A Risk-Adapted, Response-Based Therapeutic Regimen Using a Modified Stanford V Approach for the Treatment of Children with High Risk Hodgkin Lymphoma, AHOPCA LH 2004, a therapeutic regimen from the Central America and Dominican Republic Association of Pediatric Oncology.
Authors: Castellanos E. Mauricio , Metzger Monika , Baez L. Fulgencio , Gamboa Yessica , Hernandez Armando Pena , Alabi Soad , Luna-Fineman Sandra , Nieves Rosa , de Alarcon Pedro 
Published: October 2019

Abstract
Abstract 718
Hodgkin Lymphoma (HL) is highly curable with reported event-free survival (EFS) estimates of greater than 80% even in high-risk patients. Unfortunately, EFS of HL in low-income countries is much lower, about 50%. The Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA) is a collaborative group that designs therapeutic guidelines (protocols) for the treatment of selected malignant disorders in Central America and the Dominican Republic. In 2004 AHOPCA designed a new protocol for the treatment of high-risk HL (stage IIB, IIIB and IV). The purpose of the protocol (AHOPCA LH 2004) was to provide proven effective therapy that would improve survival, decrease toxicity and decrease abandonment of therapy in this group of patients. Because of its short duration (12 weeks of chemotherapy) and reported efficacy, Stanford V was selected but modified to adapt to the local circumstances. We hereby report the preliminary results of AHOPCA LH 2004 which closed to accrual in April 2009.

Methods:
All newly diagnosed biopsy proven HL patients Ann Arbor stages IIB, IIIB and IV, that presented within the seven AHOPCA centers between April 2004 and April 2009 were eligible. Treatment consisted of a modified Stanford V regimen with dose-equivalent cyclophosphamide substituting for nitrogen mustard since the latter was unavailable in Central America. Involved field radiation therapy (IFRT) was reduced from the original 35 Gy. Chemotherapy was given for 12 weeks without the use of growth factor support as follows: doxorubicin 25 mg/m2 and vinblastin 6 mg/m2 intravenous (IV) weeks 1,3,5,7,9 and 11; vincristine 1.4 mg/m2 (maximum 2 mg) and bleomycin 6 units/m2 IV weeks 2,4,6,8,10 and 12; cyclophosphamide 600 mg/m2 IV weeks 1,5 and 9; etoposide 60 mg/m2 IV daily for 2 days weeks 3,7 and 11; prednisone 40 mg/m2 (maximum 60 mg/day) orally given every other day weeks 1 through 10 with tapering of dose over weeks 11 and 12; Response evaluation with diagnostic imaging studies of the initially involved sites of disease was performed at the end of all prescribed chemotherapy. Patients that had achieved a complete response at that point received 20 Gy IFRT, patients with less than a complete response received 25 Gy. Trimethoprim and acyclovir prophylaxis was given to all patients. Patient data was collected and entered prospectively in POND, a web-based electronic data base, provided by St Jude Children's Research Hospital. Toxicities were recorded according to CTCAE 3.0.

Results:
221 patients were enrolled of which 206 were evaluable. Fifteen patients were excluded from the analysis for major protocol deviations. Male subjects predominated (79%) with a median age of 10 years (2-19). The risk distribution consisted of 49 (23%) stage IIB, 100 (48%) stage IIIB, 4 (2%) stage IVA and 50 (24%) stage IVB. Histological classification of HL was: nodular sclerosis 45%, mixed cellularity 42%, lymphocyte predominant 5%, lymphocyte depleted 2% and classical not otherwise specified 6%. The most important grade 3 and 4 toxicities were hematological (75%) and there were two grade 5 toxicities, one infectious and one pulmonary. EFS (±SE) at 3 years was 55.4 % (± 4.4), considering abandonment of therapy as an event, and the overall survival (±SE) was 75.1% (±4.2). Abandonment of therapy was 14.6% for the whole cohort, however it was worse for the largest cohort of patients, stage IIIB, 20%. EFS by stage was: stage IIB 79% (± 6%), IIIB 56% (± 7%) and IVB 29% (± 8%). Stage IVB patients clearly had the worse prognosis, however children < 5 years old had an excellent EFS of 90% regardless of stage or histology but a larger proportion had mixed cellularity HL (60%).

Conclusions:
Our modified Stanford V is a well tolerated regimen with minimal toxicities that does not require growth factor support and can be delivered in an outpatient setting. However, the EFS of patients was less than expected for the group as a whole, (55.4%), and the abandonment rate still unacceptable despite the ease of administration. We have no clear explanation for the excellent survival of children <5 years of age. In our assessment, this treatment regimen is not an effective strategy for high-risk HL in our setting, possibly related to the treatment alterations from the original protocol, or because most of our patients present with more advanced disease than patients in high-income countries.

Disclosures:
No relevant conflicts of interest to declare.