The following article features coverage from the 2021 American Society of Hematology Annual Meeting. Click here to read more of Cancer Therapy Advisor’s conference coverage.

Adding venetoclax to chemoimmunotherapy results in excess treatment-related deaths in patients with double-hit lymphoma (DHL), a phase 2/3 trial suggests.1

The increased risk of death prompted early closure of the DHL cohort of the trial, said investigator Jeremy S. Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

Dr Abramson presented results from the trial at the 2021 American Society of Hematology (ASH) Annual Meeting.

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The ALLIANCE 051701 trial ( Identifier: NCT03984448) included 66 evaluable adults with previously untreated DHL. Patients were randomly assigned to receive chemoimmunotherapy alone (30 patients) or in combination with venetoclax (36 patients) for up to 6 cycles.

The chemoimmunotherapy regimen was DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab). Patients received venetoclax at 600 mg daily on days 4 to 8 of cycle 1 and on days 1 to 5 of subsequent cycles.

The baseline characteristics were well balanced between the treatment arms. The median age was 66 years (range, 37-79 years) in the control arm and 65 years (range, 41-80 years) in the venetoclax arm. Most patients had stage III/IV disease — 87% in the control arm and 86% in the venetoclax arm.

Treatment was completed per protocol in 70% of patients in the control arm and 49% of those in the venetoclax arm. A majority of patients also received an allowed pre-protocol chemoimmunotherapy cycle — 60% in the control arm and 56% in the venetoclax arm.

Toxicity and On-Treatment Deaths

The most common grade 3 or higher adverse events (in the control and venetoclax arms, respectively) were decreased neutrophil count (77% in both arms), anemia (53% vs 63%), and decreased platelet count (53% vs 60%).

Rates of febrile neutropenia were similar between the control and venetoclax arms —37% and 40%, respectively. Sepsis was more common with venetoclax, occurring in 23% of patients in the venetoclax arm and 13% of those in the control arm.

Dose reductions of any agent were required in 63% of patients in the control arm and 60% of patients in the venetoclax arm. Dose omissions were required in 10% and 29%, respectively.

In the venetoclax arm, there were 6 on-treatment deaths (17.1%) — 4 due to sepsis and 2 due to cardiac arrest. Death on treatment occurred in 1 patient in the control arm (3.3%). The cause of death was dyspnea.

Response and Survival

In the intent-to-treat population, the end-of-treatment overall response rate was 73% in the control arm and 58% in the venetoclax arm. The complete response rates were 66% and 50%, respectively.

At a median follow-up of 7.4 months, the median progression-free survival was not reached in the control arm and was 6.7 months in the venetoclax arm (P =.13).

At a median follow-up of 9.2 months, the median overall survival was not reached in the control arm and was 8.5 months in the venetoclax arm (P =.004).


The results of this trial may not mean that venetoclax has no role in DHL, according to Dr Abramson.

He noted that a phase 1 trial showed positive results with venetoclax plus DA-EPOCH-R.2 However, that trial was smaller and enrolled younger, less sick patients than the phase 2/3 trial, which could potentially explain the different outcomes of the studies.

In fact, a multivariable analysis of the phase 2/3 data showed that advancing age was associated with inferior outcomes, Dr Abramson noted.

He said another factor to consider is that the amount of dose reductions and omissions required in the phase 2/3 trial may have meant that patients in both arms were suboptimally treated.

Dr Abramson also pointed out that the rates of neutropenia and febrile neutropenia were similar between the treatment arms. He said the excess infectious-related mortality in the venetoclax arm may be related to a longer duration of neutropenia in those patients, but that theory would require further investigation.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Read more of Cancer Therapy Advisor’s coverage of the ASH 2021 meeting by visiting the conference page.


  1. 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. Presented at ASH 2021; December 11-14, 2021. Abstract 523.
  2. Rutherford SC, Abramson JS, Bartlett NL, 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;8(11):e818-e827. doi:10.1016/S2352-3026(21)00273-8