Tycel J. Phillips, MD

Tycel Phillips, MD, clinical associate professor, the Division of Hematology and Oncology, the Rogel Cancer Center, Michigan Medicine, University of Michigan Health, discusses recent changes in the mantle cell lymphoma (MCL) treatment landscape.

During a presentation at the National Comprehensive Cancer Network 2022 Annual Congress: Hematologic Malignancies, Tycel Phillips, MD, provided background on some of the 

effective treatment options currently available for patients with MCL.

He described each of the agents in depth, including their safety profiles, effectiveness, and explained the patients who would benefit most from each therapy.

The needle shifted with the approval of the BTK [Bruton tyrosine kinase] inhibitors, which initially started with ibrutinib [Imbruvica]. The original paper from Michael Wong, MD, indicated progression-free survival of the group was around 13.9 months, which at that point was substantial in that patient population, and an overall response rate of around 60%. That shifted how we went about things. After, Simon Rule, MD, combined several ibrutinib studies indicating that the BTK inhibitor was far more effective in the second-line, and in the third-line setting. With patients who got a complete remission with ibrutinib in the second-line setting, the duration of response was almost 5 years. From that, it cemented that we should be using this agent in the second-line setting in an effort to get the longest remission possible for most of our patients.

Thereafter, we had second generation BTK inhibitors, acalabrutinib [Calquence] and zanbrutinib [Brukinsa] which have come onto the market. A lot of those have come onto the market specifically due to some of the toxicities that we know exist with ibrutinib in the hope that these drugs have more fidelity to the BTK receptor and less off target impact. We may see less side effects and we will have in patients come off of ibrutinib [due to] bleeding, atrial fibrillation, arthralgias, myalgias, which are muscle and bone pain, and joint aches and pains, infection, and some of the newer cardiovascular risks that we see like hypertension and ventricular arrhythmias.

It does appear that some of these side effects may be a class effect and not specifically related to ibrutinib. All in all, it does still appear that all these drugs are very efficacious. You have some different side effects between acalabrutinib, zanbrutinib, etc., but with more time, we will truly get a sense of the side effect profile of those drugs.

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Tycel Phillips, MD, discusses recent changes in the mantle cell lymphoma treatment landscape.


Changes in the MCL Treatment Landscape

Mantle cell lymphoma (MCL) is a rare B-cell malignancy with a heterogeneous clinical course without a true standard of care. To date, several treatment regimens have been used in the treatment of patients with newly diagnosed MCL. With few randomized phase 3 trials to pull data from, most treatments are typically dictated by region and institutional preference vs clear scientific rationale. Nevertheless, there have been marked improvements in expected remission and overall survival (OS) rates even though a cure for this disease remains elusive.

Treatment for most patients is a dichotomy based on transplant eligibility: High-dose chemotherapy, which invariably includes cytarabine (Nordic regimen, R-hyper-CVAD [rituximab, cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), dexamethasone], R-DHAOx/CHOP [rituximab, dexamethasone, high-dose cytarabine, oxaliplatin/cyclophosphamide, doxorubicin, prednisone, vincristine]), is followed by an autologous stem cell transplant (ASCT) followed by maintenance R or “less intense” chemoimmunotherapy (CIT) followed by maintenance R.

In a presentation titled, “The Role of Targeted Therapies in Frontline Treatment of Mantle Cell Lymphoma,” Tycel J. Phillips, MD, clinical associate professor, University of Michigan Health in Ann Arbor, Michigan, addressed strategies to manage high-risk patients.

Maintenance R is universally accepted as beneficial in MCL as it improves progression-free survival (PFS) and OS.

Data from 2 studies have established bendamustine-rituximab (BR) as superior to R-CHOP2,

 as initial therapy in patients considered unfit for ASCT and the regimen is preferred for most in this patient population.

Additionally, BR has blurred the lines of our dichotomy and has been used as a preferred pretransplant regimen for some patients based on its sound combination of efficacy and tolerance.

However, given the toxicities of CIT and the desire to improve outcomes in very high-risk patients, studies seeking to incorporate novel therapies into the frontline treatment of patients with MCL have been undertaken. These have included combination studies of CIT plus novel agents or agents devoid of traditional chemotherapy.

One of the first studies sought to improve outcomes of patients treated with R-CHOP by substituting the proteasome inhibitor bortezomib (Velcade) for vincristine. This regimen, VR-CAP (bortezomib, rituximab, epirubicin, cyclophosphamide, prednisone),

 was demonstrated in a randomized study to be superior to R-CHOP in participants unfit for ASCT. The addition of bortezomib to BR was also explored in a phase 2 study.

 Despite positive outcomes, neither combination has equivalent uptake to BR. The SHINE study (NCT01776840)

further explored combination therapy with BR and findings were presented at the 2022 American Society of Clinical Oncology Annual Meeting.

This study randomly assigned transplant-ineligible patients with MCL to BR vs BR plus the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib (Imbruvica). Although the study met its primary end point, demonstrating a marked difference in PFS in the experimental arm, its impact on the treatment landscape is less settled.

There was no OS benefit, likely due to higher than anticipated non–disease-related deaths in the experimental arm. Questions about how this would compare with sequential therapy and the lack of tangible benefit in patients with a 

mutation makes mainstream adoption of the regimen doubtful.

The sister study to SHINE, ECHO (NCT02972840), which is evaluating BR with acalabrutinib (Calquence), is currently maturing. We anxiously await the results before putting any nail into the coffin of combination CIT and BTKi in frontline MCL.

Other studies have explored BTKi without chemotherapy in frontline MCL. BGB-3111-306 (NCT04002297) is an ongoing trial that randomly assigns patients who are unfit for ASCT to receive zanubrutinib (Brukinsa) plus R vs BR. Additionally, investigators have been examining R + ibrutinib (IR) in 2 studies conducted at The University of Texas MD Anderson Cancer Center, WINDOW-I and WINDOW II.

The WINDOW-I7 study (NCT02427620) evaluated a year’s induction of IR followed by R-hyper-CVAD consolidation for up to 4 cycles. The data demonstrated a high ORR after the 1-year treatment of IR and led to the development of WINDOW II (NCT03710772),which is incorporating the BCL-2 inhibitor venetoclax into induction. In an elderly population, the investigators are again exploring IR.

 They noted an impressive ORR but high rates of toxicity and treatment discontinuation, suggesting that ibrutinib might not be the ideal BTKi for this patient population. The first truly chemotherapy-free regimen utilized not a BTKi but the immunomodulatory agent lenalidomide, plus R. The R2study

 by the Cornell group (NCT01472562) was the first to demonstrate a high and durable response rate without CIT with long-term follow up.10 Given the study design, the results offer some hope that CIT could be avoided in all patients irrespective of age or fitness. How to manage the 20% to 30% of high-risk patients, including those with aberrations of 

, NOTCH, complex cytogenetics, and other identified high-risk features,

 is a mystery, with poor OS noted with the regimens previously discussed.

Data from several ongoing studies are encouraging but remain too immature to fully comment on. Some promising treatments for these patients have yet to be explored in the frontline setting. Chimeric antigen receptor (CAR) T-cell therapy has mature and impressive efficacy in these high-risk groups but follow-up data have indicated continual relapses, suggesting this treatment might not be the “holy grail” for these patients.

 However, this is confounded by the nature and complexity of relapsed disease as well as the impact of bendamustine and other therapies on the function of T cells utilized in CAR T-cell therapy. Based on a similar mechanism of action, CD20/CD3 bispecific antibodies hold significant promise in MCL, but thus far, large, mature data sets are lacking. Although CAR T-cell therapy and use of bispecific antibodies are intriguing options for frontline MCL management, especially in patients with high-risk disease, both treatments are associated with several barriers. For CAR T-cell therapy, accessibility remains a crutch that we cannot seem to overcome outside select regions of the country. The adverse event profile with cytokine release syndrome (CRS)/immune effector cell–associated neurotoxicity syndrome is still not something all hematologists/oncologists can manage and it is largely hampered by patient hesitation to travel to centers that offer CAR T-cell therapy. Bispecific antibodies hold the promise of greater accessibility with less concern about insurance approval, yet still have immature data and an adverse event profile that includes CRS, which hampers their integration into the community. All in all, several attempts have been made to move targeted agents into frontline MCL treatment, with some success but not the monumental paradigm shift that has occurred in other diseases. Nevertheless, the future for these patients holds some promise as several studies are still pending readout and several newer treatments have yet to make their entrance onto the frontline stage.

1. Le Gouill S, Thieblemont C, Oberic L, et al; LYSA Group. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. 

. 2017;377(13):1250-1260. doi:10.1056/NEJMoa1701769

2. Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. 

. 2014;123(19):2944-2952. doi:10.1182/blood-2013-11-531327

3. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. 

. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2

4. Robak T, Jin J, Pylypenko H, et al; LYM-3002 Investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. 

 2018;19(11):1449-1458. doi:10.1016/S1470-2045(18)30685-5

5. Gressin R, Daguindau N, Tempescul A, et al; Lymphoma Study Association. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma. 

. 2019;104(1):138-146. doi:10.3324/haematol.2018.191429

6. Wang ML, Jurczak W, Jerkeman M, et al; SHINE Investigators. Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma.

. 2022;386(26):2482-2494. doi:10.1056/NEJMoa2201817

7. Wang ML, Jain P, Zhao S, et al. Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial. 

. 2022;23(3):406-415. doi:10.1016/S1470-2045(21)00638-0

8. Jain P, Zhao S, Lee HJ, et al. Ibrutinib with rituximab in first-line treatment of older patients with mantle cell lymphoma.

 2022;40(2):202-212. doi:10.1200/JCO.21.01797

9. Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. 

. 2015;373(19):1835-1844. doi:10.1056/NEJMoa1505237

10. Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. 

. 2018;132(19):2016-2025. doi:10.1182/blood-2018-07-859769

11. Jain P, Dreyling M, Seymour JF, Wang M. High-risk mantle cell lymphoma: definition, current challenges, and management. 

. 2020;38(36):4302-4316. doi:10.1200/JCO.20.02287

12. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. 

. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347

13. Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study.

. Published online June 4, 2022. doi:10.1200/JCO.21.02370

Articles

There have been marked improvements in expected remission and overall survival rates in mantle cell lymphoma even though a cure for this disease remains elusive.

The Role of Targeted Therapies in Frontline Treatment of Mantle Cell Lymphoma

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.

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.