Venetoclax With EPOCH-R Appears Safe in Aggressive B-Cell Lymphoma

Venetoclax with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (Rituxan; EPOCH-R) showed an acceptable safety profile and preliminary activity in patients with aggressive B-cell lymphoma, according to a results of a phase 1 study published in the Lancet Hematology.

Currently, dose-adjusted EPOCH-R is a frontline treatment for aggressive B-cell lymphomas. Approximately two-thirds of patients achieve remission with initiation chemoimmunotherapy. However, high-risk clinical and biological features predict an adverse outcome with standard therapy for many patients. This highlights a need for improved first-line treatments. One such factor is the genetic rearrangement or overexpression of the anti-apoptotic protein BCL-2, which is associated with a suboptimal response to front-line chemoimmunotherapy. Venetoclax is an oral inhibitor of BCL-2 that is approved by the FDA for chronic lymphocytic leukemia and has been studied in combination with chemotherapy in non-Hodgkin lymphomas, including diffuse large B-cell lymphoma.

The phase 1 study (NCT03036904) has an actual enrollment of 31 participants. Primary end points include the determination of maximal tolerated dose and dose limiting toxicities. Secondary end points include incidence and severity of adverse events, overall response rate, complete response rate, event-free survival, progression-free survival, and overall survival.

During the study, all patients received 6, 21-day cycles of the experimental combination. Venetoclax was administered on days 1 through 10, with the exception of cycle 1, where it was started on day 3 and continued through day 12. Three dose levels of venetoclax were tested: 400 mg, 600 mg, and 800 mg.

Between February 2017 and June 2019, 34 patients were screened for eligibility and 31 were enrolled. Thirty went on to receive the experimental combination and 19 completed all 6 cycles. Reasons for withdrawal included withdrawal of consent (5), persistent cytopenias (3), intracranial hemorrhage (1), chronic back pain (1), and death due to sepsis (1).

The median age of patients was 64 (range, 51.6-69.4), 50% were female, 80% were non-Hispanic, and 77% were white. Ann Arbor stages included II (23%), III (20%), and IV (57%). One extranodal site was seen in 53% of patients and 57% had high-intermediate or high prognoses. Diagnoses included double-hit lymphoma (50%), diffuse large B-cell lymphoma not otherwise specified (30%), primary mediastinal large B-cell lymphoma (7%), high-grade B-cell lymphoma not otherwise specified (7%), and transformed indolent non-Hodgkin lymphoma (7%). Rearrangements included MYC (60%), BCL-2 (47%), MYC and BCL-2 (17%), MYCand BCL-6 (17%), and MYC, BCL-2, and BCL-6 (17%). Immunohistochemistry expressions included MYC (57%), BCL-2 (73%), and MYC and BCL-2 (40%).

The ORR was 96.7% (95% CI, 82.8-99.9), and the complete response rate was 93.8% (95% CI, 77.9-99.2). Additionally, 1 partial response was observed. The estimated 2-year PFS and EFS were both 83% (95% CI, 63.8-92.5). The estimated 2-year OS was 89.9% (95% CI, 71.8-96.6). The 12-month EFS was 86.4% (95% CI, 67.7-94.7%). Five patients had a progression-free survival event and 3 patients died.

In patients with double-hit lymphoma, the ORR was 93.3% (95% CI, 68.1-99.8), with a complete response rate of 86.7% (95% CI, 59.5-98.3). The estimated 2-year PFS and EFS were both 65% (95% CI, 35.1-83.7). The estimated 2-year OS was 79.4% (95% CI, 48.8-92.9).

No dose-limiting toxicities were observed at dose levels 1 or 2. At dose level 2, 1 of the 6 patients (17%), had a dose-limiting toxicity of grade 4 thrombocytopenia. The maximum tolerated dose was 800 mg for 10 days. Six-hundred milligrams was selected as the recommended phase 2 dose due to better tolerability throughout the entire treatment duration.

One grade 5 incidence of sepsis was reported. Grade 4 adverse events included lymphocyte count decrease (3%), platelet count decrease (53%), white blood cell count decrease (67%), neutrophil count decrease (67%), hypokalemia (7%), and nausea (3%).

“The addition of venetoclax to dose-adjusted EPOCH-R or R-CHOP in patients with double-hit lymphoma and double-expressor lymphoma is now being evaluated in Alliance 051701, a randomized phase 2/3 trial (NCT03984448). Although it will be necessary to minimize toxicity and maximize the tolerability of this regimen, the encouraging results in our phase 1 trial, particularly in patients with double-hit lymphoma and double-expressor lymphoma, indicate that venetoclax plus dose-adjusted EPOCH-R is a combination therapy that merits further investigation,” wrote study authors.

_REFERENCE:

_{Rutherford S, Abramson J, Bartlett N, 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 Haematol2021;8:e818–27 doi: 10.1016/S2352-3026(21)00273-8.}