Venetoclax With Rituximab Improves Survival in Relapsed/Refractory CLL

John F. Seymour, MBBS, PhD

Today, we are speaking with John F. Seymour, MBBS, PhD, the director of the department of haematology at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia. Dr. Seymour is the lead author on a paper of the results of the phase III MURANO trial, which studied venetoclax in combination with rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

-Interviewed by Anna Azvolinsky

Cancer Network: First, what are the current standard-of-care options for patients with advanced CLL who have already been treated with at least one therapy?

Dr. Seymour: This is an area that is in a state of flux globally. In North America, ibrutinib has been well established in this setting, and I think is the most commonly used drug in that context. However, in many other parts of the world, chemoimmunotherapy remains the standard in the relapsed/refractory setting, particularly with bendamustine and rituximab, given that ibrutinib is not universally available or reimbursed for that indication.

Cancer Network: Can you tell us about the MURANO trial’s design and the types of patients that were recruited? Were they the average types of patients with relapsed/refractory disease or was there something distinct about the particular patient cohort on this trial?

Dr. Seymour: Sure. The eligibility required a maximum of three prior chemotherapy regimens. Unlike some other relapsed/refractory studies in which the patients could have had an unlimited number of prior treatments, this one was capped at three, although, they did need to have at least one prior chemotherapy-containing regimen. They could have had prior bendamustine, but, as it turns out, that was quite uncommon in the study. Patients with 17p deletions were allowed, but there was varying inclusion of these patients in geographic regions depending upon other therapies that were available. The median age of the patients was about 65 years. About one-quarter of the patients had a 17p deletion, with more than 80% of patients having prior fludarabine exposure-so a fairly standard cohort of patients. Adequate renal function was a requirement for study entry given the hydration and biochemical risk of tumor lysis syndrome with the venetoclax regimen.

Cancer Network: What are the important results of this study?

Dr. Seymour: The most important result, and the primary endpoint, was progression-free survival and the bendamustine/rituximab arm performed somewhat better than expected. Despite a quarter of patients having deletion 17p, the median progression-free survival in the bendamustine/rituximab arm was 17 months. So, the control arm certainly performed adequately. But, the venetoclax/rituximab arm-the investigational arm-was far superior, with a hazard ratio of 0.17 for progression-free survival; the P value for superiority of venetoclax plus rituximab was < .0001. That translated into a 2-year progression-free survival improvement, from 36% in the bendamustine/rituximab control arm to 85% with venetoclax/rituximab, so a very profound improvement in progression-free survival with the investigational arm.

In subset analyses, that magnitude of therapeutic benefit was consistent across all clinical and biological subsets, including those either with or without deletion 17p. In some jurisdictions, some people would not consider bendamustine/rituximab as an appropriate treatment for those with a deletion 17p, but the benefit here of venetoclax was the same, regardless of deletion 17p status. The investigator-assessed progression-free survival benefit was confirmed by an independent review committee where the hazard ratio was pretty much identical, at 0.19. The overall response rate was substantially higher, and the complete remission rate as assessed by the investigators was also higher, at 27% compared with 8% for the bendamustine arm.

Two elements of the trial that are not yet fully mature but are showing very encouraging results are, one, that there was also an improvement in overall survival: the 2-year overall survival rate was 92% compared with 87% (P = .018). Two, there was a very high rate of negativity of minimal residual disease (MRD) in the venetoclax/rituximab arm: 62% of patients were negative for MRD in the venetoclax arm compared with only 13% in the bendamustine/rituximab arm, so it’s likely that this depth of response as reflected by the investigator complete response and the MRD negativity rate is what accounts for the very durable response and the improved overall survival.

Cancer Network: Is there anything notable about the differences in the safety profiles between the two treatment arms?

Dr. Seymour: Yes, there are a few things. The first is that the rate of tumor lysis syndrome that had been a concern in the earlier development of venetoclax studies was quite low here, in this multinational setting: there were no incidences of clinical tumor lysis syndrome and the rate of biochemical tumor lysis was 3% in the venetoclax arm. Notably, a few cases were seen in the bendamustine/rituximab arm. The toxicity profile otherwise was consistent with what had been previously published for the regimen. The rate of grade 3/4 neutropenia was relatively high, nearly 60%, but infections were very infrequent, such that the febrile neutropenia rate was under 4% and the rate of serious infection such as pneumonia was around 5%. So, although the venetoclax arm had a relatively high rate of neutropenia, that did not translate into clinically significant infections throughout the study.

Cancer Network: Do these results suggest that there would be a significant improvement in efficacy in the real-world setting for patients who could be treated with this combination outside of a clinical trial, if this regimen were to be approved by one or several health authorities? Could you put these results in context to other clinical trials in these patients that have been read out recently?

Dr. Seymour: Yes, I do think the results are likely to be generalizable. This study was conducted in 109 sites in 20 countries, so there is very broad input from multiple investigators and clearly the regimen is safely and effectively deliverable in many geographic and healthcare settings. The nature of the population enrolled with the restriction of organ function are quite representative of relapsed/refractory CLL patients, and many practitioners now have very good experience with the package insert with venetoclax, with the weekly, graduated dose ramp-up and the need for hydration, uric acid control, and monitoring for potential tumor lysis. These precautions are now embedded in standard clinical practice, so I think the regimen is likely to be able to be delivered safely and effectively in the real-world setting.

Cancer Network:Thank you so much for joining us today, Dr. Seymour.

Dr. Seymour: A pleasure, thank you.