Guidelines for MCL Set to Change Due to COVID-19

Guidelines are available to help summarize the best treatment for patients with mantle cell lymphoma (MCL) across various stages based on the greatest level of evidence available and the most up-to-date data. However, ahead of the eighth annual Society of Hematologic Oncology (SOHO) Meeting, Robert Marcus, MA, FRCP, FRCPath, chair of the MCL session, said, “The landscape has completely changed as a consequence of COVID[-19].”

“Based on the climate, I think we are beginning to change our practice,” said Marcus, a consultant hematologist for HCA Healthcare UK, in an interview. “And I think that the takeaway message now is you need to consider the environment in which you practice….that environment now includes the risk of Covid 19 [coronavirus disease 2019] infection.”

Current Guidelines

A great deal of discussion revolves around standard-of-care induction regimens for patients with MCL and which option to choose. Although many hematologic oncologists have their preferred regimens, the National Comprehensive Cancer Network (NCCN) guidelines for MCL recommend a number of preferred chemotherapy-based treatment regimens, whether a patient is eligible for stem cell transplantation or not, usually followed by maintenance rituximab (Rituxan).¹

Marcus noted that in the United Kingdom, for example, oncologists typically use the Nordic regimen of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and high-dose cytarabine, followed by stem cell transplant for those who are eligible and maintenance therapy.

Steven Le Gouill, MD, PhD, of Nantes University Hospital in France, discussed available options for frontline treatment of patients with MCL and data supporting the various options. Optimal use of these chemoimmunotherapy regimens are constantly being refined for specific patient populations and compared to determine which combination leads to better outcomes.

Marcus suggested that in MCL treatment, as with other hematologic malignancies, there is increasingly a push to move away from chemotherapy-based regimens. As such, studies are examining the possibility of moving regimens such as combinations with Bruton tyrosine kinase (BTK) inhibitors into earlier settings.

Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, presented subgroup findings from the SYMPATICO trial of 1 such chemotherapy-free frontline regimen of ibrutinib (Imbruvica) and venetoclax (Venclexta) for the treatment of older patients with MCL or those with a TP53 mutation.

Previous data released from the safety run-in portion of this phase 3 trial demonstrated a manageable safety profile for the combination with no clinical cases of tumor lysis syndrome reported and few dose-limiting toxicities observed.²

The use of BTK inhibitors in the relapsed setting, however, is well established and has played a significant role in the treatment of patients with MCL over the past several years, starting with the first-generation BTK inhibitor ibrutinib, which now has more than 7 years of follow-up data.³ In a recent analysis of pooled data for the use of ibrutinib in patients with relapsed/refractory MCL with extended follow-up of up to 7.5 years, the BTK inhibitor induced a median progression-free survival of 25.4 months (95% CI, 17.5-51.8) and a median overall survival of 61.6 months (95% CI, 36.0-not evaluable) among patients who had only received 1 prior line of therapy.

First-generation ibrutinib has been associated with an increased risk of atrial fibrillation and bleeding, but these adverse effects are generally manageable. Use of newer second-generation BTK inhibitors, such as acalabrutinib (Calquence) and zanubrutinib (Brukinsa), are associated with reduced rates of atrial fibrillation and are gaining popularity as physicians become more comfortable with them. However, results of head-to-head comparisons between these BTK inhibitors have yet to be published

For patients who relapse, do not respond, or are intolerant to BTK inhibitors, treatment options become more limited. The latest addition to the treatment paradigm for MCL in the relapsed/refractory setting is the CAR T-cell agent brexucabtagene autoleucel (formerly KTE-X19; Tecartus), which was approved by the FDA on July 24, 2020.⁴

This represents the first chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of MCL. The approval was based on findings from the phase 2 ZUMA-2 trial, which demonstrated an objective response rate of 93% among the first 60 patients treated with the CAR T-cell agent and a complete response rate of 67%. The overall response rate was 85%, with complete responses in 59%. At 1 year, the estimated overall survival rate was 83%.⁵

However, because brexucabtagene autoleucel was associated with significant toxicities, including risk of cytokine release syndrome and neurologic toxicities, the FDA required the implementation of a risk evaluation and mitigation strategy (REMS)

Brexucabtagene autoleucel was quickly added to the most recent edition of the NCCN guidelines (updated August 4) as a new treatment option after the use of chemoimmunotherapy and BTK inhibition.1 The guidelines also call attention to the potentially severe toxicities from treatment and stress that any facility that administers brexucabtagene autoleucel must be enrolled in the REMS program.

The use of CAR T-cell therapy is interesting, Marcus said, but suggested that it may only be used when there are no other less toxic options for the patient.

The various treatment options available in the relapsed setting were reviewed during the meeting in a presentation by Jonathon B. Cohen, MD, MS, of the Winship Cancer Institute of Emory University School of Medicine in Atlanta, Georgia.

In Light of COVID-19

Treatment recommendations for patients with MCL may be changed significantly, however, due to the coronavirus disease 2019 (COVID-19) pandemic.

To avoid the risk of infection, oncologists are considering the use of treatments that would allow patients to avoid coming into medical facilities. Typically, nonchemotherapeutic agents, such as BTK inhibitors, are saved for later lines of therapy in MCL, but Marcus said that hematologic oncologists are questioning whether these agents should now be considered for earlier lines of therapy—despite the findings of randomized trials—to avoid frequent attendance for infusional chemotherapy in medical centers because these patients are often immunosuppressed, putting them at even higher risk for contracting the virus.

“The environment of this pandemic means that we should be actively considering chemotherapy-free combinations, even if the data aren’t quite strong enough yet , because although the alternative in terms of freedom from disease might be better, the risk of dying and the long term consequences of infection are significantly

greater,” Marcus said. “I think there will have to be some adaptations of our therapy, according to the immunosuppression associated with new and old therapy, and of course, not just the immunosuppression, but the facility and the country where such patients are treated .”

As such, rather than the standard induction regimens like hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and R-CHOP, many physicians and their patients may turn to chemotherapy-free options like ibrutinib so that patients can continue treatment indefinitely from home with telehealth follow-ups every few months.

Additionally, Marcus suggested that the threshold for patients with low-grade MCL who require therapy will be raised. Many patients with MCL do not require treatment, especially those with indolent, asymptomatic disease, and are instead observed until the disease becomes

symptomatic and/or more aggressive. However, this management plan may now have to extend beyond this specific patient population to more patients with low-grade disease, and active treatment will be prioritized only for patients who cannot delay treatment.

The European Society for Medical Oncology has released a set of guidelines for the management of patients with cancer during the COVID-19 pandemic. The guidelines offer recommendations for the prioritization of treatment for patients with MCL.⁶

These guidelines suggest that induction therapy is high priority, although treatment schedules can be altered to reduce the number of clinic visits, and that granulocyte colony-stimulating factor support can be given to avoid neutropenia. Systemic therapy in the setting of relapsed disease can also be modified to reduce the number of visits, but T-cell suppressive agents should be avoided. Other treatments may be delayed, including consolidation and maintenance therapy.

“We are considering whether or not bendamustine is the right drug to give for patients considering the associated long term T-cell suppression, and we are considering how many visits patients need to make to the hospital for chemotherapy given the current risk of COVID-19,” Marcus said. “I think that there’s going to be a reduction in intensity of therapy [for] patients with all hematologic malignancies except for the truly curable.

“I think there’s a whole series of factors which will, apart from the efficacy of the drugs themselves, have a major influence on the way we practice in the COVID[-19] era.”

_References:

_{1. NCCN Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2020. Accessed August 10, 2020. https://bit.ly/3ipqKGS}

_{2. Wang M, Ramchandren R, Chen R, et al. Results from the safety run‐in period of the SYMPATICO study evaluating ibrutinib in combination with venetoclax in patients with relapsed/refractory mantle cell lymphoma. Hematol Oncol. 2019;37(S2):333-335. doi:10.1002/hon.146_2630}

_{3. Rule S, Dreyling MH, Goy A, et al. Long-term outcomes with ibrutinib versus the prior regimen: a pooled analysis in relapsed/refractory (R/R) mantle cell lymphoma (MCL) with up to 7.5 years of extended follow-up. Blood. 2019;134(suppl 1):1538. doi:10.1182/blood-2019-124691}

_{4. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. News release. FDA. July 27, 2020. Accessed August 10, 2020. https://bit.ly/3gVeKwo}

_{5. Wang M, Munoz J, Goy A, et al. KTE-X19 car T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331- 1342. doi:10.1056/NEJMoa1914347}

_{6. ESMO management and treatment adapted recommendations in the COVID-19 era: diffuse large B-cell lymphoma, mantle cell lymphoma and aggressive T-cell lymphomas. European Society of Medical Oncology. Accessed August 10, 2020. https://bit.ly/3fIw86c}