International expert Professor Jan Burger from the MD Anderson Cancer Center in Houston, Texas shared his thoughts on the treatment options in relapsed/refractory chronic lymphocytic leukaemia (CLL) with delegates attending Janssen’s H3 medical education symposium in Melbourne.

“We’ve relied on chemo-immunotherapy (CIT) for salvage for some time, but overall the outcome is not good in terms of progression-free (PFS) and overall survival (OS).^1,2 It hasn’t been until the development of the small molecule inhibitors like ibrutinib that we’ve seen the game change in terms of what matters, that is PFS and OS,”³ began Prof. Burger. “Despite noise around minimal residual disease (MRD) negativity, the goals of treatment are still the same as they have always been. We want to control the disease with good quality of life and remission.⁴ To do that, we need to think about the different disease subgroups and treat according to that.”

Small molecule inhibitors have been game-changers for CLL

Prof. Burger presented data from the long-term follow up of the PCYC 1102/1103 ibrutinib monotherapy trials in a heavily pre-treated population with bulky disease.³ “The results show a major breakthrough compared with chemotherapy in terms of OS and PFS,”³ he noted. “We see 36% 7-year PFS and 55% OS in the relapsed/refractory patients.³ All of this is achieved with a predictable safety profile that clusters around the first one to two years of treatment.³ The only adverse event that appears to increase slightly over time is arterial hypertension, which can be managed.”³

Prof. Burger also shared results from a multivariate analysis for ibrutinib that confirmed del17p was the only significant predictor of PFS and OS.⁵ “When we look at the RESONATE trial, we see patients with fewer lines of therapy do better and those with del17p do worse, but you still get a response, just a shorter PFS and OS.³ Other factors do not seem to influence the outcome, which is good from a practicality standpoint.”³

Targeted molecules and their place in CLL therapy

“There’s now a number of BTK, phosphoinositide 3-kinase y (P13KY)/d, spleen tyrosine kinase (syk) and B-cell lymphoma-2 (BCL-2) inhibitors either on the market or in the pipeline. We don’t have head-to-head data, so comparing trials isn’t a fair fight. But there’s a few things we can keep in mind when deciding what to use and when,” he explained.

In discussing the data on idelalisib, Prof. Burger noted, “it’s not frequently used. While we see a similar redistribution of lymphocytosis we see with ibrutinib and the PFS is around what we would expect, the safety profile is probably why it’s not used that widely.⁶ There are effects on the T-cell compartment, which leads to autoimmune complications such as opportunistic infections.”^7,8 He noted that it still remains a treatment option as a fallback for those intolerant to BTK inhibitors.

“Probably the other drug we are focussing on a lot is the BCL-2 inhibitor, venetoclax. We see patients on venetoclax doing much better than the chemotherapy arm in the MURANO trial and it appears to be able to overcome the negative impact of del17p.^9,10 The response rates are sizable, it has the capacity to induce MRD negative remission in some patients, albeit more in the frontline than relapse setting.^9,10 MRD negativity appears important for the durability of response for venetoclax, while less so for the kinase inhibitors,”^3,9,10 he explained. “In terms of its place in therapy, there’s some data presented from Mato et al. that shows the response to subsequent therapy following initial kinase inhibitory therapy.¹¹ When you switch from ibrutinib to idelalisib the overall response rate (ORR) is 46%, from idelalisib to ibrutinib it is 75% and from a kinase inhibitor (either ibrutinib or idelalisib) to venetoclax it’s 74%. In terms of complete response, we see 0%, 5% and 32% respectively.¹¹ So I think that is quite telling in terms of the place of venetoclax as a salvage therapy after a kinase inhibitor.”

Prof. Burger’s recommendations for treatment sequencing after CIT

In concluding, Prof. Burger offered his recommendations for the treatment sequence of the relapsed/refractory CLL patient. “Most of our patients have had prior exposure to chemotherapy and the consensus has been to use a BTK inhibitor at relapse and we should continue to do that. If patients are intolerant, or a BTK inhibitor is contraindicated, then I’d choose idelalisib or venetoclax. If the patient is del17p and resistant or intolerant to a BTK inhibitor, that’s when I’d move to a venetoclax-based treatment or stem cell transplant,” he concluded.

This article was sponsored by Janssen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Janssen.

References:

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7. United States Food and Drug Administation. FDA alerts healthcare professionals about clinical trials with ydelig (idelalisib) in combination with other cancer medicines. Available at: https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-healthcare-professionals-about-clinical-trials-zydelig-idelalisib-combination-other (accessed 3 June 2019).
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