Venetoclax Plus R-CHOP Improves Outcomes in BCL2-Positive DLBCL

For the substantial portion of patients with diffuse large B-cell lymphoma (DLBCL) with overexpression of the BCL2 protein, combining the BCL2 inhibitor venetoclax with standard chemotherapy may improve response rates, according to results from the phase II CAVALLI trial. However, patients who received venetoclax experienced a higher rate of adverse events (AEs) compared with a historical control group who received chemotherapy alone.

In the CAVALLI trial, investigators, led by Franck Morschhauser MD, PhD, of Centre Hospitalier Régional Universitaire in Lille, France, studied the safety and efficacy of venetoclax plus rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), then compared these outcomes with controls in the phase III GOYA trial who received R-CHOP alone. (GOYA compared anti-CD20 monoclonal antibody obinutuzumab versus rituximab in addition to CHOP chemotherapy in patients with previously untreated DLBCL).

The present study included 208 adults with DLBCL, an International Prognostic Index score of 2 to 5, an Eastern Cooperative Oncology Group performance status of ≤2, and at least one measurable lesion ≥1.5 cm. Patients were assigned to receive six cycles of R-CHOP plus venetoclax (800 mg on days 4-10 of cycle 1, and days 1-10 of cycles 2-8). Per study protocol, two additional cycles of venetoclax plus rituximab were permitted per physician choice.

CAVALLI participants were matched with 564 patients from the GOYA trial. Patient characteristics were well matched, Dr. Morschhauser noted, except for a larger number of patients with higher-stage disease and BCL2 immunohistochemistry (IHC)- positive disease in the CAVALLI group.

The complete response (CR) rates (primary endpoint) did not differ significantly between the two cohorts: 69.2 percent versus 62.8 percent, respectively (95% CI 0-17.6). However, venetoclax appeared to improve CR rates among patients with BCL2-positive disease and double-hit lymphoma (TABLE).

After a median follow-up of 20 months in the CAVALLI trial, 29 patients had died and six experienced disease progression. These findings suggest that venetoclax improved progression-free survival (PFS) for patients with BCL2 IHC-positive disease, compared with those treated with R-CHOP alone in the GOYA trial (hazard ratio = 0.53; 95% CI 0.30-0.93). There was, however, no PFS benefit observed in BCL2 IHC-negative subgroups.

Each regimen was associated with distinct AE profiles, Dr. Morschhauser said. CAVALLI participants experienced a higher rate of grade 3/4 AEs, compared with GOYA participants: 85 percent (n=176/208) and 66 percent (n=373/574), respectively.

The higher toxicity rate in CAVALLI was driven largely by hematologic events, including (p values not reported):

  • neutropenia: 64.9% vs. 38.8%
  • thrombocytopenia: 23.6% vs. 1.5%
  • anemia: 22.1% vs. 8.9%
  • febrile neutropenia: 33.2% vs. 16.3%
  • infections: 22.6% vs. 16.0%

Infections were all bacterial, with no recorded pneumocystis or fungal infections.

More patients in the CAVALLI trial required dose interruptions or discontinuations of either venetoclax or R-CHOP. The researchers noted, however, that the higher toxicity seen in the venetoclaxtreated patients did not lead to an increase in treatment-related mortality, as the rate of AEs with fatal outcomes was 2 percent in CAVALLI versus 5 percent in GOYA (p value not reported).

The authors concluded that venetoclax added to R-CHOP improved efficacy in patients with BCL2 IHC-positive DLBCL and that these findings support exploration of this combination in high-risk populations of patients with BCL2-positive DLBCL, including those with double-hit lymphoma.

The study was limited by the reliance on a historical cohort and the lack of a comparator arm.

The authors report relationships with Hoffmann-La Roche and AbbVie, which supported the trial.

Reference

Morschhauser F, Feugier P, Flinn IW, et al. Venetoclax plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) improves outcomes in BCL2-positive first-line diffuse large B-cell lymphoma (DLBCL): first safety, efficacy and biomarker analyses from the phase II CAVALLI study. Abstract #782. Presented at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.