KEY TAKEAWAYS
- The phase III trial aimed to evaluate the efficacy and safety of Ven-Obi in previously untreated chronic lymphocytic leukemia pts.
- The primary endpoint of the CLL14 study was to assess PFS in CLL pts treated with Ven-Obi compared to those receiving Clb-Obi. Secondary endpoints were MRD, TTNT, and OS.
- The study found that Ven-Obi treatment emerged as a superior treatment for chronic lymphocytic leukemia, offering enhanced PFS and delayed need for subsequent therapy.
One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) has been established as the standard of care for previously untreated chronic lymphocytic leukemia (CLL). CLL14 study has shown strong efficacy and tolerability of Ven-Obi in CLL patients(pts) with coexisting conditions.
Researchers aimed to evaluate the efficacy and safety of Ven-Obi in previously untreated chronic lymphocytic leukemia patients. Patients with previously untreated CLL and coexisting conditions were randomly assigned in a 1:1 ratio to receive either 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab (Clb-Obi).
The primary endpoint was progression-free survival (PFS), as assessed by the investigator. Secondary endpoints included safety, rates of minimal residual disease (MRD), time to next treatment (TTNT), and overall survival (OS). Follow-up is ongoing.
Of the 432 enrolled pts, 216 were randomly assigned to receive Ven-Obi, and 216 to receive Clb-Obi. At a median follow-up of 76.4 months (IQR 52.5-80.5), Ven-Obi maintained superior progression-free survival (PFS) compared to Clb-Obi (median 76.2 vs 36.4 months; HR 0.40 [95% CI 0.31-0.52], P<0.0001).
At 6 years post-randomization, the estimated investigator-assessed PFS rate was 53.1% with Ven-Obi and 21.7% with Clb-Obi. Progressive disease (PD) occurred in 67 cases in the Ven-Obi arm with 39 second-line treatment initiations and in 141 cases in the Clb-Obi arm (with 103 second-line treatments). Time to next treatment (TTNT) was significantly longer after Ven-Obi(6-year TTNT 65.2% vs 37.1%; HR 0.44, 95% CI 0.33-0.58, P<0.0001).
The most frequent second-line treatments in both arms were BTK inhibitors (61.5% in the Ven-Obi arm, 55.4% in the Clb-Obi arm). The PFS and TTNT difference between the two arms was maintained across all risk groups, including patients with TP53 mutation/deletion (median PFS 51.9 vs 20.8 months; median TTNT 57.3 vs 29.0 months) and unmutated IGHV status (median PFS 64.8 vs 26.9 months; median TTNT 85.4 vs 40.6 months).
Multivariate analysis identified TP53 deletion/mutation, unmutated IGHV, and lymph node size ≥5 cm as independent negative prognostic factors for PFS in patients treated with Ven-Obi.
Five years post-treatment completion, 7.9%(7.9% of the intention-to-treat population) in the Ven-Obi arm still had undetectable minimal residual disease uMRD(<10-4by NGS in peripheral blood), with 10.2% having low (L)-MRD (≥10-4 and <10-2), and 10.6% having high (H)-MRD (≥10-2).
In the Clb-Obi arm, 1.9% had uMRD, 4.2% had L-MRD, and 8.3% had H-MRD. Overall, 48 deaths (9 PD-related) were reported in the Ven-Obi arm, and 70 deaths (26 PD-related) in the Clb-Obi arm. The 6-year overall survival (OS) rate was 78.7% with Ven-Obi and 69.2% with Clb-Obi(HR 0.69 [0.48-1.01], P=0.052).
Second primary malignancies were reported in 30 patients with Ven-Obi and 18 with Clb-Obi; cumulative incidences 6 years post-randomization were 14.2% and 8.5%, respectively (P=0.071). Richter transformations were reported in two cases with Ven-Obi and four with Clb-Obi. No new safety signals were observed.
The study found that Ven-Obi treatment emerged as a superior treatment for chronic lymphocytic leukemia, offering enhanced PFS and delayed need for subsequent therapy.
Clinical Trial: https://www.clinicaltrials.gov/study/NCT02242942
Al-Sawaf O, Robrecht S, Zhang C, Olivieri S, Chang YM, Fink AM, Tausch E, Schneider C, Ritgen M, Kreuzer KA, Sivcheva L, Niemann C, Schwarer A, Loscertales Pueyo J, Weinkove R, Strumberg D, Kilfoyle A, Runkel E, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. “Venetoclax-Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia: 6-Year Results of the Randomized CLL14 Study.” EHA Library. 2023; 387845; S145.
