June 10, 2022
- An important trial which compared adding the drug ibrutinib to first-line chemotherapy in patients with newly diagnosed mantle cell lymphoma (MCL) showed improvement in progression-free survival (PFS) compared to placebo.
- The trial results were released at the annual conference of the American Society of Clinical Oncology, or ASCO.
- It’s important to observe, however, that although the median progression free survival was longer in patients treated with ibrutinib, this study failed to show improvement in overall survival.
- There was also higher toxicity noted with the three drug regimen that included ibrutinib.
An important new study, revealed during the annual conference of the American Society of Clinical Oncology, finds that the drug ibrutinib shows some effectiveness in fighting mantle cell leukemia, but as of yet doesn’t increase the overall survival rate for patients with this disease.
Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma than can either grow slowly or quickly. Aggressive treatment is needed for fast-growing mantle cell lymphoma. The current approach to therapy is a combination of the monoclonal antibody, rituximab (Rituxan), and chemotherapy, bendamustine followed by stem cell transplantation. Single-agent Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib, daily oral medication is currently approved for patients with relapsed/refractory mantle cell lymphoma and has shown durable activity.
Ibrutinib in combination with the standard of care regimen can improve progression-free survival by 2.3 years among newly diagnosed patients with MCL according to new data from the randomized, phase 3 SHINE trial. PFS is the length of time from random assignment to disease progression or death. The latest SHINE findings were presented at the ASCO by Michael Wang, MD, Department of Lymphoma & Myeloma, University of Texas MD Anderson Cancer Center, Houston. The results were also published in the New England Journal of Medicine. A total of 520 treatment-naive patients (aged ≥ 65 years) participated in SHINE trial. They were randomly assigned to receive ibrutinib or placebo plus bendamustine-rituximab (BR) followed by maintenance treatment with rituximab. When looking at the PFS in years, the median PFS is 6.7 years with ibrutinib and 4.4 years with standard therapy, which is “a very meaningful benefit” with first-line treatment in this older population, Dr. Wang said.
Ibrutinib prolonged the time to the next treatment as well. The median time to next treatment was not reached in the ibrutinib arm and was 92.0 months in the standard arm (HR, 0.48; 95% CI, 0.34-0.66).
Overall survival (OS) means the time from treatment to death and is the most appropriate measure for clinical trials. However, the study failed to find any significant difference in OS. In addition, higher rates of side effects were reported with ibrutinib vs placebo: 81.5% and 77.3%, respectively. The most common side effects were rash, pneumonia, and atrial fibrillation, and the rates of all three were much higher with ibrutinib compared to placebo. The rate of any bleeding was also higher in the ibrutinib arm: 42% vs 21%, respectively.
A mixed response to the new study results
The study received mixed responses from several hematology experts.
- Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University in London, UK, highlighted the fact that the triplet treatment option has no overall survival benefit and comes with more toxicity. Dr. Bijal Shah, a medical oncologist in Moffitt Cancer Center’s Malignant Hematology Department, says “It is still too soon to say if this regimen will lead to a new standard of care for older patients with mantle cell lymphoma. I think a major challenge with the data presented relates to the need and benefit versus the toxicity of adding bendamustine. Notably, overall survival was not improved, and it suggests that a safe alternative is to deliver ibrutinib-based therapy at the time of relapse. It is hoped with future BTKi trials, we will learn more about the importance, or lack thereof, of the bendamustine component”.
- Dr. Adam Asch, division chief of the hematology-oncology department at the University of Oklahoma shared his opinion on whether to consider this trial as a practice-changing study: “SHINE trial represents some important data, it is in my mind the glass half full story. There was an improvement in PFS but no improvement in OS, and more disappointingly there was no difference in disease-free survival for those patients who have TP53 mutations, which is the group of patients who are at most risk and need improved therapy the most. And looking at the lack of difference in OS as evidence is really the efficacy of the other BTK inhibitors that are those patients had access to post-progression and that’s the question of whether one might seen OS advantage with one of the second-generation BTK inhibitors in combination with rituximab and bendamustine. So, I do not see that this article is particularly practice-changing, I think it is the discussion to have with patients but there were in fact some increased toxicities from ibrutinib and some trends towards worsen OS in the ibrutinib group. I see this is mixed results in terms of benefit and again not particularly practice changing.”
Looking ahead in the fight against mantle cell leukemia
The 2022 ASCO annual meeting also included discussions on prognostic markers TP53 to facilitate risk stratifications, the utility of CART cell, bispecific antibodies, and novel small molecules. “From CART cell therapy to bispecific antibodies to novel biologically targeted therapies, there are many new therapies available that are rapidly changing treatment paradigms in MCL,” said session chair Dr. Anita Kumar, of Memorial Sloan Kettering Cancer Center. Dr. Kumar also noted that biological risk stratification has become increasingly important in MCL, particularly with regard to testing for the presence of TP53 mutation.
The management of MCL still requires further optimization, and clinicians need updates on how to incorporate individual risk profiles into clinical decision making and better tailor treatment strategies to improve clinical outcomes.