Abstract
Significant advances have been made in the treatment of malignant lymphomas in children; however, approximately 20–30% will have refractory or recurrent disease. These patients are felt to have a relatively poor prognosis primarily because of the comprehensive and intensive nature of their frontline therapies; therefore, they are generally considered for a novel or more aggressive salvage regimen. The purpose of this study is to determine the activity and toxicity profile of the MIED regimen (high-dose methotrexate, ifosfamide, etoposide and dexamethasone) in children with refractory or recurrent non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). From 1991 to 2006, 62 children with refractory/recurrent NHL (n=24) and HL (n=38) were treated with 1 to 6 sequential cycles of MIED (methotrexate, 8 grams/m2 on day 1; ifosfamide, 2 grams/m2 on days 2–4; etoposide, 200 mg/m2 on days 2–4; and dexamethasone, 40 mg/m2 on days 1–4). Children with NHL also received intrathecal MHA (methotrexate, hydrocortisone, and cytarabine at age adjusted dosages) on day 1. Response evaluation was performed after 1 – 2 cycles of MIED. Children with either a PR or CR were considered for an intensification phase with hematopoietic stem cell transplantation (HSCT); patients with HL also received involved-field irradiation. Forty-six (75%) of the 61 evaluable children with refractory or recurrent lymphoma responded to MIED (CR, 23; PR, 23). Among the 24 children with NHL (large cell, 18 [anaplastic large cell, 8; diffuse large B-cell, 3; T-cell large cell, 2; large cell not otherwise specified, 5]; Burkitt, 3; lymphoblastic, 2; other, 1), responses included: CR (n=10), and PR (n=5) for a combined CR+PR rate of 63%. Among the 37 children with HL (nodular sclerosis, n = 29; mixed cellularity, n =4; lymphocyte predominant, n =1; and HL not otherwise specified, n=3) responses included: CR (n=13), and PR (n=18) for a combined CR+PR rate of 84% among 37 evaluable patients. MIED was generally well tolerated (associated with grade IV hematologic toxicity in most cases and frequently associated with mucositis and/or fever with neutropenia). Nineteen of 24 children with NHL and 31 of 37 children with HL received an intensification phase with HSCT support (autologous, 46; allogeneic, 4) at some point following MIED therapy. Nine of 24 children (38%) with NHL are alive and disease-free. Twenty-eight of 37 children (76%) with HL are currently alive (24 disease-free post HSCT). MIED is an active and generally well tolerated regimen for children with refractory or recurrent malignant lymphoma.
The influence of folate pathway polymorphisms on high-dose methotrexaterelated toxicity and survival in children with non-Hodgkin malignant lymphoma
