Luhua (Michael) Wang, MD, discusses the FDA approval of brexu-cel in mantle cell lymphoma and what to know about CAR T-cell therapy in clinical practice.
The approval was based on data from the phase 2 ZUMA-2 trial (cohorts 1 and 2, NCT02601313; cohort 3, NCT04880434). Data from the trial showed that patients in cohort 3 (n = 86) had achieved an overall response rate (ORR) of 91% (95% CI, 82.5%-95.9%) alongside a complete response (CR) rate of 79% (95% CI, 69.0%-87.1%) at a median follow-up of 23 months.1,2 Moreover, patients in cohort 1 (n = 60) achieved an ORR and CR rate of 87% (95% CI, 75%-94%) and 62% (95% CI, 48%-74%), respectively at a median follow-up of 8.6 months.
In an interview with OncLive®, Wang touched on the approval itself and dove into the ZUMA-2 data, key safety considerations for brexu-cel and other CAR T-cell therapies, and how to approach brexu-cel use in clinical practice.
Wang is a professor in the Department of Lymphoma/Myeloma of the Division of Cancer Medicine and the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center in Houston.
Wang:The first 2 cohorts [of ZUMA-2] enrolled BTK inhibitor–treated patients, but the third cohort had 86 patient who were BTK inhibitor naive. With the 86 patients [in cohort 3], the ORR was 91%, the CR rate was 79%, and the toxicity was balanced. If you put all 3 cohorts of patients together, there were approximately 160 patients, and their ORRs and CR rates were high. [Additionally], the cytokine release syndrome [CRS] rate with all cohorts was 12%, and immune effector cell–associated neurotoxicity syndrome [ICANS] rate was 33%. [There are] 5-year data in some cohorts, but also we also have [promising data from] another 86-patient cohort, which is more patients than the first 2 cohorts combined.
Safely Administering CAR T-Cell Therapy in Clinical Practice: Highlights
The FDA finally is convinced that [brexu-cel] is a good therapy that can deliver good efficacy with good OS, [and with] long term follow-up data, they decided to fully approve [brexu-cel for MCL]. [However], the community doctors do not have the means to deal with CAR T-cell therapy–associated toxicities, since almost all the CAR T-cell therapies are infused at CAR T-cell centers. [CAR T-cell centers are] usually tertiary centers approved by all the authorities to carry out the infusion and deal with the toxicities.
The acute toxicities [associated with brexu-cel and other CAR T-cell therapies are] CRS and ICANS. CRS events usually occur approximately 4 days after CAR T-cell infusion and last for approximately 7 days, so within 2 weeks, CRS [usually resolves]. ICANS usually occurs on day 6, but it can last for 19 days. [Therefore,] within 1 month, the most life-threatening CRS and ICANS [events are typically] dealt with, mainly at tertiary centers.
Since many years have passed, we have grown our knowledge [of managing CAR T-cell therapy–related toxicities]. We have found a new therapies for the CRS and neurotoxicity. Those [AEs] are no longer as life threatening as they were in the beginning, because over the years, our skills and knowledge have grown, but mainly because [AEs associated with CAR T-cell therapy] are dealt with in the tertiary and academic centers.
However, when the patients [returns to their primary care providers], infection can come in. Since we have gained effective skills for managing CRS and neurotoxicities, the most life-threatening AE associated with CAR T-cell therapy is now infections. Infections [can be] managed by community oncologists or hematologists. Sometimes we only see textbook [infections] like Aspergillus in the brain or histoplasmosis; even West Nile virus can be found in patients [following CAR T-cell therapy]. We studied those [infections] 30 years ago in medicine, and [we do not often see cases]. Suddenly, because of how profound CAR T-cell therapy is, [we see cases of these infections again].
[CAR T-cell therapy can cause] B-cell aplasia; that means there are fewer B-cells to produce antibodies to fight infections. [Therefore], because of the profound infection risk, community doctors need to know that the number one killer in CAR T-cell therapy are those post–CAR T-cell therapy infections.
I would recommend all community doctors to check immunoglobulin levels and [administer] intravenous immunoglobulin, which has been proven to be effective in preventing infections. [Clinicians should] screen diligently for sinus infections and kill them when they are small. For example, more than one-third of patients of patients receiving CAR T-cell therapy have sinus infections creep into the lungs that become pneumonia and life-threatening. You must pay attention to the sinuses and not only give patients antibiotics.
You also need to make sure that after you deal with [as many AEs as] you can, you tell the patients to watch their sinuses. You need to pay attention to the details. If the patient is aging, their septum might be deviated, which will block the sinuses; [in those patients], infections can never be cleared by all the above [methods]. You have to have an ear, nose, and throat [ENT] doctor correct infrastructure abnormalities [like a deviated septum]; it is important to make sure you refer patients who have recurrent sinus infections to the ENT doctor to make sure their structures are normal.
[For other infections] like urinary tract infections [UTIs], if you cannot clear them, you need to refer the patient to infectious disease doctors for them to figure out, with or without cultures, how to eradicate the UTIs. Following CAR T-cell therapy, other infection risks increase, especially COVID-19; infections have higher incidence and mortality rates. [Therefore], screen for all the viruses and make sure you find COVID-19 [if present].
Not all patients can receive CAR T-cell therapy. Data from approximately 2 years ago showed that only 20 to 30% of patients are eligible to receive CAR T-cell therapy. This is bad.
In Chinese history, philosophy, and literature, there are 3 classes of doctors. The first class of doctors are those who can change and improve the policy, making the country rich and [improving the] economy, so more money is spent on health care to make drugs available, especially therapies like brexu-cel. The second class of doctors are those who can prevent diseases before they occur. I belong to the third class [of doctors]: those who treat the disease as it is when it occurs. I cannot solve diseases with medicine alone. Medicine is an economic, social, and medical model. Countries have to have other policies [to make medicine more available]. I leave [that policy-making] to our able leaders of the world to make more money accessible for health care so we can see more patients.
