H&O What are the advantages of doublet combinations over single-agent Bruton tyrosine kinase (BTK) inhibitor therapy in the frontline therapy of chronic lymphocytic leukemia (CLL)?
NJ The single-agent therapies that the US Food and Drug Administration (FDA) has approved for use as frontline treatment in CLL are the BTK inhibitors ibrutinib (Imbruvica, Pharmacyclics/Janssen), acalabrutinib (Calquence, AstraZeneca), and zanubrutinib (Brukinsa, BeiGene). These agents are meant to be continued long term, which can mean 5 years, 10 years, or forever. The only FDA-approved doublet therapy for CLL right now is the selective BCL2 inhibitor venetoclax (Venclexta, AbbVie) plus the CD20 monoclonal antibody obinutuzumab (Gazyva, Genentech). Venetoclax is given for 1 year, and obinutuzumab is given for 6 months. The time-limited combination approach has several advantages over single-agent BTK inhibitor therapy in CLL. First, the remissions are deeper. Second, it allows patients to complete treatment in a year. Finally, the doublet combination avoids some of the adverse events that can occur with BTK inhibitors, such as atrial fibrillation, bleeding issues, and hypertension.
The downsides of the doublet combination of venetoclax and obinutuzumab include the risks of tumor lysis syndrome and neutropenia, both of which require close monitoring, as well as infusion reactions from obinutuzumab. The combination can also be difficult to use in patients who have bulky adenopathy or impaired kidney function. Additionally, in contrast to the logistically straightforward use of an oral, single-agent BTK inhibitor, the doublet combination requires frequent visits to the physician’s office, especially in the first couple of months after treatment initiation. Finally, unlike BTK inhibitor therapy, the doublet of venetoclax and obinutuzumab does not lead to durable long-term remissions in patients with del(17p) and/or TP53-mutated CLL.
Because the 2 approaches have pros and cons, it is important to discuss both options with our patients.
H&O What are the most important studies that have looked at doublet regimens in frontline CLL?
NJ The study that led to the FDA approval of venetoclax plus obinutuzumab for CLL in 2019 was the CLL14 study from the German CLL Study Group.1 The study, which enrolled patients who were older or had some comorbidities, randomly assigned 432 patients to receive either venetoclax/obinutuzumab or the older standard combination of chlorambucil (Leukeran, Aspen Global)/obinutuzumab. Now that we have more than 6 years’ worth of data regarding this study, we have seen that more than half of the patients in the venetoclax/obinutuzumab group are still in remission, with a 6-year median PFS rate of 53%.2
Another regimen, which is approved in Canada and Europe but not the United States, is ibrutinib plus venetoclax. This regimen does not require an infusion; it is just 2 pills taken together for a total of 1 year. Approval was based on the phase 3 GLOW trial, in which 211 patients were randomly assigned to either ibrutinib/venetoclax or chlorambucil/obinutuzumab.3 Progression-free survival (PFS) and overall survival (OS) were significantly longer with ibrutinib/venetoclax than with the older regimen.4
H&O What are the potential advantages of triplet combination therapy over doublet combination therapy in the frontline treatment of CLL?
NJ We have 3 important drug classes that are used in CLL: BTK inhibitors, BCL2 inhibitors, and CD20 monoclonal antibodies. All these agents hit different targets, so why not combine all 3 of them? This strategy is being investigated in several phase 2 and 3 studies. We do not know if triplet therapy will be better than doublet therapy, but single-center phase 2 data and some early phase 3 data have suggested that triplets can be highly effective, with high rates of undetectable measurable residual disease (MRD). We do not yet have evidence from head-to-head trials that a triplet would beat a doublet, however.
H&O What studies are looking at triplet regimens in CLL?
NJ The phase 3 AMPLIFY trial is comparing chemotherapy vs a doublet of acalabrutinib and venetoclax vs a triplet of acalabrutinib, venetoclax, and obinutuzumab (NCT03836261). This is one of the first prospective randomized trials in which a doublet is being compared head to head with a triplet, which is extremely helpful. According to a press release from AstraZeneca, median PFS is significantly longer in the 2 experimental arms than in the chemotherapy arm, along with a trend towards longer median OS in the experimental arms.5 We are looking forward to seeing these data presented at a future meeting.
Other trials that are looking at first-line triplet regimens are not as far along, but several combinations are under investigation. Every triplet regimen starts with a backbone of venetoclax/obinutuzumab, and then you add your BTK inhibitor of interest: ibrutinib, acalabrutinib,6 or zanubrutinib.7 Our group at MD Anderson is also conducting a phase 2 trial of venetoclax/obinutuzumab plus the noncovalent BTK inhibitor pirtobrutinib (Jaypirca, Lilly) in treatment-naive patients with CLL or Richter transformation (NCT05536349). Pirtobrutinib received approval in December 2023 for patients with previously treated CLL. In results that I presented at the European Hematology Association 2024 Congress, MRD was undetectable in both the bone marrow and peripheral blood in a large proportion of patients after 6 and 12 months of therapy, even at a next-generation sequencing sensitivity of 10-6.8
H&O What can we look forward to in the future for the frontline treatment of CLL?
NJ I would encourage oncologists to refer patients to centers that are investigating triplets vs doublets so that we can learn more about how they compare with each other. Depending on the results of the AMPLIFY trial, we may see approval of acalabrutinib plus venetoclax with and without obinutuzumab in the coming year.
H&O Would you say there is a role for chemotherapy in CLL?
NJ Chemotherapy was the standard of care for a long time, but things have changed over the last 5 to 10 years. In my opinion, chemotherapy has no role at this time in patients with CLL. The argument has been made that patients who have IGHV-mutated disease, are young and fit, and do not have del(17p) or a TP53 mutation—which describes approximately 10% of patients with CLL—can derive long-term benefit from chemotherapy with fludarabine, cyclophosphamide, and rituximab (FCR). However, randomized studies that have compared FCR with nonchemotherapy regimens have shown better PFS with the newer regimens, even for the IGHV-mutated subset. Another disadvantage of chemotherapy is the risk of therapy-related myelodysplastic syndrome or acute myeloid leukemia. In our center at MD Anderson, we have completely abandoned the use of chemotherapy in CLL. There are places around the world where newer therapies are not available or not affordable, and in those cases, chemotherapy can be considered.
Disclosures
Dr Jain has received research funding from Pharmacyclics, AbbVie, Genentech, AstraZeneca, Eli Lilly, BeiGene, Bristol Meyers Squibb, Pfizer, Cellectis, ADC Therapeutics, Adaptive Biotechnologies, Precision BioSciences, Fate Therapeutics, Kite/Gilead, MingSight, Takeda, MediSix, NovalGen, Dialectic Therapeutics, Novartis, Carna Biosciences, Newave, Sana Biotechnology, KisoJi Biotechnology, TriArm Therapeutics, and Ascentage Pharma; and has served on the advisory board of or received honoraria from Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, Eli Lilly, BeiGene, Bristol Meyers Squibb, Adaptive Biotechnologies, Kite/Gilead, Cellectis, Ipsen, MingSight, Autolus, NovalGen, and BTG.
References
1. 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.
2. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the phase 3 CLL14 study [published online July 10, 2024]. Blood. doi:10.1182/blood.2024024631.
3. Kater AP, Owen C, Moreno C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities [published online May 13, 2022]. NEJM Evid. doi:10.1056/EVIDoa2200006.
4. Moreno C, Munir T, Owen C, et al. First-line fixed-duration ibrutinib plus venetoclax (Ibr+Ven) versus chlorambucil plus obinutuzumab (Clb+O): 55-month follow-up from the Glow study [ASH abstract 634]. Blood. 2023;142 (1 suppl).
5. AstraZeneca. Fixed-duration Calquence plus venetoclax, with or without obinutuzumab, significantly improved progression-free survival in 1st-line chronic lymphocytic leukaemia in AMPLIFY Phase III trial [press release]. https://www.astrazeneca.com/media-centre/press-releases/2024/calquence-fixed-duration-combo-improved-1l-cll-pfs.html. Posted July 29, 2024. Accessed August 21, 2024.
6. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402.
7. Soumerai JD, Dogan A, Seshan V, et al. Long-term follow-up of multicenter phase ii trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in previously untreated patients with CLL/SLL [International Conference on Malignant Lymphoma abstract 153]. Hematol Oncol. 2023;41(suppl 2).
8. Jain N, Himachandana Atluri H, Ferrajoli A, et al. Combined pirtobrutinib, venetoclax, and obinutuzumab in first-line treatment of patients with chronic lymphocytic leukemia (CLL): a phase 2 trial [EHA abstract S164]. HemaSphere. 2024;8(suppl 1).
Suggested Reading
Jain N, Wierda WG, O’Brien S. Chronic lymphocytic leukaemia. Lancet. 2024;404(10453):694-706.