Blood cancers

Durable disease control achieved with BTKi salvage therapy in patients with CLL

Patients with chronic lymphocytic leukaemia (CLL) who progress on venetoclax can achieve durable disease control with Bruton tyrosine kinase inhibitor (BTKi) salvage therapy, new Australian research reveals.

The study included 23 patients with refractory/relapsed CLL who received a BTKi (ibrutinib [n=21], zanubrutinib [n=2]) after ceasing the BCL2 inhibitor venetoclax due to progressive disease.

After initiating BTKi therapy, researchers from the Victorian Comprehensive Cancer Centre and the Walter and Eliza Hall Institute of Medical Research in Melbourne report a median progression free survival (PFS) and median overall survival (OS) of 34 months and 42 months, respectively.

Speaking to the limbic about the ‘remarkable’ survival gains seen with the therapy, haematologist and co-first author on the study, Dr Thomas Lew from Peter MacCallum Cancer Centre, said the patient cohort was a particularly high risk, heavily treated group.

“These were patients who had essentially all been maximally treated with conventional chemotherapeutic options and, at the time, palliation or trial-based therapy would have been the only option available to them prior to enrolment in early phase venetoclax trials”.

“It’s safe to say that the durability of the responses that they’ve had on venetoclax and the subsequent durable responses that they’ve had on BTK inhibitor therapy is a fairly remarkable achievement in light of the situation they would have been in prior to their enrolment in these early venetoclax trials.””

Patients had received a median of four prior therapies and had been on venetoclax for a median of 29 months. All were BTKi naïve and had traditional adverse prognostic features such as TP53 abnormalities and complex carrier type.

Speaking about the groups’ experience with venetoclax, co-first author Victor Lin, says 15 patients obtained partial disease remission while six patients obtained complete remission including four patients who achieved undetectable minimal residual disease. However, all patients had come off treatment because of progressive disease, with 18 patients experiencing CLL and five experiencing Richter’s transformation.

After commencing BTKi therapy – 21 patients received ibrutinib at 420mg per day while two patients received zanubrutinib 160mg twice daily – 20 patients obtained remission with a median PFS of 34 months and a median OS of 42 months.

According to Mr Lin, univariate analysis revealed two patient subsets associated with long-term PFS when placed on subsequent BTKi.

“The first subset of patients was those who obtained a durable response to venetoclax longer than two years of remission. The other group was those who achieved deep responses on venetoclax, specifically complete remission or undetectable minimal residual disease.”

The observations come with the caveat that they are retrospective analyses of relatively small numbers, notes Dr Lew, who says larger cohorts and prospective analyses will ultimately delineate the most powerful predictors of patients who receive BTKi salvage.

But he also notes that BTKi therapy is not without significant toxicities in some patients.

“The data that we have on toxicity is somewhat limited in this particular analysis. However, it is worth noting there were four patients who had severe toxicities while on BTK inhibitor therapy and in all four of those cases the toxicities were associated with a fatality,” he said, referring to one case of sepsis, one case of pneumonia and two cases of intracranial haemorrhage – of which one occurred in the context of concomitant myelodysplasia with severe thrombocytopenia in a patient receiving azacitidine treatment.

Meanwhile other analyses revealed a trend towards improved PFS on BTKi therapy among patients with a confirmed BCL2 G101 V mutation, notes Dr Lew.

“Patients who have this resistance mutation appear to have an equivalently favourable prognosis on BTKi salvage and we report a 69% PFS at two years.”

But that observation is confounded, he says, by the fact that the BCL2 G101 V mutation develops over time.

“So we think that patients who are exposed to venetoclax long enough to develop the mutation then go on to have a favourable response to BTKi salvage because of their durable response, rather than it being a phenomenon of the mutation itself – that’s our best interpretation of the data.”

In the relapse/refractory setting, Dr Lew says it’s clear that, in patients who are naïve to targeted agents, either venetoclax or a BTKi approach is superior to chemoimmunotherapy.

“’Venetoclax, and venetoclax with rituximab, offers the advantage of time limited therapy in the pursuit of deep remission. And it’s clear that patients who cease venetoclax after two years of therapy in deep remission continue to have very durable disease control,” he says.

“But another option is clearly ibrutinib or other BTKi agents, which offer durable disease control to patients with refractory disease but carry with them the disadvantages of drug tolerance, which is a frequent reason for termination of these agents and the inevitable development of resistance when these agents are used  as monotherapy.”

The full paper can be found here.

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