Tycel J. Phillips, MD

Tycel Phillips, MD, a clinical associate professor of hematology and medical oncology at the University of Michigan, discusses the need for more effective agents for treating patients with relapsed/refractory mantle cell lymphoma (R/R MCL) as alternatives to chimeric antigen receptor (CAR) T-cell therapy.

According to Phillips, the only therapy with significant efficacy for patients with R/R MCL who have failed to benefit from Bruton tyrosine kinase (BTK) inhibitors is brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy. Other agents, including venetoclax (Venclexta), lenalidomide (Revlimid), and PI3 kinase inhibitors such as idelalisib (Zydelig), have not been effective in this setting. One option that may offer benefit for these patients is bendamustine and cytarabine, but many patients have already received these agents before BTK inhibitors.

Phillips notes that in Michigan, only 3 centers offer CAR T-cell therapy for MCL, all in the southeast part of the state, leaving many patients without easy access to treatment. Patients would need to travel long distances or be separated from their families to receive infusions, leading many patients to avoid treatment.

Therefore, he says there is a serious unmet need for new therapies that can be given post-BTK inhibitors without requiring patients to go outside their community. Phillips is currently investigating the bispecific antibody glofitamab, 

which shows potential efficacy in this setting

As of right now, the only real agent we have that has shown any demonstrable efficacy in this R/R MCL population post BTK inhibitors has been the CAR T product from [Kite Pharma]. As for agents that we've explored—venetoclax, lenalidomide, the PI3 kinase inhibitors all have shown to be very ineffective in this patient population. There is a retrospective study that has demonstrated that bendamustine and cytarabine appears to be effective, but a lot of these patients will have already seen bendamustine. And a lot of them will already receive cytarabine by the time they fail the BTK inhibitor.

Based on the limited availability of CAR T products to most patients, again, because even in our state, there are only select centers…3 sites within the state that can actually administer this treatment. And they're all for the most part saturated in the southeast corner of Michigan. There's a whole swath of our state that's not necessarily within close proximity to a CAR T center. So again, CAR T is still at this point limited for most patients because of selectivity to where they live in relation to a CAR T center.

A lot of these patients don't have access to a readily-accessible treatment option post BTK inhibitors. A lot of these patients, they can't get to a CAR T center, or they don't want to necessarily be separated from their families, they don't have a lot of great options and will succumb to their disease. So, the post BTK R/R MCL patient is still a patient that has a very high need for new and novel treatments and even more treatment that can actually be given in the community and don't necessarily require being treated at a select center.

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Tycel Phillips, MD, discusses the need for more effective agents for treating patients with relapsed/refractory mantle cell lymphoma as alternatives to chimeric antigen receptor T-cell therapy.

Alternatives to CAR T-Cell Therapy Needed Post-BTK Inhibitor in R/R MCL

Tycel Phillips, MD, a clinical associate professor of hematology and medical oncology at the University of Michigan, discusses the potential use of glofitamab as therapy for patients with relapsed/refractory mantle cell lymphoma (MCL).

Glofitamab is a bispecific antibody that binds to CD20 and CD3. According to Phillips, glofitamab showed high efficacy in a phase 1/2 trial (NCT03075696) that included patients who were previously treated with Bruton’s tyrosine kinase (BTK) inhibitors and those who were not. Patients received obinutuzumab (Gazyva) followed by fixed or step-up doses of glofitamab. Those who had prior BTK inhibitor therapy had an overall response rate (ORR) of 82.4%, while those who had no previous BTK inhibitor had an ORR of 75%.

In terms of adverse events (AEs), all reported cytokine release syndrome (CRS) events were manageable, and there was a single grade 1 neurotoxicity: an immune effector cell-associated neurotoxicity syndrome (ICANS)-like AE. Overall, glofitamab demonstrated a favorable safety profile.

Patients with MCL who do not respond to BTK inhibitors have limited options besides chimeric antigen receptor (CAR) T-cell therapy, which is only available in a small number of treatment centers and not all patients are eligible. If it continues to demonstrate efficacy and tolerability, glofitamab will offer an alternative for patients with advanced MCL that could be given in all treatment centers and private practices.

So, what we were able to establish and demonstrate in this study is a very high efficacy in those patients who were naive to BTK inhibitors and those who were actually exposed and refractory to BTK inhibitors.

So, it proves that this agent could potentially be another option for those who failed BTK inhibitors. As of right now the only effective agent we typically have that we can offer these patients is utilization of the CAR T [cell] treatment, which has its own limitations based on non-select sites that can do [CAR T-cell therapy] and also some of the complications that may prevent some of the older patients being eligible. So, I think one of the key points in addition to the efficacy is the safety of this treatment. We have very low incidence of CRS. We only reported 1 episode of neurotoxicity, which was also a grade 1 neurotoxicity; it resolved very quickly in this treatment modality.

So, in that regard, based on the off-the-shelf applicability of this agent and the ability as of right now to be to be very safe, this is something that potentially could be used in a wider array of treatment facilities, not necessarily select academic centers that are accredited to give CAR T. So in some situations, you can see this given in some private practice facilities, that they've become more accustomed with this agent, which, in essence will allow more patients to be treated with these treatments, compared to what we can sort of see right now with some of these more limited treatments such as CAR T.

Tycel Phillips, MD, discusses the potential use of glofitamab as therapy for patients with relapsed/refractory mantle cell lymphoma.

Glofitamab Shows Efficacy in BTK Inhibitor-Refractory MCL

Tycel J. Phillips, MD, assistant professor at the University of Michigan Cancer Center, discusses the design and responses at 8 weeks in a phase 2 trial of parsaclisib in patients with relapsed/refractory marginal zone lymphoma (MZL).

The CITADEL-204 trial has responses from the first 8 weeks, the AEs that occurred in result of the transition to maintenance therapy. Maintenance therapy was administered at 2.5 mg daily versus 20 mg weekly in this study. This dosing was chosen based on some of the other studies that evaluated this agent, according to Phillips. There was a difference in the maintenance dosing due to the response on the trial.

Phillips says that ultimately, the responses were great, the agent was well tolerated, and some of the information that the investigators believed was true, such as the 8-week response, came to fruition. These observations were the key takeaways from this research.

As more data are gathered, the next data that will be looked at are the mature responses, responses that are observed in different MZL subtypes, and the long-term toxicity data. Notably, the adverse events associated with PI3K inhibitors, in general, are one of the greatest roadblocks, according to Phillips. When comparing the data of parsaclisib with other approved agents in this setting, there were some similarities. Due to this, the investigators are hopeful that more agents will be approved in the future.

Tycel J. Phillips, MD, discusses the design and responses at 8 weeks in a phase 2 trial of parsaclisib in patients with relapsed/refractory marginal zone lymphoma.

Phase 2 Trial of Parsaclisib Shows Efficacy in Marginal Zone Lymphoma

Tycel J. Phillips, MD, assistant professor at the University of Michigan Cancer Center, discusses the current treatment options for patients with marginal zone lymphoma (MZL).

MZL is considered a low-grade lymphoma, says Phillips. For a long time, the only approved agent in the field for these patients was single-agent rituximab (Rituxan). The treatment approaches for patient with MZL also appear to piggy-back off those used for patients with follicular lymphoma.

Over the last 2 years, the field has seen a shift toward new advances. The Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) was granted approval for the treatment of patients with MZL, and the combination of lenalidomide (Revlimid) plus rituximab was approved for the treatment of patients with MZL who have been previously treated. These are now the only 2 agents approved for the treatment of these patients, says Phillips, but this is more so because it’s a smaller niche of patients that generally do well with most therapies.

Tycel J. Phillips, MD, discusses the current treatment options for patients with marginal zone lymphoma.

Reviewing Treatment Options for Patients With Marginal Zone Lymophoma

Tycel J. Phillips, MD, assistant professor at the University of Michigan Cancer Center, discusses an ongoing trial looking at acalabrutinib (Calquence) plus bendamustine and rituximab (Rituxan) in patients with treatment-naive or relapsed/refractory mantle cell lymphoma (MCL).

MCL is a rare subset of non-Hodgkin lymphoma and affects 5% to 6% of patients, Phillips says. It is common in patients over the age of 65, as well as in males. However, no official standard of care has been determined.

Tycel J. Phillips, MD, assistant professor at the University of Michigan Cancer Center, discusses an ongoing trial looking at acalabrutinib plus bendamustine and rituximab&nbsp; in patients with treatment-naive or relapsed/refractory mantle cell lymphoma.

Tycel J. Phillips, MD | Authors

Articles

Alternatives to CAR T-Cell Therapy Needed Post-BTK Inhibitor in R/R MCL

Glofitamab Shows Efficacy in BTK Inhibitor-Refractory MCL

Phase 2 Trial of Parsaclisib Shows Efficacy in Marginal Zone Lymphoma

Reviewing Treatment Options for Patients With Marginal Zone Lymophoma

Rationale for Combining Acalabrutinib With Bendamustine and Rituximab in MCL