This article is more than 5 years old. Information may no longer be current.
Venetoclax plus R-CHOP improves outcomes among certain patients with diffuse large B-cell lymphoma
Click Here to Manage Email Alerts
SAN DIEGO — The addition of venetoclax to first-line R-CHOP chemotherapy improved outcomes among patients with BCL2-positive diffuse large B-cell lymphoma, according to results of the phase 2 CAVALLI study presented at ASH Annual Meeting and Exposition.
Patients who received the BCL2 inhibitor venetoclax (Venclexta; AbbVie, Genentech) experienced higher rates of cytopenia, infection and febrile neutropenia than patients in a matched controls who received chemotherapy alone.
However, the data support further exploration of first-line venetoclax plus R-CHOP in this high-risk population, including those with double-hit disease, Franck Morschhauser, MD, professor of hematology at Centre Hospitalier Universitaire in France, and colleagues concluded.
BCL2 overexpression — common in blood cancers — results in evasion of apoptosis.
Half of patients with DLBCL overexpress the BCL2 protein. Thirty percent overexpress BCL2 and MYC, known as double-expressor disease. An estimated 5% to 10% have BCL2 and MYC translocations, known as double-hit lymphoma.
All of these factors are associated with poor prognosis.
Based on preclinical and early clinical data, Morschhauser and colleagues hypothesized that the addition of venetoclax to chemotherapy would improve outcomes for patients with DLBCL.
The ongoing single-arm, multicenter phase 2 component of the CAVALLI study evaluated venetoclax plus R-CHOP chemotherapy — which consists of cyclophosphamide, doxorubicin, vincristine and prednisone plus rituximab (Rituxan; Genentech, Biogen) — for first-line treatment of DLBCL.
Researchers assessed efficacy outcomes among all 208 evaluable patients, as well as by BCL2 immunohistochemistry status within cell-of-origin subtypes, by BCL2 fluorescence in situ hybridization, and among patients with double-expressor or double-hit disease.
All patients in the CAVALLI study were aged at least 18 years. They all had ECOG performance status of 0 to 2, International Prognostic Index scores of 2 to 5, and at least one measurable lesion greater than 1.5 cm.
All patients received six 3-week cycles of R-CHOP plus venetoclax, which was dosed at 800 mg daily on days 4 to 10 of the first cycle, then 800 mg daily on days 1 to 10 of the second through sixth cycles.
Patients then received two 3-week cycles of 800 mg venetoclax administered on days 1 through 10 plus rituximab on day 1.
Response assessed by PET/CT 6 to 8 weeks after the last rituximab dose served as the primary endpoint. PFS and safety served as secondary endpoints.
Researchers aimed to compare outcomes from this cohort with a matched patient population from the phase 3 GOYA study who received R-CHOP alone (n = 564).
Investigators used pretreatment tumor samples from the CAVALLI and GOYA trials to perform biomarker analyses. These included BCL2 immunohistochemistry (cutoff, 50% medium/high expression), MYC immunohistochemistry assay (cutoff, 40% signal), BCL2 and MYC by fluorescence in situ hybridization, and the COO assay (Nanostring).
Patient characteristics were similar between the CAVALLI and GOYA trials except for higher percentages of patients with Ann Arbor stage IV disease (65.4% vs. 47.1%) and patients with BCL2 immunohistochemistry-positive disease (57.7% vs. 50%) in the CAVALLI trial.
The end-of-treatment complete response rate among all patients did not differ significantly between the CAVALLI and GOYA cohorts (69.2% vs. 62.8%).
However, the addition of venetoclax improved response among BCL2-positive subgroups (BCL2 FISH-positive, 70% vs. 47.5%; double-hit, 71.4% vs. 25%).
Median follow-up was 20 months in the CAVALLI trial and 57 months in the GOYA trial.
PFS comparisons between the CAVALLI and GOYA trials favored venetoclax-treated patients from the CAVALLI trial (HR = 0.67; 95% CI, 0.46-0.97).
After adjustments for baseline covariates, researchers observed even greater PFS benefit for the venetoclax regimen for patients with BCL2 overexpression as determined by immunohistochemistry (HR = 0.52; 95% CI, 0.3-0.93), including those with activated B-cell subtype (HR = 0.43; 95% CI, 0.19-0.94) and germinal center B-cell subtype (HR = 0.41; 95% CI, 0.17-0.95).
Among patients who tested negative for BCL2 overexpression by immunohistochemistry, results showed no PFS benefit with venetoclax for those in the germinal center B-cell subgroup. The activated B-cell subgroup was too small for evaluation.
A higher percentage of patients in the CAVALLI trial than GOYA trial experienced grade 3 to grade 4 adverse events (85% vs. 66%). These included neutropenia (64.9% vs. 38.8%), febrile neutropenia (33.2% vs. 16.3%), anemia (22.1% vs. 8.9%), thrombocytopenia (23.6% vs. 1.6%), infections (22.6% vs. 16%) and leukopenia (10.6% vs. 9.6%).
A lower percentage of adverse events in CAVALLI were fatal (1% vs. 5%).
A higher percentage of patients in CAVALLI required dose interruptions or discontinuation of both venetoclax and R-CHOP.
In CAVALLI, 61% of patients had greater than 90% relative dose intensity of venetoclax and 73.2% had greater than 90% relative dose intensity of doxorubicin and cyclophosphamide. In GOYA, rates were 76.4% for doxorubicin and 77.6% for cyclophosphamide.
Researchers reported no major differences between the intention-to-treat and BCL2-positive subgroups with regard to rate of grade 3/grade 4 adverse events or the relative dose intensity of R-CHOP. – by Mark Leiser
Reference:
Morschhauser F, et al. Abstract 782. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Morschhauser reports consultant/advisory roles with, board of directors roles with, or honoraria from Bristol-Myers Squibb, Celgene, Epizyme, Gilead, Janssen, Roche/Genentech and Servier. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
Back to Top
Jennifer Amengual, MD
I was impressed with the findings of venetoclax in combination with R-CHOP. About 50% of patients with DLBCL have BCL2 overexpression, and nearly 40% have rearrangement of BCL2. Patients harboring BCL2 rearrangements are always challenging to treat. They are often refractory to upfront therapy and generally do not respond well to salvage therapy followed by transplant.
In this study, the complete remission rate among patients with BCL2 rearrangement, including those with double-hit lymphoma, was extraordinarily impressive at 70%. PFS also was prolonged. It will be interesting to see what the readout will be for OS.
This regimen was fairly well tolerated. There were some dose delays and interruptions, but the majority were able to get the recommended dose intensity.
We have had a constant challenge in terms of how to treat double-hit lymphoma patients upfront. The investigators on this study treated 208 patients and compared their cohort to a historical control. The next step may be to perform a head-to-head study and potentially could compare and contrast the effects of venetoclax/R-CHOP to R-EPOCH for double-hit lymphomas. I think the findings of the venetoclax/R-CHOP study are really exciting, and it will be interesting to see how treatment for double-hit lymphomas can be improved from here.
Read more about
Click Here to Manage Email Alerts