|The following article features coverage from the European Hematology Association 2020 virtual meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.|
Nearly 60% of evaluable patients with previously untreated, chronic lymphocytic leukemia (CLL) characterized by chromosomal deletion of 17p (del[17p]) and/or a deleterious TP53 mutation treated with obinutuzumab, ibrutinib, and venetoclax triplet therapy achieved either complete remission (CR) or a CR with incomplete recovery of the bone marrow, according to results of a single-arm, phase 2 study presented during the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.1
While less than 10% of patients diagnosed with CLL have disease characterized by del(17p), this biomarker is present in up to half of patients with refractory disease.2 Hence, there is an unmet need for efficacious and safe treatment regimens for this subgroup of patients. Furthermore, compounding this need is the finding that TP53 mutations, another biomarker of poor prognosis, have been reported to be present in approximately 90% of patients with disease characterized by del(17p) although only about 40% of those with TP53-mutant CLL also have del(17p).An unmutated IGHV gene is another risk factor for poor prognosis in the setting of CLL.2
The multicenter, open-label CLL2-GiVe trial (ClinicalTrials.gov Identifier: NCT02758665) is evaluating the efficacy and safety of a chemotherapy-free regimen consisting of 3 classes of novel agents, obinutuzumab, an anti-CD20 monoclonal antibody, ibrutinib, a BTK inhibitor, and venetoclax, a BCL-2 inhibitor, in patients with previously untreated, poor prognosis CLL characterized by del(17p) and/or a TP53 mutation. All 3 of these agents been shown to be efficacious and tolerable in patients with CLL and have received approval from the U.S. Food and Drug Administration either as single-agent therapy or in combination with another agent for the treatment of patients with CLL.
In this study, obinutuzumab, venetoclax, and ibrutinib were administered during cycles 1 through 6, cycles 2 through 12, and cycles 1 through 12, respectively, with single-agent ibrutinib continued until at least cycle 15, and beyond to cycle 36 for patients requiring maintenance therapy.
The primary study endpoint was the proportion of patients achieving a CR or a CR with incomplete recovery of the bone marrow (CRi) as best response on day 1 of cycle 15. Secondary study endpoints included safety, overall response rate (ORR), the proportion of patients with undetectable minimal residual disease (when assessed by an assay with a sensitivity of 10-4) in peripheral blood, and overall survival (OS).
Baseline characteristics of the 41 patients enrolled in the study included a median age of 62 years; 78% of patients had intermediate/high risk disease according to Binet staging; high or very high risk classification according to the CLL-International Prognostic Index was seen in 10.8% of patients with del(17p) and 89.2% of patients with TP53 mutation; and del(17p), TP53 mutation, and unmutated IGHV was present in 63%, 95%, and 78% of patients, respectively. In addition, 95% of patients were classified as being at an increased risk of tumor lysis syndrome.
Median follow-up was 18.6 months. Of the 37 patients assessed for minimal residual disease (MRD) status, undetectable MRD status in the peripheral blood and bone marrow at cycle 15 was achieved by 80.4% and 68.3% of patients, respectively. Regarding the primary study endpoint, CR/CRi and partial response rates at cycle 15 were observed in of 58.5% and 34.2% of evaluable patients, respectively. Furthermore, 95.8% of those with CR/CRi at day 1 of cycle 15 had undetectable MRD in the blood and 87.5% were classified as having undetectable MRD in the bone marrow. However, only 71.4% and 50.0% of those achieving a partial response as best response at cycle 15 had an undetectable MRD status in the blood and bone marrow, respectively.
Treatment was discontinued at cycle 15 due to undetectable MRD status according to the study protocol in 22 patients, and 13 patients discontinued treatment by this time for other reasons including adverse events (AEs). The remaining patients continued ibrutinib therapy beyond this point and 4 patients experienced progressive disease at cycle 27 or beyond.
In the 39 patients included in the safety analysis, rates of grade 3 or higher AEs reported through day 1 of cycle 15 included neutropenia (43.9%), infections/infestations (19.5%; including 1 patient with grade 4 cerebral aspergillosis), thrombocytopenia (14.6%), infusion-related reactions (7.3%), atrial fibrillation (2.4%), headache (2.4%), and arthralgia (2.4%).
In her concluding remarks, the presenting author, Henriette Huber, MD, of the University Hospital of Ulm in Germany, noted that while some high-grade infections were a concern, this triplet regimen is a promising first-line therapy for patients with high-risk CLL.
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- Huber H, Edenhofer S, von Tresckow J, et al. CLL2-GIVe, a prospective, open-label, multicenter phase II trial of obinutuzumab (GA101, G), ibrutinib (I), plus venetoclax (VE) in untreated patients with CLL with 17P deletion/TP53 mutation. Presented at: Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress; June 2020. Abstract S157.
- Strati P, Keating MJ, O’Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. 2014; 99: 1350-1355.