A/Prof Eliza Hawkes

Acalabrutinib plus rituximab, delivered in a sandwich approach before and after R-DHAOx chemotherapy plus or minus autologous transplant, is safe and highly active in fit young patients with treatment-naive mantle cell lymphoma (MCL).

Associate Professor Eliza Hawkes, from Melbourne’s Austin Health and the Olivia Newton John Cancer Research Institute, told ASH 2023 that the ALLG NHL33 ‘Wamm’ trial aimed to minimise the toxicity associated with the direct combination of BTK inhibitor and intensive chemotherapy.

“So we explored a sandwich model to improve the therapeutic response of an intensive regimen and minimise the additional toxicity,” she said.

The Australian study recruited 44 patients with newly diagnosed MCL who were 18-70 years of age and fit for ASCT.

Patients received two cycles of acalabrutinib plus rituximab (AR) followed by four cycles of R-DHAOx. Patients with an objective response (complete or partial response) underwent BEAM ASCT then AR maintenance.

The study found 88% of patients had a complete response at the end of induction with an overall response rate of 95%. And in those who proceeded to ASCT, 93% of patients achieved CR.

Associate Professor Hawkes said a high proportion of patients with PET CR remained MRD positive after AR (81%). However by the end of induction, after the four cycles of R-DHAOx, MRD negativity had increased from 19% to 94% of patients.

“Two cycles of AR as a window yields a high initial overall response rate and improves post- chemotherapy induction CR rates and MRD negativity compared to historical controls,” she said.

The two-year PFS was 73.3% and the two-year overall survival was 79.3% on about 30 evaluable patients.

“These are very preliminary results and likely to alter as the follow-up increases and more patients become evaluable,” she said.

Of the six deaths to date, five were due to progressive disease.

“They’re not getting onto the multiple relapsed studies so they’re missing out and this has already been demonstrated quite nicely by my colleague Adrian Minson in Melbourne in a recent publication.” [link here]

“Although this represents an incredibly poor risk group who have progressed through rituximab, acalabrutinib and relatively intensive chemotherapy, there are a mix of high risk and low risk features within the cohort and it is quite heterogeneous.”

Safety

Associate Professor Hawkes said adverse events occurred in >5% of patients during induction with the most common serious adverse events being infection and febrile neutropenia.

There were no excess acalabrutinib-related AEs of special interest observed and two cardiac arrhythmias were both sinus tachycardia.

“The maximum grade toxicities occurring during the eight weeks of acalabrutinib-rituximab window, which is a very short period of time, were predominantly grade one and two and in line with previous reports of this combination.”

Associate Professor Hawkes said the study had employed a successful telehealth hub and spoke model allowing rapid recruitment of a rare disease and rural patient participation in a unique environment.

“The hub sites delivered the more intensive components of the treatment paradigm and provided trial management and intermittent telehealth appointments while the spoke sites, which are often smaller and further into the rural and regional areas, cared for the patients locally for other aspects, complications and medication dispensing.”

Importantly, it allowed rural and remote patients access to novel therapies without having to travel huge distances to get them.

Eliza Hawkes presents data from a window study to test acalabrutinib and rituximab before chemo and autologous HSCT in 44 fit patients with treatment naïve mantle cell lymphoma. The treatment schedule was designed to reduce the toxicity of the therapy #ASH23 pic.twitter.com/NETeEO30Z5

— The Lancet Haematology (@TheLancetHaem) December 11, 2023