Abstract
Purpose:
Brentuximab vedotin (BV) incorporation into frontline chemotherapy regimens improved outcomes for Hodgkin lymphoma (cHL). The shared mechanism of action of BV and vinca alkaloids as microtubulin inhibitors increased the potential risk of chemotherapy-induced peripheral neuropathy (CIPN). Rates of CIPN and use of protocol-stipulated dose modifications of a microtubulin inhibitor were examined on the Children’s Oncology Group AHOD1331 study, which compared BV, doxorubicin, vincristine (VCR), etoposide, prednisone, cyclophosphamide (BV-AVE-PC; BV arm) to bleomycin containing ABVE-PC (standard arm) in high-risk cHL patients ages 2–21 years.
Methods:
AHOD1331 required clinician grading and reporting of ≥grade 2 CIPN. Protocol-stipulated dose modifications of VCR preceded modification of BV for ≥grade 2 CIPN in the BV arm, but only required modification of VCR for ≥grade 3 in the standard arm. Outcomes included CIPN rates, dose modification of microtubulin inhibitors by study arm, clinical factors associated with dose modifications, and event-free survival (EFS) by presence of dose modification.
Results:
Among the 582 patients who began protocol therapy, 112 developed ≥grade 2 CIPN. Cumulative incidence of CIPN did not differ by study arm (19.2 vs 19.8%, p=0.91). CIPN dose modifications occurred more frequently in the BV arm (9.5% vs. 2.8%, p=0.001), however, most patients with CIPN on the BV arm received full dose BV. EFS did not differ by the presence of dose modifications after accounting for study arm, age, sex, and stage, though older age was significantly associated with the risk of VCR dose modifications for CIPN.
Conclusion:
A staged dose modification plan for vinca alkaloids and BV as administered in AHOD1331minimized the impact of incorporating a second microtubulin inhibitor on CIPN without compromising treatment efficacy in the BV-AVE-PC arm.
Introduction
Classic Hodgkin lymphoma (cHL) is highly curable, even among those with high-risk or advanced stage disease, with the incorporation of novel targeted therapies into contemporary multi-agent chemotherapy regimens.1,2 The growing number of long-term survivors underscores the importance of minimizing treatment-related morbidity and late sequelae of treatment including chemotherapy-induced peripheral neuropathy (CIPN).3 CIPN is associated with several classes of chemotherapy, including vinca alkaloids4 that have traditionally been used in cHL. The incorporation of brentuximab vedotin (BV), a novel, anti-CD30-directed antibody-drug conjugate with monomethyl auristatin E, a highly potent microtubulin inhibitor, has highlighted CIPN in cHL as a treatment-limiting toxicity in adults.5 The shared mechanism of action of BV and vinca alkaloids, as microtubulin inhibitors, creates a unique challenge in preventing and managing CIPN. In the ECHELON-1 study, clinician reported rates of any grade of CIPN among adults with advanced stage cHL were 67% in the BV arm as compared to 43% in the standard arm inclusive of vinblastine (VBL).1 In longer term follow up, while most CIPN improved or resolved, at a median of 73 months, 18.9% and 9.0% reported ongoing CIPN in the BV and standard arm, respectively.6
The American Society of Clinical Oncology (ASCO) guidelines on CIPN recommend repeated clinical assessment and if intolerable neuropathy or functional impairment develops, a discussion with patients around the appropriateness of dose delaying, dose reduction, or discontinuation of chemotherapy to prevent long term morbidity.7 Clinical trials are typically designed to dose modify the investigational agent before dose modifying commercially available agents. On ECHELON-1, dose modifications at the discretion of the treating physician were 66% for BV and 57% for VBL.1
The impact of dose modifications on disease outcomes in cHL is not clear. Multiple studies have demonstrated the importance of maintaining dose intensity using MOPP chemotherapy (mechlorethamine, vincristine (VCR), procarbazine, and prednisone).8–10 Additionally, in a retrospective analysis of heterogeneously treated older adults with cHL evaluating dose intensity, patients who received ABVD (adriamycin, bleomycin, VBL, and dacarbazine) with preserved dose intensity had superior overall survival (OS) compared to ABVD with decrease relative dose intensity or MOPP-like therapy.9 In contrast, analysis of impact of bleomycin and VCR modifications on cHL patients treated with BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, VCR, procarbazine, and prednisone) on the German Hodgkin Study Group HD12 and HD15 trials showed no difference in OS or progression-free survival (PFS).11 Similarly, real world analysis of 179 patients treated with BV-AVD (brentuximab, adriamycin, VBL, and dacarbazine) found 55% of patients had dose modifications of BV, but decreased cumulative BV dose did not significantly impact PFS.12 Since dose modifications may impact the efficacy of treatment, developing a dose modification strategy that balances efficacy and toxicity is critical for successful future use of BV.
We examined the use of prespecified dose modification of microtubulin inhibitors in the Children’s Oncology Group (COG) AHOD1331, a phase 3 randomized comparison of BV containing with two microtubulin inhibitors (BV and VCR, delivered Day 1 and 8, respectively) versus standard multi-agent chemotherapy including a single microtubulin inhibitor (VCR, delivered both day 1 and Day 8) in high-risk cHL.2 Among children, adolescents and young adults ages 2–21 years with clinician-graded CIPN, we examined which of the microtubulin inhibitors were modified, time to dose modification, patient factors leading to dose modification, and impact of dose modification on event-free survival (EFS). We hypothesized that the prescriptive nature of the protocol’s dose modification that preserved BV dosing over VCR would minimize CIPN without compromising regimen efficacy.
Methods
Trial Design
The COG AHOD1331 trial design has been previously reported.2 Briefly, eligible patients ages 2–21 years with high-risk cHL were enrolled from 2015–2019.2 Patients were randomized to receive 5 cycles of BV, doxorubicin, VCR, etoposide, prednisone, and cyclophosphamide (BV-AVE-PC; BV arm) or the standard pediatric regimen inclusive of bleomycin (ABVE-PC; standard arm). Patients in the BV arm received BV (1.8 mg/kg, maximum dose 180mg) on Day 1 and VCR on Day 8. Patients in the standard arm received VCR on days 1 and 8 of each 21-day treatment cycle. Clinician grading of CIPN was required at each cycle, using the Balis PN Scale.13 Sites were required to report ≥ grade 2 sensory and motor CIPN. Protocol stipulated dose modifications of VCR preceded modification of BV in cases of CIPN ≥ grade 2 based on both day of chemotherapy cycle and grade of neuropathy within a cycle (Supplemental Table 1). Demographic information was reported by individual sites per investigator report.
AHOD1331 was approved at the institutional review boards of all participating sites and conducted in accordance with Declaration of Helsinki. 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.
Statistical Analysis
Cumulative incidence of grade ≥ 2 motor or sensory CIPN was calculated by study arm, and raw rates of CIPN reported by treatment cycle among patients who started protocol therapy. Patient and disease characteristics for participants with dose modifications due to CIPN were compared between study arm by modified agent (VCR alone or BV+VCR). Time to CIPN and to first dose modification of a microtubulin inhibitor was estimated by study arm. EFS was estimated by presence or absence of a dose modification for grade ≥ 2 CIPN within study arms using Kaplan-Meier methodology and compared with log-rank tests. Cox proportional hazards models were used to test for a significant interaction effect on EFS between study arm and dose modification, and to assess the impact of dose modification on EFS adjusted for age, sex, and disease stage, stratified by study arm. A multivariable Cox proportional hazards model stratified by study arm was used to evaluate the impact of patient age, sex, and stage on time to VCR dose modification in the eligible cohort who started protocol therapy, while due to the small number of events (BV dose modifications) observed, univariable Cox models were used to evaluate the independent effects of the same factors on time to BV dose modification for CIPN among those treated with BV. All tests were 2-sided and a p-value <0.05 was considered statistically significant. Statistical analysis was conducted using SAS 9.3 (SAS Institute Inc., Cary, NC).
Results
AHOD1331 enrolled and randomized 600 patients of whom 587 were eligible. Demographics did not differ between study arms.2 Among the eligible cohort, 295 initiated treatment on the BV arm and 287 initiated treatment on the standard arm; together these 582 patients comprise the overall cohort evaluable for toxicity and dose modifications in the present analysis (Figure 1).
Figure 1.
CONSORT Diagram
CONSORT diagram for study enrollment, AHOD 1331 (NCT02166463). Interim FDG-PET-CT (iPET) was performed after 2 cycles. The 587 patients who were eligible are the cohort for the intent-to-treat analysis of the primary endpoint. Central review confirmed the stage at diagnosis and the designation of large mediastinal adenopathy (LMA). At iPET central review confirmed the response as having rapid responding lesions (RRL) or slow responding lesions (SRL).
*None of the ten patients who were previously deemed to be not evaluable reported CIPN ≥ grade 2.
Rate/Incidence of CIPN
Among 582 patients initiating treatment on AHOD1331, 112 (19.2%) developed grade 2 or greater CIPN. Grade 2 or higher Motor CIPN was reported in 7.7% of patients and 15.3% reported ≥ grade 2 sensory CIPN. Overall cumulative incidence of clinician-reported CIPN (grade ≥2) did not differ by study arm (19.8% vs. 19.2%, p=0.91) (Figure 2). Cumulative incidence of ≥ grade 2 motor CIPN was lower in the BV arm (6.2% vs. 10%, p=0.05) but cumulative incidence of ≥ grade 2 sensory neuropathy did not differ by study arm (15.7% vs. 14.8%, p=0.85). Time to CIPN did not differ between study arm (BV 44.3 vs. control 50.5 days, p=0.29). Point prevalence of CIPN by treatment cycle are shown in Supplemental Table 2. By cycle 5, the hypothesized dose peak of microtubulin inhibitors, the point prevalence of ≥ grade 2 CIPN was only 2.8% in the BV arm and 7.8% in the standard arm (p = 0.007).
Figure 2.
Overall cumulative incidence of clinician-reported CIPN (grade ≥2) did not differ by study arm (19.8% vs. 19.2%, p=0.91).
Dose Modifications Associated with CIPN
Dose modification of the microtubulin inhibitor VCR due to CIPN occurred more frequently (p=0.001) in patients on the BV arm with 9.5% (28 / 295) compared to 2.8% (8/287) in the standard arm. Most patients in the BV arm requiring dose modifications for CIPN were still able to receive full dose BV with 64.3% (18/28) requiring only dose modifications for VCR and 35.7% (10/28) requiring both VCR and BV modifications for CIPN. All reported incidents of CIPN resulting in dose modifications were grade 2 or 3.
Time to dose modification of microtubulin inhibitors for CIPN did not differ significantly on the BV arm compared to the standard arm (61.5 vs. 73 days, p=0.07). Demographics of patients with dose modification are included in Table 1. In a multivariable Cox regression model for time to VCR dose modification stratified by study arm, only older age was significantly associated with risk of dose modification (p = 0.04; Table 2); no demographic or disease characteristics were associated with time-to-BV modification in univariable models, though only 10 BV dose modifications were observed in the experimental arm (Table 3).
Table 1.
Dose modification for CIPN between study arms
| Variable | BV Arm (BV-AVE-PC) | Standard Arm (ABVE-PC) | |
|---|---|---|---|
| Dose Mod in VCR n=18 | Dose Mod in BV and VCR n=10 | Dose Mod in VCR n=8 | |
| Age (Years) Mean ±sd | 16.3±1.9 | 15.3±4.5 | 16.1±2.6 |
| Sex | |||
| Female | 8 (44.4%) | 3 (30.0%) | 5 (62.5%) |
| Male | 10 (55.6%) | 7 (70.0%) | 3 (37.5%) |
| Race and Ethnicity | |||
| Hispanic | 3 (16.7%) | 2 (20.0%) | 1 (12.5%) |
| Non-Hispanic Black | 2 (11.1%) | 2 (25.0%) | |
| Non-Hispanic White | 11 (61.1%) | 7 (70.0%) | 5 (62.5%) |
| Other and Unknown | 2 (11.1%) | 1 (10.0%) | |
| Albumin | |||
| <3.5 | 7 (38.9%) | 1 (10.0%) | 4 (50.0%) |
| ≥3.5 | 11 (61.1%) | 9 (90.0%) | 4 (50.0%) |
| B symptoms | |||
| No | 3 (16.7%) | 1 (10.0%) | 1 (12.5%) |
| Yes | 15 (83.3%) | 9 (90.0%) | 7 (87.5%) |
| Stage | |||
| Stage IIB | 6 (33.3%) | 3 (30.0%) | 1 (12.5%) |
| Stage III | 3 (16.7%) | 2 (20.0%) | 4 (50.0%) |
| Stage IV | 9 (50.0%) | 5 (50.0%) | 3 (37.5%) |
Table 2.
Characteristics associated with hazard of vincristine dose modification for clinician graded CIPN (grade >=2) in BV-AVE-PC (n=295) and in ABVE-PC (n=287)
| Variable (Ref) | Class | Hazard Ratio (95% CI) | Level p-value | Overall p-value |
|---|---|---|---|---|
| Age | 1.14 (1.01–1.29) | − | 0.04 | |
| Sex (Female) | Male | 1.13 (0.59–2.18) | − | 0.72 |
| Stage (IIB) | IIIB | 0.90 (0.37–2.21) | 0.82 | 0.35 |
| IVA | 0.59 (0.27–1.29) | 0.18 |
Table 3.
Characteristics associated with hazard of BV dose modification for CIPN (grade ≥2) in the BV arm (n=295)
| Variable (Ref) | Class | Hazard Ratio (95%CI) | Level p-value | Overall p-value |
|---|---|---|---|---|
| Age | 1.06 (0.85–1.31) | − | 0.62 | |
| Sex (Female) | Male | 2.06 (0.53–7.96) | − | 0.30 |
| Stage (IIB) | IIIB | 0.65 (0.11–3.91) | 0.64 | 0.72 |
| IV | 0.55 (0.13–2.31) | 0.41 | ||
Event-Free Survival
Three-year EFS in the intention-to-treat analysis was previously reported as 92.1% (95% CI, 88.4 to 94.7) in the BV arm and 82.5% (95% CI, 77.4 to 86.5) in the standard arm (P<0.001).2 In the present analysis, now with a median follow up of 5.27 years in the BV arm and 5.02 years in the standard arm, 3-year EFS did not differ by the presence vs. absence of dose modification for CIPN within the BV arm (89.3% vs. 92.4%, p= 0.66, Figure 3a) or in the standard arm (72.9% vs. 82.9%, p=0.58; Figure 3b). A test for dose modification by study arm interaction effect on EFS was not significant (p = 0.90). In a multivariable Cox proportional hazards model for EFS, stratified by study arm and including dose modification, age, sex, and stage at diagnosis, no variable was significant (Supplemental Table 3).
Figure 3.
EFS comparison by dose modifications for CIPN by study arm A) EFS in the BV arm (BV-AVE-PC) by dose modification B) EFS in standard arm (ABVE-PC) by dose modification
Discussion
We describe the effectiveness of protocol-stipulated approach to dose modification when using two microtubulin inhibitors, VCR and BV, aimed at preserving the delivery of the novel anti-CD30 antibody-drug conjugate with sequential dose modification, beginning with VCR. With this approach rates of CIPN were not significantly different between those receiving BV-AVE-PC versus ABVE-PC. Despite higher rates of CIPN-associated dose modifications in the BV arm, largely due to VCR modifications, EFS remained higher with BV-AVE-PC and resulted in low rates of clinician reported CIPN by the end of therapy.
While direct comparisons of rates of CIPN in the current study with the previously reported ECHELON-1 study are complicated by different definitions of CIPN (≥ grade 2 in the AHOD1331 study vs. ‘any grade’ in the ECHELON-1 study), rates of CIPN in the ECHELON-1 study were substantial.1 Several factors may account for the differences in the magnitude of CIPN including patient demographics (age and ethnicity), cumulative BV dosing (9 mg/kg in AHOD1331 and 14.4 mg/kg in ECHELON-1), but similar dose density(0.6mg/kg/week), differing vinca alkaloids (VCR vs. VBL), and concurrent vinca alkaloid dose modifications.1 Previous work in rhabdomyosarcoma suggests an age-based tolerability of VCR with younger patients needing fewer dose reductions and discontinuations for CIPN than older pediatric and adolescent and young adult (AYA) patients,14 which is consistent with older age being associated with more VCR dose modifications for CIPN on AHOD1331. However, in a recent subgroup analysis of AYA participants on ECHELON-1, similar rates of CIPN were reported to what had previously been described for the overall study sample.15 These findings suggest additional factors may have contributed to lower rates of CIPN in the AHOD1331 study, such as lower cumulative BV dosing. Table 4 includes review of dosing and modification schemes for ECHELON-1 and pediatric trials utilizing BV in upfront therapy.1,16,17 Cumulative doses of both BV and the vinca alkaloid VCR were lower on AHOD1331 than single arm and randomized trials. Only ECHELON-1 co-administer BV and vinca alkaloid on the same day. Other pediatric trials have also prioritized BV dosing over vinca alkaloid by omitting vinca alkaloids altogether and have found low rates of CIPN and avoided dose reductions of BV.16,17
Table 4.
Review of CIPN and dose modifications across clinical trials using upfront BV
| Study | AHOD1331 (BV Arm)2 | ECHELON-1 (BV Arm)1 | HLHR1316 | ANHL12P117 |
|---|---|---|---|---|
| Rate of CIPN | ||||
| ≥ grade 2 | 18.8% (n=56) | 30% (n=200/662) | 0% | |
| ≥ grade 3 | 6.7% (n=20) | 11% (n=70/662) | 4% (n=3/77) | 0% |
| Grade 4 | <1% (n=1/662) | 0% | ||
| Method of monitoring | Balis | CTCAE v4.0 | CTCAE.v4.0 | CTCAE.v4.0 |
| Cumulative BV dose | 9 mg/m2 | 14.4 mg/kg | 16.8 mg/kg | 10.8 mg/kg |
| Initial BV dose | 1.8 mg/kg | 1.2mg/kg | 0.6mg/kg | 1.8 mg/kg |
| BV dose density | 0.6 mg/kg/week | 0.6 mg/kg/week | 0.84 mg/kg/week | 0.6 mg/kg/week |
| Dose modification plan for BV | Grade 2: no change (VCR dose reduction) | Grade 2: reduce to 0.8mg/kg | Grade 2: reduce to 0.9 mg/kg | Grade 2: reduce to 1.2 mg/kg |
| Grade 3: hold therapy for 1 week. If improved to < grade 2 proceed to next cycle with dose reduced BV. If still grade 3 hold BV for cycle & dose reduce. When < grade 2 resume dose reduced BV | Grade 3: hold BV until ≤ grade 2 then dose reduce | Grade 3: hold BV until ≤ grade 1 then dose reduce | Grade 3: delay treatment up to 1 week. If improves to ≤ grade 2 proceed with reduced BV. Hold until ≤ grade 2 then dose reduce. Grade 3 after dose reduction of BV, DC subsequent BV | |
| Grade 4: DC BV | Grade 4: DC BV | Grade 4: DC BV | Grade 4: DC BV | |
| % dose modification BV | 8% (n=24) | 66% (n=434) | 0% | 0% |
| Concurrent alkaloid | Vincristine | Vinblastine | None | None |
| Same day administration of alkaloid & BV | No | Yes | No | No |
| Initial alkaloid dose | 1.4 mg/m2/dose (max VCR 2.4 mg) | 6 mg/m2/dose (no max) | N/A | N/A |
| Cumulative alkaloid | 7 mg/m2 | 72 mg/m2 | N/A | N/A |
| % dose modification alkaloid | 13.4% (n=40) | 57% (n=378) | N/A | N/A |
| Modification from previous backbone | Omit day 1 VCR (no concurrent BV and VCR) | None | Omitted VCR | N/A |
| Alkaloid modification plan | Based both on day of cycle and grade | Investigator choice per applicable label/summary of product characteristics | N/A | N/A |
Dose reductions or omission of chemotherapy theoretically could limit treatment efficacy8–12. Importantly, despite more dose modifications for CIPN occurring in the BV arm, EFS was preserved. Our data support dose modifications of the alternate tubulin inhibitor as an important strategy for mitigating CIPN in the setting of BV therapy for cHL. Previous pharmacogenomics research from patients with Acute Lymphoblastic Leukemia receiving VCR has identified genetic polymorphisms predisposing to development of CIPN, such as CEP72 rs924607,18,19 In vitro, the leukemia cells of the patient with this high-risk genetic variant were also more sensitive to the antileukemic effects of VCR.18 It is plausible that a similar mechanism may be at play here, but future research is needed to confirm this and identify further at risk alleles.
Our study has several limitations that warrant discussion, primarily that clinicians were only required to report grade 2 or higher CIPN. Therefore, the extent of grade 1 CIPN by either study arm is not known. COG trials typically require mandatory reporting of grade 3 or higher adverse events unless protocol-specified; previous COG cHL trials had not captured grade 2 CIPN, precluding our ability to compare findings from this study with prior studies in cHL with regimens including VCR. Secondly, motor CIPN was less commonly reported than sensory CIPN, consistent with previous reports.1 While the lower reported rate of motor CIPN in the BV arm is interesting and different than ECHELON-1, our protocol stipulated dose modifications did not differentiate between motor and sensory neuropathy. Finally, our prescriptive dose modification scheme did not include language for dose modification for symptoms of ileus/constipation, which is also a known manifestation of microtubulin inhibitor-induced neuropathy and frequently requires medical management in patients with cHL.20 Our data support prescriptive dose modification (including first reducing VCR) to mitigate severe CIPN toxicity and preserve the intended dosing of the targeted agent toward preserved efficacy.
Supplementary Material
Context Summary.
Key objective:
Can a protocol-stipulated dose modification approach aimed at preserving delivery of the novel anti-CD30 antibody-drug conjugate, when using two microtubulin inhibitors (vincristine and brentuximab vedotin (BV)), minimize the development of chemotherapy-induced peripheral neuropathy (CIPN) without compromising treatment efficacy in children, adolescents, and young adults with high-risk Hodgkin lymphoma on Children’s Oncology Group AHOD1331?
Knowledge generated:
Incidence of CIPN was low and did not differ with the incorporation of a second microtubulin inhibitor. Dose modifications occurred more frequently in the BV arm, however, most patients with CIPN still received full dose BV and event-free survival (EFS) did not differ by the presence of dose modifications.
Relevance:
A dose modification scheme prioritizing BV dosing resulted in higher rates of CIPN-associated dose modifications in the BV arm, due to more VCR modifications, but EFS remained higher and resulted in low rates of CIPN by the end of therapy.
Acknowledgments of research support:
The funder did not play a role in the design of the study; collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.
This work was presented in abstract form at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, New Orleans, LA, USA, December 202222 and the 5th International Symposium on Childhood, Adolescent, and Young Adult Hodgkin Lymphoma, Memphis, TN, USA, October 2023.23
Funding
This work was supported by grants from the National Institutes of Health (U10CA098543, U10CA180899, and U10CA180886; all to the Children’s Oncology Group), National Cancer Institute at the National Institutes of Health Community Oncology Research Program (NCORP) Grant (UG1CA189955; to the Children’s Oncology Group); the Quality Assurance Review Center (U10CA29511); the Leukemia & Lymphoma Society (to SKP and TOH); and St. Baldrick’s Foundation (to the Children’s Oncology Group).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflicts of Interest
MBH scientific advisory board Bristol Meyers Squibb; SKP consultant Seagen; FGK Merck scientific advisory committee member; JAB scientific advisory board Bristol Meyers Squibb; TOH research funding from Seagen to University of Chicago for clinical research associate support to collect PRO data; KMK scientific steering committee for Merck and scientific advisory board Seagen; SMC scientific advisory board Seagen and Bristol Meyers Squibb.
Data availability
The COG data sharing policy describes the release and use of COG’s individual subject data for use in research projects in accordance with National Clinical Trials Network Program and National Cancer Institute Community Oncology Research Program Guidelines.21 Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee are available to be shared. Data from this study are available following the primary publication. An individual-level de-identified dataset containing the variables analyses in the primary results paper can be expected to be available upon request. Requests for access to COG protocol research data should be sent to datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use.
References
- 1.Connors JM, Jurczak W, Straus DJ, et al. : Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. N Engl J Med 378:331–344, 2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Castellino SM, Pei Q, Parsons SK, et al. : Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin’s Lymphoma. N Engl J Med 387:1649–1660, 2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pophali PA, Morton LM, Parsons SK, et al. : Critical gaps in understanding treatment outcomes in adolescents and young adults with lymphoma: A review of current data. eJHaem n/a [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Park SB, Goldstein D, Krishnan AV, et al. : Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin 63:419–37, 2013 [DOI] [PubMed] [Google Scholar]
- 5.Younes A, Connors JM, Park SI, et al. : Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol 14:1348–56, 2013 [DOI] [PubMed] [Google Scholar]
- 6.Ansell SM, Radford J, Connors JM, et al. : Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma. N Engl J Med 387:310–320, 2022 [DOI] [PubMed] [Google Scholar]
- 7.Loprinzi CL, Lacchetti C, Bleeker J, et al. : Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update. Journal of Clinical Oncology 38:3325–3348, 2020 [DOI] [PubMed] [Google Scholar]
- 8.Carde P, MacKintosh FR, Rosenberg SA: A dose and time response analysis of the treatment of Hodgkin’s disease with MOPP chemotherapy. J Clin Oncol 1:146–53, 1983 [DOI] [PubMed] [Google Scholar]
- 9.Landgren O, Algernon C, Axdorph U, et al. : Hodgkin’s lymphoma in the elderly with special reference to type and intensity of chemotherapy in relation to prognosis. Haematologica 88:438–44, 2003 [PubMed] [Google Scholar]
- 10.van Rijswijk RE, Haanen C, Dekker AW, et al. : Dose intensity of MOPP chemotherapy and survival in Hodgkin’s disease. J Clin Oncol 7:1776–82, 1989 [DOI] [PubMed] [Google Scholar]
- 11.Haverkamp H, Boll B, Eichenauer DA, et al. : Impact of Bleomycin and Vincristine Dose Reductions in Patients With Advanced Hodgkin Lymphoma Treated With BEACOPP: An Analysis of the German Hodgkin Study Group HD12 and HD15 Trials. J Clin Oncol 33:2430–6, 2015 [DOI] [PubMed] [Google Scholar]
- 12.Steiner RE, Hwang SR, Khurana A, et al. : Impact of Cumulative Dose of Brentuximab Vedotin on Outcomes of Frontline Therapy for Advanced Stage Hodgkin Lymphoma. Blood Adv, 2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Lavoie Smith EM, Li L, Hutchinson RJ, et al. : Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. Cancer Nurs 36:E49–60, 2013 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kojima Y, Hashimoto K, Ando M, et al. : Comparison of dose intensity of vincristine, d-actinomycin, and cyclophosphamide chemotherapy for child and adult rhabdomyosarcoma: a retrospective analysis. Cancer Chemother Pharmacol 70:391–7, 2012 [DOI] [PubMed] [Google Scholar]
- 15.Crosswell HE, LaCasce AS, Bartlett NL, et al. : Brentuximab vedotin with chemotherapy in adolescents and young adults (AYAs) with stage III or IV Hodgkin lymphoma: A subgroup analysis from the phase 3 Echelon-1 study. Journal of Clinical Oncology 39:7528–7528, 2021 [Google Scholar]
- 16.Metzger ML, Link MP, Billett AL, et al. : Excellent Outcome for Pediatric Patients With High-Risk Hodgkin Lymphoma Treated With Brentuximab Vedotin and Risk-Adapted Residual Node Radiation. J Clin Oncol 39:2276–2283, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Lowe EJ, Reilly AF, Lim MS, et al. : Brentuximab vedotin in combination with chemotherapy for pediatric patients with ALK+ ALCL: results of COG trial ANHL12P1. Blood 137:3595–3603, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Diouf B, Evans WE: Pharmacogenomics of Vincristine-Induced Peripheral Neuropathy: Progress Continues. Clin Pharmacol Ther 105:315–317, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Stock W, Diouf B, Crews KR, et al. : An Inherited Genetic Variant in CEP72 Promoter Predisposes to Vincristine-Induced Peripheral Neuropathy in Adults With Acute Lymphoblastic Leukemia. Clin Pharmacol Ther 101:391–395, 2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Belsky J, Stanek J, Yeager N, Runco D: Constipation and GI diagnoses in children with solid tumours: prevalence and management. BMJ Support Palliat Care, 2022 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.COG Data Sharing, 2023 [Google Scholar]
- 22.Parsons SK, Keller FG, Pei Q, et al. : Peripheral Neuropathy in Children with High Risk Hodgkin Lymphoma (HL): The Role of Protocol-Stipulated Dose Modification in the Children’s Oncology Group (COG) AHOD1331 Study. Blood 140:6550–6551, 2022 [Google Scholar]
- 23.Parsons SK, Heneghan MB, Keller FG, et al. : The role of protocol-stipulated dose modification in the Children’s Oncology Group AHOD1331 study to manage chemotherapy-induced peripheral neuropathy. Presented at the International Symposium on Childhood, Adolescent and Young Adult Hodgkin Lymphoma, Memphis, TN, USA 2023 [Google Scholar]
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Supplementary Materials
Data Availability Statement
The COG data sharing policy describes the release and use of COG’s individual subject data for use in research projects in accordance with National Clinical Trials Network Program and National Cancer Institute Community Oncology Research Program Guidelines.21 Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee are available to be shared. Data from this study are available following the primary publication. An individual-level de-identified dataset containing the variables analyses in the primary results paper can be expected to be available upon request. Requests for access to COG protocol research data should be sent to datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use.