Fixed-duration venetoclax plus obinutuzumab: a new standard for untreated patients with chronic lymphocytic leukemia and coexisting comorbidities
Results of the phase III CLL14 trial presented during the presidential session of EHA 2019 demonstrate that fixed-duration treatment with venetoclax and obinutuzumab is associated with a significant improvement in progression-free survival (PFS) and overall response rate (ORR) compared to a chemoimmunotherapy with chlorambucil and obinutuzumab. In addition to this, the venetoclax-obinutuzumab combination induced an unprecedented level of sustained MRD negativity in this setting.
Background
The current first-line treatment for unfit patients with CLL consists of either fixed duration chemoimmunotherapy (i.e. chlorambucil-obinutuzumab, bendamustine-rituximab) or a continuous treatment with a targeted agent (i.e. ibrutinib). The phase III CLL14 trial evaluated a combination of both strategies by comparing a fixed-duration combination of the Bcl2 inhibitor venetoclax with the CD20 antibody obinutuzumab (VenG) to standard chemoimmunotherapy with chlorambucil and obinutuzumab (ClbG).
Study design
In the phase III CLL14 trial, 423 previously untreated patients with CLL and coexisting comorbidities (a CIRS score >6 and/or an estimated creatinine clearance <70 ml/min) were randomized (1:1) to receive 12 cycles of standard Clb or Ven 400mg daily in combination with G for the first 6 cycles. The primary endpoint of the study was PFS. A key secondary objective of the trial was the rate of MRD negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment. MRD was analyzed serially from cycle 4 every 3 months by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10-4) and by next generation sequencing.
Results
The median age of patients in CLL14 was 72 years, and they had a median CIRS score of 8 and a median creatinine clearance of 66.4 ml/min. After 29 months of follow-up, VenG was found to be associated with a significantly superior PFS compared to ClbG (medians not reached; HR [95%CI]: 0.35[0.23-0.53]; p< 0.0001). At 24 months, 88% of patients treated with VenG were alive and free of progression as compared to 64% in the ClbG arm. In addition to this, VenG doubled the CR rate compared to ClbG (50% versus 23%; p< 0.001). The percentage of patients with MRD negativity 3 months after treatment completion was also significantly higher with VenG than with ClbG, both in the PB (76% versus 35%; p< 0.0001) as in the BM (57% versus 17%; p<0. 0001). Overall, 75% of VenG MRD negative patients in PB were also MRD negative in BM (versus 49% in the ClbG group). Furthermore, the MRD negativity rates were also more sustainable with VenG, reflected by a 81% MRD negativity rate 12 months after treatment completion in the VenG arm versus 27% with ClbG (HR [95%CI] for MRD conversion: 0.19[0.12–0.30]).
Grade 3 or 4 neutropenia occurred in 52.8% of patients in the VenG group and in 48.1% of patients in the ClbG group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% with VenG and 7.9% with ClbG. These differences were not significant.
Conclusions
In summary, fixed-duration VenG can be safely administered to elderly patients with CLL and relative comorbidity. The combination provided a superior outcome compared to ClbG in terms of PFS, ORR, CR rate and was associated with an unprecedented level of MRD negativity. This clinical benefit of VenG over ClbG was seen in all relevant subgroups, including in patients with IGHV unmutated tumors and in patients with a del(17p) or a TP53 mutation. Based on these findings the authors concluded that VenG has the potential to become the new standard of care for untreated CLL patients with coexisting comorbidities.
Reference
Fischer K, Al-Sawaf O, Bahlo J, et al. Fixed-duration venetoclax plus obinutuzumab improves progression-free survival and minimal residual disease negativity in patients with previously untreated CLL and comorbidities. Presented at EHA 2019; Abstract S149.
