Eichhorst B, Niemann CU, Kater AP, et al. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754
In this large randomized phase 3 clinical trial (CLL13/GAIA), previously untreated patients with chronic lymphocytic leukemia (CLL) with a median age of 61 years were randomly assigned (1:1:1:1) to treatment on one of the following four arms: 1) chemoimmunotherapy (CIT) consisting of either fludarabine, cyclophosphamide and rituximab (FCR) or bendamustine and rituximab (BR; patients <65 years received FCR and those over 65 years received BR); 2) venetoclax-rituximab; 3) venetoclax-obinutuzumab; or 4) ibrutinib-venetoclax-obinutuzumab. All patients met the 2018 International Workshop on CLL guidelines for CLL therapy, and did not have del17p by FISH. At month 15 after starting therapy, the rates of undetectable measurable residual disease (uMRD) in the FCR/BR arm were significantly lower compared to venetoclax-obinutuzumab (52% vs. 86.5%, P<0.001) and also significantly lower compared to the ibrutinib-venetoclax-obinutuzumab arm (52% vs. 92.2%, P<0.001). There was no difference in the uMRD rates between the CIT arm and venetoclax-rituximab (52% vs. 57%, P=0.32). Correspondingly, the progression-free survival (PFS) was significantly longer in both the venetocalx-obinutuzumab and the ibrutinib-venetoclax-obinutuzumab arms compared to patients who received venetoclax-rituximab or CIT. Early discontinuation of treatment owing to adverse events occurred in 33/216 (15.3%) patients in the CIT group, 14/237 (5.9%) patients in the venetoclax–rituximab group, 13/228 (5.7%) patients in the venetoclax–obinutuzumab group, and 29/231 patients in the ibrutinib-venetoclax-obinutuzumab group.
The vast majority of clinicians in the United States have moved away from using CIT in their routine practice in the frontline management of CLL (as is also recommended by the National Comprehensive Cancer Network [NCCN] guidelines). Current treatment options include continuous treatment with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib, acalabrutinib and zanubrutinib (which are all approved in CLL). The results of this trial show fixed duration treatment with venetoclax-based combinations are feasible, efficacious, and well tolerated among patients with previously untreated CLL, when compared to standard CIT based approaches. Several other noteworthy points from this trial include: 1) the preferred anti-CD20 monoclonal antibody with venetoclax is obinutuzumab compared to rituximab; 2) there does not appear to be any significant benefit with respect to uMRD rates or 3-year PFS rates among patients treated with venetoclax-obinutuzumab compared to ibrutinib-venetoclax-obinutuzumab, suggesting that triplet based combinations are not necessarily better and should not be used in routine clinical practice yet; 3) the risk of clinical ≥ grade 3 tumor lysis syndrome (according to the Cairo-Bishop criteria) with appropriate step-up dosing schedule of venetoclax was seen in 10/696 (1.4%) patients who received venetoclax containing regimen; 4) atrial fibrillation occurred more commonly in patients (18/231, 7.7%) who received ibrutinib-venetoclax-obinutuzumab. In summary, time-limited combination of venetoclax-obinutuzumab represents an excellent frontline treatment approach for patients with CLL. Results from future clinical trials (such as CLL17) will inform whether patients should receive continuous BTKi treatment or fixed duration treatment with venetoclax-obinutuzumab or with another doublet fixed duration therapy consisting of ibrutinib-venetoclax for the frontline management of CLL.