Abstract
BACKGROUND
In adults with advanced-stage Hodgkin’s lymphoma, the CD30-directed antibody–drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin’s lymphoma is unclear.
METHODS
We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin’s lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography–computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed.
RESULTS
Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.
CONCLUSIONS
The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.)
Hodgkin’s lymphoma can serve as a model for balancing curative-intent therapy with long-term effects in populations who have decades of life ahead. The refining of contemporary approaches to treatment in children with advanced-stage and high-risk Hodgkin’s lymphoma requires improving initial disease control to reduce the risk of late disease and premature death that have been associated with high-dose salvage chemotherapy and stem-cell transplantation.1–3
The treatment approach in children and adolescents diverges from that in adults in terms of risk classification, conventional chemotherapy regimens, the application of response as assessed on 18F-fluorodeoxyglucose (FDG)–positron-emission tomography (PET) and computed tomography (CT) to subsequent modifications to therapy and the use of consolidative radiation therapy. Trials involving children also include second malignant neoplasms in the primary end point of event-free survival.4 In contrast to the chemotherapy regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) that is used in adults with Hodgkin’s lymphoma, regimens in children with advanced-stage disease include etoposide and cyclophosphamide with continued use of glucocorticoids, while limiting cumulative doses of doxorubicin and bleomycin.5
The phase 3 EuroNET-PHL-C1 trial involving children with Hodgkin’s lymphoma showed a 5-year event-free survival of 88.0% (95% confidence interval [CI], 84.3 to 91.8) with chemotherapy alone among patients with stage IIBE, IIIAE, IIIBE, IIIB, or IV disease who had an early metabolic response to treatment with vincristine, etoposide, prednisone, and doxorubicin and 85.9% (95% CI, 83.0 to 88.9) with intensified chemotherapy and consolidative involved-site radiation therapy after an inadequate early response.6 With the dose-intensive regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide, the Children’s Oncology Group found that the 5-year event-free survival was 79.1% among patients with stage IIIB or IVB disease, with 76% of the patients receiving involved-site radiation therapy.7 In contrast, 5-year progression-free survival was 75.3% (95% CI, 71.7 to 78.5) among adults who had been treated with ABVD.8 Despite greater disease control with pediatric approaches, contemporary combination therapy has not resulted in sustained disease control with initial therapy in 15 to 25% of children and adolescents with Hodgkin’s lymphoma. This situation necessitates additional therapies that have been associated with late effects, including second cancers, infertility, and cardiovascular disease and with subsequently reduced overall survival.9
The antibody–drug conjugate brentuximab vedotin targets CD30 on the Hodgkin’s lymphoma Reed–Steenberg cell. The ECHELON-1 trial, which was limited to patients 18 years of age or older, showed that the substitution of brentuximab vedotin for bleomycin in the chemotherapy regimen resulted in a risk of disease progression, death, or noncomplete response leading to use of subsequent anticancer therapy at 2 years that was 4.9 percentage points lower than the risk with ABVD.10 A recently updated analysis of the trial results indicated that the 5-year progression-free survival with brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine was 82%.8 Febrile neutropenia and peripheral neuropathy are limiting toxic effects of brentuximab vedotin therapy in adults with advanced-stage Hodgkin’s lymphoma.
The experience of the Children’s Oncology Group in early-phase trials indicated an acceptable safety profile of brentuximab vedotin treatment in children with relapsed or refractory disease and established the safety of a dose of 1.8 mg per kilogram of body weight.11 A single-group, multicenter trial involving children with newly diagnosed high-risk disease replaced the vincristine doses with brentuximab vedotin in the combination therapy that had been used in the EuroNet-PHL-C1 trial and showed a 3-year event-free survival of 97%, with a 4% incidence of severe neuropathy.12 We therefore conducted an open-label, phase 3 trial (AHOD1331) comparing a regimen of brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide with the standard bleomycin-containing chemotherapy regimen in children and adolescents with high-risk classic Hodgkin’s lymphoma.
Methods
OVERSIGHT
We conducted this National Cancer Institute (NCI)–sponsored prospective, multicenter, phase 3, randomized trial through the Children’s Oncology Group cooperative research network. Brentuximab vedotin was supplied by Seagen to the NCI under a Cooperative Research and Development Agreement. Neither the NCI nor Seagen had a role in the trial design or analysis. All the data were maintained by the Children’s Oncology Group Statistics and Data Center and were reviewed by the Children’s Oncology Group data and safety monitoring committee. The academic authors designed the trial; collected, analyzed, and interpreted the data; and prepared the manuscript. The academic authors vouch for the completeness and accuracy of the reported data and for the fidelity of the trial to the protocol, which is available with the full text of this article at NEJM.org.
Data collection occurred at each participating Children’s Oncology Group institution after approval by the Pediatric Central Institutional Review Board and by local institutional review boards in accordance with institutional policies. Written informed consent was obtained from all patients 18 years of age or older; for all patients younger than 18 years of age, written informed consent was obtained from a parent or guardian, with assent obtained from the child or adolescent. The trial was conducted in accordance with the Declaration of Helsinki.
TRIAL DESIGN
Patients were randomly assigned in a 1:1 ratio to receive five cycles of chemotherapy in one of the two trial groups. Brentuximab vedotin (at a dose of 1.8 mg per kilogram) plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide or the standard bleomycin-containing chemotherapy regimen (Table S1 in the Supplementary Appendix, available at NEJM.org) was administered every 21 days, with granulocyte colony–stimulating factor support in both trial groups.
After two cycles of therapy, patients were evaluated with an interim FDG-PET-CT (interim PET assessment). Metabolic response at involved sites was evaluated with the use of a 5-point scale on which higher scores indicate greater uptake of 18F-fluorodeoxyglucose on PET. A score of 1 signifies no uptake, a score of 2 uptake that is less than or equal to the uptake at the mediastinum, a score of 3 uptake that is greater than uptake at the mediastinum but less than or equal to uptake at the liver, a score of 4 uptake that is moderately increased as compared with the uptake at the liver, and a score of 5 markedly increased uptake at any site or uptake at a new site of disease.13 A score of 1 to 3 indicates rapid-responding lesions, and a score of 1 or 2 indicates a complete metabolic response. Involved-site radiation therapy (at a dose of 21 Gy) was prescribed after five cycles of systemic therapy in patients with large mediastinal adenopathy (transverse tumor diameter greater than one third the thoracic diameter on chest radiography) and in those with slow-responding lesions, defined as a score of 4 or 5 (on the 5-point scale) at the interim PET assessment; a boost dose of 9 Gy was administered to sites with an incomplete metabolic response (a score of 3 to 5 on the 5-point scale) at the end of the fifth cycle. Lesion-based response was applied in order to limit areas receiving radiation therapy. Imaging and plans regarding radiation therapy were centrally reviewed in real time at the Quality Assurance Review Center (Imaging and Radiation Oncology Core Rhode Island) to determine metabolic response and to review the delivered radiation therapy.
PATIENTS
Children and adolescents 2 to 21 years of age with newly diagnosed classic Hodgkin’s lymphoma of Ann Arbor stage IIB with bulk tumor or stage IIIB, IVA, or IVB were eligible for enrollment. Bulk tumor was defined as either a large mediastinal mass (see above) or an extramediastinal mass (continuous nodal aggregate, >6 cm). Patients were ineligible if they had histologic findings indicating nodular lymphocyte–predominant disease, were pregnant, had a known immunodeficiency, or had received antineoplastic therapy within the 28 days before enrollment.
EFFICACY END POINTS
The primary end point was event-free survival, which was defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Key secondary end points included interim response (response as determined on interim PET after two cycles of chemotherapy) and use of involved-site radiation therapy. Prespecified second end points also included clinician-reported chemotherapy-induced peripheral neuropathy. The end point of overall survival, which was defined as the time from randomization to death from any cause, was exploratory. Events were reported by the trial investigators.
RESPONSE ASSESSMENT
FDG-PET-CT was required at baseline and after the receipt of two cycles of chemotherapy (interim PET assessment). FDG-PET-CT was also required at the completion of chemotherapy in patients with slow-responding lesions and after radiation therapy in patients with an incomplete metabolic response at the completion of five cycles of chemotherapy. Response and progression were specified with the use of the modified Lugano criteria (Table S2A).14
SAFETY END POINTS
Adverse events were graded with the use of the NCI Common Toxicity Criteria, versions 4.0 and 5.0, and adverse events of grade 3 or higher were reported. Investigators reported neuropathy of grade 2 or higher using the Balis Pediatric Scale of Peripheral Neuropathy.15 Criteria for dose modifications were prespecified according to adverse-event category and grade.
STATISTICAL ANALYSIS
Enrollment and randomization in a 1:1 ratio were stratified according to disease stage. On the basis of previous trials, 3-year event-free survival (the primary end point) was expected to be 82% in the standard-care group. Because this trial was designed to evaluate the efficacy of adding brentuximab vedotin to doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide, the trial was powered on the basis of a one-sided log-rank test at an alpha level of 0.05 (comparable to a two-sided test at a significance level of 0.1).16 We calculated that 77 events or deaths would need to be observed in order for the trial to have 86% power to detect a difference of 8 percentage points in event-free survival in the brentuximab vedotin group as compared with the predicted event-free survival of 82% in the standard-care group. A between-group comparison of event-free survival was conducted according to the intention-to-treat principle. All the patients who had undergone randomization and met the eligibility criteria were included in the analysis. Consistent with Journal policy, results are reported with the use of a two-sided log-rank test at a significance level of 0.05.
Descriptive statistics were used to tabulate the incidence of toxic effects, the incidence of interim response that was categorized as being positive on the interim PET assessment if any slow-responding lesion was present, the percentage of patients with a metabolic response at the end of therapy, and the receipt of involved-site radiation therapy to a large mediastinal mass or slow-responding lesion (as an as-treated analysis). Post hoc comparisons of event-free survival between the two treatment groups according to demographic and disease characteristics of interest and for prespecified interim and end-of-chemotherapy response categories were included.
The statistical analysis plan did not include a provision for correction for multiplicity when tests for secondary or other outcomes were conducted. Corresponding hazard ratios are presented with 95% confidence intervals on the basis of univariate Cox regression without adjustment for multiplicity; thus, the intervals should not be used in place of a hypothesis test. The final analysis of event-free survival was based on the database lock that took place on December 31, 2021. Analyses were conducted with the use of SAS software, version 9.4 (SAS Institute), and RStudio software, version 1.1.463.
RESULTS
Patients
Between March 16, 2015, and August 2, 2019, a total of 600 patients were enrolled at 153 Children’s Oncology Group institutions in North America. A total of 13 patients were ineligible (Fig. S1). Among 587 eligible patients, 311 (53.0%) were male, and 338 (57.6%) were non-Hispanic White. A total of 353 patients (60.1%) had stage IV disease, 320 (54.5%) presented with a large mediastinal mass, and 418 (71.2%) had B symptoms (i.e., weight loss, night sweats, and fever) (Table 1). The median age of the patients was 15.6 years (range, 3.4 to 21.99), and 497 patients (84.7%) were at least 12 years of age at enrollment. A total of 298 patients were randomly assigned to receive the brentuximab vedotin–based regimen, and 289 to receive the standard regimen. The characteristics of the patients at baseline were balanced across the two treatment groups.
Table 1.
Demographic and Disease Characteristics of the Patients at Baseline (Intention-to-Treat Population).*
| Characteristic | Brentuximab Vedotin+Chemotherapy (N = 298) |
Standard Care (N = 289) |
Overall (N = 587) |
|---|---|---|---|
| Age† | |||
| Median — yr | 15.4 | 15.8 | 15.6 |
| Range — yr | 3.4–21.99 | 4.6–21.5 | 3.4–21.99 |
| Distribution — no. (%) | |||
| <12 yr | 52 (17.4) | 38 (13.1) | 90 (15.3) |
| 12–21 yr | 246 (82.6) | 251 (86.9) | 497 (84.7) |
| Female sex — no. (%) | 138 (46.3) | 138 (47.8) | 276 (47.0) |
| Race and ethnic group — no. (%)‡ | |||
| Non-Hispanic White | 172 (57.7) | 166 (57.4) | 338 (57.6) |
| Non-Hispanic Black | 29 (9.7) | 30 (10.4) | 59 (10.1) |
| Hispanic | 63 (21.1) | 56 (19.4) | 119 (20.3) |
| Other or unknown | 34 (11.4) | 37 (12.8) | 71 (12.1) |
| Ann Arbor stage at diagnosis — no. (%) | |||
| IIB with bulk tumor§ | 62 (20.8) | 59 (20.4) | 121 (20.6) |
| IIIB | 59 (19.8) | 54 (18.7) | 113 (19.3) |
| IVA | 84 (28.2) | 83 (28.7) | 167 (28.4) |
| IVB | 93 (31.2) | 93 (32.2) | 186 (31.7) |
| Large mediastinal adenopathy — no. (%) | 157 (52.7) | 163 (56.4) | 320 (54.5) |
| B symptoms — no. (%)¶ | 213 (71.5) | 205 (70.9) | 418 (71.2) |
| Histologic findings — no. (%)‖ | |||
| Nodular sclerosis | 224 (75.2) | 225 (77.9) | 449 (76.5) |
| Mixed cellularity | 18 (6.0) | 15 (5.2) | 33 (5.6) |
| Classic Hodgkin’s lymphoma, not otherwise specified | 52 (17.4) | 46 (15.9) | 98 (16.7) |
| Lymphocyte-rich disease | 4 (1.3) | 3 (1.0) | 7 (1.2) |
Patients in the brentuximab vedotin group received brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide, and those in the standard-care group received the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide. The demographic and disease characteristics of the patients did not differ significantly in the two treatment groups. Enrollment was stratified according to disease stage. The intention-to-treat analysis included all the patients who had undergone randomization. Percentages may not total 100 because of rounding.
The trial was initially open only to patients younger than 18 years of age. After enrollment in the ECHELON-1 trial10 closed, the protocol for the current trial was amended to extend the upper age limit to 21 years.
Race and ethnic group were reported by the investigator on the basis of documentation in the electronic health record.
Bulk tumor was defined as large mediastinal adenopathy (transverse tumor diameter more than one third the thoracic diameter at the dome of the diaphragm on a 1.83-meter posterior–anterior upright chest radiograph) or extramediastinal bulk (a continuous aggregate of nodal tissue outside the mediastinum that measured >6 cm in the transverse dimension on axial CT or the longest dimension on coronal or sagittal reformatted CT).
B symptoms were defined as weight loss, night sweats, and fever.
Histologic testing was assessed by the investigator.
EFFICACY
At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival in the intention-to-treat analysis was 92.1% (95% CI, 88.4 to 94.7) in the brentuximab vedotin group and 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (Fig. 1A), indicating that the risk of an event or death was 9.6 percentage points lower in the brentuximab vedotin group than in the standard-care group (P<0.001 by a two-sided log-rank test). The assumptions of a Cox proportional-hazards model were assessed and considered to be adequate. The hazard ratio for an event or death was 0.41 (95% CI, 0.25 to 0.67) in favor of therapy with brentuximab vedotin.
Figure 1. Event-free Survival and Relapse.
Event-free survival was defined as the time to disease progression, relapse, a second malignant neoplasm, or death. Patients in the brentuximab vedotin group received brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide, and those in the standard-care group received the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide. The hazard ratio for event or death was calculated with the use of a Cox proportional-hazards model. Tick marks indicate censored data. In Panel B, the inset shows the same data on an enlarged y axis.
First events occurred in 23 patients in the brentuximab vedotin group and in 51 patients in the standard-care group. Nonrelapse events included two second cancers (therapy-associated acute myeloid leukemia in 1 patient in the brentuximab vedotin group and papillary thyroid carcinoma in 1 patient in the standard-care group who had received radiation therapy) and a death due to motor vehicle accident in 1 patient in the standard-care group whose disease was in remission after the receipt of therapy. The independent data and safety monitoring committee recommended the release of the results after the occurrence of 74 events or deaths, because the pace of events made it unlikely that 77 events or deaths would be reached in a time period that would allow for the timely reporting of the results (Table S3). Subgroup analyses of the primary end point indicated consistent effects of the brentuximab vedotin–based regimen across a variety of demographic and disease characteristics (Fig. 2 and Fig. S3).
Figure 2. Subgroup Analysis of Event-free Survival.
Race and ethnic group were reported by the investigator on the basis of documentation in the electronic health record. B symptoms were defined as weight loss, night sweats, and fever. Bulk tumor was defined as large mediastinal adenopathy (transverse tumor diameter more than one third the thoracic diameter at the dome of the diaphragm on a 1.83-meter posterior–anterior upright chest radiograph) or extramediastinal bulk (a continuous aggregate of nodal tissue outside the mediastinum that measured >6 cm in the transverse dimension on axial CT or the longest dimension on coronal or sagittal reformatted CT).
The cumulative incidence of relapse was lower in the brentuximab vedotin group (7.5%; 95% CI, 4.9 to 10.9) than in the standard-care group (17.1%; 95% CI, 12.9 to 21.8) (Fig. 1B). The 3-year overall survival was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group.
Among 577 patients who could be evaluated in a prespecified analysis to examine interim response, the percentage of patients with slow-responding lesions according to the interim PET assessment was similar in the brentuximab vedotin group and the standard-care group (18.8% and 19.3%, respectively) (Table S2B). The percentage of patients with a complete metabolic response at the completion of chemotherapy was likewise similar in the brentuximab vedotin group and the standard-care group (89.7% and 86.7%, respectively). Post hoc analysis indicated that patients who received the brentuximab vedotin–based regimen and had slow-responding lesions according to the interim PET assessment had a 3-year event-free survival of 90.7%, as compared with 68.3% among the patients who received the standard regimen and had slow-responding lesions according to the interim PET assessment (hazard ratio for event or death, 0.28; 95% CI, 0.10 to 0.76) (Fig. 3 and Fig. S2). Among those with rapid-responding lesions, 3-year event-free survival was 92.3% in the brentuximab vedotin group and 85.7% in the standard-care group (hazard ratio, 0.48; 95% CI, 0.27 to 0.84). Although the percentage of patients with large mediastinal masses who had rapid-responding lesions according to the interim PET assessment was similar in the brentuximab vedotin group and the standard-care group (39.4% and 41.8%, respectively), the hazard of an event or death differed among patients who received the brentuximab vedotin–based regimen and among those who received standard care (hazard ratio, 0.34; 95% CI, 0.14 to 0.80).
Figure 3. Event-free Survival According to Results on Interim Positron-Emission Tomographic (PET) Assessment.
In a post hoc analysis involving patients with slow-responding lesions according to the interim PET assessment, 3-year event-free survival was 90.7% in the brentuximab vedotin group, as compared with 68.3% in the standard-care group (hazard ratio for event or death, 0.28; 95% CI, 0.10 to 0.76). Among patients with rapid-responding lesions, 3-year event-free survival was 92.3% in the brentuximab vedotin group and 85.7% in the standard-care group (hazard ratio, 0.48; 95% CI, 0.27 to 0.84).
A total of 170 of 292 patients (58.2%) in the brentuximab vedotin group and 174 of 285 patients (61.1%) in the standard-care group could have received protocol-directed radiation therapy according to the protocol. However, in the astreated analysis, the percentage of patients who received radiation therapy was 53.4% (95% CI, 47.7 to 59.0) after receipt of the brentuximab vedotin–based regimen and 56.8% (95% CI, 51.0 to 62.5) after the receipt of standard care (Table S4). Overall, 10.9% of the patients (57.3% of the patients with slow-responding lesions according to the interim PET assessment) had an incomplete metabolic response after the receipt of five cycles of therapy, which necessitated a boost to 30 Gy to the slow-responding lesions that remained persistently avid on PET, defined by a score of more than 2 at the completion of chemotherapy. Although the percentage of patients with an incomplete metabolic response did not differ between the two treatment groups, in a post hoc analysis, the 3-year event-free survival among these patients was 92.6% in the brentuximab vedotin group and 63.8% in the standard-care group (hazard ratio for event or death, 0.19; 95% CI, 0.04 to 0.85).
Safety
The overall incidence of clinically significant adverse events was similar in the two groups (73.5% with the brentuximab vedotin–based regimen and 68.2% with the standard regimen) (Table 2). Febrile neutropenia was reported in 30.9% of the patients who received the brentuximab vedotin–based regimen and in 32.5% of those who received the standard regimen, and sepsis occurred in 2.7% and 4.2%, respectively. No pneumonitis was reported in the brentuximab vedotin group. No deaths occurred during treatment.
Table 2.
Key Adverse Events.*
| Event | Brentuximab Vedotin+Chemotherapy N = 298) |
Standard Care (N = 289) |
Overall (N = 587) |
|---|---|---|---|
| Any adverse event of grade ≥3 | 219 (73.5) | 197 (68.2) | 416 (70.9) |
| Febrile neutropenia | 92 (30.9) | 94 (32.5) | 186 (31.7) |
| Sepsis | 8 (2.7) | 12 (4.2) | 20 (3.4) |
| Mucositis or oral adverse event | 31 (10.4) | 21 (7.3) | 52 (8.9) |
| Enterocolitis or typhlitis | 13 (4.4) | 5 (1.7) | 18 (3.1) |
| Allergic reaction or anaphylaxis | 12 (4.0) | 15 (5.2) | 27 (4.6) |
| Infusion-related reaction | 0 | 4 (1.4) | 4 (0.7) |
| Vascular-access complication | 3 (1.0) | 4 (1.4) | 7 (1.2) |
| Elevated alanine aminotransferase level | 12 (4.0) | 9 (3.1) | 21 (3.6) |
| Any peripheral neuropathy† | |||
| Grade ≥2 | 56 (18.8) | 56 (19.4) | 112 (19.1) |
| Grade ≥3 | 20 (6.7) | 16 (5.5) | 36 (6.1) |
| Thromboembolic event | 11 (3.7) | 5 (1.7) | 16 (2.7) |
| Pancreatitis | 4 (1.3) | 2 (0.7) | 6 (1.0) |
| Pneumonitis | 0 | 1 (0.3) | 1 (0.2) |
| Constipation | 2 (0.7) | 1 (0.3) | 3 (0.5) |
Clinically significant adverse events were defined as events of grade 3 or higher according to the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0 (through 2019), and version 5.0 thereafter (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40).
The reporting of peripheral neuropathy of higher than grade 2 on the Balis Pediatric Scale of Peripheral Neuropathy was required by the protocol; this scale includes indicators of activities of daily living specific to children and indicators of use of medication to manage symptoms (see the protocol).15 Grades range from 1 to 4, with higher scores indicating greater severity. Grade 2 indicates pain leading to the use of nonnarcotic medications for symptoms not interfering with function. Grade 3 includes pain leading to the use of narcotic medications and motor disruption leading to assistance with activities of daily living.
Most cases of chemotherapy-induced peripheral neuropathy of grade 2 of higher (which occurred in 19.1% of patients; 95% CI, 15.9 to 22.3) and of grade 3 or higher (which occurred in 6.1%; 95% CI, 4.2 to 8.1) were attributed to sensory neuropathy, with no difference according to treatment group or age (Table S5). The dose of brentuximab vedotin was modified in 8.1% of the patients. The dose of vincristine was modified in 13.4% of the patients (95% CI, 9.6 to 17.3) in the brentuximab vedotin group and in 4.2% of those (95% CI, 1.9 to 6.5) in the standard-care group (Table S6). Dose modifications of chemotherapy other than brentuximab vedotin or vincristine differed between the two groups, with modifications occurring in 12.8% (95% CI, 9.0 to 16.5) of the patients in the brentuximab vedotin group, as compared with 22.5% (95% CI, 17.7 to 27.3) of those in the standard-care group.
Discussion
Increasing survival and reducing the incidence of long-term treatment-associated organ dysfunction among children with high-risk Hodgkin’s lymphoma starts with enhanced disease control at initial treatment. In this phase 3, randomized trial of the CD30-targeted antibody–drug conjugate brentuximab vedotin in children, we found superior event-free survival with the brentuximab vedotin–based regimen in a large, representative, racially and ethnically diverse cohort of patients in North America (Table S7). The addition of brentuximab vedotin to chemotherapy resulted in a 9.6-percentage-point improvement in 3-year event-free survival as compared with conventional chemotherapy alone. Separation of the event curves occurred early, with a plateau in the cumulative incidence of relapse events in the brentuximab vedotin group by 2 years after diagnosis. Although it is myelosuppressive, the brentuximab vedotin–based regimen was safe in children and adolescents, with a much lower incidence of severe neuropathy than has been reported in adult cohorts.
The 3-year event-free survival of 92% in the brentuximab vedotin group was attained with tailored radiation therapy in 53% of the patients. This finding contrasts with the results of the recent EuroNet-PHL-C1 trial6, in which 5-year event-free survival was 88% among patients with an early response and 86% among those with a slow response; 65% of the patients received radiation therapy, and a boost to 30 Gy was necessitated in 29%. Our data are also consistent with the results of a single-group, multicenter, phase 2 trial that incorporated brentuximab vedotin in the treatment of patients with high-risk disease, with a lower cumulative anthracycline dose but with 66% of the patients receiving radiation therapy and with a substantially higher incidence of prednisone-associated toxic effects in bone.12
The improvement in the current trial over previous trials involving adults and children was attained with the elimination of bleomycin and with limiting the cumulative anthracycline exposure to 250 mg per square meter of body-surface area, in combination with vincristine, etoposide, prednisone, and cyclophosphamide treatment and with response-adapted radiation therapy. The benefit of brentuximab vedotin–based therapy in adolescents 12 years of age or older contrasts with inferior outcomes in this age group with the response-adapted approaches with standard chemotherapy (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) that have been used in previous Children’s Oncology Group trials.17 A post hoc analysis indicated that the efficacy of the brentuximab vedotin–based regimen did not extend to children with stage IVB disease; additional work is needed to understand whether alternative dose regimens or treatment schedules are needed. Alternative approaches, perhaps including checkpoint inhibitor therapy, may be useful in this patient population.
Differences in trial design, inclusion criteria, the age of the cohorts, and the defined primary end points limit a direct comparison of the efficacy of brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide with the efficacy of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in the ECHELON-1 trial.10 However, complete metabolic response at the completion of chemotherapy is a common metric; the percentage of patients with a complete metabolic response was 73% after the receipt of six cycles of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in adults,10 as compared with 89.7% after the receipt of five cycles of brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide in children and adolescents. The high percentage of patients with a complete metabolic response in our trial may be attributable to differences in the chemotherapy approach and the trial design. With a brentuximab vedotin dose of 1.8 mg per kilogram per cycle every 3 weeks (vs. 1.2 mg per kilogram every 2 weeks in the ECHELON-1 trial) and with a cumulative dose of brentuximab vedotin of 9 mg per kilogram (vs. 14.4 mg per kilogram), the children and adolescents in our trial were able to receive a dose-intensive regimen with low incidences of severe peripheral neuropathy and infection. The AHOD1331 trial used prespecified dose-modification guidelines to reduce the day 8 vincristine dose with the intent of preserving the prescribed dose of brentuximab vedotin in the event that peripheral neuropathy occurred. The success of this strategy was clear, given that only 8% of the patients in our trial had a dose reduction of brentuximab vedotin, as compared with 26% of the adult patients in the ECHELON-1 trial.10 In addition, on the basis of pharmacokinetic studies of brentuximab vedotin that have indicated a higher drug clearance in children and adolescents than in adults, it is possible that the therapeutic ratio is better in young patients.18
The tailoring of treatment on the basis of the interim PET assessment after the receipt of two cycles was initiated during the era of conventional therapy. The presence of slow-responding lesions at interim PET assessment has been associated with inferior disease control in trials involving adults and children,7,19,20 including in the ECHELON-1 trial, in which patients who had slow-responding disease according to the interim PET assessment had a 5-year progression-free survival of 60.6%.8 Our trial showed that patients with slow-responding lesions on interim PET assessment who were treated with standard therapy and response-adapted radiation therapy had a 3-year event-free survival of 68.3%, as compared with 85.7% among the patients who had rapid-responding lesions according to the interim PET assessment. However, the addition of brentuximab vedotin eliminated the predictive value of the interim PET assessment, because patients who had slow-responding lesions and had been treated with the brentuximab vedotin–based regimen and response-adapted radiation therapy had a 3-year event-free survival of 90.7%, as compared with the 3-year event-free survival of 92.3% among those with rapid-responding lesions on the interim PET assessment. Predictors of chemosensitivity beyond the current 5-point visual-analogue response scale based on FDG-PET-CT findings are warranted in future observational studies and randomized trials of brentuximab vedotin–based chemotherapy.
The superior event-free survival that we found with brentuximab vedotin plus dose-intensive chemotherapy with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide in this randomized, phase 3 trial involving children and adolescents provides support for its use as first-line therapy in children and adolescents with high-risk Hodgkin’s lymphoma. Long-term follow-up will be important to more thoroughly assess the occurrence of late events and overall survival.
Supplementary Material
Acknowledgments
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), the Leukemia and Lymphoma Society (to Drs. Parsons and Henderson), and St. Baldrick’s Foundation (to the Children’s Oncology Group). Support for editing of an earlier version of the manuscript was provided by the Children’s Healthcare of Atlanta and Emory University Pediatric Grant Editing and Manuscript Support Core.
Footnotes
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, June 3–7, 2022.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Contributor Information
Sharon M. Castellino, Department of Pediatrics, Emory University School of Medicine, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta
Qinglin Pei, Department of Biostatistics, Children’s Oncology Group, Statistics and Data Center, University of Florida, Gainesville, Canada
Susan K. Parsons, Institute for Clinical Research and Health Policy Studies and Tufts Cancer Center, Tufts Medical Center, Boston, Canada
David Hodgson, Department of Radiation Oncology, Princess Margaret Cancer Centre and University of Toronto, Canada
Kathleen McCarten, Imaging and Radiation Oncology Core Rhode Island, Lincoln
Terzah Horton, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston
Steve Cho, Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison
Yue Wu, Department of Biostatistics, Children’s Oncology Group, Statistics and Data Center, University of Florida, Gainesville, Canada
Angela Punnett, Division of Hematology–Oncology, Hospital for Sick Children and University of Toronto, Canada
Hema Dave, Department of Pediatrics, Children’s National Hospital, and George Washington School of Medicine and Health Sciences, Washington, DC
Tara O. Henderson, Department of Pediatrics, University of Chicago Pritzker School of Medicine, Comer Children’s Hospital, Chicago
Bradford S. Hoppe, Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, Canada
Anne-Marie Charpentier, Department of Radiation Oncology, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
Frank G. Keller, Department of Pediatrics, Emory University School of Medicine, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta
Kara M. Kelly, Department of Pediatrics, Roswell Park Comprehensive Cancer Center, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY
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