Too short or unnecessarily long: walking the fine line

In this issue of Blood Advances, Ahmed et al¹ reported retrospective analytical data to guide post–chimeric antigen receptor (CAR) T-cell therapy monitoring, for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) in a framework for improving physical and economic implications on patients.

Because the once-novel CAR T-cell therapy brought about an overhaul in the treatment of B-cell malignancies, risk evaluation and mitigation strategies (REMS) were set up to maintain caution, supervise monitoring of the unknowns, and ensure patient safety with this otherwise promising therapy. The REMS requirement mandated patients to stay within a 2-hour driving distance from the CAR T-cell treatment center for 4 weeks following the CAR T-cell infusion for most products. This was determined to allow for close monitoring for acute toxicities like CRS and ICANS that may occur in the weeks following CAR T-cell infusion.² Although these instructions added a layer of caution for patients when little was known, they now stand on the pedestal of evaluation as they also thicken the barrier to CAR T-cell therapy access, especially for patients who live farther away from CAR T-cell treatment centers. The work by Ahmed et al provides the critically needed real-world experience from 475 patients across 9 institutions and demonstrates the rarity of CRS or ICANS beyond 2 weeks with axicabtagene ciloleucel, tisagenelecleucel, and lisocabtagene autoleucel, with only 1 new ICANS occurring beyond day 14.¹ This is a much-awaited respite, especially for situations involving resource limitations which may preclude patients to live away from home for prolonged time periods and pose challenges to optimal care. Consequently, REMS requirements are already shifting. Kite Pharmaceuticals, for instance, in their most recent iteration of guidance, has removed the specification of “2 hours driving distance” from treatment although they continue to recommend staying in close proximity of the treatment center for 4 weeks. Furthermore, as of 26 June 2024, the Food and Drug Administration, recognizing the burden of REMS on health care, has modified the requirements to remove education and training materials, favoring instead the use of product labeling as a source of information related to the CAR-T product.

As is true for any shifting paradigm though, a shift in practice begs caution to accompany itself. Although 14 days may suffice for monitoring of acute inflammatory events, consequential adverse effects of CAR-T can linger beyond 14 days. In fact, with an evolving experience and better management of CRS and ICANS, the prominent cause of morbidity, mortality, and health care utilization with CD19-directed CAR T-cell therapy has shifted more toward delayed hematopoietic recovery^3,4 and infections.⁵ More recently, secondary primary malignancies following CAR T cells have garnered attention although the incidence may vary with products and needs ongoing follow-up for a prolonged period.⁶ Do these require staying within a defined distance of the CAR T-cell treatment center? And even if they do, is that feasible in real-life situations as the delays in hematopoietic recovery and risk of infections can persist for several months following CAR T-cell infusion?

The answers to these questions may reside not in staying within a close distance and following up at the CAR T-cell therapy center frequently but in engaging oncologists beyond the specific centers in the aftercare of CAR T-cell therapy. As of the last update, there are about 150 centers across the United States that provide CAR-T care and cater to referrals from a variety of distances such that relocations are necessitated in at least 25% of patients, not accounting for those who do not make it to CAR T-cell therapy due to distance or resource limitations. The onus is now upon the CAR T-cell treatment centers and manufacturing companies perhaps in partnership with the leading academic societies to foster collaboration with oncologists over the map of the United States and allow a safe transition of care after early follow-up at the CAR T-cell treatment center. Awareness of complications in the various time periods following CAR T-cell infusion (see figure), diagnostic and clinical recognition, and close communication with the CAR T-cell therapy team are critical. Several bodies of data have now led to the recommendation of antimicrobial prophylaxis and intravenous immunoglobulin replacement following CAR T-cell infusion to obviate the risk of infections.^4,7 Although the biology of cytopenias is complex, transfusion support, growth factors, thrombopoietin-receptor agonists, and situationally stem cell boost considerations appear to have a role in alleviation.^4,8 Timely recognition (recrudescence of fever, new or persistent cytopenias, rapid rise in ferritin among others) and intervention with steroids or other immunosuppressive strategies beyond interlukin-6 receptor antagonism for immune effector cell–associated hemophagocytic lymphohistiocytosis-like syndrome can be life-saving.⁹ Rarer, yet consequential, cases of cardiac and gastrointestinal toxicities, autoimmune conditions, graft-versus-host disease (in someone with prior allogeneic transplantation), and secondary primary neoplasms have also been brought to attention.^6,10,11 

A related segue into improving access, health care resource utilization, and balancing quality of life while living with cancer has been outpatient administration and follow-up for CAR T-cell therapy. This has been seen as a rising trend with more data and guidance on safety and feasibility from several centers including ours.^12,13 Outpatient administration paired with earlier relocation back home and a careful transition to the local oncology team has the potential to augment the humane experience of getting treated for a life-threatening condition with a therapy that has possible life-threatening complications.

The next question to emphasize is whether this applies to products not included in the study. Well, the authors have made that easier by demonstrating a similar experience with idecabtagene vicleucel and ciltacabtagene autoleucel for multiple myeloma.¹⁴ Two out of 129 patients developed new ICANS after day 14. None of the studies capture brexucabtagene autoleucel experience. As this dust settles on further and a broader range of experience becomes available, the future can optimistically turn toward liberalization or at least personalization of the close monitoring period following CAR T-cell therapy.

Conflict-of-interest disclosure: T.J. reports institutional research support from CTI Biopharma, Kartos Therapeutics, Incyte, and Bristol Myers Squibb, and advisory board participation with Bristol Myers Squibb, Incyte, AbbVie, CTI Biopharma, Kite Pharmaceuticals, Cogent Biosciences, Blueprint Medicine, Telios Pharma, Protagonist Therapeutics, Galapagos, TScan Therapeutics, Karyopharm, and MorphoSys. C.S. declares no competing financial interests.