Frontline induction treatment with ibrutinib (Imbruvica) and rituximab (Rituxan) followed by rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) for young patients with mantle cell lymphoma (MCL) showed promising clinical activity and maintained a tolerable safety profile, according to results from the phase 2 WINDOW-1 trial (NCT02427620) published in Lancet Oncology.

Part A of the trial showed that patients (n = 131) had an overall response rate (ORR) of 98% (95% CI, 95%-100%), which included a complete response (CR) rate of 87% (95% CI, 80%-92%) and a partial response (PR) rate of 11% (95% CI, 7%-18%).

“A chemotherapy­free ibrutinib-rituximab induction followed by short course of consolidative chemotherapy with R­HCVAD and methotrexate-cytarabine is a feasible and active frontline treatment option for young patients with mantle cell lymphoma,” the investigators wrote.

Eligibility for this single center, single­arm trial required patients to be aged 65 years or younger and with a serum bilirubin of less than 1.5 mg/dL, creatinine clearance of 30 mL/min or more, an ECOG performance status of 2 or less, and cardiac ejection fraction of 50% or more.

Part A was the induction portion of the trial in which patients received a combination of ibrutinib at 560 mg orally given daily with rituximab at 375 mg/m2 intravenously once weekly during the first 28-day cycle, then given on day 1 of cycles 3 through 12 thereafter. Induction was administered for 12 cycles or until complete response, response plateau, disease progression, unacceptable toxicity, or consent withdrawal.

Part B included short­course R­HCVAD, which included intravenous treatment with rituximab at 375 mg/m2 on day 1, cyclophosphamide at 300 mg/m2 every 12 hours for 6 doses on days 2 to 4, mesna (Mesnex) at 600 mg/m2 24 h continuous infusion on days 2 and 3, vincristine at 1.4 mg/m2 on day 5, doxorubicin 50 mg/m2 per day 1 day after last dose of cyclophosphamide, and oral or intravenous dexamethasone at 40 mg on days 1 to 4.

ORR after Part A, defined as CRs or PRs, was the primary end point of the study. Secondary end points included progression­free survival (PFS), overall survival (OS), CR, duration of response, and toxicities in both parts.

The study enrolled patients with a median age of 56 years between June 12, 2015, and December 6, 2018. Most patients in the study population were male (79%), White (92%), and all but 1 patient had an ECOG performance status of 1 or less (99%). Thirty-one percent of patients had low-risk disease, 33% had intermediate-risk disease, and 36% had high-risk disease measured via biological MIPI score.

For part A, the 16-week ORR was 89% (95% CI, 83%-94%) with a CR rate of 14% (95% CI, 8%-21%). The median time to CR was 5 months, and response rates were similar between high-risk and low-risk patients.

In part B, the best ORR was 90% (95% CI, 84%-95%), which included a CR rate of 89% (95% CI, 83%-94%) and a PR rate of 1.0% (95% CI, 0.2%-4.2%). A CR by investigator assessment was observed in 99% of evaluable patients.

Both median PFS and median OS were not reached after a median follow-up of 42 months. Three-year PFS and 3-year OS rates were 79% (95% CI, 70%-85%) and 95% (95% CI, 89%-98%), respectively. The median duration of response was also not reached.

Most adverse effects (AEs) observed in the WINDOW-1 trial were grade 1 or 2. The most common grade 3/4 hematological AE in part A was lymphocytopenia, which was seen in 14% of patients. Common grade 3/4 non­hematological AEs included skin rash (12%), infections (8%), and fatigue (8%).

In part B, common grade 3/4 hematological AEs were lymphocytopenia (73%), leukocytopenia (32%), thrombocytopenia (30%), neutropenia (20%), and anemia (17%). Common grade 3/4 non-hematological AEs included fatigue (19%), elevated liver enzymes (11%), and myalgia (9%).

“Randomised studies comparing standard chemoimmunotherapy with BTK inhibitor­based therapies will establish the efficacy and safety of these approaches in patients with mantle cell lymphoma,” the investigators concluded.

https://www.cancernetwork.com/view/induction-ibrutinib-rituximab-plus-r-hcvad-yields-positive-frontline-activity-in-mantle-cell-lymphoma