecting resistant clones to a given therapy.

Generally, a patient in the 1st or 2nd line of treatment is predictably younger and usually less comorbid than one who has been pre-treated more extensively. Therefore, if possible, it seems appropriate to start with time-limited targeted therapy. Conversely, in subsequent relapses, the simpler application of BTK inhibitors could be advantageous, with low TLS risk, no need for hospitalizations or anti-CD20 antibody applications, and more patients having TP53 aberration, etc.

The question remains about repeating venetoclax therapy if it was administered for a time-limited period and remission was achieved. Current data indicate it can be safely and effectively reused in relapse, but available data are still limited. It’s unclear how long the previous remission should last, or after what period venetoclax can be used again (12–24 months or longer?). It's also not clear what the optimal duration of venetoclax administration should be. Fixed therapy duration cannot ideally suit everyone – some might benefit from extended administration, while others with rapid MRD-negative remission might end treatment sooner, reducing their overall therapeutic burden.

Conclusion

Venetoclax-based therapeutic regimens, especially with fixed-duration administration, have already become a cornerstone in the treatment of CLL patients, both in 1st-line and in relapses. Strategically, it seems preferable for these time-limited regimes to be directed towards earlier therapy lines. Venetoclax is expected to be a key drug in future combinations of targeted preparations. The first data from studies evaluating venetoclax in combination with ibrutinib look very promising. Monitoring MRD with subsequent individualized treatment duration may also be promising.

MUDr. Martin Špaček, Ph.D.
1st Internal Clinic – Department of Hematology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague

Literature:
1. Seymour J. F., Kipps T. J., Eichhorst B. et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 2018; 378 (12): 1107–1120, doi: 10.1056/NEJMoa1713976.
2. Al-Sawaf O., Zhang C., Tandon M. et al., Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2020; 21 (9): 1188–1200, doi: 10.1016/S1470-2045(20)30443-5.
3. Fischer K., Al-Sawaf O., Bahlo J. et al., Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 2019; 380 (23): 2225–2236, doi: 10.1056/NEJMoa1815281.
4. Kater A., Wu J. Q., Kipps T. et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results. J Clin Oncol 2020; 38 (34): 4042–4054, doi: 10.1200/JCO.20.00948.