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

Abstract

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 91Á9% [95% confidence interval (CI): 86Á1-95Á3%], below the projected baseline of 95% (P = 0Á038). Fiveyear first EFS and overall survival (OS) rates are 79Á1% (95% CI: 71Á5-84Á8%) and 95% (95% CI: 88Á8-97Á8%). 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.

Predictive value of interim and post-treatment PET/CT for clinical evaluation in pediatric and adolescent Hodgkin lymphoma: A comparison of the Deauville Criteria and the International Harmonization Project Criteria

“…18 F-FDG-PET/CT has been formally incorporated into the standard initial staging, interim response evaluation, and residual disease evaluation at the end of treatment for both adult and pediatric patients with HL [23][24][25] . PET/CT-based, response-adapted treatment has been proven to improve survival and reduce the risk of long-term toxicity in pediatric HL patients 5 . It is critical that the response assessment is reliable and reproducible, but the interpretation of interim and post-treatment PET/CT scans can be difficult due to false-positive results 8,26,27 .…”

“…18 F-Fluorodeoxyglucose positron-emission tomography-computed tomography ( 18 F-FDG-PET/CT) is widely used for staging, response evaluation, and surveillance in lymphoma 2 . The outcomes of pediatric and adolescent patients with HL have improved since the application of PET/CT-based, response-adapted therapy [3][4][5] . In a study by the Children's Oncology Group, the cumulative incidence of relapse in pediatric and adolescent HL patients was 17%, and the 5-year progression-free survival (PFS) rate was 83% 6 .…”

Closing the survivorship gap in children and adolescents with Hodgkin lymphoma

“… ‡ On Children's Oncology Group (COG) trials AHOD0831 (Kelly et al , ), AHOD0031 (Friedman et al , ) the cumulative dose of cyclophosphamide was 3200 mg/m 2 ; this contrasts to AHOD1331 (NCT02166463) where the dose is 6000 mg/m 2 . …”

“…A comprehensive review in 2015 summarized contemporary paediatric treatment approaches for de novo HL (Kelly, ). Five‐year DFS in paediatric HL ranged from 79·8% to 97% for low risk HL (Landman‐Parker et al , ; Mauz‐Korholz et al , ; Metzger et al , ; Tebbi et al , ; Wolden et al , ; Keller et al , ) to 77 to 90 % for high risk disease (Schwartz et al , ; Mauz‐Korholz et al , ; Kelly et al , ; Wolden et al , ; Friedman et al , ; Kelly et al , ) in completed trials. With the goal of lowering cumulative doses of anthracyclines to a doxorubicin equivalent dose of ≤250 mg/m 2 and alkylating agents to <7 g/m 2 (cyclophosphamide equivalent dose) (Green et al , ), contemporary paediatric chemotherapy regimens have diverged from the conventional adult approaches of ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) and BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, prednisone, procarbazine) by using combination chemotherapy with non‐cross‐resistant agents [adriamycin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE‐PC) or vincristine, etoposide, prednisone, adriamycin/ cyclophosphamide vincristine, prednisone, dacarbazine (OEPA/COPDac)] (Mauz‐Korholz et al , ; Friedman et al , ).…”

“…These studies demonstrate anti‐lymphoma efficacy with lower cumulative doses of alkylating agents and anthracyclines (Table ) than are customary with adult treatment regimens (Kelly, ). Furthermore, risk‐based response adapted approaches, facilitated by interim imaging in recent paediatric trials have decreased RT delivery (Friedman et al , ; Keller et al , ; Kelly et al , ).…”