Ibrutinib Plus Venetoclax Induced Improved Immunity in R/R Mantle Cell Lymphoma

The phase II AIM trial (NCT02471391) explored the safety and efficacy of ibrutinib (Imbruvica) in combination with venetoclax (Venclexta) in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). The trial included patients who had initially failed to respond to chemotherapy or had short remissions after treatment.

Overall, the combination of venetoclax and ibrutinib demonstrated encouraging efficacy in this patient population. In a substudy presented at the 2019 American Society of Hematology (ASH) Annual Meeting, which looked at the longitudinal changes in the peripheral blood immunology, investigators found that long-term treatment with the combination was associated with immune recovery. The majority of patients had normalization of their immune status, as well as improvement in innate immunity cells.

Changes in inflammatory biomarker expression were also observed in the patients with R/R MCL who were treated with the combination regimen. Overall, there was an improvement in the monocytes, dendritic cells, gamma delta T cells, and natural killer (NK) cells. This analysis suggests that the combination of venetoclax and ibrutinib may provide better immunological recovery over conventional chemotherapy treatments.

In an interview with Targeted Oncology, David Ritchie, MD, PhD, hematologist, head of allogeneic stem cell transplantation, Peter MacCallum Cancer Centre, discussed the findings from the substudy of the AIM clinical trial, which evaluated the combination of venetoclax and ibrutinib in patients with MCL.

TARGETED ONCOLOGY: Could you provide some background to the AIM study and the substudy analysis?

Ritchie: The AIM clinical trial was an investigator-initiated study of the combination of venetoclax and ibrutinib in patients with R/R MCL. It was published in the New England Journal of Medicine in [2019]. The substudy that was presented at ASH was the long-term immunological status of those patients at enrollment and the subsequent changes with follow-up that now goes out to 2 years from enrollment.

TARGETED ONCOLOGY: What were the findings from this analysis?

Ritchie: The substudy analysis aimed to determine whether with adequate disease control of the MCL and with the ongoing addition of those 2 drugs, could we see normalization of immune responses in the patients on the study with MCL.

That analysis concluded that we did for patients who had ongoing responses which was the majority of the patients who remained on drug, although 2 patients came off the drug for non-progressive reasons, but they also showed sustained immunological improvement. Overall, the majority of the patients showed normalization of their immune status and improvement particularly in their measures of innate immunity, such as monocytes, dendritic cells, gamma delta T cells, and NK cells.

TARGETED ONCOLOGY: What was the target patient population of this analysis?

Ritchie: The population overall is what you might consider poorest risk of MCL. These patients have either failed to respond to initially chemotherapy or had short remissions, and many patients had gone through intensive chemotherapy including ASCT and had subsequent relapses. These are patients who had no other therapeutic options.

The primary driver of the study was to explore the safety and efficacy of the combination of these 2 targeted drugs. We recognize the importance of having comprehensive biomarker specimens as part of that study, and that allowed us to go on and look at this immunological reconstitution, as well as looking for the biomarkers in the compliment species.

TARGETED ONCOLOGY: What is the key takeaway from these data?

Ritchie: The important take home message from that immunological analysis is that those responses took time to evolve. When we analyzed the immunological status at diagnosis or conclusion of the study and looked just 16 weeks later, we saw no improvement of the immunological status, but we showed complete normalization of their immunological status at a year post-treatment, which was sustained for 2 years post-treatment. The reason why that is important is that initial exposure to both venetoclax and ibrutinib can be associated with immunological impairment, and that is certainly true, but the subsequent normalization and improvement of the immune status likely reflects the lower rates of opportunistic infections that those patients saw on clinical trial, as well as the potential for those patients to be treated with immunotherapy subsequently.

We thought the findings were uniform across the group associated with sustained responses, but you had to be patient in order to find those responses. The other thing about our study was that it showed there may be some biomarkers with respect to inflammatory factors in the blood, including compliment species which were significantly elevated in patients who subsequently didn’t respond to venetoclax and ibrutinib. Those patients who did respond had much more normal levels, so we are starting to explore potential biomarkers for response.

TARGETED ONCOLOGY: Were there any challenges in this analysis?

Ritchie: One of the difficulties of the study is that the drug combination is so effective that there was a relatively small population of non-responders or patients who had non-sustained responses. A number of these patients had mutations in their Bruton’s tyrosine kinase pathway, and that is being published separately. The important thing here is patients who managed to stay on drug had long-term responses and normalization of their immunity. We seem to think that if that normalization can occur by a year post-treatment, it is likely to be sustained beyond that time. It may identify a group of patients who have sustained antitumor responses but a much more normalized and recovered immune system as well, which might be important for their next treatment should they relapse.

TARGETED ONCOLOGY: Are there any other trials underway at your center examining immunotherapy in this patient population?

Ritchie: There are plenty of studies out there, and we certainly have studies in related conditions at my center, particularly in chronic lymphocytic leukemias, where we show similar immunological effects. We are working on a clinical trial design based around minimal residual disease assessment and the potential for immunotherapy as a consequence of the disease control, potentially immune recovery which then allows the introduction of immunotherapy. One of the implications of this is if we are starting with a more normal T cell repertoire and fitness, those patients may be in a better position to have chimeric antigen receptor (CAR) T cells manufactured, for example. Those are all elements we may incorporate in future studies.

TARGETED ONCOLOGY: Are there any other next steps planned in terms of determining biomarkers?

Ritchie: Concerning biomarkers, we have a fairly large MCL service at my center. It’s emphasized mainly around chemotherapy induction and ASCT. We are recognizing the implications of the TP53 mutations in patients with MCL and exploring other options for those patients, including immunotherapy. Across our program, we are incorporating correlative sample collection to allow these biomarkers to be retested in different populations. It seems to be a recurring thing that these patients who have the best immune reconstitution do the best ultimately, whether that is directly due to antitumor effects or just general better global health. We are very disciplined in ensuring that when our patients are enrolled on these novel agents that we get correlative samples at the same time points to allow cross-comparison.