Emerging Chemotherapy-Free Approaches Raise Sequencing Questions in MCL Management

Martin F. Dietrich, MD, PhD

Although chemotherapy and autologous stem cell transplant (ASCT) have historically served as standard-of-care (SOC) treatment options for patients with mantle cell lymphoma (MCL), the paradigm continues to evolve and expand with novel combinations comprised of BCL-2 and BTK inhibitors and the emergence of CAR T-cell therapy, according to Martin F. Dietrich, MD, PhD, who projected that the future of care will focus on chemotherapy-free approaches.

“We are currently experiencing a cultural clash between the traditionally established chemotherapy-based regimens and newer targeted- or immunotherapy-based approaches by either monoclonal antibody blockade or cell-based CAR T-cell approaches,” Dietrich said. “[As such,] the question [goes beyond] what are the unmet needs, [and shifts to,] what is the right sequence for patients? How can we provide an optimal outcome in the long run for patients that is including the curative-intent setting as well as maintaining the best quality of life and the lowest [toxicity] burden?”

In an interview with OncLive^®, Dietrich, a medical oncologist at the Florida Cancer Specialists & Research Institute, highlighted recent updates in MCL treatment, explained how new developments have raised sequencing questions, and projected where future research efforts will focus.

OncLive^®: What is the current SOC for MCL?

Dietrich: MCL is a complex disease; it is a highly aggressive lymphoma subtype. Treatment has tremendously evolved over the past couple of years. First-line treatment is dependent on the risk assessment of the disease, as well as a patient’s performance status. It typically consists of combination therapy, [specifically] chemotherapy plus rituximab for clinically fit and higher-risk patients, and de-escalatory chemotherapy strategies for patients with lower-risk disease or [those with] poor performance status.

In follow-up to high-risk disease, ASCT has found a role, [although] it is not clear whether this [approach] is going to be as impactful now as subsequent lines of therapy have improved. [Regardless,] ASCT is certainly still recommended in many circumstances, as well as maintenance rituximab for those in the post-chemotherapy setting after initial induction.

The phase 2 WINDOW-1 trial (NCT02427620) examined the combinations of ibrutinib (Imbruvica) and rituximab (Rituxan) in the frontline setting. What are the clinical implications of using this chemotherapy-free regimen?

The WINDOW-1 study evaluated the possibility of utilizing a chemotherapy-free combination option in the first-line setting, followed by chemotherapy, allowing for an interim analysis of response to treatment up front. We have seen fantastic responses to BTK inhibitors in second-line treatment. We have [seen] FDA approvals for 3 agents that are currently available for treatment; [these agents] have served, not only as a bridge to CAR T-cell therapy, but as standalone treatment. [They have bee] well developed [for] single-agent [use]. We have seen improving efficacy with the addition of rituximab.

WINDOW-1 was an attempt to learn from our experiences in the second-line setting [and apply these lessons] to the first-line setting [and it had] an overwhelming impact. [We saw] a response rate of 98%, with a tremendous amount of pathological responses. [The data demonstrated that] ibrutinib and rituximab hold not only the potential of being moved into the first-line setting as a combination strategy, but [also [potentially] in a standalone setting, [although those data are still maturing]. It may be possible to take [ibrutinib and rituximab] out of the second-line setting and maybe spare patients from significant toxicities [that they had been experiencing with] first-line therapy.

As more novel strategies, such as CAR T-cell therapies, targeted therapies, and immunotherapy-based approaches continue to emerge, what are some of the factors that need to be considered when making treatment decisions?

We have seen very impressive and durable responses in the ZUMA-2 trial [NCT02601313] targeting surface epitopes in the MCL patient population. Those can be a viable carrier of antitumor response and effective in [providing] long-term, durable control. Oftentimes, unfortunately, [these products] have been used in a setting where patients already have had significant pretreatment. We need to figure out what the right sequence is for patients.

Cost is also something we need to keep in mind—not just [the cost] for individual therapies, but a whole cost analysis. When looking at chemotherapy plus ASCT plus maintenance rituximab, which is the current SOC in the first-line setting, that does not have to be cheaper and more cost effective than a later-line CAR T-cell therapy. It is going to require additional experience and economic analysis to aid in that decision making to not only harden the scientific evidence that first-line usage of targeted therapies and immunotherapy-based therapies is feasible, but also cost efficient.

From a patient perspective, this would be highly desirable. Although those medications are not free [of toxicities], the overall experience for patients is more favorable. We see a lesser burden of [toxicity] and the chance for long-term, positive disease outcomes.

Where is research headed?

For [the] future of MCL treatment, we are going to see a [pattern of] development [that is like what] we have [observed] in chronic lymphocytic leukemia and other hematologic malignancies, where we are moving away from chemotherapy into combination strategies

One particular interest is the targeting of antiapoptotic proteins, the BCL-2 inhibitors that are going to be feasible [because] we know that a favorable toxicity profile already exists [with them], both in combination with BTK inhibitors, as well as combinations with anti-CD20 antibodies. This might be coming sooner rather than later and may push the need for chemotherapy back further.

[It will also be important to make] therapy accessible and available for patients of poorer performance status or for those who are declining chemotherapy, based on age or concern about AEs. The combination strategies and the sequencing questions that are being posed are going to be the most important next steps for the development of MCL treatment.

I am excited about all the new [advances] that we have [made]. Just a few years ago, chemotherapy [alone] and chemotherapy plus [ASCT] were the only available options in the multi-line setting of relapses. Opening up this space for more precise and elegant therapies is a tremendous progress for patients. Plenty more therapies will [emerge]. The question will then become: How do we optimize the individual application [of these new agents]? Are there certain factors that would favor [the use of 1 agent over another in certain] patients?

Going back to the ibrutinib/rituximab combination [examined] in WINDOW-1, many patients really did not seem to require chemotherapy. Allowing chemotherapy to become obsolete eventually is 1 of the major points of excitement for MCL treatment.

What is your take-home message regarding key advances in MCL that your colleagues should be aware of?

MCL is now becoming a more complex disease. We must discuss and present a patient with all options; this is especially[ important] for those of us who are community-based. For both ASCT and CAR T-cell therapy, the involvement of an academic center [is needed], as their broad availability is not yet ready. [Regardless,] these [options] should be discussed. This is also an opportunity for clinical trials and innovative cell-based therapies that should be reviewed in a multidisciplinary setting from the get-go.

Clearly, the MCL patient population is still facing a high-risk disease. Working together as a team and providing the best possible care [through] a multidisciplinary approach is the key to optimizing outcomes and simplifying the experience for patients.

CAR T-cell therapies, like other therapies, have been democratized in their geographical distribution. Hopefully, they will be available soon in many more locations so that [more] patients will have access. I also hope that we will be able to move these therapies up in our treatment paradigm.

This is a complex space, and I always recommend a second opinion for these difficult-to-treat diseases. [We need] look at all aspects of a patient's care, [and then follow this with the] execution of a plan with a goal of cure for patients and a long-term remission.