Eliza A Hawkes, MD, Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia, shares findings from the phase 2 WAMM trial, which assessed the use of an acalabrutinib plus rituximab “window,” followed by rituximab, dexamethasone, cytarabine, oxaliplatin (RDHAOx) chemotherapy, autologous stem cell transplantation (ASCT), and maintenance among young, fit patients with treatment naive mantle cell lymphoma (MCL). This treatment sequence is called the “sandwich model.” 

These findings were included as an oral presentation at the 65th American Society of Hematology (ASH) Annual Meeting in San Diego, California. 

Transcript: 

Thank you for the opportunity to highlight our investigator-initiated study, a window study of acalabrutinib and rituximab, followed by chemotherapy and an autograft in fit patients with treatment-naive mantle cell lymphoma. This is the first report of the investigator-initiated Australasian Leukemia and Lymphoma Group (ALLG) NHL33 WAMM study. My name is Eliza Hawkes. I'm an associate professor and clinician at the Olivia Newton-John Cancer Research Institute at Austin Health, as well as Monash University in Melbourne, Australia. 

This study was presented as an oral presentation at the American Society of Hematology Annual Scientific Meeting in San Diego in 2023. This was an investigator-initiated trial that we developed in the ALLG in Australia using a sandwich approach with a novel agent and chemotherapy and mantle cell lymphoma. The reason we used a sandwich model where we gave acalabrutinib, a Bruton tyrosine kinase (BTK) inhibitor, before and after chemotherapy was [that] there have been challenges in previous studies of giving this very effective novel therapy in combination with other chemotherapies.

Certainly, that's been the case with studies such as the TRIANGLE study, which did show some improvement in efficacy with the addition. But, ibrutinib, which is a BTK inhibitor, had to be intermittently dosed with the [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone] (R-CHOP) component of R-CHOP-[dexamethasone, cytarabine, cisplatin] (DHAP) and other studies which have really shown high rates of toxicity. 

The sandwich approach allowed the evaluation of this novel therapy and the improvement in efficacy without significant additional toxicity. The other thing that was novel about our study was that as a cooperative group, we were able to employ a unique telehealth hub-and-spoke model for the non-transplant sites and remote locations in Australia. Australia is the size of the [United States] (US) in terms of land mass or Europe, but we have a population of just over 25 million people in that large area. So, we have a lot of patients who live very far away from the large centers.

The hub sites delivered the transplant and some of the more toxic components, also providing trial management and receiv[ing] and manag[ing] the acalabrutinib [investigational medicinal product] (IMP). The spoke sites, sometimes, which [were] a thousand kilometers apart, really did the local patient management and dispens[ing] medications. This allowed recruitment of a rare disease to occur or to be completed in half the expected time and also allowed patients in very remote and rural locations access to novel therapies without having to travel thousands of kilometers. 

Our population was pretty similar to most other studies of chemotherapy or intensive regimens and novel agents in young fit mantle cell lymphoma groups. Our primary endpoint was [a] complete metabolic response (CMR) rate at the end of the induction–that was after 2 cycles of rituximab and acalabrutinib plus 4 cycles of RDHAOx chemotherapy. The complete metabolic response rate was combined with a dual toxicity endpoint.

The formal primary endpoint was [a] complete metabolic response rate in the absence of prohibitive toxicity. The definition of that was not ceasing treatment early for toxicity permanent cessation. Our [complete response] (CR) rate at the end of induction was 88%. It's higher than most historical controls of chemotherapy alone. We also tested minimal residual disease (MRD) and the MRD negativity at the same time point after the RDHAOx chemotherapy was achieved in 94% of patients. We obviously have more time points that we will be assessing as patients continue on their treatment, and we have [a] longer follow-up to come, but this is a really pleasing early result reporting. Our primary endpoint also of note, the rituximab and acalabrutinib window, which was only 8 weeks of treatment, achieved an overall response rate in 91% of patients. This is a relatively high-risk group, so we are going to scrutinize that result a little bit more.

The toxicity that we saw was no different [from] other studies of rituximab and acalabrutinib and then chemotherapy. It was all very consistent and we weren't concerned. We did have quite a bit of COVID because this study did recruit during the 2020 pandemic prior to vaccinations and use of antivirals. The [progression-free survival] (PFS) and overall survival in this study [are] very preliminary. We have a median observed follow-up of 25 months only. We had 7 progression events and 6 deaths—5 of these were due to progression and 1 due to COVID-pneumonitis. The 2-year PFS was 73% and the overall survival was 79%.

Those who did progress did have at least 1 or 2 features of high-risk disease, but this is really acknowledging that with short follow-up, most of those patients are genuinely primary progressive patients having progressed very shortly after receiving a BTK inhibitor, that's [the] acalabrutinib-rituximab combination, chemotherapy, and a transplant. They're very poor-risk biology. We noted that we had 3 relapses in the central nervous system, and so we're scrutinizing that a bit more as well. 

In summary, acalabrutinib and rituximab delivered in our sandwich model before and after RDHAOx chemotherapy was safe and highly active in these younger fit patients with mantle cell lymphoma, treatment-naïve. The window did provide a high overall response rate as well as augmenting the post-chemotherapy induction CMR, which was 88%, and MRD negativity of 94%. We also are very proud of our collaborative group, successful hub and spoke, and telehealth model, which I think allows more access for patients who do not live near the larger centers. Thank you.

Source: 

Hawkes EA, Lee ST, Churilov L, et al. A window study of acalabrutinib & rituximab, followed by chemotherapy & autograft (ASCT) in fit patients with treatment naïve mantle cell lymphoma (MCL): first report of the investigator-initiated Australasian leukaemia & lymphoma group NHL33 ‘Wamm’ trial. Presented at the ASH 65th Annual Meeting & Exposition; December 9-12 2023; San Diego, California. Abstract 735