A Phase III Study for the Treatment of Children and Adolescents with Newly Diagnosed Low Risk Hodgkin Lymphoma (HL)

Optimal therapy for favorable risk HL in children and adolescents continues to evolve. Although the great majority of children will be cured, the potential for long-term adverse sequelae of treatment remains significant. Current regimens seek to define less toxic approaches that effectively treat low risk HL patients. The Children's Oncology Group (COG) HL studies have focused on the use of a response based paradigm for reduction of therapy.

COG protocol AHOD0431 was a single arm study designed to investigate: 1) the rate at which three cycles of doxorubicin, vincristine, prednisone and cyclophosphamide (AVPC) induces complete response (CR), 2) whether achieving CR after 3 cycles of chemotherapy alone allows elimination of involved-field radiation therapy (IFRT), while maintaining excellent disease control and 3) whether very early response as measured by [¹⁸F]–fluorodeoxyglucose-positron emission tomography (FDG-PET) after the first course of chemotherapy is predictive of outcome. Eligibility requirements were: ages 0–21 years with newly diagnosed Stages IA and IIA HL without bulk and without lymphocyte predominance (LP) histology. All subject received chemotherapy. Patients who achieved a CR after 3 cycles of AVPC received no further therapy. Those with a partial response (PR) received 21 Gy IFRT. CR was defined as at least 80% reduction in the size of each of the nodal masses, or return to normal size, and negative findings on FDG-PET or Gallium scanning. Imaging studies were centrally reviewed.

287 subjects were enrolled between February, 2006 and December, 2008. 9 subjects were subsequently found to be ineligible, and an additional 3 were inevaluable for 3-cycle response. The CR rate after 3-cycles of AVPC was 63.6%, lower than the goal rate of 80%. However, event free survival (EFS) for the entire cohort at 2 years was 84%, and overall survival (OS) was 100%. Analysis by CR vs. PR status after 3 cycles of chemotherapy showed a 2 yr EFS of 80% for those achieving CR after 3 cycles of AVPC (no IFRT) vs. 88% for those achieving PR and therefore receiving IFRT (p=0.11). 227 subjects had evaluable FDG-PET results after one cycle of chemotherapy (PET1). Among subjects who achieved a CR (no IFRT) the 2 year EFS for PET1 positive/equivocal vs. negative was 65% vs. 87% (p=0.005). Among subjects who achieved a PR after 3 cycles of chemotherapy and received IFRT per protocol, 2 year EFS for PET1 positive/equivocal vs. negative was 82% vs. 96% (p=0.047). In December, 2008 the Study Committee recommended IFRT for all CR patients who were PET1 positive or PET1 status unknown, and were within one year of completing chemotherapy. 12 subjects received IFRT based on this recommendation, and all remain in CR. At a median f/u of 25 months, 46% of the entire cohort remain in CR without receiving any radiation therapy.

Low risk HL in pediatric and adolescents is well recognized to be a highly curable malignancy, however late toxicities of therapy are frequent and may be life threatening or substantially affect quality of life. Nearly half of our patients have not received radiation therapy on this protocol. These outcomes are similar to other published pediatric regimens for low risk HL (excluding LP histology), even those that incorporated radiation therapy for all or most patients. The OS of 100% suggests that those who did recur after limited therapy were quite salvageable, many without aggressive salvage regimens or stem cell transplant. CR status after 9 weeks of chemotherapy may not optimally identify patients in whom IFRT can be avoided. Very early response, as measured by FDG-PET after 3 weeks of therapy, had significant prognostic implications in both CR and PR subjects, suggesting that this assessment may have a role in identifying a cohort of patients for whom limited volume/low dose RT remains an important component of therapy. Alternatively, AVPC may require intensification to optimize EFS while limiting need for IFRT. The role of a limited intensity chemotherapy regimen with low-dose IFRT for those subjects that experience localized recurrence after chemotherapy alone is the subject of an ongoing investigation.

No relevant conflicts of interest to declare.