Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, has a 5-year survival rate of 63%. However, patients with non-germinal center B-cell-like (non-GCB) disease and high MYC and BCL2 expression face a poorer prognosis, with limited treatment options. In the phase 3 PHOENIX trial, Wyndham Wilson, MD, the Head of the Lymphoma Therapeutics Section at the National Cancer Institute, and colleagues investigated a combination of ibrutinib and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with non-GCB DLBCL and found that it did not improve survival in the overall study population. However, in a subgroup analysis of the trial, Dr. Wilson and colleagues determined that ibrutinib/R-CHOP significantly improved both event-free and overall survival in patients whose tumors had high MYC and BCL2 expression, with the greatest benefit seen in patients under 60 years of age. Dr. Wilson presented the results of the analysis at the American Society of Hematology (ASH) Annual Meeting on Sunday, December 8th. In this interview with i3 Health, Dr. Wilson discusses the significance of the trial's results and the benefits of ibrutinib/R-CHOP for patients with non-GCB DLBCL and high MYC and BCL2 expression.
What are some of the most challenging aspects of treating patients with non-GCB DLBCL with high MYC and BCL2 expression?
Wyndham Wilson, MD: We've known for many years now that tumors of the activated B-cell (ABC) type are associated with worse outcomes compared with tumors of the GCB type. The difference between non-GCB and ABC can be confusing for some people. Non-GCB is a surrogate for ABC, and it can be identified using the immunohistochemistry method. Therefore, we decided to use immunohistochemistry as a way to identify patients for the PHOENIX trial.
Tumors with very high levels of MYC and BCL2 expression have also been associated with poorer outcomes. MYC is an important protein that is associated with cellular growth. While many people think of it as mostly having to do with proliferation, it really involves a combination of both proliferation and growth. BCL2 is a protein associated with resistance to undergoing spontaneous apoptosis. Cells tend to want to undergo apoptosis if they're being driven at a very high rate, and this is one reason why we think that having high levels of both MYC and BCL2 expression leads to a more aggressive cell and poorer outcomes.
Can you comment on the significance of your findings?
Dr. Wilson: A question we asked in the PHOENIX trial was whether the subset with high MYC and BCL2 expression would have an even better outcome with ibrutinib added to R-CHOP, and the answer was yes. The whole idea here was that we knew that with R-CHOP alone, the ABC/non-GCB type has a worse outcome compared with the GCB type. Ibrutinib actually has preferential activity in ABC/non-GCB DLBCL, and the hope was that if we added ibrutinib to R-CHOP, outcomes would be improved. The benefit of ibrutinib was greatest in patients with high MYC and BCL2 expression, which was about a third of the study population. However, one of the things we found in the original trial was that ibrutinib did not seem to improve outcomes when considering the overall study group, because patients over 60 who received ibrutinib/R-CHOP actually had worse outcomes compared with R-CHOP alone. We did not see this effect in patients under 60; among this group, those who received ibrutinib/R-CHOP had significantly better outcomes. Additionally, when we looked at the subset that had high MYC and BCL2 expression, the benefit of ibrutinib/R-CHOP was seen across all age groups, albeit not significantly in older patients.
To what do you attribute ibrutinib/R-CHOP's improvement in overall survival in patients under 60 years old, but not in patients over 60?
Dr. Wilson: It turns out that the reason for this was that patients over the age of 60 had a fair degree of unexpected toxicity from the ibrutinib, leading to premature discontinuation of R-CHOP, which is necessary to cure these people. It is for this reason that the overall group of patients who received ibrutinib/R-CHOP in the original trial had worse outcomes compared with R-CHOP alone. Why do we now see better outcomes in patients over 60? It is most likely because the benefit of ibrutinib was particularly powerful in this group with high MYC and BCL2 expression, and that compensated for the toxicity of ibrutinib.
Do you have any words of advice for community oncologists and hematologists treating patients with non-GCB DLBCL with high MYC and BCL2 expression?
Dr. Wilson: The toxicity and poorer outcomes seen in older patients put a sort of pall over the original trial, so we cannot say that ibrutinib should be used for patients with non-GCB disease. However, this subgroup analysis provides compelling evidence that ibrutinib improves outcomes in patients with high MYC and BCL2 expression, especially in those under 60. While it ultimately has to be up to each individual doctor, I do think that medically and scientifically speaking, there is very good evidence that ibrutinib/R-CHOP does in fact help.
About Dr. Wilson
Wyndham Wilson, MD, is the Head of the Lymphoma Therapeutics Section and a Senior Investigator in the Lymphoid Malignancies Branch of the National Cancer Institute at the National Institutes of Health in Bethesda, Maryland. He is also the former Chair of the FDA's Oncologic Drug Advisory Committee. Dr. Wilson specializes in the treatment of various types of lymphomas, and his research focuses on the development of novel therapeutics to improve outcomes in patients with these malignancies.
For More Information
Johnson P, Balasubramanian S, Hodkinson B, et al (2019). Clinical impact of ibrutinib with R-CHOP in untreated non-GCB DLBCL co-expressing BCL2 and MYC genes in the phase 3 Phoenix trial. 61st American Society of Hematology Annual Meeting and Exposition. Abstract 354.
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.