Weathering the storm when the end of the road is near: A qualitative analysis of supportive care needs during CAR T cell therapy in pediatrics

Abstract

Background:

Chimeric Antigen Receptor (CAR) T cell therapy provides promising outcomes in relapsed/refractory B Acute Lymphoblastic Leukemia (ALL) yet still carries high toxicities rates and relatively poor long-term survival. Efficacy has yet to be demonstrated in other diagnoses while toxicity and risk profiles remain formidable. To date, treatment-related symptom burden is gleaned from clinical trial toxicity reports; the patient perspective remains understudied.

Methods:

English or Spanish-speaking patients (ages 8–25 years) undergoing CAR T cell therapy for any malignancy and their primary caregiver were recruited from Seattle Children’s Hospital (SCH), St. Jude Children’s Research Hospital (SJCRH), and the Pediatric Oncology Branch of the National Cancer Institute (NCI). Both patient and caregiver completed semi-structured dyadic interviews 3-months post-treatment. We used directed content analysis for codebook development and thematic network analysis for inductive qualitative analysis.

Results:

Twenty families completed interviews (13 patients, 15 parents). Patients were a median age 16.5 years, predominantly female (65%), white (75%), and diagnosed with ALL (75%). Global themes included “A clear decision,” “Coping with symptoms,” and “Unforeseen psychosocial challenges.” When families were asked to describe the “most challenging part of treatment,” most described “the unknown.” Most reported “the symptoms really weren’t that bad,” even among patients hospitalized for severe toxicity events. Fatigue, pain, and nausea were the most prevalent symptoms. Importantly, only one family would have chosen a different therapy, if given another opportunity.

Conclusions:

Although physical symptoms were largely tolerable, recognizing supportive care opportunities remains imperative, particularly psychosocial concerns.

Introduction

The modern era of cancer treatment is ripe in number and variety of therapies.^{1, 2} Chimeric antigen receptor (CAR) T cell therapy is a prime example of this complex paradigmatic shift. Promising early response outcomes in acute lymphoblastic leukemia (ALL) opened the door to applying adoptive cell therapies to other malignancies and patient populations.^3–5 Despite this promise, CAR T cell therapy remains an experience of advanced cancer; CAR T cell therapy is exclusively used in advanced disease and survival after therapy for all indications remains relatively unfavorable.^{6, 7}

Best practices in palliative and supportive care need to parallel this evolution in cancer care.^8–12 Decision-making becomes increasingly complex for both clinicians and families. Prognostic uncertainty, unfamiliar toxicity profiles, and the unclear significance of tumor-specific molecular profiles are now routine considerations in the family decision-making process.¹³ Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), two hallmark acute toxicity events following CAR T cell therapy, are commonly encountered in the first month after therapy.¹⁴ Symptom burden has been described as significant in adults after CAR T cell therapy, particularly those who experience CRS and ICANS.^15–17 Different from other early phase clinical trials, CAR T cell therapy clinical trials often require family relocation to one of a limited number of centers, typically for weeks of close observation for acute toxicity. However, few patient-centered supportive care recommendations exist for this population.¹⁸ Further, supportive care needs, particularly from the perspective of the patient and family, are largely undescribed.^19–21

The objective of this qualitative study was to understand supportive care needs during CAR T cell therapy from the perspectives of pediatric patients and their parent caregivers. We aimed to identify opportunities for improvement in symptom management, communication, and psychosocial support, with the greater goal of informing optimal supportive care management.

Methods

Design, Setting, and Participants

The “CAR T Patient Reported Outcome (PRO)” study was a prospective, mixed methods study with a primary objective to describe patient-centered outcomes in children and young adults during CAR T cell therapy. Seattle Children’s Hospital (SCH), St. Jude Children’s Research Hospital (SJ), and the Pediatric Oncology Branch of the National Cancer Institute (NCI) served as study sites. All sites are large referral centers for CAR T cell therapy, primarily delivered as part of clinical trials. Local IRB approval was granted at all centers in accordance with the US Federal Policy for the Protection of Human Subjects.

Recruitment took place from February 2020 through December 2022. Patient and parent caregiver (“parent”) participants were recruited as dyads (patient and parent together). Enrollment of both patient and parent was not required for study participation. Patient eligibility criteria included age 8–25 years, ability to speak/read English or Spanish, and scheduled to receive CAR T cell therapy for any malignancy. Parent eligibility included being a primary caregiver of a patient aged 2–25 years undergoing treatment with CAR T cell therapy as described above and ability to speak/read English or Spanish. Exclusion criteria included lack of fluency in English or Spanish, impairment preventing interview participation, or parent refusal to allow minor participation. Study staff reviewed clinic schedules to identify eligible participants. Participants were sequentially recruited in-person before lymphodepleting chemotherapy. Per institutional standards, written informed consent (>18 years)/written assent with parental permission (<18 years) was obtained by a trained study member. As participants approached three-months post-infusion, they were sequentially invited to participate in an optional interview. Recruitment continued until thematic saturation was achieved, determined by study team consensus.

Data Collection

Demographic and clinical data were abstracted from the patient’s medical record at time of enrollment. Additional self-reported demographic data were collected from both patient and parent participants at time of enrollment via REDCap. Qualitative data collection and analysis followed the Standards for Reporting Qualitative Research guidelines.²² Study staff trained in qualitative methods conducted interviews at their local institution (SCH: AS, KS; SJ: AK; NCI: LW). The interview guide was based on models of HRQOL and symptom burden^{23, 24} and informed by the research team’s clinical experience. The finalized interview guide consisted of open-ended questions and optional probes to facilitate semi-structured interviews (Appendix A). Interviews were completed by phone three months post-infusion (+/− four weeks). For families where both the child and parent participated, families chose joint or separate interviews per personal preference. Interviews were audio-recorded, de-identified, and transcribed verbatim. The mean duration was 34 minutes (range 10–70 minutes). A $25 gift card was offered to each participant following interview completion.

Data Analysis

We used directed content analysis for codebook creation followed by in-depth thematic networks analysis to explore supportive care needs with CAR T cell therapy in pediatrics.^25–29 The multi-disciplinary analysis team included a health services investigator (KS), physician-researchers trained in palliative care and pediatric oncology (AS, SS, DL, HS), a social work clinician-researcher (LW), and clinical research staff with qualitative research experience (KP, JN, DV). The research team used directed content analysis for iterative codebook development and coding structure, applying models of HRQOL and symptom burden (Appendix B).^{23, 24} Starting with 5 transcripts, two coders (KS, AS) independently reviewed transcripts in their entirety and deductively applied the existing a priori codes for codebook refinement. Separate codes for “patient viewpoint” and “parent viewpoint” were used to organize perspectives. We continued this process until no further code categories emerged and consensus was reached.

Interviews and the finalized codebook were imported into Dedoose for analysis [Dedoose Version 7.0.23 (2016). Los Angeles, CA: SocioCultural Research Consultants, LLC www.dedoose.com]. A core of five study team members (AS, SS, KP, JN, DV) reviewed five transcripts together to establish a standard coding process. For the remaining 17 transcripts, two members of the core analysis team independently and blindly coded each transcript. A third coder reviewed each transcript, serving as a tie-breaker in code reconciliation. The core analysis team met weekly to discuss inconsistencies, resolve discrepancies, refine code definitions, and reach consensus.

After coding completion, the full analysis team (AS, SS, KP, JN, DV, DL, HS, LW) applied thematic networks analysis to examine recurring concepts among interviews.²⁷ The relationship between concepts was then used to create basic themes. Basic themes were then used to create three organizing themes. Organizing themes were reorganized to deductively develop three overarching global themes representing the unique perspective of pediatric patients treated with CAR T cell therapy and their parents. Through an iterative process, the study team refined and synthesized themes within the network until inductive thematic saturation was reached.³⁰

Results

Twenty families were interviewed (13 patients, 15 parents; Table 1), at which point no new information emerged. Of the patient interviews, six were completed with their parent, two separate from their parent, and five without a corresponding parent interview. Of the parent interviews, seven were completed without a corresponding patient interview. Ten patients were treated at SCH, six at SJ, and four at the NCI. The median age of the patient participant at time of enrollment was 16.5 years (range: 8–24). Patients predominantly identified as female (65%) and white (80%). Most patients received CAR T cell therapy for treatment of ALL (80%). The parent participant median age was 47 years (range: 31–54). Parents predominantly identified as female (93%) and white (93%). All interview participants spoke English as a primary language. Three global themes summarize the family-centered experience with CAR T cell therapy: “A clear choice,” “Coping with symptoms,” and “Unforeseen psychosocial challenges.” (Table 2). Responses from the patient perspective did not significantly differ thematically from the parent perspective.

Table 1.

Patient and parent demographics

Characteristic	N (%)*
	All Patients (N=20)	Interviewed Patients (N=13)	Interviewed Parents (N=15)
Age (years) at enrollment [median (quartiles)]	16.5 (9.75; 18.5)	17 (13; 23)	47 (41; 51)
Sex
Male	7 (35)	4 (30)	1 (7)
Female	13 (65)	9 (70)	14 (93)
Race
White/Caucasian	16 (80)	11 (78)	14 (93)
Asian	0	0	1 (7)
Black	0	0	0
Undisclosed	4 (20)	2 (22)	0
Diagnosis
Leukemia/Lymphoma	16 (80)	10 (77)
Sarcoma	4 (20)	3 (23)
Site
Seattle Children’s Hospital	10 (50)
St. Jude	6 (30)
NCI	4 (20)

^*unless otherwise noted

Table 2.

Themes and exemplary quotes reflecting patient and family experience during CAR T cell therapy. Patient perspective in grey.

Global theme	Organizing theme	Representative excerpts
A clear choice	Hope	We saw it like not a miracle, but a next opportunity. We were really ready and excited (which is weird to say) to have that option to do. It was a decision that was made quite easily, since it was we were joyful about it. CTP063
		We wanted to try. Just hope for the best. CTP020P
	Trust	He said that it was more than likely going to be what was best for me and my situation. I talked to my mom and my dad and <Fiancé>, and I told them that I wanted to do it because it was what my doctor thought was best for me, to help me get through to transplant, and they agreed with me. CTP066
		We were just told that that was the best next step, so we just said ‘Okay.’ CTP047P
	Self-efficacy	It’s your child, so don’t be afraid to ask again and again, and if you don’t understand, ask somebody to explain it again, or in a different way, so that you can make an informed decision. CTP051P
		Ask questions. Your voice should be heard, and you’re the advocate for your child. CTP005P
Coping with symptoms	Normalcy	Just feeling like I can… Like I wasn’t feeling lethargic or in pain. I just felt like I could eat normal. I could walk normal. Everything was just like if I wasn’t on any chemotherapy treatments or anything. CTP005
		I mean he’s now, I think, able to feel more normal than he has felt in a long time CTP029P
	Perspective	It’s not like the chemo that we got with the (BMT), you know kind of making room for the new cells. It’s not like it was ‘Oh, go to the bathroom. Puke.’ It wasn’t really severe like that. CTP017
		It was so much easier than chemotherapy treatments that he had had before CTP051P
	Symptom paradox (a desire for symptoms)	It was really hard, when especially… Kind of exciting in the beginning, when he went into CRS, because we wanted… It was like ‘Okay, great. This is working,’ but then it was hard to watch him have the fevers and then have to go up to ICU and spend ten days there. CTP051P
		You know as crazy as it sounds, I’m glad that she does not have the side effects that could come along with it, but at the same time, as a parent, I would like to see some of those side effects with it. I was hoping to see something, without it being too extreme, just to know that they were doing something. CTP010P
Unforeseen psychosocial challenges	The toll of being away from home	Honestly, I think being so far away from home was the worst part. I don’t know. There’s something about being able to sleep in your own bed, and with the time difference, too, so it was hard communicating with people back home, family and stuff. Obviously we adjusted, but I personally think that the hardest part was being away from my sister, my dogs, my dad, ‘cause my parents would switch off, but I always liked them all together, so that part was really hard. CTP017
		The cost of renting something for weeks was quite expensive, not to mention groceries, food, transportation, flights, etc. CTP028P
	The unexpected	Expect the unexpected. It’s different for everybody. CTP10
		There was more damage than what we had anticipated going in, and certainly almost losing him, I mean even though they tell you that that’s a possibility, it’s not something that you’re prepared for. CTP002P
	The unfamiliar	We were nervous about how the CAR T was going to go because it’s just a new thing in general, and also we’ve never walked this path before. So you never know how it’s gonna affect your child. CTP015P
		I think if I would’ve known more about it, and been more prepared of those kind of things happening, maybe it wouldn’t have been such a scary thing to go through at the time. CTP026P

“A clear choice”

Deciding to pursue CAR T cell therapy was described as a “clear choice” by all families. Factors facilitating the decision-making process were organized into three themes: hope, trust, and self-efficacy.

Expressions of hope were pervasive when families reflected upon their decision-making process. When families shared their reason for choosing CAR T cell therapy, n=13 families felt that CAR T cell therapy was unequivocally “the next best step,” offering the best chance for cure or to buy time until a possible cure would be available. One parent explained, “That’s my goal is just to keep him going as long as possible in the hope that somebody figures it out.” (CTP029P). Hope for comfort and minimal toxicity was also common. For example, one parent shared, “We really want what’s best for her, what was her best shot, and what will be the best way for her to be comfortable” (CTP055P).

Families expressed tremendous trust in their medical teams. Although families expressed great gratitude for their specialized CAR T cell therapy team, this trust was predominantly in their primary oncologist. For some families, this was a product of the therapeutic relationships developed with their primary oncologist. For example, one parent expressed, “I think getting the doctor’s opinion, from a doctor that knows <Child> and has been with her through her whole treatment is probably the most helpful, because I think he’s got her best interest at heart.” (CTP026P). Some families felt that they had reached the “end of a road” and trusted their oncologist’s recommendations for next steps. One patient explained, “It was really the only thing I had left, after 12 rounds of chemo, radiation, and a bone marrow transplant not working” (CTP041). When asked how they arrived at their decision to pursue CAR T cell therapy, this patient went on to explain: “I mean I have all the trust in the world in my Oncology doctor, and so I told my mom from the beginning, whatever <Doctor> suggested is what I was gonna do.” (CTP041).

Despite expressing deep trust in their medical teams and hope for treatment success, families voiced a critical need for taking ownership in preparing themselves for treatment. This was organized into the theme “self-efficacy.” Multiple families shared they felt a duty to ask questions to advocate for their child. When asked about advice for future families preparing for CAR T cell therapy, one parent offered, “Ask a lot of questions and just make sure that you’re going into it as informed as you possibly can. We know our child better than anybody else. So just having the ability to not be afraid to ask questions and follow up with things and make sure that things aren’t forgotten is really important, just to be a part of the medical team” (CTP002P).

All but one family, whose child experienced a severe adverse event from treatment, reported being satisfied with their decision and would make the same choice again. Notably, none of the families interviewed had a child who died before the interview.

“Coping with symptoms”

The family perspective of the symptom experience was organized into three subthemes: normalcy, perspective, and symptom paradox. Pain, fatigue, and nausea were the three most prevalent physical symptoms described. Overwhelmingly, families reported that physical symptoms during CAR T cell therapy were tolerable. Families were struck by a sense of “feeling normal.” Multiple patient participants noted a resolution of baseline physical symptoms shortly after infusion, such as pain or nausea, allowing them to regain a sense of independence, with n=4 participants using the word “normal.” Further, families remarked on how life generally felt “ordinary” during and after treatment. One participant shared, “I really enjoyed being somewhat independent, a little bit, considering the past four years I’ve kind of been pretty dependent on my parents and caregivers” (CTP017). This participant then described being able to resume college classes in the time since their infusion. Another parent reflected, “Its been really nice to be able to be at home and to kind of feel like we are living a somewhat normal life because he feels probably better than he can remember feeling… He just feels well. He feels like a normal little boy” (CTP015P).

Most symptoms were attributed to lymphodepleting chemotherapy. Symptoms from CRS and ICANS were infrequently discussed, including among patients with reported severe toxicity. Symptoms were often compared to prior therapies, including hematopoietic stem cell transplant, reporting that symptoms experienced with prior therapies were more significant than those experienced with CAR T cells. To reflect this viewpoint, we organized this experience into the theme “Perspective.”

Finally, families acknowledged grappling with a “symptom paradox,” a counterintuitive desire for symptoms to occur with therapy, attributing the presence of symptoms to be a sign of efficacy. One family explained: “Strangely enough, it made us sort of feel comforted when he did spike a high fever because it made us think that maybe it was working, ‘cause that’s what we were told beforehand… It might not happen, but if it does happen, that could be a good indication that it’s working.’ So as soon as it did happen and he spiked a fever, my husband called me and he was like ‘He spiked a fever!’ and we both (it was weird) got a little bit excited like ‘Okay, this is good!’” (CTP015P). Further, when symptoms were not seen, families expressed disappointment and worry that the treatment may not be working (Table 2).

“Unforeseen psychosocial challenges”

Challenges of CAR T cell therapy were organized into three themes: the toll of being away from home, the unexpected, and the unfamiliar. First, families reflected on the emotional and financial sacrifices of being away from home, organized into the theme “The toll of being away from home.” Many families relocated for treatment, requiring the family to live local to the treating center for weeks. One parent shared, “You just don’t see the people you’re used to seeing every day. She made a lot of new friends and with video chat, life has turned out to be a whole lot different, but it’s still hard to not sit and watch movies together, or eat dinner together as a family, or call her brothers to come over and visit. You have to call them on video chat. It wasn’t awful; it was just different” (CTP066P). Other families described the financial costs of transportation or lodging. For example, one family shared, “I mean it’s a financial strain. Things work out. You give-and-take in different places, but just being that far away from home is costly” (CTP020P).

The second challenge described was navigating unexpected scenarios, organized into the theme “The unexpected.” Predominantly this related to development of toxicity, requiring longer than expected hospitalizations or changes in subsequent therapy. One parent shared, “The last thing I would expect is that the clinical trial would then cause a reason to not get treatment after that. I mean and in <Patient’s> case, she’s had a lot of progression since then, so I can’t blame anyone and I don’t have a magic ball, but it does make us wonder like if we didn’t have that issue and we were able to get her on another treatment after the trial, would she have this level of progression since the trial” (CTP028P).

Finally, families endorsed the challenges of navigating novel therapies, organized into the theme “The unfamiliar.” One family explained, “I feel like if it was farther along in the CAR T development and research and knowledge, that maybe they could’ve ironed out a few more kinks and understand more about how it works and why it works” (CTP047).

Discussion

This qualitative study seeks to describe supportive care needs during CAR T cell therapy from the child and parent perspectives. Among families who chose to proceed with CAR T cell therapy, we found most families felt this was a clear decision. Symptoms were tolerable and some families reported a “symptom paradox,” a desire for some toxicity to feel like the treatment was working. Families described feeling challenged by the emotional and financial burdens of relocating and the unpredictability of navigating a novel therapy. Altogether, these insights highlight opportunities for future supportive care intervention.

Families predominantly felt the path to their decision was straightforward. Hope, trust, and self-efficacy facilitated the decision-making process. Qualitative decision satisfaction was prevalent in our sample, with all but one family disclosing they would make the same decision again. Confirmation bias may partly explain this degree of decision satisfaction, as described in another general pediatric oncology study.³¹ Prevalence of hopeful patterns of thought, trust in the medical team, and perceived self-efficacy were previously described as protective against regret,^31–34 which may also be the case in our sample. Moreover, these constructs are important mitigators of uncertainty-related distress, a source of emotional distress common not only to our pediatric cohort, but another study among adult patients treated with CAR T cell therapy.^{21, 35} Supporting hope, trust, and self-efficacy are likely important in providing quality supportive care for families during CAR T cell therapy. This may be accomplished through transparent communication of prognostic information and utilizing a patient-centered approach that prioritizes the patient experience.^{36 37, 38}

Families generally reported tolerable symptoms with CAR T cell therapy, with many families remarking that their child felt “normal.” While it is possible that patients may experience an absence of symptoms or a symptom profile favorable in comparison to other intensive phase of therapy, our themes expose risks of inadequate symptom management. Experiential knowledge undoubtedly produced a response shift affecting families’ perception of symptom burden during therapy.³⁷ This may contribute to symptom normalization, where both clinicians and families perceive that symptom-related suffering is a “normal” part of treatment and that adequate symptom control is unattainable.³⁸ For example, when families accept nausea and vomiting to be a “normal” part of chemotherapy, they may be less likely to request support in symptom management. Specific to CAR T cell therapy, normalizing the experience of CRS and ICANS may lead families to consider symptom management unnecessary. Further, when early toxicity with CAR T cell therapy is considered an indication of efficacy,³⁹ symptoms become a welcomed experience, resulting in a so-called “symptom paradox” effect.

An inverse “symptom paradox” was also noted. Uncertainty-related distress may develop in anticipation of CRS or ICANS. When symptoms are not experienced, families may feel disappointment or worry when symptoms are not experienced. This highlights two times in treatment where families may benefit from additional psychosocial support. Further, it underscores the importance of using intentional language when discussing toxicity as a possible indication of efficacy.

Although we made every effort to recruit a diverse sample, our sampling procedures were limited by interviewing families who chose and successfully completed treatment with CAR T cell therapy. Thus, the full spectrum of decision-making is not represented. Importantly, the rationale and needs probably differ between families that choose CAR T cell therapy and those who do not. Further, our study does not represent the experience of families with prohibitive access to such investigative therapy. The families in our study emphatically articulated the importance of self-efficacy in accessing CAR T cell therapy and in adequately preparing themselves for the medical and emotional complexities of treatment. Paired with the deep sense of trust our participants shared with their medical team, this poses a serious threat among disenfranchised people to access CAR T cell therapy.⁴⁰ Racial, ethnic, and payor disparities exist in referral practices for CAR T cell therapy and inclusion in clinical trials.⁴¹ Identifying interventions to mitigate these risks must be a priority for future investigation.

Several additional limitations of this study must also be noted. Despite recruiting Spanish-speaking participants, only English-speaking participants volunteered for interview participation. Thus, our findings likely do not represent the experience of non-English speaking families. Only one father was represented in the parent participants. Our participants described predominantly positive experiences. This may reflect social desirability bias or recall bias. We chose to interview patients receiving CAR T cell therapy for any malignancy type; we continued data collection until thematic saturation was achieved and thematic differences were not appreciated between diagnosis groups. Finally, because memory impairment and severe illness are common with CAR T cell therapy, we chose to interview parents and their children together to capture a cohesive narrative. This approach may limit participant disclosure from both the parent and child perspectives. However, we did not appreciate a difference in themes between those interviewed alone and those interviewed together. Despite these limitations, our findings expose opportunities for possible intervention and priorities for future investigation.

Children undergoing CAR T cell therapy and their families, like families pursuing other advanced cancer therapies, are at risk for distress from decision making, symptoms, and uncertainty. Supportive care practices that minimize the impact of these risk factors and support hope, trust, and self-efficacy are opportunities to improve clinical care and patient and parent quality of life.

Abbreviations:

AYA

Adolescent and young adult

CAR

Chimeric Antigen Receptor

CTCAE

Common Terminology Criteria for Adverse Events

HRQOL

Health-related quality of life

PRO

Patient reported outcome