Venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) led to high rates of durable complete responses (CRs) in patients with Richter syndrome (RS), according to a recent study in Blood. The study reports the highest CR rate and longest median overall survival (OS) in patients with RS to date and supports the use of VR-EPOCH with close monitoring in clinical practice, given that no effective standard treatment exists for this patient population.
Researchers enrolled patients with RS, defined as a confirmed chronic lymphocytic leukemia (CLL) diagnosis and biopsy-proven diffuse large B-cell lymphoma. Patients were treated with R-EPOCH for one cycle. After count recovery, patients then received accelerated inpatient venetoclax ramp-up, which consisted of a 20 mg initial dose of venetoclax and daily escalating doses of 50 mg, 100 mg, 200 mg, and 400 mg. The researchers performed close monitoring of patients for tumor lysis syndrome (TLS).
After patients received the maximum venetoclax dose, they subsequently received up to five cycles of VR-EPOCH
in 21-day intervals. Responding patients were eligible to come off the study to receive cellular therapy or maintenance therapy with 400 mg of continuous daily venetoclax. All patients received granulocyte colony-stimulating factor and prophylaxis against Pneumocystis jiroveci pneumonia and herpes viruses.
The multisite study enrolled a total of 27 patients (median age = 63 years). Approximately 42% of patients had CLL with TP53 aberrant disease and 52% of patients had complex karyotype. Overall, patients received a median of one prior therapy for CLL, but some patients had received up to seven prior therapies for the disease. More than half (52%) of patients had previously received a novel therapy agent. More than one in five patients (22%) were previously untreated for CLL, while two patients received prior treatment for RS.
Approximately 65% of patients (n=20) achieved CR, which was the study’s primary endpoint. The best overall response rate (ORR) was 80% (n=16), which included three evaluable patients with partial response. The CR rate in all patients who received any study treatment was 50% (n=13), while the ORR in this group of patients was 62% (n=16).
A CR was achieved in 56% of evaluable patients who had progressed on ibrutinib (n=5) and both patients who progressed to RS on venetoclax. Response was achieved in seven of the nine known clonally related patients. Undetectable measurable residual disease (MRD) for CLL was achieved in 11 of the 12 patients who achieved CR and had a bone marrow biopsy.
The median progression-free survival (PFS) over the median follow-up period of 17 months was 10.1 months. Additionally, the median OS over this period was 19.6 months. The median PFS was significantly shorter in patients with complex karyotype versus patients without (3.1 vs. 19.6 months, respectively; p=0.015). The researchers noted that these findings suggest “a particular need to explore alternative therapeutic options for this group.”
Around half of patients who were considered candidates for cellular therapies at study entry later underwent allogeneic transplant (n=8) or chimeric antigen receptor (CAR) T-cell therapy (n=1). The researchers explained that this suggests VR-EPOCH, when used as a bridge to cellular therapies, could be a curative strategy for a subset of patients.
The most frequently reported adverse events with the study therapy were hematologic in nature and included grade III and higher neutropenia (65%), grade III anemia (62%), and grade III and higher thrombocytopenia (50%). There were no opportunistic infections during the study period. All patients who received venetoclax were safely ramped up to 400 mg in five days without TLS.
While the study population was relatively small, the researchers stated that it represents one of the largest prospective clinical trials focused specifically on RS. The investigators noted they recently created an expansion cohort to examine the effects of venetoclax plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in these patients. Additionally, the researchers suggested a future study may be needed to compare the efficacy and safety of venetoclax plus chemoimmunotherapy versus chemoimmunotherapy alone in patients with RS.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Davids MS, Rogers KA, Tyekucheva S, et al. Venetoclax plus dose-adjusted R-EPOCH (VR-EPOCH) for Richter’s syndrome [published online ahead of print, 2021 Nov 17]. Blood. doi: 10.1182/blood.2021011386.
Perspectives
Patients with CLL have experienced improved outcomes because of significant advances in available treatments during the past decade. However, for the 5% of patients whose disease transforms into diffuse large B-cell lymphoma (DLBCL), commonly referred to as Richter syndrome (RS), outcomes remain dismal and there is no established standard of care. This study appropriately addresses this unmet need by combining venetoclax, a “tried-and-true” anti-CLL agent, with dose-adjusted (DA) EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab), a pharmacodynamically adjusted anthracycline-based chemotherapy regimen that has been used successfully in the treatment of subsets of high-grade B-cell lymphomas.
The trial demonstrated the feasibility of combining a BCL2 inhibitor (venetoclax) with cytotoxic chemotherapy. The response rates were far superior to what has been previously reported in RS, yielding a median OS of 19.6 months, in comparison to the expected OS of six months with traditional cytotoxic chemotherapy. Although there was a high incidence of neutropenic fever (38%), there were no deaths associated with the addition of venetoclax to DA-EPOCH-R.
These findings contrast with the A051701 study,1 which showed a 17% mortality rate in the venetoclax plus DA-EPOCH-R arm for patients with double-hit, high-grade B-cell lymphoma. The cumulative dose of venetoclax used in the Davids, et al. study was 4 g per cycle, whereas it was 2 g per cycle in the A051701 study. Unfortunately, the reported excess mortality in A051701 raises concerns in evaluating this regimen further in RS. Alternatively, the venetoclax plus R-CHOP study proposed by Davids, et al. may provide a less toxic approach.
This study showed that a rapid ramp-up schedule for venetoclax is feasible once there is initial debulking of
disease. Usual ramp-up for venetoclax takes five weeks because of the risk for TLS, and it is cumbersome on patients and providers. In this study, after the initial cycle of DA-EPOCH-R, patients underwent a rapid five-day
ramp-up to the usual 400 mg/day dosing, without any occurrence of TLS. Evaluation of a similar ramp-up
schedule for venetoclax after usual debulking with anti-CD20 monoclonal antibodies in CLL is underway and will best inform the field on this approach.
Alan Skarbnik, MD
Novant Health Cancer Institute
Charlotte, North Carolina
Dr. Skarbnik has received honoraria for consulting and speakers’ bureau from AbbVie, AstraZeneca, ADC Therapeutics, BeiGene, Celgene, Epizyme, Genentech, Jazz Pharmaceuticals, Janssen, Kite Pharma, Lilly Oncology, Novartis, Pharmacyclics, MorphoSys, Genmab, and TG Therapeutics.
Reference
- Abramson JS, Ruppert AS, Giri S, et al. Randomized phase II/III study of DA-EPOCH-R +/- venetoclax in previously untreated double hit lymphoma: initial results from alliance A051701. Abstract #523. Presented at the 2021 American Society of Hematology Annual Meeting, December 12, 2021.