Ibrutinib/rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial
Mené sur 131 patients atteints d'un lymphome à cellules du manteau et âgés de moins de 65 ans (âge médian : 56 ans), cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale, et la toxicité d'un traitement d'induction combinant ibrutinib et rituximab dispensé avant une chimio-immunothérapie de première ligne de type R-HCVAD (rituximab plus cyclophosphamide, vincristine, doxorubicine et dexaméthasone administrés de façon hyper fractionnée)
Background : Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety ofibrutinib–rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin,and dexamethasone (R-HCVAD) alternating with methotrexate–cytarabine in previously untreated patients with mantle cell lymphoma.
Methods : We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and hadserum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more,Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejectionfraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib–rituximabinduction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3–12). As soon as patientshad a complete response, four cycles of R-HCVAD alternating with methotrexate–cytarabine(part B) were administered. If they did not have a complete response or had a partialresponse, patients received two cycles of R-HCVAD alternating with methotrexate–cytarabinefollowed by reassessment, up to a total of eight cycles. Patients were taken off studyif they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treatbasis. This trial is registered with ClinicalTrials.gov, number NCT02427620.
Findings : 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49–60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%,95% CI 95–100) of 131 patients had an overall response in part A. The most commongrade 3–4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]),thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part Aand lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]),and neutropenia (26 [20%]) in part B. There was one on-study death, which was notdeemed to be treatment-related.
Interpretation : Induction with ibrutinib–rituximab in the frontline treatment of young patients withmantle cell lymphoma is active and safe. This approach allowed minimisation of thenumber of chemotherapy cycles, thereby reducing the adverse events associated withchemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitorsinto the frontline setting might obviate the need for chemotherapy altogether in patientswith mantle cell lymphoma.
Funding
The Lancet Oncology , résumé, 2021