Phase III Study of Response Adapted Therapy for the Treatment of Children with Newly Diagnosed Very High Risk Hodgkin Lymphoma (Stages IIIB/IVB) (AHOD0831): A Report from the Children's Oncology Group
Authors: Kelly Kara M. , Cole Peter D. , Chen Lu , Roberts Kenneth B , Hodgson David C. , McCarten Kathleen , Cho Steve Y , Schwartz Cindy 
Published: October 2019

Abstract
PURPOSE: The AHOD0831 study tested a response-based treatment approach for pediatric patients with very high risk Hodgkin lymphoma (HL). Central response review following 2 cycles of dose intensive chemotherapy by FDG-PET was utilized to assign consolidation chemotherapy and risk-adapted radiotherapy. The primary outcome was second event-free survival (2nd EFS), defined as freedom from second relapse or malignancy. Because many patients with relapsed HL can be successfully cured with retrieval therapy, 2nd EFS more accurately reflects long-term overall survival (OS). AHOD0831 was designed to test whether this treatment protocol will maintain 4-year 2nd EFS ≥95%.
PATIENTS AND METHODS : Patients aged ≤ 21 with stage IIIB or IVB HL were nonrandomly assigned to receive two 21-day courses of ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide). Rapid Early Response (RER) was defined by FDG-PET negativity (i.e. no activity above background), irrespective of size of residual masses. Patients with RER were consolidated with 2 additional cycles of ABVE-PC. Slow early responders (SER) received 2 cycles of ifosfamide/vinorelbine (IFOS/VINO) followed by 2 more cycles of ABVE-PC. Radiotherapy (RT), 21 Gy in 14 fractions, was administered to sites of initial bulky involvement (large mediastinal mass, nodal aggregate >6cm, splenic macronodular involvement) and regions of SER. For the primary aim of 2nd EFS, second events were defined as any relapse/progression of HL or SMN, new SMN or death after a first event which can be relapse/progression, SMN, persistent bone marrow involvement at completion of chemotherapy, or biopsy proven HL for SER at completion of chemotherapy.
RESULTS: Among 165 eligible patients, median age was 15.8 yrs (5.2-21.4), 61% were male, 71 (43%) were stage IIIB, and 94 (57%) IVB. 50% were RER (stage IIIB: 58%; IVB: 45%). At time of current analysis the median follow-up was 42 months. 2nd EFS at 4 years is 89.8% (95% CI:80.8%-94.8%), below the projected baseline with 4-yr rate of 95% (P=0.01). Subgroup analyses showed that 4 yr 2nd EFS for RER (n=77) is 91.9% (76.3%-97.4%), SER (n=68) is 87.8% (75.8%-94.1%) and stage IVB 89.6% (76.3%-95.7%). 20 patients were excluded from 2nd EFS analysis secondary to premature termination or deviation of protocol therapy. 31 patients had reported at least one event for EFS (first event: 29 relapse/progressions, 1 SMN, and 1 death secondary to disseminated fungal infection during RT). Standard 1st EFS rates at 4 yrs are: 80.2% (73%-85.6%). 4 yr OS 95.9% (90%-98.4%). 12 SER patients had persistent PET positive lesions at end of chemotherapy. Eight of these 12 had clinical evidence of active disease (3 biopsy-proven HL, 2 with progressive disease by clinical or radiographic criteria, and 3 later relapses). In retrospective analysis, no specific Deauville score could be identified to predict which patients were at highest risk for progression.
CONCLUSIONS: Among pediatric patients with very high risk HL (IIIB, IVB), a response directed approach utilizing limited chemotherapy (4 cycles for RER; 6 cycles for SER) and risk directed RT did not reach the ambitiously high pre-specified target for 2nd EFS. However, 4 year EFS and OS rates are comparable with results of recent trials for this population (POG 9425: IIIB/IVB, n=88: 4 yr EFS 81.7% (71.8%-88.3%); 4 yr OS 92.9% (84.9%-96.8%)). Our study achieved these similar outcomes, despite the reduction in RT volumes from historical involved fields (which did not account for relapse risk). Persistent PET at end of chemotherapy identifies a cohort at an especially high risk for relapse/early progression. Novel approaches incorporating enhanced risk stratification beyond stage and B symptoms, identification of better predictive factors beyond PET response, and incorporation of novel agents are still needed for this highest risk group of patients with newly diagnosed pediatric HL.

Disclosures
No relevant conflicts of interest to declare.