Subsequent malignant neoplasms among children with Hodgkin lymphoma: a report from the Children's Oncology Group.

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children's Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Durable remission for four pediatric patients with high-risk relapsed classical Hodgkin lymphoma treated with brentuximab vedotin plus gemcitabine but without autologous stem cell transplantation: A report from the Children's Oncology Group.

Patients with therapy-refractory or high-risk relapsed classical Hodgkin lymphoma are typically treated with the high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) to consolidate the response to salvage therapy. The combination of brentuximab vedotin with gemcitabine has recently been shown to be an effective and safe salvage regimen. While the majority of patients with complete responses to this regimen ultimately underwent HDC/ASCT consolidation, four subjects, reported herein, achieved durable complete remissions lasting more than 4 years after the study treatment but without ASCT consolidation. Further investigation of treatment strategies incorporating targeted agents may allow omission of HDC/ASCT for select patients.

Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): a report from the Children's Oncology Group.

The AHOD0831 study for paediatric patients with high risk Hodgkin lymphoma tested a response-based approach designed to limit cumulative alkylator exposure and reduce radiation volumes. Patients (Stage IIIB/IVB) received two cycles of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid early responders [RER, no positron emission tomography (PET) activity above mediastinal blood pool] were consolidated with 2 cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine and 2 cycles of ABVE-PC. Radiotherapy was administered to sites of initial bulk and/or SER. By intent-to-treat analysis, 4-year second event-free survival (EFS; freedom from second relapse or malignancy) was 91·9% [95% confidence interval (CI): 86·1-95·3%], below the projected baseline of 95% (P = 0·038). Five-year first EFS and overall survival (OS) rates are 79·1% (95% CI: 71·5-84·8%) and 95% (95% CI: 88·8-97·8%). Eight of 11 SER patients with persistent PET positive lesions at the end of chemotherapy had clinical evidence of active disease (3 biopsy-proven, 5 with progressive disease or later relapses). Although this response-directed approach did not reach the ambitiously high pre-specified target for second EFS, EFS and OS rates are comparable with results of recent trials despite the reduction in radiotherapy volumes from historical involved fields. Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression.

Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1-2 trial.

BACKGROUND: Patients with primary refractory Hodgkin's lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkin's lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkin's lymphoma or early relapse. METHODS: In this Children's Oncology Group, multicentre, single-arm, phase 1-2 trial, we recruited patients with Hodgkin's lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m2 intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662. FINDINGS: Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m2. 24 (57%) of 42 evaluable patients (95% CI 41-72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51-80]). The most common grade 3-4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths. INTERPRETATION: Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials. FUNDING: National Institutes of Health and the St. Baldrick's Foundation.

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group.

BACKGROUND: The Children's Oncology Group AHOD0431 study evaluated a response-directed treatment paradigm in which minimal initial chemotherapy and low-dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low-dose radiation salvage regimen was received by those who had a protocol-defined, low-risk recurrence. METHODS: Patients younger than 21 years who had stage IA or IIA nonbulky disease were eligible. The treatment strategy was evaluated by determining the proportion that received minimal chemotherapy alone, the proportion that had a first or second remission without the receipt of high-dose chemotherapy/stem cell rescue or higher dose involved-field radiation therapy (>21 grays), and overall survival. RESULTS: In total, 278 patients were eligible. At 4 years, 49.0% had received minimal chemotherapy and no radiation, 88.8% were in remission without receiving high-dose chemotherapy with stem cell rescue or >21 grays of involved-field radiation therapy, and the overall survival rate was 99.6%. Patients who had mixed cellularity histology had a 4-year event-free survival (EFS) rate of 95.2%, which was significantly better than the 75.8% EFS for those who had nodular sclerosis histology (P = .008). A red blood cell sedimentation rate ≤20 mm/hour and a negative fluorodeoxyglucose-positron emission tomography scan after 1 cycle of chemotherapy (PET1) were associated with a favorable EFS outcome. The study was closed early when the receipt of radiation therapy exceeded the predefined monitoring boundary. CONCLUSIONS: This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.

Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

PURPOSE: Optimal management of patients with intermediate-risk lymphocyte-predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Children's Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate-risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies. PROCEDURE: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to two additional ABVE-PC cycles ± two dexamethasone, etoposide, cisplatin, and cytarabine cycles and all received involved field radiotherapy (IFRT). Rapid early responders (RERs) received two additional ABVE-PC cycles. RERs with complete response (CR) were randomized to IFRT or no further therapy. RERs without CR received IFRT. RESULTS: Ninety-six (5.6%) of 1711 patients on AHOD0031 had LPHL. Patients with LPHL were more likely to achieve RER (93.6% vs. 81.0%; P = 0.002) and CR (74.2% vs. 49.3%; P = 0.000005) following chemotherapy compared with patients with classical HL. Five-year event-free survival (EFS) was superior in patients with LPHL (92.2%) versus classical HL (83.5%) (P = 0.04), without difference in overall survival (OS). Among RERs with CR following chemotherapy (n = 33), there was no difference in EFS or OS between those randomized to receive or not receive IFRT. CONCLUSION: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes. The majority of patients treated with the ABVE-PC backbone achieve RER with CR status and can be treated successfully without IFRT.

Survival by Race and Ethnicity in Pediatric and Adolescent Patients With Hodgkin Lymphoma: A Children's Oncology Group Study.

PURPOSE: Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite-non-Hispanic black (NHB) and Hispanic-patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children's Oncology Group trials. PATIENTS AND METHODS: This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy. RESULTS: At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% (P < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively. CONCLUSION: In patients who were treated for de novo HL in contemporary Children's Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.

Patterns of Involved-Field Radiation Therapy Protocol Deviations in Pediatric Versus Adolescent and Young Adults With Hodgkin Lymphoma: A Report From the Children's Oncology Group AHOD0031.

PURPOSE: The presented protocol for pediatric intermediate-risk Hodgkin lymphoma evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, prednisone]) with response-based therapy augmentation (addition of DECA [dexamethasone, etoposide, cisplatin, cytarabine]) or therapy reduction (elimination of radiation). METHODS AND MATERIALS: A central review of the radiation therapy data for quality assurance was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in the pediatric group (age <15 years) and adolescent and young adult (AYA) group (age ≥15-21 years). Involved-field radiation therapy (IFRT) planning was reviewed before the start of treatment and at treatment completion. The records were reviewed through the Quality Assurance Review Center's central review to identify RPD, classified according to dose deviation (DD), volume deviation (VD), undertreatment (UT), and overtreatment (OT). DDs and VDs were further classified as major or minor. RESULTS: Of the 1712 patients enrolled, 1155 received IFRT, of whom, 216 (18.7%) had RPDs. The DD and VD patterns were similar between the pediatric and AYA groups. Minor VDs were most common. UT RPDs accounted for 69% in the pediatric group and 75% in the AYA group. Of the 35 patients with relapse and a RPD, 29 had an undertreatment RPD. Among the patients who received IFRT, a significant difference was found in the cumulative incidence rates of relapse between the pediatric and AYA groups (P = .03); however, no significant difference was found between patients with and without RPD (P = .2). CONCLUSIONS: Most RPDs were minor and consisted of UT in the AYA and pediatric populations both. No difference was observed in RPDs between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, the RPD distributions for AYA patients will be similar to those for pediatric population. However, the increased cumulative incidence of relapse in the AYA patients who had received IFRT compared with the pediatric population requires further exploration, given the potential differences in clinical outcomes in the AYA population.