Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study
Mené sur 34 patients atteints d'un lymphome aggressif à cellules B (âge : 18-80 ans), cet essai de phase I évalue la dose maximale tolérée du vénétoclax en combinaison avec une chimiothérapie de type EPOCH-R à doses ajustées, en traitement de première ligne
Background : Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin,and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. Weaimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma.
Methods : We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18–80 years with histologically confirmed, previouslyuntreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma,high-grade B-cell lymphoma with double-hit or not otherwise specified, or primarymediastinal B-cell lymphoma, with Ann Arbor stage II–IV and Eastern Cooperative OncologyGroup performance status of 0–2. Participants received six cycles of oral venetoclax400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R(one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m2 on day 1, intravenous etoposide 50 mg/m2 on days 1–4, oral prednisone 60 mg/m2 twice daily on days 1–5, intravenous vincristine 0·4 mg/m2 on days 1–4, intravenous cyclophosphamide 750 mg/m2 on day 5, and intravenous doxorubicin 10 mg/m2 on days 1–4). A subsequent cohort received venetoclax 600 mg once daily for 5 daysper cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities,and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. Thistrial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed.
Findings : Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility,and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6–69·4). The maximum tolerated dose was 800 mgfor 10 days and the established recommended phase 2 dose was 600 mg for 5 days dueto tolerability for treatment duration. One (3%) of 30 patients had a dose-limitingtoxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most commongrade 3–4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropeniaoccurred in 19 (63%) patients. Grade 3–4 non-haematological adverse events includedhypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverseevents included infection (n=7) and gastrointestinal toxicities including abdominalpain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). Therewas one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI82·8–99·9); 28 (93·3% [77·9–99·2]) of 30 patients had complete response and one (3·3%[0·1–17·2]) had a partial response.
Interpretation : Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high riskof adverse outcomes, and is worthy of further study. The combination is being investigatedin Alliance 051701 (NCT03984448).
The Lancet Haematology , résumé, 2020