Longitudinal Health-Related Quality of Life among Patients with High Risk Pediatric Hodgkin Lymphoma Treated on the Children’s Oncology Group AHOD 1331 Study

Abstract

Purpose:

There have been no prior longitudinal assessments of health-related quality of life (HRQoL) during treatment for pediatric Hodgkin lymphoma (HL). The addition of Brentuximab vendotin (BV) to a multi-drug chemotherapy backbone demonstrated superior efficacy to standard chemotherapy for pediatric high-risk HL patients in the AHOD 1331 trial. However, the impact on HRQoL is unknown.

Patients and Methods:

Following treatment randomization, 268 participants ages 11+ years were enrolled in a prespecified, longitudinal, patient-reported outcomes substudy. HRQoL was assessed using the seven-item Child Health Ratings Inventories (CHRIs)–Global scale prior to treatment (T1), at cycle 2 (T2), cycle 5 (T3), and end of treatment (T4). A clinically meaningful increase in HRQoL was considered 7 points on the CHRIs-Global. Multivariable linear regression estimated associations between demographic/clinical variables and HRQoL at T1. Linear mixed models estimated changes in HRQoL across treatment arm..

Results:

Participant characteristics were balanced by treatment arm. 93% of participants completed the CHRIs at T1, 92% at T2, 89% at T3, and 74% at T4. At T1, female sex and fever (p-values<0.05) were each associated with worse HRQoL. By T2, participants in the BV arm experienced a statistically and clinically significant improvement in HRQoL (β=7.3 95%CI 3.2–11.4; p≤0.001), which was greater than the change in the standard arm (difference in change β=5.1 95%CI −0.2–10.3; p=0.057). The standard arm did not experience a statistically or clinically significant increase in HRQoL until T4 (β=9.3 95%CI 4.7–11.5; p<0.001).

Conclusion:

These data demonstrate successful collection of serial HRQoL from youth with high-risk pediatric HL and improvement in HRQoL over the course of initial therapy, sooner and to a greater extent in the group receiving the novel agent BV.

Context Summary

Key Objective:

How is health-related quality of life (HRQoL) impacted by high-risk disease among youth with Hodgkin lymphoma, and further, how does therapy alter the HRQoL trajectory?

Knowledge Generated:

Among 268 patients enrolled on the Children’s Oncology Group-led AHOD1331 trial, 44% of patients had poor HRQoL prior to the start of therapy. HRQoL improved during therapy, however, this improvement was larger and occurred earlier in patients treated with the novel agent Brentuximab vedotin, as compared to standard therapy.

Relevance (written by Dr. Smita Bhatia):

A consistently superior quality of life among patients treated with the novel agent Brentuximab vedotin, despite comparable clinical outcomes, serves as a paradigm for inclusion of patient-reported outcomes in pediatric studies when making treatment-decisions.

Introduction

While five-year overall survival approaches 98% for pediatric Hodgkin lymphoma (HL), curative intensive therapies for HL have expected acute toxicity and little is known about child and adolescent health-related quality of life (HRQoL) during treatment. Data from long-term survivors of childhood or adolescent HL demonstrate impairments in HRQoL, specifically in emotional and social functioning, and persistent fatigue.^1–3 However, our knowledge of HRQoL during therapy is limited to studies in adults with early stage HL which demonstrate impaired HRQoL prior to therapy and worsening of HRQoL during therapy that persists up to 5 years.^4–7 There are currently no longitudinal HRQoL data from pediatric patients undergoing contemporary therapy for HL, nor data on the impact of novel agents on HRQoL.

HL patients treated with conventional therapy have significantly elevated rates of morbidity and mortality in the decades following therapy compared to their peers.^8,9 Therefore, a challenge in developing novel therapies and regimens is to maintain disease control, but minimize acute and long-term burden.¹⁰ The Children’s Oncology Group (COG) AHOD 1331 trial demonstrated that the anti-CD30 targeted antibody-drug conjugate Brentuximab vendotin (BV) with a multi-agent chemotherapy backbone of AVE-PC (doxorubicin, vincristine, etoposide, prednisone and cyclophosphamide, hereafter “BV arm”) had superior efficacy to ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide, hereafter “standard arm”) for pediatric patients with high-risk HL (3-years EFS 92% vs. 83%).¹¹ Toxicity profiles, defined by on-treatment adverse events, and three-year overall survival were similar in both arms. Incorporating data from the patient experience on HRQoL may help to inform clinical decision-making.

A pre-planned sub-study of AHOD 1331, limited by study sponsors to the first half of planned enrollment, aimed to examine between-arm differences in patient-reported HRQoL, and to characterize host factors associated with HRQoL prior to therapy initiation. In the absence of previous data on the HRQoL impact from either the standard arm or novel agents, we hypothesized HRQoL would be similar between arms, employing a non-inferiority design. These data provide a unique opportunity to understand the feasibility of including patient reported outcomes in a large-scale clinical trial and the trajectory of HRQoL from diagnosis through treatment in children and adolescents with HL in an era of novel agents, providing much needed insights about tolerability.

Methods

Participants

Patients with newly diagnosed high-risk classic HL (stage IIB with bulk, IIIB, or IVA and IVB) aged 2–21 years were eligible to enroll on COG AHOD 1331 (NCT02166463).¹¹ Patients were ineligible if they had nodular lymphocyte predominant HL, were pregnant, had a known immunodeficiency, or received systemic corticosteroids within 28 days of enrollment. A pre-planned patient-reported outcomes (PRO) sub-study, limited to the first half of planned enrollment (n=309), included 280 age-eligible participants ≥11 years, 268 of whom completed serial collection of PROs unaided by parent or site staff, including HRQoL (Figure 1). The sample size estimate of the PRO study was calculated using a non-inferiority margin of 7 points. Enrollment in the PRO sub-study was required for the first 309 AHOD 1331 participants, with no opt-in or opt-out procedures; PRO collection spanned from April 2015 to September 2017. Demographic and clinical characteristics did not differ between the PRO sub-study participants and the subsequent trial enrollees (Supplemental Table 1¹²). The protocol was reviewed and approved by the NCI, the Pediatric Central Institutional Review Board, and the local IRBs per institutional policies of participating sites. Written informed consent from children ≥18 years and parents/guardians and child assent for those <18 was obtained in accordance with the Declaration of Helsinki.

Figure 1: Participant enrollment flowchart.

The first 309 subjects enrolled in AHOD 1331 were required to participate in the pre-planned patient reported outcomes (PRO) sub-study, irrespective of treatment arm. Demographic and clinical characteristics were similar among those in the PRO sub-study compared to the rest of the trial sample (see Supplemental Table 1).

Treatment Protocol

Patients were randomly assigned to receive 5 cycles of chemotherapy in one of two study arms: standard arm or BV arm. Dosing and specific guidelines for dose modification in the presence of toxicity are published elsewhere.¹¹ Patients with large mediastinal adenopathy (LMA) were given 21 Gy of involved site radiation therapy (ISRT) after the fifth cycle of chemotherapy. Additionally, slow-responding lesions based on interim PET scans (at second cycle) were given 21Gy, with a boost dose of 9 Gy to sites with incomplete metabolic response after the fifth cycle.

HRQoL

HRQoL was assessed using the Child Health Ratings Inventories (CHRIs)-global scale, a 7-item unidimensional global HRQoL measure, which has been validated in pediatric cancer populations and is available in English and Spanish ¹³. At the time of study approval/accrual this was the only global measure of HRQoL validated for use across the study’s targeted age range (11–21 years). Participants are asked about the previous seven days and endorse each item on a 5-point Likert scale. Scores are scaled from 0 to 100 where higher scores indicate better functioning. Based on previous research ¹³, a minimal clinically important difference (MCID) on the CHRIs global scale is considered a difference of 7 points (1/3 of standard deviation).¹⁴

Participants completed the CHRIs global scale prior to therapy (T1), day 8 of cycles 2 (T2) and 5 (T3), and 6–8 weeks after the end of all planned therapy, inclusive of radiation (T4). Time points during therapy (T2 and T3) did not include a completion window because they aligned with protocol-specific therapeutic visits. However, time points off treatment (T4), included a 3-week collection window because they did not always align with clinical visits. Participants were approached in person during clinic visits and measures were collected on paper. Clinical research associates at each site uploaded completed measures into a Rave database. Then a central research associate, supported by extramural funding, downloaded the measures and entered them into a study-specific data base securely stored and maintained at the University of Chicago; the analytic team scored the measures in a blinded fashion.

Statistical Analysis

We first describe the frequency of participants completing the HRQoL assessment at each time point and calculated descriptive statistics for demographic and clinical characteristics. Mean HRQoL summary scores and 95^th % confidence intervals were calculated for each time point by treatment arm. In univariate linear regression models, we estimated the associations between clinical or demographic variables and HRQoL prior to any therapy (T1). Any variable where p<0.10 was included in a multivariate model with separate models to assess stage and individual B-symptoms (e.g. fever) as they are colinear.

To inform on potential selection bias due to loss to follow up, those with and without HRQoL data at T4 were compared on demographic and clinical characteristics. Linear mixed models estimated the mean change in HRQoL over time across treatment arms relative to pre- therapy (T1) controlling for a priori identified covariates. The fixed effects were time (T1, T2, T3, and T4), treatment arm (BV arm vs. standard arm), age, sex, and race/ethnicity, and a treatment arm by time interaction. The random effect was subject specific HRQoL score, independent of residual error. A second model was estimated additionally adjusting for fever (or stage), histology, and a time-varying covariate for radiation therapy at T4 based on associations demonstrated with baseline HRQoL. We also examined frequency of participants reaching their first MCID at each time point and those who never reach MCID (relative to T1 HRQoL scores). Cox-proportional hazards models estimated the hazard of reaching an MCID (at any time) in the BV arm relative to the standard arm, adjusting for age, sex, and race/ethnicity. Our use of Cox proportional hazard models is justified by the absence of on-treatment mortality and little disease progression (n=11) and thus, less concern about competing risks. All statistical testing was 2-sided and considered statistically significant with a p-value <0.05. All analyses were completed using SAS 9.4 (SAS Institute, Cary, N.C.). Where appropriate, we followed the recommendations of the Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium (SISAQOL) international standards for the analysis of HRQoL endpoints in cancer randomized trials (e.g. linear mixed models, MCID).¹⁵

Results

Of the 280 age-eligible participants ≥11 years, 268 (95.7%) completed the CHRIs-Global at one or more time points (Figure 1). Participant and disease characteristics were balanced by treatment arm; mean age at enrollment was 15.6 years (SD=1.9), 52% were female, 57% Non-Hispanic White, 60.4% had LMA, and 58% were stage IV (Table 1). Completion rates for the CHRIs-Global were high: 93% at T1, 92% at T2, 89% at T3, and 77% at T4. Completion rates were similar in both treatment arms (Supplemental Figure 1). Although not statistically significant, those that did not complete the CHRIs-Global at T4 were more often Hispanic or Non-Hispanic Black, had a lower income, were privately insured, and had mixed cellularity histology compared to those that did (Supplemental Table 2).

Table 1:

Participant Characteristics

	ABVE-PC (n=137)	Bv-AVEPC (n=131)
Age
Mean (SD)	15.8 (1.9)	15.5 (1.9)
Sex
Female	74 (54.0)	65 (49.6)
Male	63 (46.0)	66 (50.4)
Race and Ethnicity1
Hispanic	27 (20.8)	29 (24.0)
Non-Hispanic Black	27 (20.8)	13 (10.7)
Non-Hispanic White	76 (58.5)	78 (64.5)
Other and Unknown	0 (0.0)	1 (0.8)
Parent Employment2
Full time	69 (56.1)	66 (56.4)
Part-time	14 (11.4)	14 (12.0)
Full-time homemaking	24 (19.5)	23 (19.7)
Other	16 (13.0)	14 (12.0)
Household Income3
<$20,000	29 (24.2)	15 (13.5)
$20–39,999	21 (17.5)	24 (21.6)
$40–59,999	22 (18.3)	15 (13.5)
$60–79,999	12 (10.0)	15 (13.5)
>=$80,000	36 (30.0)	42 (37.8)
Parent Education4
< High School	18 (14.8)	11 (9.7)
High School	41 (33.6)	41 (36.3)
Some College	46 (37.7)	43 (38.1)
≥College Degree	17 (13.9)	18 (15.9)
Insurance5
Private	74 (57.4)	65 (53.7)
Public	48 (37.2)	48 (39.7)
Private and Public	5 (3.9)	3 (2.5)
None	2 (1.6)	5 (4.1)
Stage
IIB	32 (23.4)	26 (19.9)
IIIB	26 (19.0)	28 (21.4)
IVA	32 (23.4)	33 (25.2)
IVB	47 (34.3)	44 (33.6)
Histology
Mixed Cellularity	3 (2.2)	5 (3.8)
Nodular Sclerosis	113 (83.1)	100 (76.3)
Other histology	20 (14.7)	26 (19.9)
LMA6	84 (61.8)	78 (60.0)
B symptoms	104 (77.0)	97 (74.6)

LMA: large mediastinal adenopathy; B symptoms: fever, night sweats, weight loss

¹17 missing race/ethnicity

²28 missing parental employment

³37 missing household income

⁴33 missing parental education

⁵18 missing insurance type

⁶LMA defined as transverse tumor diameter > 1/3 the thoracic diameter at the dome of the diaphragm on a 6-foot posterior-anterior upright chest radiograph.

Pre-treatment HRQoL

Prior to any therapy (T1), approximately half (43.7%) of the patients scored ≥2standard deviations (SD=20) below the maximum HRQoL score (< 60points). Females patients scored, on average, 10 points lower on the CHRIs-Global compared to male patients (β=−10.62 95%CI −16.22, −45.03, Table 2). Patients with fever at baseline scored, on average, 8 points worse on the CHRIs-Global compared to those without fever (β=−7.84 95%CI −13.53, −2.14). There were no associations between night sweats, weight loss, or socioeconomic factors and HRQoL at baseline (Supplemental Table 3).

Table 2:

Multivariable models of predictors of baseline global CHRIs scores.

	Stage Model1		B-Symptom Model1
	Mean Difference β(95%CI)	p-value	Mean Difference β(95%CI)	p-value
Sex
Female	−10.62(−16.22,−5.03)	<0.001	−9.45(−15.01,−3.89)	0.001
Male	Ref. (0.0)		Ref. (0.0)
Household Income
<$20,000	1.45(−6.54,9.45)	0.720	0.99(−6.88,8.86)	0.805
$20–39,999	6.77(−1.19,14.73)	0.095	6.11(−1.74,13.96)	0.126
$40–59,999	9.97(1.57,18.36)	0.020	10.58(2.28,18.87)	0.013
$60–79,999	3.67(−5.95,13.28)	0.453	2.16(−7.29,11.61)	0.653
>=$80,000	Ref. (0.0)		Ref. (0.0)
Stage
IIB	Ref. (0.0)		-
IIIB	−4.44(−13.11,4.22)	0.3132	-
IVA	5.2(−3.29,13.68)	0.2285	-
IVB	−0.59(−8.32,7.15)	0.8812	-
Histology
Mixed Cellularity	−18(−35.21,−0.78)	0.041	−18.17(−35.14,−1.2)	0.036
Nodular Sclerosis	−0.9(−8.49,6.69)	0.814	−1.81(−9.25,5.64)	0.632
Other histology	Ref. (0.0)		Ref. (0.0)
Fever
Yes	-		−7.84(−13.53,−2.14)	0.007
No	-		Ref. (0.0)

¹Multivariate models include any variable w/p<0.10 in univariate models (see Supplemental Table 3). Two separate models were generated due to the collinearity between stage and the presence of any B-symptoms (e.g. fever).

Changes in HRQoL Over Time

While patients on both treatment arms experienced improvements in HRQoL over time (Figure 2), at T2 participants in the BV arm experienced a statistically and clinically significant increase in HRQoL compared to pre-treatment (T1) (Table 3; β=7.41 95%CI 3.36, 11.46; p≤0.001), which was greater than the change experienced in the standard arm (difference in change β=5.2 95%CI −0.01, 10.37; p=0.050). At T3 and T4 the BV arm again experienced statistically significant improvements in HRQoL relative to T1 (T3 β=5.50 95%CI 0.96, 10.04; p=0.018; T4 β=14.69 95%CI 10.39, 19.00; p≤0.001). The standard arm did not experience a statistically or clinically significant increase in HRQoL until the end of planned therapy at T4 (β=9.21 95%CI 4.67, 13.75; p<0.001). However, the change in HRQoL at T4 relative to T1 was still greater among those in the BV arm (difference in change β=5.48 95%CI −0.74, 11.70; p=0.084).

Figure 2: Observed Mean CHRIs global scores (95%CI) by treatment arm.

Table 3:

Linear mixed model estimating the marginal mean difference (95%CI) in global CHRIs scores comparing treatment arms.

	Age, sex, race/ethnicity adjusted		Fully adjusted 1
	Mean Difference in HRQoL β(95%CI)	P-value	Mean Difference in HRQoL β(95%CI)	P-value
Comparing T2 to T1
BV-AVE-PC	7.14(3.24, 11.04)	<0.001	7.41 (3.36, 11.46)	<0.001
ABVE-PC	1.65(−1.52, 4.83)	0.304	2.23 (−1.05, 5.51)	0.182
Change in BV-AVE-PC vs. Change in ABVE-PC	5.48(0.48, 10.49)	0.032	5.18 (−0.01, 10.37)	0.050
Comparing T3 to T1
BV-AVE-PC	6.30(2.02, 10.58)	0.004	5.50 (0.96, 10.04)	0.018
ABVE-PC	2.40(−1.20, 6.01)	0.189	2.40 (−1.35, 6.16)	0.207
Change in BV-AVE-PC vs. Change in ABVE-PC	3.89(−1.68, 9.46)	0.170	3.10 (−2.77, 8.96)	0.299
Comparing T4 to T1
BV-AVE-PC	14.47(10.37, 18.58)	<0.001	14.69 (10.39, 19.00)	<.0001
ABVE-PC	8.84(4.45, 13.23)	<0.001	9.21 (4.68, 13.75)	<0.001
Change in BV-AVE-PC vs. Change in ABVE-PC	5.63(−0.35, 11.61)	0.065	5.48 (−0.74, 11.70)	0.084
Type III effects
Time		<0.001		<.0001
Treatment Arm		0.106		0.135
Time*Treatment Arm		0.158		0.200

T1: prior to therapy, T2: after cycle 2, T3: after cycle 5, T4: end of therapy.

¹Fully adjusted model is adjusted for age at baseline, sex, race/ethnicity, fever (yes or no), histology, and a time-varying covariate for radiation received before T4.

Although not statistically significant, a higher proportion of participants treated on the BV arm ever achieved a MCID in HRQoL compared to the standard arm (41.7% vs. 31.1%, p=0.074; Figure 3). In Cox proportional hazards-models, adjusted for age, sex, and race/ethnicity, participants in the BV arm were more likely to achieve an MCID, although not statistically significant (HR=1.24 95%CI 0.92, 1.57; p=0.196).

Figure 3: Percent reaching their first Minimal Clinically Important Difference (MCID) at each time point.

MCID defined as an increase of 7 points, relative to Time 1 on the global CHRIs HRQoL scale. Groups are mutually exclusive, participants can only reach a MCID once.

Discussion

We report the first longitudinal assessment of HRQoL in a cohort of children and adolescents with high risk HL assessed in a Phase 3 randomized clinical trial examining the efficacy of novel frontline therapy in high-risk disease.¹¹ Approximately half of patients reported significantly impaired HRQoL prior to treatment, indicative of the large impact of disease burden on HRQoL. While, on average, patients experienced improvements in HRQoL, the addition of BV to a dose-dense, 5-cycle pediatric regimen for high-risk HL was associated with significant improvements in HRQoL within 2 cycles of therapy. In addition to the previously demonstrated benefits in event-free survival ¹¹, our analysis shows that treatment with BV-AVE-PC was associated with more rapid and sustained improvements in HRQoL that were clinically meaningful.. This is despite evidence of similar disease response in both arms at cycle 2. These findings inform clinician understanding of patient perspective on quality of life at baseline and over time during the administration of dose dense therapy for children and adolescents, inclusive of the novel agent, brentuximab vedotin.

The NCI and FDA have placed increased emphasis on the collection and reporting of patient-reported outcomes, specifically HRQoL, in clinical trials.^16–18 Despite these priorities, recent data suggest only 25% of COG-led phase 3 therapeutic trials included a patient-reported endpoint.¹⁹ Evaluating HRQoL is especially germane with novel therapy and we demonstrate feasibility of embedding this as a pre-specified key secondary endpoint in a multi-center clinical trial. Strikingly, despite the burden of disease and treatment in a trial for high-risk HL, we were able to collect serial HRQoL from participants ≥11 years of age throughout therapy at rates of 90% or higher. HRQoL collection at T4 (end of treatment), however, was less successful. Sites reported logistical issues with data collection and a malalignment with planned clinical visits. Non-completion at T4 also was associated with Hispanic ethnicity, Non-Hispanic Black race, and lower household income, characteristics which other studies report may be associated with lower HRQoL.²⁰ Specific strategies, informed by key stakeholders, need to be employed to collect PRO data from historically underrepresented sub-groups that may face unique challenges in completing study assessments or clinical visits. We also recommend in future studies precisely defining the “end-of-treatment” time point, linking it to planned clinical follow up, and giving consideration to community-specific barriers to completing post-treatment time points.¹⁶ In the recently activated, COG-led AHOD 2131 trial (NCT05675410) an electronic direct-to-patient battery is being evaluated to enhance PRO collection.²¹

Despite known rates of clinically graded treatment-related adverse events (e.g., neuropathy) being similar by treatment arm on the parent trial, HRQoL was consistently superior in patients treated on the BV arm. This is especially notable early in the course of therapy when there was no difference in imaging-based disease response (e.g., interim PET + rates) by arm. While the proportion of patients with slow responding lesions after cycle 2 and the proportion of patients receiving RT did not differ between arms, the HRQoL was superior in those who received the BV-based regimen. This suggests there may be unmeasured factors outside objective measures of disease response (e.g. interim PET) or that disease burden was lowered beyond what is reflected in the PET scan. Therefore, it may be just as important to understand how the patient experiences the therapy through HRQoL assessments.

Similar to our findings, Heutte et al. reported improving HRQoL during therapy among adults with early-stage HL.⁴ In contrast to our findings, a report by Kreissl et al. from the German Hodgkin Study Group (GHSG) found that across 3 randomized trials of adults with HL, including advanced stage disease, HRQoL declined during therapy, with modest improvement post-therapy.⁶ Two of the GHSG trials included treatment with escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), although they report no differences in long-term HRQoL by treatment arm. Our data may reflect that BV is better tolerated among younger patients and delivered at a lower cumulative dose compared with previous studies published in adults.^11,22 Future analyses will directly inform the question of improved regimen tolerance, given robust enrollment and treatment across the age continuum.

Our results highlight the interesting juxtaposition between improvement in short-term HRQoL during therapy and the well-published diminished HRQoL in long-term survivorship among those treated with historic conventional therapy and significant late morbidity.^1,3,8,23 Among survivors of adult HL,declines in HRQoL are associated with new onset cardiopulmonary conditions.^24,25 Thus, the current analysis responds to the imperative to understand how novel therapies may impact HRQoL in a pediatric cohort and subsequent patient-reported morbidity. Yet there is a large disconnect in available data between the acute treatment setting and long-term survivorship cohorts. Efforts are ongoing to fill this gap including serial collection of patient-reported HRQoL, symptom assessment, and self-reported health beyond the typical 5 years of clinical trials follow up. Such information will enhance our understanding of how trajectories of HRQoL change into early survivorship and how the onset of subsequent medical conditions influences HRQoL. The inclusion of patient-reported HRQoL, symptoms, and outcomes into clinical trials and long-term surveillance is essential as we aim to understand the potential for novel agents in reducing both short- and long-term morbidity, thus allowing for informed choice about treatment selection and real-time interventions.

Interestingly, we found female patients had worse HRQoL compared to males. Previous groups reported differential HRQoL by sex and/or gender in adults²⁶ and children^27–29 with females consistently having worse HRQoL. Differences are hypothesized to be associated with physiology (e.g., hormonal changes), coping mechanisms, and societally defined affect.²⁹ In the context of our study in HL, we are unsure of the specific drivers of this difference. In a separate analysis we found females reported more peripheral neuropathy.¹² Additional analyses are needed to understand if this is correlative or a driver of the sex-specific differences in HRQoL.

This study has many strengths including its novel collection of patient-reported HRQoL in pediatric HL, high completion rates, and ability to inform on the short-term impact of cancer and therapy on HRQoL using international guidelines recommended by SISAQOL.¹⁵ In fact, this trial is the first model for PRO collection in either COG-led or cross-intergroup-led trials, and has set a precedent for PRO collection moving forward.³⁰ However, several limitations should be considered. First, only the first half of the total study sample completed the PRO sub-study given the pre-specified requirement by the study sponsors. We found no consistent differences between those in the PRO sub-study and the remaining trial participants, allowing us to generalize our findings.¹² Second, the CHRIs-Global, is used primarily in the hematopoietic transplant setting³¹; is a unidimensional measures of HRQoL. In contrast, adult measures such as the adult PROMIS Global measure is multidimensional, yielding instead two subscale scores for physical and mental health, making comparisons more difficult.³³ Additionally, while participation was robust, there was a drop-off in completion rates at the end of treatment that was associated with various sociodemographic factors consistent with historically underrepresented populations. Previous literature suggests these groups experience disproportionately lower HRQoL.^20,34 In contrast, there was little attrition due to disease progression and no mortality. However, HRQoL is not independent of acute toxicity and side-effects of therapy and we were not able to account for how the onset and mitigation of these may have influenced HRQoL. Ongoing intergroup trials include serial self-reported symptom assessment and will inform the inter-relatedness of HRQoL and symptom/disease burden and treatment tolerability, leading to the identification of vulnerable subgroups and targets for intervention.

In conclusion we report the successful collection of serial HRQoL from youth with high-risk pediatric Hodgkin lymphoma, despite burden of disease and intensity of treatment. We demonstrate improvement in HRQoL over the course of initial therapy, sooner and to a greater extent in the group receiving the novel agent BV. These findings, coupled with superior clinical outcomes, suggest the emergence of incorporation of BV in the treatment of pediatric HL with high risk disease.

Supplementary Material

PV Appendix Figure 1

Supplemental Figure 1: Longitudinal Consort Diagram. Participants were included in the analysis if they were age 11 or older and completed the CHRIs at one or more time points. Linear mixed models do not require participants to have complete data across all time points. Therefore, participants were evaluable if they completed the CHRIS-Global at that time point.