At the Venclexta (venetoclax) in chronic lymphocytic leukaemia (CLL) meeting in Sydney last month, session chair Professor Stephen Mulligan, Director of Haematology at Laverty Pathology and Senior Staff Specialist Haematologist at Royal North Shore Hospital, Sydney set the bar high from the start. “It’s an exciting time for healthcare professionals who manage patients with CLL. We’re in a position where we can offer patients a chemotherapy-free choice,“ he began. For an international perspective, he introduced the keynote speaker, Peter Hillmen, a Professor of Experimental Haematology and Consultant Haematologist at Leeds Teaching Hospitals in the United Kingdom who shared his thoughts on how clinicians should approach the treatment of relapsed/refractory CLL in 2019 and beyond.

With choice comes more questions

The possibility of a chemotherapy-free future was a sentiment shared by Prof. Hillmen, who began by posing a few questions. “There’s a lot more choice compared to when I first started my career. With the agents now available, will we see a chemotherapy-free future? Will continuous or time-limited therapy be the mainstay of treatment? I think these are some of the questions we are asking ourselves at this point in time,” he stated.

Prof. Hillmen said  that advances in the treatment of CLL were a result of  what we now know about the heterogenous clinical course of disease, which can be explained by differences in tumour proliferation and apoptosis.^1-6 He said the overexpression of B-cell lymphoma 2 (BCL-2) receptors play a crucial role in allowing cancer cells to evade apoptosis.^1-3 “Venetoclax binds selectively to BCL-2, and allows pro-apoptotic proteins previously sequestered by BCL-2 receptors, to initiate apoptosis.”^4-6

Shifting the goal posts in CLL

An early phase 2 trial of venetoclax in a heavily pre-treated population demonstrated minimal residual disease (MRD) negativity was possible.^7,8 In another study of venetoclax, Prof. Hillmen discussed how the “depth of response (particularly MRD negativity) correlated with durability of response (PFS), and it seemed that level of disease may be a predictor for which patients will progress sooner.”⁹ He suggested that “in future, depth of response could be a better way to monitor disease than computed tomography (CT) scans.”

“Eradication of measurable residual disease (MRD) is now the strongest predictor of survival in CLL, and we’ve got a fair amount of data on MRD with venetoclax in CLL now. Because if they can’t detect MRD this means you’re likely to survive not progress” – Prof. Hillmen

Five years ago, the MURANO trial compared fixed duration treatment (venetoclax + rituximab; VEN+r) with bendamustine + rituximab; BR.¹⁰  In this trial, patients randomised to VenR received six cycles of combination therapy, followed by a further 18 months of venetoclax monotherapy for a total of two years.¹⁰ The results were positive, and “a second line treatment like venetoclax proved to be a gamechanger, without significantly adding to the side effect profile of rituximab”¹⁰ remarked both Prof. Hillmen and Mulligan. “We see a synergistic action with VenR that translated to a superior PFS compared to BR – even with an additional 1 year of follow-up off treatment.¹¹ What’s reassuring is that results were consistent across all patient subgroups with no differences between subgroups in terms of PFS,”¹⁰ explained Prof. Hillmen.

Overall survival (OS) also showed improvements,¹⁰“but it’s hard to say what we get out of looking at OS, knowing that CLL treatments are rapidly evolving,” Prof. Hillmen noted. He added that there was also a need to factor in second-line patients who have not been exposed to targeted therapies.¹⁰ “Given the pre-treatment of patients varies considerably and in the case of MURANO, the standard of care (SOC) has changed between now and when the trial was designed.¹⁰These are all things to take into consideration when we look at OS,” said Prof. Hillmen.

Prof. Hillmen noted that trials like MURANO give clinicians confidence about the tolerability of venetoclax, “The rate of neutropenia was as expected and the rate of TLS was low. Plus no cardiotoxicity was observed.”¹⁰

Does the sequence of treatments matter?

Prof. Hillmen presented the case to “use our best treatments like venetoclax + rituximab (VenR) and ibrutinib earlier,” rather than reserving them for later, in light of changing evidence-based algorithms for CLL, and managing toxicity with other treatments. “When it comes to the question of fixed regimens like VenR in MURANO versus continuous regimens like ibrutinib, we don’t have a head-to-head trial, so we can’t make comparisons between the two. Comparing continuous vs short, fixed-duration treatment is also not a fair fight, particularly when it comes to adverse events,”^10,12 argued Prof. Hillmen. “What I do question now is the role of chemotherapy in relapsed disease. It might be something we eventually fall back on, but at the moment it’s definitely moved down the line.”

Reflecting on what choice means for the management of CLL moving forward, Prof. Mulligan noted, “patients are going to play a role in treatment choice. Aside from just looking at treatment format, we need to be clear in our own minds which option to recommend when so that we can help our patients select the option that’s best for them.” Prof. Hillmen added, “I couldn’t agree more. It’s up to us to have a clear picture of when and in whom to use these agents, and with MRD, potentially redefine how we make treatment decisions in the future.”

“Stick to the dose escalation regimen and don’t be fearful” – Prof. Mulligan

When the decision to use venetoclax has been made, both Prof. Mulligan and Prof. Hillmen stressed the importance of getting the venetoclax dosage schedule right, since gradual dose escalation on a weekly basis was “critical to gradually reduce tumour burden while managing side effects like tumour lysis syndrome (TLS),”¹³ Prof. Hillmen noted. With regards to TLS, “it’s a rare event we see now that we have increasingly effective targeted therapies. But we shouldn’t be fearful. It’s something we can monitor and manage quite well so long as we and our patients are aware and on the lookout. Our monitoring is often done in the outpatient setting,”¹⁴  he added.

This article was commissioned and sponsored by AbbVie Pty Ltd (NZ: AbbVie Ltd), which has no control over editorial content. The content is entirely independent and based on published studies and the speakers’ opinions and the views expressed are not necessarily those of AbbVie. Please consult the full Product Information for any medications mentioned in this article at www.tga.gov.au before prescribing. Treatment decisions based on this information are the full responsibility of the prescribing healthcare professional.

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AU-VENC-190034 Date of Prepared: May 2019