Expert Makes Case for Frontline Targeted Therapy in Select MCL Subtypes

Ezzat Elhassadi, MD, highlights research being done to address the unmet need of patients with p53-mutant mantle cell lymphoma and the challenges faced in the current treatment paradigm.

Patients with mantle cell lymphoma (MCL), particularly those with p53 mutations and those who have a poor prognosis, should be treated with targeted therapy upfront, said Ezzat Elhassadi, MD.

In a study presented at the 2019 European Hematology Association Congress, 29 patients with MCL were observed over a 10-year period. Researchers found that patients harboring p53 mutations correlated directly with overall survival (OS). Median OS in the 20% of patients with p53-mutated disease was approximately 4 years; OS had not been reached in the wild-type subset (P = .007).

“From these data, we are advocating about using targeted therapy upfront in MCL—especially in patients who are not fit for the standard of care, including autologous stem cell transplant (ASCT),” explained Elhassadi, a consultant hematologist at University Hospital Waterford. “Potentially, if we use our targeted therapy early in the disease course upfront, there are data supporting that the response rates will be better.”

In the study, 83% of patients were treated upfront with standard chemoimmunotherapy. While patients with p53 mutations may achieve tumor debulking with this standard approach, they will relapse rather quickly because the benefit from chemoimmunotherapy relies on intact p53 protein, explained Elhassadi. Overall response rate in the study was 79%, which comprised a 55% complete response rate and a 24% partial response rate.

In an interview with OncLive, Elhassadi highlighted research being done to address the unmet need of patients with p53-mutant MCL and the challenges faced in the current treatment paradigm.

OncLive: Could you discuss your findings on the 10-year single-center experience with p53-mutated MCL?

Elhassadi: MCL is a very rare disease. I have great interest in p53 mutations. I decided to review the outcomes for our center's treatment of patients with MCL who have p53 mutations. We did a retrospective study that looked back at 10 years. We managed to accrue 29 patients and evaluate 32 samples; this was because some of the patients had relapsed disease. One patient had 2 sites of disease. The outcome was comparable with the reported literature in this disease. We used a variety of drug combinations. We had 11 mortalities over the study period, 6 of which were non-lymphoma related, while 5 of them were lymphoma-related.

When we did our p53 mutation screening in the lymphoma-related cohort, we found that in up to 80% of those lymphoma-related deaths, patients harbored p53 mutations. Part of the study looked at immunohistochemistry (IHC) for p53 expression, and interestingly, we saw a 100% correlation between p53 profile expression by IHC and mutation status. Interestingly, when we use Sanger sequencing alone, we could pick only 3 mutations in the overexpressed cohort—these were 6 patients. When we did next-generation sequencing (NGS) for the overexpressed group, we could pick up the subclone, which is quite fascinating because I'm not aware of NGS being introduced in MCL. Equally, we did Sanger sequencing to all the samples, so the people who had a low expression by IHC did not have underlying mutations; this correlates nicely with the mutation status.

Since then, we introduced p53 IHC screening into our routine practice. This subset of patients has been reported in different trials and they tend to have a very dismal outcome. The Nordic MCL-1 and -2 [trials] have reported a median OS of 1.3 years [for these patients], which means they do very badly despite [treatment with] intensive chemotherapy, ASCT, and rituximab maintenance. As you know, MCL is a disease [that tends to affect patients] with a median age of 65. We know ASCT is the only curative option, and most of our patients are not eligible for this.

What does p53 status tell us about a patient's prognosis?

To use chemoimmunotherapy, which is the standard of care in MCL, you need intact p53 protein. If you have a disrupted protein, in my interpretation, using chemotherapy in these patients will be more problematic than beneficial. First, chemotherapy will not work. You may debulk the disease, but the clone will escape after you finish your treatment. That's why these patients have a median OS of 1.3 years in most trials. Second, because of the selective advantage of resistance clones, if you hit the normal hematopoietic cells, you will allow expansion of resistance clones. That partially explains why if you're using targeted therapy as a second-line treatment, it will not work as effectively as it would if you used it upfront.

Therefore, I'm advocating that for patients with p53 mutations, we use targeted therapy upfront rather than in the second-line setting. I do understand there are emerging data suggesting that using single-agent ibrutinib (Imbruvica) won't overcome p53 mutations, but I strongly believe these patients need a combined doublet or triplet therapy. Basically, these patients tend to respond to chemoimmunotherapy but relapse very quickly and have a dismal outcome.

This study focused on a single center's experience. Is there potential to explore this in multiple institutions?

This work has been done in the Nordic Group. They confirmed the poor prognosis of this subset of patients. That work has been replicated in a large cohort of patients. What's different in my small cohort—although MCL is a rare disease—is that the sample size is small, but it is enough to confirm that patients with p53 mutations need to be treated differently with alternative approaches rather than the standard of care.

Chronic lymphocytic leukemia (CLL) is a few steps ahead of MCL, and p53 mutations now dictate how we treat those patients upfront. I do believe that MCL, which has the highest genetic instability, should follow that approach. The more genetically unstable a disease is, the more prone to resistance it is. Treatment for these patients continues to be an unmet clinical need. Based on the CLL experience, I am proposing a phase II study where we could use B-cell receptor inhibitors, BCL-2 inhibitors, and monoclonal antibodies. In my opinion, obinutuzumab (Gazyva) will be better than rituximab in that context.

What else is known about MCL subtypes?

MCL is a spectrum of diseases with an indolent form, which people need to be aware of. Most of these patients don't even require a treatment or intervention. Certainly, they have a genetic operation where they behave differently. Within MCL, there is a very strong signal that the blastoid variant doesn't behave like the classical one. For sure, the subset of patients with a very high Ki-67 behave differently than those with low Ki-67. In my study, we looked at the Mantle Cell Lymphoma International Prognostic Index (MIPI) scoring system, and we demonstrated that the higher the MIPI, the worse the outcome. The main point that needs to be taken from this is that blastoid subtypes, and patients with high Ki-67, and obviously, p53 disruption, need to be treated differently.

Additionally, this might be a provocative statement, but we also may be overtreating the classical subtype of patients. We use intensive induction therapy, ASCT, and rituximab maintenance. We can't prove this until we have a randomized trial, but I strongly believe this.

Elhassadi E, Hennessy B, Kumar S, et al. TP53 status in mantle cell lymphoma (MCL)-a 10 year single center experience. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract PF493.

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