One year of first-line therapy for CLL for the prospect of more than 5 years of treatment freedom¹

The BCL2 inhibitor venetoclax has been approved in Switzerland as a first-line therapy for chronic lymphocytic leukemia (CLL) since November 16, 2023 [2]. This is based on the results of the CLL14 study, the 6-year data of which were presented at the European Hematology Association Congress in Frankfurt on June 9, 2023 [1]. The data give CLL patients the prospect of more than 5 years of treatment freedom after less than one year of combined treatment with venetoclax and obinutuzumab [1, 2].

The combination of chlorambucil (Clb) + obinutuzumab (Obi) was considered the standard of care in the first-line treatment of CLL, but the BCL2 inhibitor Venclyxto® (Ven) has also shown good efficacy in the past in second-line treatment after at least one prior treatment [3, 4]. In the randomized, multicenter, open-label Phase III CLL14 study, first-line treatment with Ven + Obi was tested in comparison to Clb + Obi over a fixed period of time in patients with previously untreated CLL and additional comorbidities. Ven + Obi showed a significant advantage in progression-free survival (PFS) [5]. Updated efficacy and safety data are now available from the ongoing follow-up of the CLL14 study, whereby at this point all patients have not received the study drug for ≥ 5 years [1].

Consistently high PFS rates with Venclyxto®

A total of 432 patients with previously untreated CLL and additional comorbidities were included in the CLL14 study, with study participants randomized 1:1 to receive either 12 cycles of Ven with 6 cycles of Obi (Ven-Obi, n=216), or 12 cycles of Clb with 6 cycles of Obi (Clb-Obi, n=216) [1]. The median follow-up time in the updated follow-up study was 76.4 months (interquartile range 52.5-80.5) [1]. During follow-up, the median PFS in the Ven-Obi arm remained superior at 76.2 months compared to 36.4 months in the Clb-Obi arm (HR = 0.40; 95% CI [0,31-0,52], p<0.0001). The estimated PFS rate according to the investigators was 53.1 % in the Ven-Obi group and 21.7 % in the Clb-Obi arm 6 years after randomization [1].

With Venclyxto® for long-lasting freedom from therapy

In the Ven-Obi group, 67 patients experienced disease progression (PD) and 39 second-line treatments, while 141 cases of PD occurred in the Clb-Obi group. 103 of these patients underwent second-line treatment [1]. The time to next treatment (TTNT) after 6 years of follow-up was 65.2 % in the Ven-Obi arm and 37.1 % after Clb-Obi (HR = 0.44; 95% CI [0,33-0,58], p<0.0001; Figure 1) [1]. Second-line treatment with Ven (monotherapy or in combination with rituximab) took place in 17.9% of patients after Ven-Obi and in 14.6% after Clb-Obi [1].

High survival rates even ≥ 5 years after the end of treatment

The 6-year overall survival rate was 78.7% after Ven-Obi treatment and 69.2% after Clb-Obi treatment (HR = 0.69; 95% CI [0,48-1,01], p=0.052), with 48 deaths in the Ven-Obi arm and 70 in the Clb-Obi arm [1]. Second primary malignancies were reported in 30 patients in the Ven-Obi arm and 18 in the Clb-Obi arm.

Previous studies have shown no differences in tolerability between the two treatment regimens and no new safety signals have emerged even after 6 years of follow-up [1, 5]. The most common adverse events (≥ 20%, all grades) in patients treated with Ven in the combination study with Obi were neutropenia, diarrhea and thrombocytopenia [1,2].

Conclusion

Overall, the updated data confirm a long-term PFS benefit of Ven-Obi treatment compared to Clb-Obi [1]. In addition, around 65% of patients treated with Ven-Obi still did not require second-line treatment ≥ 5 years after treatment, which underlines the long-term effect of the Ven-Obi first-line therapy regimen and allows patients valuable treatment-free time [1].

Areas of application of VENCLYXTO®

VENCLYXTO® in combination with obinutuzumab is approved for the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL) and additional comorbidities [2]. VENCLYXTO® is approved in combination with rituximab in CLL patients after at least one prior therapy and is reimbursed by health insurance companies [2, 6]. VENCLYXTO® is also used as a monotherapy for CLL patients with a del(17p) or TP53 mutation following treatment failure with a B-cell receptor signaling pathway inhibitor. VENCLYXTO® is also available in combination with azacitidine, decitabine or low-dose cytarabine for adult patients with newly diagnosed acute myeloid leukemia (AML) for whom intensive chemotherapy is not an option [2].

Figure 1) Time to next anti-CLL treatment (TTNT) 5 years after end of therapy (EoT) with Venclyxto®+ obinutuzumab (Ven-Obi; yellow) and chlorambucil + obinutuzumab (Clb-Obi; gray).
* 336 days in first-line therapy with Ven-Obi [2]. Adapted from Al Sawaf O. et al, 2023 [1].

Abbreviations:

HR: Hazard Ratio; CI = Confidence Interval

Brief technical information on VENCLYXTO®

This article was produced with the financial support of AbbVie AG, Alte Steinhauserstrasse 14, Cham.

CH-VNCLY-230063 11/2023

Literature

1 Al-Sawaf, O., et al, Venetoclax-Obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized CLL14 study. Abstract S145 (Oral). European Hematology Association Congress 2023, June 8-11 Frankfurt, Germany.
2. current technical information ^Venclyxto® . www.swissmedicinfo.ch .
3 Eichhorst, B., et al, appendix 6: Chronic lymphocytic leukemia: eUpdate published online September 2016 ( http://www.esmo.org/Guidelines/Haematological-Malignancies ). Ann Oncol, 2016. 27(suppl 5): p. v143-v144.
4 Fischer, K., et al, Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood, 2017. 129(19): p. 2702-2705.
5 Fischer, K., et al, Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med, 2019. 380(23): p. 2225-2236.
6. Specialty list ^Venclyxto®. Federal Office of Public Health. www.spezialitaetenliste.ch. Status of the information: 06.07.2023.