Community physicians play essential role in long-term care after CAR-T
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Despite an overall positive safety outlook, the scope of potential toxicities related to chimeric antigen receptor T-cell therapy remains unclear due to lack of long-term follow-up.
It has been barely a decade since the modality produced the first reported remission in a child with B-cell acute lymphoblastic leukemia.
Since then, some possible effects — such as prolonged B-cell aplasia or susceptibility to infection — have been well established. But how do clinicians approach long-term survivorship care for a treatment so new that there are few long-term survivors on which to guide recommendations?
Physicians who treat patients after CAR-T operate within a fluid dynamic, using emerging research, institutional guidance, and a strong line of communication between the CAR-T center and referring oncology practice to guide survivorship care.
This effort is tricky, according to Colleen Elizabeth Annesley, MD, attending physician at Seattle Children’s Hospital and associate professor in the department of pediatrics at University of Washington.
“Many patients come to referral centers to get CAR T-cell therapy and then — after the acute treatment period — they go back home to their referring provider,” Annesley told Healio.
“We request medical records at prescribed time points after CAR-T so that we can follow up with patients and learn how they’re doing,” Annesley added. “We really depend on ongoing communication from the local referring providers and getting long-term follow-up information on patients from them.”
Role of community physicians
Seattle Children’s Hospital does not have a dedicated survivorship clinic for CAR-T recipients, although oncology patients who receive treatment and follow-up care at its facility are referred to the institution’s cancer survivorship clinic.
Community-level oncologists play an essential role in CAR-T survivorship care, according to Annesley — especially when it comes to alerting CAR-T centers about possible late-term effects. When patients return to the care of their local referring physician, they are provided with a description of side effects to be on the lookout for.
“Late-onset events of interest that we really want to know about from community physicians include whether [patients] develop a second cancer, a new autoimmune disease, a new neurologic disorder or a new blood disorder,” she said. “They may or may not be related [to treatment], but we want to know about it so we can track incidence over time and determine if there's any increased risk of these issues ... after CAR T-cell therapy. This information will allow us to better inform future patients of any possible late-onset risks.”
Susanne Baumeister, MD — clinical director of the cellular immunotherapy program at Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and assistant professor of pediatrics at Harvard Medical School — agreed community-level physicians who refer younger individuals for CAR-T play a critical role in long-term survivorship care.
“[They are] a very important part of the patient's care, and we tend to have very close collaborative relationships with the referring providers because we see patients from many of New England states, and sometimes international patients,” Baumeister said.
The cell therapy clinic at Boston Children’s ties CAR-T survivorship care to the institution’s program for hematopoietic stem cell transplantation, because so many patients are referred for CAR-T after failed HSCT or will receive subsequent transplant as consolidation therapy after CAR-T.
There is no way to quantify the long-term effects that treatment-related cytokine release syndrome can have on organ function despite recovery over the short term, Baumeister said.
For this reason, community physicians should report any suspicion of long-term organ dysfunction, in addition to endocrine/developmental, cognitive or cardiovascular effects due to the chance they may be related to CRS or neurotoxicity that often occurs after CAR-T infusion, she said.
Referring oncologists receive guidance on monitoring and long-term care for CAR-T recipients when they receive therapy at Boston Children’s and return to the community setting, Baumeister added.
“We are in the process of developing a more comprehensive CAR-T-specific survivorship program where members of the cellular therapy group will see those patients at certain sentinel visits over time,” Baumeister said. “We envision seeing those patients at regular intervals to guide their survivorship going forward as we explore different cellular therapies and guidelines change.”
Hypogammaglobulinemia management
B-cell aplasia and the subsequent hypogammaglobulinemia it causes among those who receive CD19-directed CAR-T cell therapy is perhaps the most significant issue that patients and their physicians encounter during the long-term survivorship period.
Annesley and Baumeister said their experience shows approximately half of patients who received the CD19-directed CAR-T tisagenlecleucel (Kymriah, Novartis) for relapsed or refractory B-cell ALL had persistent B-cell aplasia at 6 months after therapy.
This matches real-world data collected and published by Center for International Blood and Marrow Transplant Research and Cellular Therapy Registry.
A subsequent analysis by Shannon Maude, MD, PhD, and colleagues at University of Pennsylvania suggested incidence of persistent B-cell aplasia after CD19-directed CAR-T in real-world settings is underreported. It may be as high as 83% among pediatric and young adult patients, the researchers concluded.
Treating long-term hypogammaglobulinemia is a core element of survivorship care for most CAR-T programs.
At Seattle Children’s Hospital, the discussion with CAR-T recipients and their caregivers begins before treatment, Annesley said.
“We talk about the risk [for] ongoing lost B cells and the effects of not having that part of your immune system with patients and families before they enroll on a trial for CAR T cells,” Annesley said. “[We] explain that it could be a lifelong side effect and potentially require immunoglobulin replacement indefinitely unless they lose persistence of their CAR T cells.”
Because up to half of younger CD19-directed CAR-T recipients develop B-cell aplasia lasting more than 6 months after infusion, long-term follow-up of hypogammaglobulinemia with immunoglobulin supplementation often falls to community-level physician — typically the referring oncologist.
How long supplementation lasts depends on the individual and is determined — in part — by how long CAR T cells persist within a recipient’s body, Annesley said.
Immunoglobulin supplementation is often given in these cases because of the impact of the loss of B cells on the immune system, Annesley said.
“Whether or not the loss of B cells translates into increased risk [for] infection is an area of active study,” Annesley said.
“There’s no definitive data to say for sure whether getting immunoglobulin replacement is necessary,” she said. “However, because there is the potential to prevent primarily viral infections, it is generally recognized as the standard of care to provide immunoglobulin replacement, and counsel patients on this possibility of needing ongoing replacement.”
Other survivorship concerns
Other survivorship concerns should be discussed with younger CAR-T recipients and their families — and referring physicians should be alerted to report these developments to CAR-T providers, Annesley and Baumeister said.
“There is a theoretical risk [for] secondary cancers from CAR T cells that should be discussed with patients,” Annesley said. “The risk arises from the use of lentiviral vectors to create genetically modified cells. Adding genetic material to cells in this way creates the possibility for the development of a secondary malignancy.”
Such an issue has not yet been observed, Annesley said. However, it is important to discuss this with patients and for clinicians to monitor for this possibility, she said.
There is no evidence to suggest CAR-T would diminish a recipient’s fertility, but it is unknown how circulating CAR T cells in the body may affect a new pregnancy, Annesley said.
Clinical trial participants at Seattle Children’s Hospital are advised to use highly effective contraception and refrain from trying to have a child for the first year after CAR T-cell therapy.
“We don’t yet know what effect, if any, that circulating gene-modified T cells could have on sperm ... or a developing fetus,” Annesley added. “Until there's more data, we discuss this as a potential risk with patients during our consent process for CAR-T trials.”
Baumeister agreed that fertility concerns are unlikely but can’t yet be ruled out.
“So far there’s nothing to suggest that [CAR-T] has a negative effect on pregnancies, but the data [are] very limited and require further study,” she said.
Information on pregnancy after CAR-T is limited to just a handful of reports of live births, Baumeister added.
“It is an area that needs further attention ... and I don’t believe that many centers have a comprehensive approach to fertility,” she said. “This is a particular concern for pediatric patients.”
Further prospective studies and longer follow-up of registrational clinical trials are needed to determine what late-term effects of CAR T-cell therapy must be accounted for in survivorship care plans, Annesley and Baumeister said.
Prospective studies should include patient-reported outcomes on the perceived effects of the therapies and the long-term issues that CAR-T recipients face to help inform clinical practice guidelines and cell therapy-specific survivorship care programs, Baumeister said.
“[This is] an active area of investigation that needs to be studied further for pediatric patients,” she added. “Given the known toxicities associated with immunotherapies, it is important to be cautious of potential long-term risks.”
References:
- Grupp S, et al. Blood. 2019;doi:10.1182/blood-2019-129279.
- Maude SL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1709866.
For more information:
Colleen Elizabeth Annesley, MD, can be reached at colleen.annesley@seattlechildrens.org.
Susanne Baumeister, MD, can be reached at susanne_baumeister@dfci.harvard.edu.
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