The treatment of chronic lymphocytic leukemia (CLL) continues to improve and the goal of achieving a cure is clearly in sight. Treatment of CLL with FCR chemotherapy has been replaced by newer combinations of precision medicines because they delay CLL progression and prolong survival compared to FCR. These precision medicines belong to one of 3 classes.
Bruton’s tyrosine kinase (BTK) inhibitors.
BTK is a protein/carbohydrate complex that is involved in maintaining cellular survival and replication. By inhibiting the activity of BTK, a BTK inhibitor reduces the growth of leukemia cells and causes cellular death. Drugs that block BTK stop the flow of these growth signals and the CLL cells die.
- Imbruvica (ibrutinib)
- Calquence (acalabrutinib)
- Brukinsa (zanubrutinib)
BCL-2 Inhibitors
The BCL-2 protein is a type of protein that contributes to CLL cell’s survival. Over expression of the BCL-2 protein in CLL cells is associated with increased survival time of the leukemia cells as well as resistance to standard chemotherapy. Venclexta (venetoclax) is a precision cancer medicine that binds to the BCL-2 protein, thereby disabling its ability to keep cancer cells alive.
- Venclexta (venetoclax)
CD20 Monoclonal Antibodies
Gazyva® (obinutuzumab) and Rituxan (rituximab) are both engineered monoclonal antibodies designed to attach to CD20, a protein found only on B-cells. It attacks targeted cells both directly and together with the body’s immune system. Gazyva is preferred and can be used alone or in combination to treat newly diagnosed or recurrent CLL.
There are currently three “doublet” combination regimens that appear most effective for the treatment of newly diagnosed CLL.
- Calquence + Gazyva
- Venclexta + Imbruvica
- Venclexta + Gazyva
A key difference between these doublet regimens is that the Venclexta based regimens are given for a fixed duration of time and appear effective in the highest risk patients compared with the calquence doublet which is administered indefinitely. MDACC and the FLAIR clinical trial both suggest a greater than 95% 5-year overall survival benefit irrespective of mutational status with the Venclexta-Imbruvica combination. A key question is the appropriate duration of Venclexta therapy? Doctors are using minimal residual disease (MRD) assessment to determine the optimal length of treatment.
“Triplets”
Combination time‐limited therapy with Gazyva, and Venclexta has emerged as a standard frontline option for previously untreated CLL. In a recent phase III trial, fixed‐duration treatment with Gazyva plus Venclexta induced undetectable minimal residual disease (uMRD) responses in the majority of patients with newly diagnosed CLL, with uMRD rates of 76% and 57% in the peripheral blood (PB) and bone marrow (BM), respectively.
Combinations of all three drug classes however including a BTKi, Venclexta, and Gazyva may be the most promising, especially for patients at the highest risk of relapse. Triplet combinations are currently undergoing evaluation in clinical trials. Initial results of the GAIA/CLL13 trial demonstrated that Venclexta-Gazyva combinations are clearly superior to FCR chemotherapy and Venclexta + Rituxan and an initial analysis suggests that the addition of Imbruvica further delays CLL progression but longer follow up is required to determine if there is a survival benefit.
Additional early‐phase data support the combination of Venclexta with a BTKi as frontline therapy for CLL. In two recent phase II trials, frontline treatment with inbruvica plus venclexta induced uMRD responses of 65%–75% in patients with previously untreated CLL.3,4 Brukinsa is a BTK inhibitor with fewer side effects than first‐generation BTK inhibitiors and is associated with durable responses and a favorable safety profile.5
Building on these findings, researchers created a novel three‐drug combination regimen of Brukinsa, Gazyva, and Venclexta (BOVen) and designed a clinical trail to test the hypothesis that MRD‐directed, time‐limited treatment with BOVen will lead to more rapid disease eradication and durable responses in patients with previously untreated CLL.1
To date, the trial has enrolled 39 patients with previously untreated CLL or small lymphocytic lymphoma (SLL) with leukemic involvement who require treatment. All patients were treated with BOVen in 28‐day cycles and after patients completed a minimum of 8 cycles a assessment of uMRD determined the remaining duration of treatment. Once uMRD was determined in the PB and confirmed in BM patients, 2 additional treatment cycles were completed for a maximum total of 24 cycles.
Treatment with BOVen induced rapid uMRD responses in 62% of patients enabling them to stop therapy after an average of 8 months of treatment. In total, 84% of patients achieved uMRD in the blood and 73.0% percent achieved uMRD in the BM. Other novel triplet therapy combinations are being evaluated as well.
Gazvya, Imbrvica, and Venclexta in High-Risk CLL
In the CLL2-GIVe trial, 41 patients with high-risk disease (del(17p) or TP53 mutations) were treated with induction therapy consisting of Gazvya (obinutuzumab), Imbruvica, (ibrutinib), and Venclexta (venetoclax) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Patients who did not reach a CR with undetectable minimal residual disease (MRD) after consolidation continued to receive ibrutinib as monotherapy for cycles 13 through 36.
The CR rate was 59% and 78% of patients had undetectable MRD in peripheral blood and 66% of patients had undectable MRD in bone marrow. The estimated progression-free and overall survival rates at 24 months were 95%.6
References:
- 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: 2225– 2236.
- Tam CS, Siddiqi T, Allan JN et al. Ibrutinib plus venetoclax for first‐line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at the 61st American Society of Hematology Annual Meeting and Exposition; December 7‐10, 2019; Orlando, FL. Abstract 35.
- Jain N, Keating M, Thompson P et al. Ibrutinib and venetoclax for first‐line treatment of CLL. N Engl J Med 2019; 380: 2095– 2103.
- Tam C, Opat S, D’Sa S et al. ASPEN: Results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). Presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. May 29–31, 2020. Abstract 8007. Available at
- Soumerai JD, Mato AR, Carter J et al. Initial results of a multicenter, investigator‐initiated study of MRD driven, time‐limited therapy with zanubrutinib, obinutuzumab, and venetoclax in patients with previously untreated CLL. Presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. May 29–31, 2020. Abstract 8006.
- Huber H, Edenhofer S, von Tresckow J, et al. Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia. Blood. 2022 Mar 3;139(9):1318-1329. doi:10.1182/blood.2021013208.
