The standard front line therapy for B-cell lymphomas is a combination of chemotherapeutic drugs referred to as EPOCH-R. This includes drugs such as etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. However, alterations in genes such as BCL-2 can result in resistance to therapeutic options in B-cell lymphomas. A highly efficient inhibitor, venetoclax is known to selectively inhibit BCL-2. A recent study by Rutherford et al has investigated the efficacy of combining venetoclax with dose-adjusted EPOCH-R as a first line treatment option for aggressive B-cell lymphoma.
A single arm, phase –I clinical study was conducted across seven centers in USA where 30 previously untreated patients (median age 64; IQR 51·6–69·4, ECOG 0-2) diagnosed with aggressive B-cell lymphomas were enrolled for accessing the efficacy of venetoclax with dose adjusted EPOCH-R. venetoclax was administered orally in six cycles of 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle. Additionally, patients received one cycle of dose adjusted EPOCH-R (day1- rituximab 375 mg/m2, day 1-4- etoposide 50 mg/m2, vincristine 0.4 mg/m2 and doxorubicin 10 mg/m2, day 1-5- prednisone 60 mg/m2 twice daily, day 5- cyclophosphamide 750 mg/m2) every three weeks. Patients in subsequent cohort received 600 mg venetoclax once daily for 5 days per cycle. The primary endpoints of this trial were recommended dose of venetoclax for phase-2 along with maximum tolerable dose (MTD) and dose-limited toxicities.
The researchers determined that venetoclax was tolerable at 800 mg for 10 days, the recommended phase 2 dose was established at 600 mg for 5 days, and one patient suffered dose-limited toxicity in cycle one. An overall response rate of 96% was observed in patients (95% CI 82·8–99·9); 28 (93·3% [77·9–99·2]). All the patients responded well to the treatment except one with partial response (3·3% [0·1–17·2]). Safety results were consistent with the known tolerability profile of venetoclax and no new safety concerns were reported during the study. The adverse events (AE) of grade 3-4 included cytopenias (28/30) and febrile neutropenia(19/30), whereas grade 3-4 non-haematological AEs included hypophosphataemia (10/30), hypokalaemia (7/30), and hyperglycaemia (5/30). Serious AEs such as infection (7/10), abdominal pain (3/10), colonic perforation (1/30), and small intestinal obstruction (1/30) were observed in few patients. One patient died due to treatment.
The proposed combination in the phase-1 study showed encouraging results for aggressive B-cell lymphomas patients. Due to high-risk of adverse outcomes in these patients, it is important to further explore these treatment options in phase-II studies.
Sarah C Rutherford, Jeremy S Abramson, Nancy L Bartlett, Stefan K Barta, Nadia Khan, et al. Venetoclax with dose-adjusted EPOCH-R as initial therapy for patients with aggressive B-cell lymphoma: a single-arm, multicentre, phase 1 study. Lancet Haematol. 2021 Nov; 8(11):e818-e827