Abstract
Background:
Outcomes for high-risk pediatric classic Hodgkin lymphoma (cHL) improved with the addition of brentuximab vedotin (Bv) to AVEPC chemotherapy. We evaluated the prognostic implications of distant extranodal sites contributing to stage IV disease.
Methods:
On AHOD1331 (NCT02166463), patients aged 2–21 years with high-risk cHL (stage IIB with bulk/IIIB/IVA/IVB) were randomized to 5 cycles of ABVE-PC versus Bv-AVE-PC. Patients with stage IV disease, determined by protocol-defined and centrally reviewed PET-CT, were identified. Baseline characteristics and progression-free survival (PFS) were compared by pattern of stage IV involvement (lung, bone, bone marrow, multiple sites, other).
Results:
340 patients (median age 15 years) with stage IV disease were included. 173 (51%) received ABVE-PC and 167 (49%) Bv-AVE-PC. PFS was highest with lung-only involvement (4-year PFS 88.6%) and lowest with bone marrow-only involvement (4-year PFS 71.9%). Compared to ABVE-PC, Bv-AVE-PC improved PFS among all stage IV patients (HR 0.53, 90% CI 0.33–0.85) and in lung-only and bone-only subgroups. However, no PFS benefit was observed in those with bone marrow-only involvement.
Conclusions:
Among pediatric patients with stage IV cHL, Bv-AVE-PC improved PFS across most patterns of stage IV disease, except in those with bone marrow involvement. These results will guide efforts to improve outcomes among children with stage IV cHL.
Keywords: classic Hodgkin lymphoma, pediatric oncology, stage IV disease
INTRODUCTION
Outcomes for pediatric and adolescent and young adult (AYA) classic Hodgkin lymphoma (cHL) have improved over time, allowing for the integration of response-based strategies and a focus on reducing therapy historically associated with late effects.1,2 For patients with high-risk cHL specifically, the addition of brentuximab vedotin (Bv) to AVEPC (doxorubicin, vincristine, etoposide, prednisone, cyclophosphamide) chemotherapy has been shown to greatly improve survival.3 However, in subgroup analyses, patients with stage IVB disease did not seem to benefit from the addition of Bv, and overall, there remains room for further improvement in initial disease control and maximization of the therapeutic ratio among those with stage IV disease. The prognostic significance of sites contributing to stage IV cHL (i.e., the anatomic distribution of distant extranodal sites) remains unknown, but is important for understanding the limitations of novel therapies and how to improve outcomes for children with stage IV disease. As such, we evaluated the prognostic implications of disease sites contributing to stage IV disease on AHOD1331 and the therapeutic effect of Bv on outcomes.
METHODS
Treatment Protocol
AHOD1331 (ClinicalTrials.gov identifier: NCT02166463) was a prospective, multicenter phase III randomized trial run through the Children’s Oncology Group (COG) cooperative research network and sponsored through the National Cancer Institute (NCI). Patients aged 2–21 years with high-risk cHL (defined as stage IIB with bulk, IIIB, IVA, and IVB) were eligible for enrollment. Stage was defined by individual institutions and further confirmed with a delineation of all disease sites by central review of imaging including contrast CT and FDG-PET-CT. Protocol approval was obtained from the Pediatric Central Institutional Review Board as well as local institutional review boards. Patients 18 years of age or older provided written informed consent, while a parent or guardian provided consent for those less than 18 years of age, with assent from children and adolescents.
On AHOD1331, patients were randomized (1:1) to 5 cycles of chemotherapy delivered every 21 days with AB (bleomycin)VE-PC (arm 1) versus Bv-AVE-PC (arm 2). Details of therapy and response criteria have been previously defined.3
Stage IV disease on AHOD1331
Patients with stage IV disease, as determined by protocol defined and centrally reviewed contrast CT and PET-CT, were identified. For our analysis, we included patients determined to be stage IV by central review imaging regardless of marrow status, as well as those labeled as stage II–III by central review imaging but with documented marrow positivity by institutional biopsy. Stage IV was defined per protocol as disseminated involvement of ≥1 extralymphatic organ or tissues (with or without lymph node involvement) or isolated extralymphatic organ involvement with distant nodal involvement. Bone involvement was specifically defined via imaging as focal bone lesions that were permeative, sclerotic, or both and PET positive. Bone marrow involvement was defined by either imaging or institutional histology report via a protocol-mandated bone marrow biopsy. On imaging, bone marrow involvement was defined as the involvement of 3 or more PET positive lesions in the bone marrow. For our analysis, the PET definition of bone marrow positivity (if deemed stage IV otherwise by central review) and/or bone marrow biopsy positivity was considered as bone marrow involvement. Lung involvement was defined as at least one intrapulmonary focus that was PET positive or 3 or more lesions between 0.5 and 1 cm, regardless of FDG-PET activity. Of note, E-lesions were distinguished from sites of stage IV involvement in the lung, but any liver and/or bone marrow involvement, regardless of contiguity, was considered stage IV.
Statistical Analysis
The main objective of this analysis was to examine the association between progression-free survival (PFS) and stage IV disease. PFS was defined as the time until disease progression, relapse, or death and calculated via the Kaplan-Meier method. PFS was compared by pattern of stage IV involvement (lung, bone, bone marrow, multiple sites, other). Overall survival (OS) was also evaluated by pattern of stage IV involvement using Kaplan-Meier estimation and Cox proportional hazards regression models, with 90% confidence intervals (CI) corresponding to the one-sided alpha = 0.05 used in the primary study design of AHOD1331. Baseline patient, tumor, and treatment characteristics were analyzed via descriptive statistics and compared by pattern of stage IV involvement with Chi-square and rank tests or non-parametric alternatives where appropriate.
RESULTS
Patients
In total, 340 patients with stage IV disease treated on AHOD1331 were included in our analysis, of which 173 (51%) were treated with ABVE-PC and 167 (49%) with Bv-AVE-PC. Median age was 15.3 years (range, 3.4 to 21.99), 184 (54%) were male, and 251 (74%) white. One-hundred and ninety-six (59%) presented with B symptoms and 168 (50%) with large mediastinal adenopathy (LMA).
The 340 patients were divided into several groups based on patterns of involvement: Bone marrow only (n=33), bone only (n=39), lung only (n=178), liver only (n=3), adrenal only (n=1), or multiple sites (n=86). Table 1 provides the distribution based on demographics and baseline clinical conditions for the subgroups. Supplementary Table 1 provides a more detailed breakdown of the specific anatomic distribution of distant extranodal sites of involvement. The comparisons among the involvement groups show that: patients with lung only or other (i.e. adrenal, liver only) involvement were more likely to have nodular sclerosing histology and a lower mean erythrocyte sedimentation rate (ESR) compared to other subgroups. In addition, patients with bone or bone marrow involvement were more likely to present with B symptoms. There were no other significant differences in patient enrollment age, sex, race, ethnicity, LMA, and treatment assignment based on pattern of stage IV disease (Table 1).
Table 1:
Patient and Disease Characteristics by Site(s) of Stage IV Disease
| Characteristic | Lung Only, N = 1781 | Bone Only, N = 391 | Marrow Only, N = 331 | Other Only, N = 41 | Multiple, N = 861 | Overall, N = 3401 | p-value2 |
|---|---|---|---|---|---|---|---|
| Age (Years) | 0.745 | ||||||
| Mean | 14.68 | 15.07 | 14.17 | 15.43 | 14.99 | 14.76 | |
| SD | 2.75 | 3.36 | 3.78 | 1.46 | 3.22 | 3.04 | |
| Sex | 0.174 | ||||||
| Female | 85 (48%) | 12 (31%) | 13 (39%) | 3 (75%) | 43 (50%) | 156 (46%) | |
| Male | 93 (52%) | 27 (69%) | 20 (61%) | 1 (25%) | 43 (50%) | 184 (54%) | |
| Race | 0.740 | ||||||
| White | 138 (78%) | 27 (69%) | 26 (79%) | 4 (100%) | 56 (65%) | 251 (74%) | |
| Black or African American | 17 (9.6%) | 4 (10%) | 3 (9.1%) | 0 (0%) | 10 (12%) | 34 (10%) | |
| Asian | 7 (3.9%) | 1 (2.6%) | 1 (3.0%) | 0 (0%) | 2 (2.3%) | 11 (3.2%) | |
| Multiple Races | 1 (0.6%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (3.5%) | 4 (1.2%) | |
| Unknown | 10 (5.6%) | 4 (10%) | 1 (3.0%) | 0 (0%) | 8 (9.3%) | 23 (6.8%) | |
| Not Reported | 5 (2.8%) | 3 (7.7%) | 2 (6.1%) | 0 (0%) | 7 (8.1%) | 17 (5.0%) | |
| Ethnicity | 0.252 | ||||||
| Not Hispanic or Latino | 145 (85%) | 28 (76%) | 22 (71%) | 3 (75%) | 60 (76%) | 258 (80%) | |
| Hispanic or Latino | 26 (15%) | 9 (24%) | 9 (29%) | 1 (25%) | 19 (24%) | 64 (20%) | |
| Unknown | 7 | 2 | 2 | 0 | 7 | 18 | |
| Histology | 0.014 | ||||||
| Hodgkin Lymphoma, NOS | 23 (13%) | 8 (21%) | 2 (6.1%) | 0 (0%) | 19 (22%) | 52 (15%) | |
| Lymphocyte Rich | 0 (0%) | 1 (2.6%) | 1 (3.0%) | 0 (0%) | 1 (1.2%) | 3 (0.9%) | |
| Mixed Cellularity | 4 (2.2%) | 2 (5.1%) | 5 (15%) | 0 (0%) | 8 (9.3%) | 19 (5.6%) | |
| Nodular Sclerosis | 151 (85%) | 28 (72%) | 25 (76%) | 4 (100%) | 58 (67%) | 266 (78%) | |
| B Symptoms | 92 (53%) | 27 (71%) | 25 (76%) | 2 (50%) | 50 (59%) | 196 (59%) | 0.070 |
| Unknown | 5 | 1 | 0 | 0 | 1 | 7 | |
| ESR (mm/hr) | <0.001 | ||||||
| Mean | 60 | 78 | 85 | 55 | 78 | 69 | |
| SD | 32 | 37 | 37 | 5 | 35 | 35 | |
| LMA | 95 (53%) | 15 (38%) | 17 (53%) | 3 (75%) | 38 (44%) | 168 (50%) | 0.272 |
| Unknown | 0 | 0 | 1 | 0 | 0 | 1 | |
| Arm | 0.881 | ||||||
| ABVE-PC | 89 (50%) | 23 (59%) | 16 (48%) | 2 (50%) | 43 (50%) | 173 (51%) | |
| Bv-AVEPC | 89 (50%) | 16 (41%) | 17 (52%) | 2 (50%) | 43 (50%) | 167 (49%) |
n (%)
Kruskal-Wallis rank sum test; Pearson's Chi-squared test
“Other” sites of stage IV disease consist of adrenal (N = 1) and liver (N = 3).
Clinical Outcomes
PFS varied based on pattern of stage IV disease, with the highest PFS seen in those with lung only involvement (4-year PFS 88.6%, 90% CI 84.7–92.6), and lowest PFS in those with bone marrow only involvement (4-year PFS 71.9%, 90% CI 59.9–86.2, Figure 1a, p=0.07). Overall survival (OS) was also affected by pattern of stage IV disease, with worse OS in those with bone marrow only involvement (4-year OS 93.8%, 90% CI 87.0–100) compared to those with bone only (4-year OS 100%, 90% CI n/a), lung only (4-year OS 100%, 90% CI n/a), or multiple site involvement (4-year OS 98.8%, 90% CI 96.8–100).
Figure 1A:
Progression-free survival (PFS) by Site Group
Among all stage IV patients, Bv-AVE-PC significantly improved PFS compared to ABVE-PC: 4-year PFS 89.6% (90% CI 85.8–93.6) vs 79.2% (90% CI 74.1–84.5), HR =0.53 (90% CI 0.33–0.85), p=0.02, Figure 2a. See Figure 2b–d for PFS by any involvement of the following (irrespective of whether other localizations are also affected): lung (2b), bone (2c), and bone marrow (2c). Among patients with any lung involvement, PFS was similarly improved with Bv: 4-year PFS 91.2% (90% CI 87.0–95.7) vs 84.2% (90% CI 78.7–90.0), HR = 0.52 (90% CI 0.27–1), p=0.09, Figure 2b. Among patients with any bone involvement (including those with bone and bone marrow involvement), there was a non-significant trend toward improved PFS with Bv-AVE-PC compared to ABVE-PC: 4-year PFS 87.6% (90% CI 80.1–95.7) vs 74.5% (90% CI 65.1–85.4), HR=0.64 (90% CI 0.3–1.35), p=0.32, Figure 2c. However, among patients with any bone marrow involvement, there was no difference in PFS with Bv: 4-year PFS 79.4% (90% CI 70.0–90.2) vs 75.4% (90% CI 65.0–87.4), HR = 0.89 (90% CI 0.43–1.87), p=0.8, Figure 2d. Subgroup analyses evaluating PFS by specific anatomic distribution of disease confirmed the superior PFS with Bv among all patterns of stage IV disease except those with bone marrow involvement or multiple site involvement (Forest Plot, Figure 3). Specifically, PFS was improved with Bv among patients with lung only involvement (Hazard Ratio, HR = 0.40, 90% CI 0.18–0.89) and bone only involvement (HR = 0.15, 90% CI 0.03–0.86), but not among patients with bone marrow only involvement (HR = 0.73, 90% CI 0.24–2.21) or multiple site involvement (HR = 0.98, 90% CI 0.43–2.24). There was no difference in OS by treatment arm across the various patterns of stage IV involvement (Supplementary Figures 1a–1d).
Figure 2A:
Progression-free survival (PFS) by Treatment Arm, Overall Stage IV Cohort
Figure 2B:
PFS by Treatment Arm, Patients with Lung Involvement
Figure 2D:
PFS by Treatment Arm, Patients with Marrow Involvement
Figure 2C:
PFS by Treatment Arm, Patients with Bone Involvement
Figure 3.
Forest plot of progression-free survival with ABVE-PC vs Bv-AVE-PC stratified by anatomic distribution of stage IV disease
DISCUSSION
Patients with stage IV pediatric cHL have typically been grouped together in trials and studies with other high-risk patients, limiting the ability to distinguish the prognostic implications of stage IV disease despite the overall poor outcome.4–6 Furthermore, the prognostic value of the anatomic distribution of stage IV disease (i.e., the organs involved) has not been previously evaluated. Our study is the first, to our knowledge, to evaluate the prognostic implications of sites contributing to stage IV disease in a large cohort with pediatric cHL treated on a prospective clinical trial. Among children and adolescents with stage IV cHL, we found that PFS was notably improved with Bv-AVE-PC compared with standard chemotherapy in patients with most patterns of stage IV disease, including those with lung involvement and bone involvement. However, the benefit of Bv did not extend to stage IV patients with bone marrow involvement. This suggests that marrow disease may represent a distinct manifestation of stage IV cHL,7 potentially reflecting unique underlying biologic or microenvironmental differences compared with other distant extranodal sites.
Similar to our analysis, a benefit of Bv was observed among adults with cHL treated on ECHELON-1. This benefit was observed in subgroup analyses among those with stage IV disease as well as those with B symptoms; however, the prognostic implications and benefit of Bv among those with bone marrow involvement was not specifically reported.8 Additionally, on HD21, among adults with advanced-stage cHL, Bv (in combination with etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone, BrECADD) resulted in less toxicity and improved oncologic outcomes compared to escalated dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (eBEACOPP). A similar trend towards improvement with BrECADD was seen among the patients with stage IV disease, however, the benefit of BrECADD among those with bone marrow involvement specifically was not reported.9 On AHOD0831, evaluating response-adapted therapy for pediatric high-risk cHL with B symptoms, there was no difference in survival outcomes for stage IIIB vs IVB patients.6 Like ECHELON-1 and HD21, though, the prognostic implication of bone marrow involvement was not evaluated nor reported. On SWOG S0816, where the value of a PET-adapted approach for advanced cHL among adults was evaluated, there was no statistically significant difference in progression events by stage or presence of B symptoms.10 However, a difference in outcome by stage was observed on the RATHL trial among adults with advanced disease, with inferior PFS observed among those with stage IV disease compared to earlier stages (although no difference in PFS among stage IV patients with a negative PET treated with or without the omission of bleomycin).11 In the aforementioned studies, like ECHELON-1 and AHOD0831, the prognostic implications of bone marrow involvement or anatomic distribution of distant extranodal sites were not investigated.
Our data suggest that alternative therapies may need to be considered for pediatric and adolescent patients with cHL and bone marrow involvement. As shown on SWOG S1826, nivolumab in combination with AVD is efficacious for patients with stage IV cHL.12,13 Although not directly comparable to our cohort (different inclusion criteria, cohort age, and systemic backbone), further investigation of the benefit of immune checkpoint inhibition among those with bone marrow involvement specifically is warranted via subset analyses from S1826, if feasible.
On AHOD1331, bone marrow involvement was defined both by a protocol-mandated biopsy as well as by a protocol-specified FDG-PET definition. Regardless of the definition utilized, patients with bone marrow involvement did not appear to benefit from Bv. Regarding other stage IV sites, pre-specified imaging definitions were utilized to define sites of involvement (i.e., lung, bone). Central review of institutional staging was performed for our analysis. The significance of central imaging review for determination of PET response for adaptive treatment has been previously demonstrated on AHOD1331,14 supporting its use to define stage IV sites as a strength of the current study.
Although the focus for stage IV patients has typically emphasized improvement in disease control over reduction in late effects, the superior and excellent PFS (of approximately 90% at 4 years) in stage IV patients with Bv-AVE-PC allows for a shift in focus to reducing long-term morbidity from treatment.15 In contrast to earlier COG studies (e.g., AHOD0031), among patients with lung involvement, AHOD1331 omitted whole lung radiotherapy (WLRT) as well as partial lung irradiation to pulmonary sites after a complete response to systemic therapy. The excellent outcomes observed on AHOD1331 indicate that WLRT is unnecessary for cHL, with systemic therapy alone sufficient for pulmonary disease control. In addition, with such favorable outcomes, the role of radiotherapy for pediatric patients with stage IV disease will likely further diminish (beyond the reduction already observed on AHOD1331), as is true for adults with stage IV cHL treated on ECHELON-18 and AYAs treated on SWOG S1826.12 Furthermore, with an improvement in initial disease control with novel agents such as Bv and checkpoint inhibition therapy, the need for salvage therapies such as high-dose chemotherapy and stem cell transplantation should decrease.
As a post hoc analysis, this study included a subset of patients treated on AHOD1331, and the initial trial design was not powered to evaluate only those with stage IV disease. In addition, given the limited sample size within certain subgroups (i.e., those with lung only involvement, multi-site involvement, etc.), conclusions regarding the effect of Bv based on specific pattern of stage IV involvement should be interpreted with caution. Nevertheless, we find consistent results with the larger AHOD1331 cohort, that Bv-AVE-PC results in superior PFS compared with standard chemotherapy among patients with most patterns of stage IV disease, with the exception being those with bone marrow involvement. Long term follow-up for overall survival and comparison to alternative therapies such as checkpoint inhibition therapy will help us further understand strategies to improve outcomes among stage IV pediatric cHL.
Supplementary Material
Figure 1B:
Overall Survival (OS) by Site Group
Funding information:
Supported in part by grants from the National Institutes of Health (U10CA098543, U10CA180899, and U10CA180886; all to the Children’s Oncology Group), the Quality Assurance Review Center (U10CA29511), Imaging and Radiology Oncology Core Rhode Island (U24CA180803), St. Baldrick’s Foundation (to the Children’s Oncology Group), and Leukemia and Lymphoma Society (now Blood Cancer United). Seattle Genetics Inc. (now Pfizer Inc.) supplied Brentuximab vedotin (AdcetrisTM) to the NCI under a Cooperative Research and Development Agreement. Dr. Castellino receives funding through NCI R50 CA285492-01.
This manuscript is the result of funding in whole or in part by the National Institutes of Health (NIH). It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make this manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH.
Conflicts of Interest:
SMC reports the following: BMS (Pediatric advisory board - fees); Pfizer (grant to institution); Lymphoma Research Foundation (scientific advisory board; meeting reimbursement); Blood Cancer United (no reimbursement)
No other relevant conflicts of interest to disclose.
Footnotes
Clinical Trial: NCT02166463
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Data availability:
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.