CONTRALTO: Evaluating a Chemotherapy-Free Approach With Venetoclax in Relapsed/Refractory Follicular Lymphoma

A chemotherapy-free approach comprising venetoclax and rituximab (VEN+R) showed modest efficacy in the treatment of patients with relapsed/refractory follicular lymphoma and was outperformed by combinations of bendamustine and rituximab (BR) and venetoclax and BR, according to findings published in Blood.

Although the study authors, led by Pier Luigi Zinzani, MD, PhD, of the University of Bologna in Italy, reported a higher incidence of adverse events (AEs) in the venetoclax-containing arms, they noted that a chemotherapy-free approach such as VEN+R would offer a potentially safer treatment option in the earlier-line setting or for patients who are frail and cannot tolerate chemotherapy.

This open-label, multicenter, phase II study enrolled patients with relapsed/refractory follicular lymphoma into three arms:

  • arm A: VEN+R (n=52)
  • arm B: VEN+BR (n=51)
  • arm C: BR only (n=51)

Treatment in the chemotherapy-free arm consisted of venetoclax 800 mg/day and rituximab 375 mg/m2 on days one, eight, 15, and 22 of cycle one and day one of cycles four, six, eight, 10, and 12. In chemotherapy-containing arms B and C, patients received bendamustine 90 mg/m2 on days one and two of each treatment cycle and rituximab 375 mg/m2 on day one, plus a run-in phase of venetoclax 600 mg/day then 800 mg/day in arm B. Responses were assessed via positron emission tomography at six to eight weeks following day one of treatment cycle six.

At baseline, the median ages were 63 years in arm A, 66 years in arm B, and 61 years in arm C. Nearly or more than half of patients in each arm were older than 65.

At the primary response assessment, the complete metabolic response/complete response (CMR/CR) rates were 75% with VEN+BR and 69% with BR, compared with 17% in patients who received VEN+R. At one-year follow-up, CMR/CR rates remained lower in the chemotherapy-free arm, compared with the bendamustine-containing arms: 19% with VEN+R versus 43% with VEN+BR and 51% with BR.

The authors noted, however, that most patients who received VEN+R had advanced stage disease, were refractory to last treatment, or were heavily pretreated, and approximately one-third were refractory to rituximab. “Responding patients had deep and sustained responses, similar to those receiving [bendamustine]-containing regimens,” they wrote, adding that patients receiving VEN+R who were nonrefractory to last treatment had superior response rates and measurable residual disease negativity rates, compared the total arm A population.

Regarding safety, most patients in arm A (98%) and all patients in the VEN+BR and BR-only arms experienced at least one AE, and the authors reported that more patients in the VEN+BR treatment group had at least one serious AE. Rates of grade 3/4 AEs were 51.9% for arm A, 93.9% for arm B, and 60.0% for arm C.

There were no clinical tumor lysis syndrome (TLS) events in this study, but four patients developed grade 3/4 laboratory TLS (in arms A and B), and all patients eventually restarted their assigned therapy.

Three patients in arm A, 20 in arm B, and two in arm C experienced AEs that led to treatment discontinuation. Overall toxicity was higher with the VEN+BR approach, and a greater number of hematologic toxicities in this arm led to more dose reductions or treatment discontinuation in patients treated with VEN+BR versus BR only.

“Only 27% of patients achieved ≥90% venetoclax dose intensity in the VEN+BR arm, showing the limited tolerability of this regimen at the given dose and schedule,” the investigators wrote. They also noted that, despite lower BR exposure in arms B and C, similar efficacy outcomes were observed. “Further investigation is needed to determine the optimal dose and schedule of BR in combination with venetoclax [to] maximize efficacy while minimizing toxicity.”

According to the investigators, a limitation of the study’s protocol included the lack of standardized and mandatory guidance regarding dose reduction and discontinuation. Instead, doses in this study were modified at the discretion of the investigator and at a higher rate than a historical comparator.

Study authors report relationships with Genentech and AbbVie, which sponsored this trial.


Zinzani PL, Flinn IW, Yuen SLS, et al. Venetoclax-rituximab with or without bendamustine vs bendamustine-rituximab in relapsed/refractory follicular lymphoma. Blood. 2020;136(23):2628-2637.