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

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 (2^ndEFS), 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 2^nd 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 1^stEFS 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.