Venetoclax Shows Marked Responses and Distinct Resistance Mechanisms in MCL

Venetoclax (Venclexta)-based therapy was shown to be highly effective in patients with high-risk mantle cell lymphoma (MCL) in a small, prospective study, said Preetesh Jain, MD, PhD, who added that acquired resistance to the BCL-2 inhibitor was predominantly associated with non–BCL-2 mutations.

At a median follow-up of 17 months, patients who received venetoclax-based therapy (n = 24) experienced an overall response rate of 50% and a complete response (CR) rate of 21%. Patients had received a median of 5 prior lines of therapy. Sixty-seven percent of patients had progressed on BTK inhibitors, and 54% had blastoid or pleomorphic histology.

The median progression-free survival, overall survival, and post-venetoclax survival were 8 months, 13.5 months, and 7.3 months, respectively.

Seven patients underwent whole-exome sequencing. Investigators identified SMARCA4 and BCL-2 alterations in patients who had progressed on venetoclax. However, TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2, and ATM mutations were 2 to 4 times more common after progression on venetoclax.

“Our lab is now focused on understanding the pattern of resistance [to venetoclax] in a larger number of samples, particularly non–BCL-2 histone modifier mutations, such as LSD2 and KMT2D,” said Jain, who is an author on the study. “We are conducting further studies to identify potential therapeutic targets.”

In an interview with OncLive, Jain, a clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, evaluated mechanisms of resistance to venetoclax in patients with heavily pretreated MCL and the next phase of this research.

OncLive: Could you discuss the objective of the study?

Jain: Our aim was to evaluate patients who had received venetoclax. In a phase 1 trial [which evaluated venetoclax in non-Hodgkin lymphoma], the investigators reached a dose of 800 mg. The highest CR rate of 21% was reported in the cohort of patients with MCL. However, these patients had not progressed on a BTK inhibitor.

[In our study], we did a prospective analysis of 24 patients who received venetoclax monotherapy or in combination [with another agent] as salvage therapy. These patients were heavily pretreated. Patients had received a median 5 prior lines of therapy. A few patients had also relapsed after CAR T-cell therapy. The overall response rate was 50%. Although this is a smaller study, it is a very important finding. This highlights that even in combination, venetoclax works well in patients with highly refractory disease that has progressed on a BTK inhibitor.

However, patients do progress after [receiving venetoclax]. These patients have a very poor outcome of around 6 to 7 months. No other salvage therapies work after venetoclax failure.

Notably, patients who progressed on CAR T-cell therapy and responded to venetoclax only had a transient response.

We wanted to understand what happens to these patients. What are the mutation dynamics in these patient samples? We had 5 patients with before and after samples who had progressed on venetoclax.

In 2 patients, we demonstrated a pattern of clonal evolution with fishplots, particularly in histone modifier mutations, such as KM2TD, TP53, and SMARCA4, which was also increased in frequency. We also saw CELSR3, which is an [adhesion molecule] mutation that has never been described in MCL before.

One patient progressed on CAR T-cell therapy. The fishplot clearly demonstrates the pattern of evolution of these mutations. SMARCA4, CELSR3, TP53, and KMT2D increase in allele frequency. Why do they increase in frequency? What happens to the clones? We are working under the leadership of Dr. Michael Wang and Dr. Christopher Flowers, to study these questions in detail. We anticipate precise answers to these questions in the coming months.

What is the main takeaway from this research?

We had a small number of patients in this analysis, but it shows that venetoclax resistance is a real finding. In chronic lymphocytic leukemia (CLL), we know BCL-2–based mutations are very important. However, in our study, only 17% of patients had a BCL-2 mutation, suggesting that the pattern of resistance with venetoclax in MCL is distinct from CLL.

These findings need further validation in a larger cohort of prospectively collected samples. We’re going to conduct similar types of studies in other ongoing trials with venetoclax and ibrutinib (Imbruvica) in the frontline setting to understand the pattern of resistance [in less heavily pretreated patients. To do this], we’ll have to look at pretreatment samples, meaning samples that never received any treatment. In this study, the pretreatment samples had been previously treated with some other agents, such as ibrutinib or chemotherapy, so their pretreatment clonal evolution findings were not depictive of what an untreated sample would look like.

Even in poor-risk MCL, the response rate was very impressive [with venetoclax]. These findings are very provocative, even though it’s a retrospective study with a small number of patients and a small number of samples available for whole-exome sequencing. These are very preliminary findings, which will [lead us towards] studying this particular pattern of resistance in a larger number of samples.

[Then, we’ll need to determine] how we can target these mutations or look at the different patterns of BCL-2 receptor signaling pathways with RNA sequencing.

The patients [in the trial] are currently being treated with CAR T-cell therapy, but there is a pattern of resistance with CAR T-cell therapy as well. I believe early administration of these drugs in combination with BTK inhibitors in untreated samples would suppress resistant clones. Longer-term follow-up from these studies is required, and a greater number of patients are needed to be studied in a prospective and systematic way to answer those questions in a precise way.

Reference:

Zhao S, Kanagal-Shamanna R, Navsaria L, et al. Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) – outcomes and mutation profile from venetoclax resistant MCL patients. Am J Hematol. 2020;95(6):623-629. doi:10.1002/ajh.25796