What are the key considerations for deciding on the use of CAR T-cell therapy for patients with follicular lymphoma?

For patients with relapsed/refractory B-cell lymphoma after multiple lines of therapy, outcomes historically were dismal. For patients with aggressive B-cell lymphoma subtypes, median overall survival (OS) was 6 months, and less than 25% of patients had any response to subsequent therapies[1]. Even for patients with so-called indolent lymphomas, such as grade 1–3A follicular lymphoma (FL), patients being treated in 3^rd line and beyond were found to have a median EFS of 14.4 months, and for patients who have progression of disease at 24 months from treatment initiation (POD24), median event-free survival (EFS) was 11.8 months[2]. Median time to next treatment was 14.6 months. A similar analysis found median progression-free survival (PFS) to be 12.7 months with median time to next treatment of 23.4 months[3]. ReCORD-FL, SCHOLAR-5, as well as other analyses [4] show that outcomes diminish with each subsequent line beyond 3^rd line. The review of CAR T-cell therapies for FL in this journal issue demonstrate that this therapy, which has recent FDA approvals for axicabtagene ciloleucel [5,6] and tisagenlecleucel [7], improves upon previous standard of care with overall response rates (ORR) of 94% and 86%, complete response rates (CRR) of 79% and 69%, median PFS of 40 months and 12 month PFS of 67% (median follow-up of tisagenlecleucel on ELARA trial on 16 months), respectively, with median OS and duration of response (DOR) not yet reached. Longer follow-up is still needed to determine maximum durability of response. CAR T-cell therapy is a preferred option for many patients with FL having received 3 or more prior lines of therapy.

Although these data are exciting, it is important to remember that indolent lymphomas, even in the relapsed/refractory setting, diverge from aggressive B-cell lymphomas when it comes to outcomes of overall survival. ReCORD-FL and SCHOLAR-5 demonstrated a median OS of 5 years for patients receiving historical therapies [2,3], as opposed to the median OS of 6 months in SCHOLAR-1[1]. Because the urgency of starting next line of therapy is less, additional factors beyond efficacy are often considered, such as the patient’s proximity to a center that offers CAR T-cell therapy, the current overall burden of disease on activities of daily living (ADLs), relative financial toxicity of the available treatment options, side effect profiles, ease of therapy delivery, patient social supports, etc.

Beyond the improvement in efficacy compared to standard of care therapies, CAR T-cell therapy also offers the convenience of a ‘one and done’ mode of treatment delivery as opposed to either multiple cycles for 6 months or longer (ie cytotoxic chemotherapy), or therapies taken daily until progression of disease (ie PI3 kinase inhibitors and other small molecule inhibitors). These therapies may affect quality of life and activities of daily living for duration of treatment. The first month of CAR T-cell therapy can be accompanied by hospital admissions for the management of cytokine release syndrome or neurologic toxicity. Many elderly patients who experience grade 3 or higher neurologic toxicity become physically deconditioned or impaired to the point that even after resolution of neurologic toxicity, post-discharge rehabilitation at a skilled nursing facility may be required. Patients are unable to drive for 8 weeks after infusion of CAR T-cell therapy, and many patients therefore need significant social support during that time. Patients who lack social support or who are fiercely independent may opt for alternative therapies, reserving CAR T-cell therapy for future lines. Additionally, long-term toxicities include B-cell aplasia with accompanying hypogammaglobulinemia and infection risks.

What the data presented in the accompanying manuscript do suggest, however, is that any patient with FL needing 3^rd line or later therapy (of note, in the EU, axicabtagene ciloleucel is approved in 4^th line and beyond, compared to 3^rd line and beyond for tisagenlecleucel, both are approved in 3^rd line in the US) should be evaluated at a center that provides CAR T-cell therapy for a detailed discussion of the risks and benefits of treatment. While the patient’s primary oncologist is essential in discussing treatment options with the patient, there may be multiple mitigating factors (outpatient administration of therapy, updated side effect profiles, access to patient assistance programs, travel/food/housing assistance, caregiver supports, etc.) to ease the burden of therapy that the primary oncologist may be unaware of. Discussion of these factors in detail may influence a patient’s ultimate decision of which therapy to pursue in the 3^rd line and beyond.

For the cellular therapist, considerations for the use of CAR T-cell therapy for follicular lymphoma patients include all of the above, with the addition of deciding which of the FDA approved agents to use. While cross-trial comparisons are difficult, there are multiple trials of axicabtagene ciloleucel [5,8–10] and tisagenlecleucel [7,11,12] for multiple B-cell malignancies to better allow for comparison of efficacy and toxicity. In general, while absolute response rates tend to be higher with axicabtagene ciloleucel, rates of grade 3+ neurologic toxicity and cytokine release syndrome have been lower in clinical trials to date with tisagenlecleucel. Many patients with follicular lymphoma are in the 8^th or 9^th decade of life – for patients with significant comorbidities (i.e. heart failure with reduced ejection fraction, chronic kidney disease, compromised pulmonary function, poor performance status), it may be in the patient’s best interest to utilize the CAR T-cell product with the most favorable toxicity profile rather than the product with the highest reported response rates. These decisions are nuanced and require detailed discussion between the patient and her cellular therapist.

In the future, additional approvals for therapies in this space are expected. The data from the TRANSCEND FL trial (Anonymized) using lisocabtagene maraleucel for relapsed/refractory FL are awaited. CD20/CD3 bispecific antibodies have shown impressive data as single-agents [13–16] and have also shown response rates in combination with standard therapies reaching 100% [17,18]. While bispecific antibodies still carry a risk of cytokine release syndrome and neurologic toxicity, their rates of toxicity are likely lower than those of CAR T-cell therapy. Furthermore, due to their toxicity profile and the fact that they are not autologous products, it is possible that they may be able to be administered in the office of the general oncologist (with inpatient support if needed) and not require referrals to specialized treatment centers. What remains unknown, however, is how long these treatments need to be administered. In clinical trials to date, therapy has been administered as often as every 1–2 weeks for multiple cycles, and then continued monthly until progression. It is possible that 20 or more infusions locally in the firstyear of therapy may be more of a burden to a patient than traveling for 4 weeks to receive CAR T-cell therapy. It also remains to be seen if the median progression free survival for patients receiving bispecific antibodies will be able to rival or surpass that of CAR T-cell therapy, or if either therapy can be considered to be of curative intent. Lastly, most CAR T-cell and bispecific antibody trials have been single arm, making it difficult to truly determine hard clinical endpoints, such as PFS, EFS, and OS.

Both current and future therapies for FL are likely to yield an abundance of riches regarding treatment choice for the patient with FL and her oncologist. Frequently, the more good choices that exist, the more complicated the decision becomes about which treatment to use. Many patient and disease factors must be weighed for a patient to be able to make an individualized ‘best’ decision. At this time, cellular therapists should be an integral part of treatment decisions for all patients with FL being treated in the 3^rd line and beyond.

Declaration of interest

B Hunter has received honoraria from AbbVie, ADC Therapeutics, Bristol Myers Squibb, Genmab, Janssen, Kite Pharma, Notable Labs, Novartis, and has received speaker’s fees from Kite Pharma. Added two companies and now it is correct.

B Hunter has received honoraria from AbbVie, ADC Therapeutics, Bristol Myers Squibb, Genmab, Janssen, Kite Pharma, Notable Labs, Novartis, and has received speaker’s fees from Kite Pharma. Added two companies and now it is correct.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.