Intriguing Strategies Taking Shape in Mantle Cell Lymphoma

Michael Wang, MD

The mantle cell lymphoma (MCL) paradigm is facing a time of exploration, as researchers examine different therapeutic options beyond chemotherapy, with a focus on CAR T-cell therapy and combination regimens, explained Michael Wang, MD.

“Lymphoma treatment is progressing very fast. We leave the accelerated history of my kind,” said Wang, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center. “I am very happy to be sitting at the center of the storm to cure MCL and hematologic malignancies.”

Wang is reaching the end of a small pre-study that is part of the large, multicenter, double-blinded ECHO study (NCT02972840), which is looking at bendamustine/rituximab (Rituxan) plus acalabrutinib (Calquence) versus placebo, including patients with newly diagnosed MCL.

CAR T-cell therapy also is a focus of MCL treatment and is being explored in the TRANSCEND NHL 001 trial of lisocabtagene ciloleucel (liso-cel) and the ZUMA-2 trial of axicabtagene ciloleucel (axi-cel; Yescarta). Phase I data of the TRANSCEND NHL 001 trial showed that liso-cel induced an objective response rate (ORR) of 71% among patients with relapsed/refractory MCL. The anti-CD19, 4-1BB—containing CAR T-cell product also had a low incidence of grade 3/4 cytokine release syndrome and neurotoxicity.

In an interview with OncLive during the 2019 SOHO Annual Meeting, Wang discussed ongoing studies in the MCL field.

OncLive: Could you discuss research involving adding acalabrutinib to bendamustine and rituximab in patients with relapsed/refractory MCL?

Wang: The standard of therapy for MCL is still bendamustine/rituximab. Bendamustine is a very modern chemotherapy drug, but it is still chemotherapy. By adding the second-generation BTK inhibitor, we hope to improve the response rate of progression-free survival and possibly overall survival. This is a small study of about 20 patients who relapsed on upfront therapy. It is the pre-study before the massive double-blinded, placebo-controlled ECHO trial. This is now enrolling all over the world into 250 centers, including 550 patients with MCL patients, to compare bendamustine/rituximab plus acalabrutinib with placebo. It will change the standard of therapy.

This data cutoff is in 2019, but we want a later data cutoff. In the meantime, we will continue the ECHO clinical trial enrollment. It could possibly change the international standard of MCL treatment in the elderly patient population with newly diagnosed disease.

CAR T-cell therapy is being explored in MCL; one study of which is the TRANSCEND NHL 001 trial of lisocabtagene ciloleucel. Are there any updates?

The TRANSCEND NHL 001 study has very good trial results for CD19-targeting CAR T-cell therapy. The major difference between [that study and the ZUMA-2 trial is in TRANSCEND NHL 001], the cold stimulator molecule is 4-1BB. With this cold molecule difference, I have experienced a very good safety and efficacy profile [with liso-cel]. There is [also] a good possibility that the FDA may consider the approval of CAR T-cell therapy against CD19 with the ZUMA-2 study [of axi-cel].

My patients with MCL really need a cellular therapy, but cellular therapies are lagging behind diffuse large B-cell lymphoma data. We want to catch up to treat these patients with MCL, save their lives, and move the MCL cohort forward.

How could CAR T-cell therapy play a role in MCL treatment?

CAR T-cell therapy is the answer for the resistant tumors that we are facing. We know that not one modality could cure any disease, especially when we are talking about the lymphoma therapies. Initially, we started with a chemotherapy era. We were able to cure a big portion of patients with Hodgkin lymphoma, but only a small portion of those with non-Hodgkin lymphoma (NHL). Once this lymphoma progressed, we figured out that targeted antibodies, such as rituximab, ibrutinib (Imbruvica), and venetoclax (Venclexta), could rescue some of the patients who are already resistant to chemotherapy.

Now, we are facing double resistance. Patients with NHL are resistant to both chemotherapy and the targeted therapies. We have a new modality: CAR T-cell therapy. Thus far, about 30% to 40% of people with NHL treated with CAR T-cell therapy could go into a long-term remission, but 60% to 70% of patients become resistant to CAR T-cell therapy. Therefore, we are facing triple resistance.

What are we going to do after CAR T-cell therapy in patients with triple resistance? In my opinion, precision medicine is the only medicine. We need to use the multimodality sequencing in DNA, RNA, progenomics, and epigenetics, the biological methods that decide on resistance in patients. The patient could be resistant to three [types of] therapies, but each of them would have a different mechanism. With personalized therapy, we could find that the driving resistance in mechanisms for each patient.

Moving onto other agents, what potential does zanubrutinib have?

There are 2 generations of BTK inhibitors. The first-generation, which includes ibrutinib, was approved in 6 indications, but the first indication was in relapsed MCL in November 2013. The second-generation BTK inhibitor acalabrutinib is a similar mechanism, but is slightly different in the molecular design. However, it still binds to the BTK target.

Zanubrutinib is a very positive drug. The first- and second-generation BTK inhibitors do not differ in any significant manner in the efficacy, but they differ in toxicity profile. For example, ibrutinib leads to atrial fibrillation, infection, muscle spasms, infection, and rash. Acalabrutinib is very different. It has a common adverse event (AE) of headache, but the other categories of AEs caused by the first generation is very different with acalabrutinib.

Zanubrutinib is the newest BTK inhibitor and does not have significant follow-up time. There are a lot of interesting points for zanubrutinib, and I can see that this agent is more potent than any other BTK inhibitor.

My center is studying the LOXO-305, which is a reversible BTK inhibitor. I am very excited to share some data [of this agent] at the 2019 ASH Annual Meeting.

What are your thoughts on the phase I/II data of vorinostat (Zolinza), cladribine (Mavenclad), and rituximab showing a high overall response rate (ORR) in newly diagnosed MCL?

I really like this study. In the newly diagnosed patients with MCL, the ORR is very high at nearly 100% and the complete response rate is also very high at over 90% with vorinostat and rituximab. [These results are] very good, but it's a very small study. It has less than 50 patients and there should be a larger study to investigate this.

Wang M, Gordon LI, Palomba ML, et al. Safety and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (Liso-cel) in TRANSCEND NHL 001. J Clin Oncol. 2019;37(suppl; abstr 7516). doi: 10.1200/JCO.2019.37.15_suppl.7516.