Acalabrutinib Plus Venetoclax and Obinutuzumab Achieve Elevated Level of uMRD in Bone Marrow in CLL

Good activity has been observed with acalabrutinib in combination with venetoclax and obinutuzumab as the first line in some patients with chronic lymphocytic leukemia.

In patients with chronic lymphocytic leukemia (CLL) and minimal undetectable residual disease (MRD) in the bone marrow, the first-line combination of acalabrutinib (Calquence), venetoclax (Venclexta) and obinutuzumab (Gazyva) was very active and well tolerated, according to the results of the phase 3 study published in The Lancet Oncology.1

“These are 3 of the most active new drugs approved for patients with CLL, and our trial is the first published study to examine the effectiveness of this triplet as an initial treatment for CLL. Previous experience with chemoimmunotherapy has shown that combining our best drugs first is the most effective strategy in this disease, and our study is one of the first to assess whether the same may be true with a new agent-only treatment, said Matthew Davids, MD, MMSc, ​​principal investigator and director of clinical research, Division of Lymphoma and physician at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School , in an interview with Targeted Oncology ™.

Preclinical studies in CLL have specifically shown that Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors have a synergy. The first generation BTK inhibitor ibrutinib (Imbruvica) in combination with venetoclax, in particular, elicited a profound response in CLL models with undetectable MRD in peripheral blood and / or bone marrow .

Whereas acalabrutinib was shown to have non-inferior efficacy compared to ibrutinib in the phase 3 clinical trial ELEVATE RR (NCT02477696) in patients with high-risk CLL, with less cardiotoxicity, the investigators hypothesized that the use of acalabrutinib with BCL-2 inhibition would be beneficial in the CLL MRM-negative subgroup, including in patients with high risk disease.2

The single-arm, open-label, investigator-sponsored Phase 2 study (NCT03836261) was conducted at both the Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center. A total of 37 patients were included. Patients had to be 18 years or older with an ECOG performance index of 0 to 2 and measurable disease. At baseline, patients were also required to have a total bilirubin of 1.5 × upper limit of normal (ULN) or lower; aspartate aminotransferase and alanine aminotransferase 2.5 × ULN or less; creatinine clearance of 50 ml / min or more, absolute neutrophil count of 750 cells per mm³ or more, and platelet count of 50,000 per mm³ or more.1

In 28-day cycles, patients were treated with acalabrutinib 100 mg orally twice daily cycle 1. Then on day 1 of cycle 2, patients received 100 mg of obinutuzumab followed by 900 mg on day 2 , 1000 mg on day 8 and 1000 mg on day 15. Obinutuzumab was administered intravenously (IV) with acalabrutinib continuously. On day 1 of cycles 3 to 7, treatment with obinutuzumab 1000 mg IV was continued. Oral venetoclax was added to study therapy on Day 1 of Cycle 4 and was administered on an accelerated dosing schedule. Specifically, 20 mg of venetoclax was administered on day 1, then patients received 50 mg of venetoclax on days 2 to 7, 100 mg for homosexuals 8 to 14, 200 mg on days 15 to 21 and 400 mg on days 22.

The protocol required that patients at high risk for tumor lysis syndrome (TLS) initiate treatment with venetoclax 20 mg and 50 mg during hospitalization in cycle 4. Those at low or medium risk of TLS could start. their treatment with venetoclax in hospital or outpatient, at the discretion of clinicians. After obinutuzumab in cycle 7, all patients continued acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until the end of 15 cycles. Acalabrutinib plus venetoclax was continued until disease progression or unacceptable toxicity. However, patients had the option of stopping if they achieved complete remission.

The rate of CR with undetectable MRD in the bone marrow at the start of cycle 16 was the primary endpoint of the study. The study was designed to detect 60% OR with undetectable MRD in the bone marrow, assuming the null hypothesis rate was 40%. The secondary endpoint explored in the study included undetectable CR and MRM in the bone marrow at the start of cycles 8 and 25, partial remission rate (PR) and Cr level defined by the criteria of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) at the start of cycle 16, in addition to undetectable MRD in peripheral blood and bone marrow at the start of cycles 8.16 and 25, better overall response rate, better CR rate, better rate overall undetectable MRD in bone marrow and peripheral blood, and the association between established prognostic indicators and responses to acalabrutinib plus venetoclax and obinutuzumab.

Secondary safety / tolerability endpoints, including the rate of adverse events (AEs) of particular interest, the rate of atrial fibrillation of any grade, the rate of grade 3 or worse bleeding events, and the rate of Clinical and laboratory SLT were also evaluated. during the study.

At baseline, the median age of patients was 63 years (range, 57-70) and most patients were male (73%) and identified as non-Hispanic Caucasian (89%). No patient had an ECOG performance index of 2, and 54% had a score of 1 while the remaining 46% of patients had a score of 2. The largest percentage of patients (35%) had a Rai stage of 2 at the time of treatment. started in the study, and 30% had a score of 3, 24% had a score of 4, and 11% had a score of 1.

In terms of baseline cytogenetics, 13q deletions were the most frequent (49%), and 6q deletions were the least frequent (5%). There were also patients with 17p deletions (27%), 11q deletions (35%), trisomy 12 (14%) and a complex karyotype (19%). Most patients did not have IGHV– mutated disease (73%) and 49% were negative for ZAP-70. In terms of high risk factors, 27% of the population had both a TP53 17p mutation and deletion, and 19% had a NOTCH1 mutation.

All patients received at least 1 dose of each treatment in the study. Thirty-six of the patients were evaluable for the secondary endpoints. At a median follow-up of 27.6 months (interquartile range, 25.1-28.2), there was no clinical progression and all patients remained alive by the data cut-off date.

The CR rate with undetectable MRD at the start of Cycle 16 was 38% (95% CI, 22-55), missing the primary endpoint of the study. But, in particular, the rate of CR fell from 14% in cycle 8% to 35% in cycle 16% and was still 38% in cycle 25. It was also notable, according to the authors of the study, that those who achieved CR by cycle 8 all had IGHV– non-mutated disease and 5 of them have TP53 aberration.

Acalabrutinib with venetoclax and obinutuzumab achieved an ORR of 100% in the study, the best CR rate being 46%, and this result was independent of IGHV mutation status or the presence of TP53 aberrations.

In the subgroup of patients with undetectable MRM in both peripheral blood and bone marrow, the response status did not appear to have an impact on the undetectability rate, which was 92% in the peripheral blood and 86% in the bone marrow. In addition, in all mutational subgroups, the rate of MRD undetectability in blood and bone marrow was similar.

Adverse effects were observed in all patients in the study, but were mainly of low grade. No AEs were considered to be treatment-related and no deaths were caused by AEs. One patient in the study discontinued treatment due to a higher grade AE.

Grade 1/2 hematologic AEs were most commonly neutropenia (41%), thrombocytopenia (54%) and anemia (54%). Low-grade non-haematologic AEs were most commonly fatigue (86%), headache (73%), and bruising (59%).

The most common grade 3/4 hematologic AE was neutropenia, which occurred in 43% of patients. the most common non-haematologic AEs included hyperglycemia and hypophosphatemia, which occurred in 8% of patients each.

“We have learned since we first designed the study that getting an undetectable MRD is a better predictor of long-term PFS than getting a CR from a patient. Therefore, in retrospect, the primary endpoint was not optimal. Our triple therapy achieved one of the highest bone marrow uMRD levels ever reported [86%] despite the fact that our population has been enriched with high-risk patients TP53-CLL aberrant, ”Davids explained. “This suggests that the responses with this time-limited therapy are likely to be very durable. Additionally, the tolerability of this triple therapy was excellent, suggesting that it could be a regimen that could be used on a large population of patients with CLL, including those who are older and / or have other medical co-morbidities.

In about 780 patients with previously untreated CLL. The primary endpoint of the study is progression-free survival.

“The phase 3 CL-311 study comparing AVO versus AV versus chemoimmunotherapy is now fully established. This recording study is potentially labeling for the AVO triplet and / or the AV doublet. We are also about to open a global phase 3 study called “MAJIC”, which will compare the AV to VO doublet, with both arms having an MRD-guided therapy duration. MAJIC will help define the optimal combination partner for venetoclax for the initial treatment of CLL, ”Davids said.

Reference:

1. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as first-line treatment for chronic lymphocytic leukemia: a single-arm, open-label phase 2 study. Lancet Oncol. 2021; 22 (10): 1391-1402. doi: 10.1016 / S1470-2045 (21) 00455-1

2. Byrd JC, Hillmen P, Ghia P, et al. First results of a comparative trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2021; 39 (suppl 15): 7500. doi: 10.1200 / JCO.2021.39.15_suppl.7500

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