MCL Armamentarium Expands, But Quest Continues for Curative Approaches

Ann S. LaCasce, MD, MMSc

The field of mantle cell lymphoma (MCL) has progressed considerably in recent years with the emergence of several practice-changing agents that have led to significant increases in survival, said Ann S. LaCasce, MD, MMSc. Now, investigators are shifting their focus to CAR T-cell therapy in the hunt for a curative approach.

“We have seen a lot of progress in mantle cell lymphoma, even before the novel agents came along using more intensified induction regimens followed by autologous transplant in younger patients,” said LaCasce, director of Dana-Farber/Partners CancerCare Hematology-Medical Oncology Fellowship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School. “We have patients with median survivals of 7 or 8 years where it used to be 3 years, even before ibrutinib (Imbruvica) came on the scene.”

The FDA granted an accelerated approval to ibrutinib in 2013 for the treatment of patients with MCL who have received at least 1 prior therapy. The decision was based on data from a single-arm, phase II clinical trial, which showed that the agent induced a durable improvement in overall response rates (ORR).¹ Since then, ibrutinib has been a key player in the treatment of these patients.

The accelerated approval of acalabrutinib (Calquence) followed in 2017. Long-term follow-up data with the agent, which was presented at the 2018 ASH Annual Meeting, demonstrated that responses, progression-free survival (PFS), and overall survival (OS) confirmed its efficacy in patients with relapsed/refractory disease.² Although ibrutinib and acalabrutinib have not been compared head-to-head, the latter may have better tolerability, according to LaCasce.

In recent years, venetoclax (Venclexta) has also emerged as a promising agent in the space. Long-term follow-up data from a dose-escalation phase I trial, which were also presented at the 2018 ASH Annual Meeting, showed that single-agent venetoclax resulted in durable responses in those with relapsed/refractory disease, with a low rate of late-onset toxicities.

At a median follow-up of 27 months, investigators reported that the median duration of response was 15.7 months (95% CI, 4.2-30.4) among responders in the study, which included 28 patients with MCL. Furthermore, the ORR in those who received the agent was 75.0% (n = 21), with 21.4% (n = 6) of patients achieving a complete response and 53.6% (n = 15) of patients experiencing a partial response.³

Despite these advances, an unmet need remains in the form of patients who develop resistance to BTK inhibitors. These patients are often incurable, as they are left with minimal options. Now, the hope is for CAR T-cell therapy to be the approach that could help fill that void.

The CD19-targeted CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) is being evaluated in the ongoing, phase II ZUMA-2 trial (NCT02601313). The trial is currently enrolling patients with relapsed/refractory MCL into 2 dose level cohorts that will contain approximately 40 patients each. Following leukapheresis and manufacturing, patients will undergo conditional chemotherapy and then receive a single infusion of KTE-C19 cells at a dose of 0.5 x 10⁶ CAR T cells/kg. The estimated primary completion date of the study is July 2019.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, LaCasce highlighted the therapeutic progress in the treatment of patients with MCL, key remaining challenges, and where future research is headed.

OncLive: What are some of the key advances that have been made in the MCL paradigm?

LaCasce: Ibrutinib is a very active drug, as is acalabrutinib. We’re using a lot of acalabrutinib in the first relapse setting because it is a little bit better tolerated than ibrutinib, with very similar efficacy. That has been a great option, and then there is venetoclax, too. Venetoclax is a very well-tolerated drug with the exception of the risk of tumor lysis, which has been very well laid out in terms of how you manage that.

It's going to be very interesting to see [where future research goes]. Should we be combining these drugs and adding an antibody to [achieve] minimal residual disease status? What about CAR T cells? [Should we be using that approach] as a bridge? It is really the first time that we're seeing some great [options in the] second-line setting and beyond for MCL.

What are some key challenges that need to be addressed?

[The challenge is] the blastoid variant in patients who have p53 mutations. We know those patients tend to have very aggressive disease. When [these patients are] on ibrutinib and [the treatment is stopped], their disease can accelerate extremely rapidly, and this is a huge challenge. We know that patients with p53 mutations probably don't benefit from autologous stem cell transplant, so we need better options for that subset of patients.

Where do you see the field heading?

We need more curative options; perhaps CAR T-cell therapy [will be curative]. We presume that most patients will fail autologous stem cell transplant at some point, so having more trials, more novel immunotherapy treatments, combinations of CAR T-cell therapies, other approaches, or off-the-shelf immunotherapies, are where we need to see the field going.

References

1. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516. doi: 10.1056/NEJMoa1306220.
2. Wang ML, Rule S, Zinzani PL, et al. Long-term follow-up of acalabrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 2876.
3. Davids MS, Roberts AW, Wierda WG, et al. Long-term follow-up of patients with mantle cell lymphoma treated with venetoclax monotherapy. Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 2883.