MRD Could Guide Venetoclax/Ibrutinib Duration in Previously Untreated, Intermediate-Risk CLL

Anne-Sophie Michallet, MD, PhD

The duration of treatment with the combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) could be guided by both toxicities and minimal residual disease (MRD) kinetics in previously untreated patients with intermediate-risk chronic lymphocytic leukemia (CLL), according to interim results from the phase 2 ERADIC trial (NCT04010968) presented at the 2023 iwCLL Annual Meeting.¹

Findings from the study, which randomly assigned patients to receive venetoclax plus ibrutinib or the combination of fludarabine, cyclophosphamide, and rituximab (Rituxan; [FCR]), showed that at month 9, venetoclax/ibrutinib (n = 54) elicited a complete response (CR)/CR with incomplete hematologic recovery (CRi) rate of 66% and a partial response (PR) rate of 33%. In the FCR arm (n = 56), the CR/CRi and PR rates were 56% and 39%, respectively.

However, at month 9, 33% of patients in the venetoclax/ibrutinib arm experienced undetectable MRD in the bone marrow at 10-4 compared with 59.6% of patients in the FCR arm. When evaluating MRD in peripheral blood in the venetoclax/ibrutinib cohort, the undetectable MRD rates at 9 months (n = 49), 15 months (n = 48), and 21 months (n = 43) were 52%, 70%, and 67%, respectively. For the FCR cohort, at 9 months (n = 50), 15 months (n = 48), and 21 months (n = 44), the peripheral blood undetectable MRD rates were 68%, 65%, and 52%, respectively.

“The results of MRD kinetics suggest that a 9-month course of [the] ibrutinib/venetoclax combination is too short to achieve a very good immunophenotypic response in terms of MRD,” presenting study author Anne-Sophie Michallet, MD, PhD, said. Michallet is the head of the Hematology Department at Léon Bérard Cancer Center in Lyon, France.

ERADIC enrolled patients with treatment-naïve, intermediate-risk CLL who did not have a contraindication to either venetoclax/ibrutinib or FCR. Intermediate-risk disease was defined as unmutated IGHV, 11q deletions, and/or a complex karyotype, as well as no TP53 abnormalities.

Patients were randomly assigned to receive FCR once every 4 weeks for 6 cycles, or venetoclax plus ibrutinib. In the experimental arm, patients received lead-in treatment with ibrutinib monotherapy at 420 mg per day for the first 3 months, followed by 400 mg of venetoclax plus 420 mg of ibrutinib per day for the next 6 months. Patients with bone marrow MRD of less than 0.01% continued with venetoclax for 6 additional months, ending after month 15, and those with MRD of at least 0.01% continued receiving the combination for 18 months, ending after month 27.

The study’s primary end point is the rate of patients with bone marrow MRD of less than 0.01% at month 27.

The trial enrolled 120 patients between September 2019 and February 2021. The median follow-up at this analysis was 29.7 months (range, 25.3-32.8). The median age was 59 years (range, 34-72) in the FCR arm (n = 60) and 61 years (range, 34-74) in the venetoclax/ibrutinib arm (n = 60). The male-to-female ratio was 2.57 in the FCR arm and 2.84 in the venetoclax/ibrutinib arm. In the FCR arm, patients were Binet stage A with active disease (15%), stage B with active disease (64%), or stage C (21%). Those rates were 9%, 59%, and 32%, respectively, in the venetoclax/ibrutinib arm.

Ninety-eight percent of patients in the FCR arm and all patients in the venetoclax/ibrutinib arm had unmutated IGHV. Other cytogenetic characteristics included 11q deletions (20% and 24% in the FCR and venetoclax/ibrutinib arms, respectively), a complex karyotype with at least 3 abnormalities (16% and 15%), and a complex karyotype with more than 5 abnormalities (2% and 5%).

In the FCR arm, all patients were evaluated at month 9; these patients all received a minimum of 4 cycles of FCR, and 90% received all 6 cycles. Evaluation ended after month 9 for 4 patients due to death related to acute myeloid leukemia (AML) at month 13 (n = 1), progression at month 9 (n = 1), and progression at month 15 (n = 2).

In the venetoclax/ibrutinib arm, 6 patients were not evaluable at month 9 due to investigator decision at cycle 1, day 1 (n = 1), ischemic stroke at month 1 (n = 1), hemolysis at month 1 (n = 1) tumor lysis syndrome (TLS) at month 3 (n = 1), hepatitis at month 3 (n = 1), and sudden death at month 7 (n = 1). Evaluation ended after month 9 for 2 additional patients due to sudden death at month 12 (n = 1) and colorectal cancer (CRC) at month 13 (n = 1). Ibrutinib doses were reduced in 3 patients and discontinued in 4 patients due to cardiac adverse effects (AEs). Four patients permanently discontinued venetoclax due to digestive toxicities and grade 4 neutropenia.

Among the 20 patients in the venetoclax/ibrutinib arm with undetectable bone marrow MRD at month 9, 16 patients discontinued treatment at month 15 per study protocol. Two patients discontinued at month 21, and 2 additional patients in PR were continuing treatment at the discretion of the investigator. Notably, 2 patients converted to detectable MRD at month 27.

In 21 patients in the venetoclax/ibrutinib arm with detected bone marrow MRD at month 9 who continued treatment, 8 patients converted to undetected bone marrow MRD at month 15. One of these patients had detectable MRD again at month 21.

Regarding safety, the rates of serious AEs for cardiovascular disorders, infestations/infections, myelosuppression, and TLS were 3%, 40%, 22%, and 10%, respectively, for patients treated in the FCR arm. In the venetoclax/ibrutinib arm, those rates were 23%, 27%, 3%, and 16%, respectively.

Grade 3 or 4 serious AEs occurred in 33 patients in the FCR arm and 30 patients in the venetoclax/ibrutinib arm. Serious AEs included TLS (FCR, n = 3; venetoclax/ibrutinib, n = 5), hyponatremia (n = 1; n = 0), hypokalemia (n = 1; n = 1), infusion rate reaction (n = 2; n = 0), COVID-19 (n = 4; n = 4), infection (n = 2; n = 0), pneumonia (n = 3; n = 2), pyrexia (n = 3; n = 1), bursitis (n = 0; n = 1), febrile neutropenia (n = 5; n = 0), hemolytic anemia (n = 1; n = 1), neutropenia (n = 0; n = 1), thrombocytopenia (n = 1; n = 0), syncope (n = 0; n = 1) angina (n = 1; n = 0), acute coronary syndrome (n = 0; n = 1), atrial fibrillation (n = 0; n = 2), ischemic stroke (n = 0; n = 1), sudden death (n = 0; n = 2), diarrhea (n = 0; n = 1), vomiting (n = 1; n = 0), cytolysis (n = 0; n = 1), acute renal failure (n = 1; n = 2); chest pain (n = 1; n = 0) osteoporotic fracture (n = 0; n = 1), cognitive disorders (n = 1; n = 0), myelodysplastic syndrome (n = 1; n = 0), AML (n = 1; n = 0), CRC (n = 0; n = 1), and basal cell carcinoma (n = 0; n = 1).

Two deaths occurred in the FCR arm due to AML (n = 1) and septic shock (n = 1). Three deaths were reported in the venetoclax/ibrutinib arm due to sudden death (n = 2) and COVID-19 (n = 1).

“Toxicity remains an important parameter in both treatment arms that should be taken into account when determining whether treatment should be continued because of detectable bone marrow MRD at month 9,” Michallet said.

She concluded by saying the upcoming data for the primary end point of MRD analysis at month 27 will be crucial for determining the best treatment strategy.

Disclosures: Michallet reported serving on advisory boards for receiving honoraria from Janssen, AbbVie, and AstraZeneca.

Reference

Quinquenel A, Letestu R, Legarff-Tavernier M, et al. Minimal residual disease-guided combination of ibrutinib and venetoclax compared to FCR in untreated patients with CLL of intermediate risk: interim results of MRD kinetics in the ERADIC trial from the FILO group. Presented at: 2023 iwCLL Annual Meeting; October 6-9, 2023; Boston, MA. Abstract 1547411.