Chemotherapy Without Methotrexate Achieves Superb Results in Children With NHL

NEW YORK—Short-term, intensive multiagent chemotherapy without high-dose methotrexate produces excellent outcomes in children with advanced non-lymphoblastic non-Hodgkin’s lymphoma, according to a Children’s Cancer Group (CCG) study. The estimated 5-year event-free survival (EFS) was 77% and the overall survival rate was 80% for the 39 patients enrolled in the pilot study, according to lead researcher Mitchell S. Cairo, MD, director of Pediatric Blood and Marrow Transplantation at Columbia University, New York.

Results were markedly different, however, for high-risk vs standard-risk patients—96% estimated 5-year EFS for standard-risk vs 61% for high-risk. High-risk patients were defined as those with bulky disease, bone marrow or central nervous system (CNS) involvement, and lactate dehydrogenase (LDH) levels more than twice the normal upper limit.

"The regimen appears to achieve superb results in children with advanced disease," Dr. Cairo said. "But it’s significantly inferior to therapy that includes methotrexate for those with bulky disease, high LDH, or CNS or bone marrow involvement."

Comparing Results

Dr. Cairo compared the study results with those of research published by Reiter et al in Blood in 1999. Reporting on a regimen that was similar but included methotrexate, the Reiter article showed a comparable 5-year EFS for standard-risk patients of 96%, but better outcomes for high-risk patients—78% 5-year EFS—than the CCG study.

Nicknamed "Orange" because it was devised at the Children’s Hospital of Orange County, California, the regimen used in the CCG study included a 3-week induction based on CHOP (cyclophosphamide, doxorubicin, Oncovin [vincristine], prednisone) and 3 to 4 weeks of ifosfamide (Ifex)/etoposide consolidation and DECAL (dexamethasone, etoposide, cytosine arabinoside, L-asparaginase) intensification. Reduced doses of the same agents were administered during a maintenance phase.

Standard-risk patients received one course of maintenance or about 5.5 months of therapy, while high-risk patients received two courses of maintenance or 7 months of therapy. In contrast, standard-risk patients in a previous large randomized CCG trial received COMP (cyclophosphamide, Oncovin [vincristine], methotrexate, prednisone) therapy for as long as 18 months and had a significantly inferior outcome.

Sixteen patients in the present study were considered high risk, while 16 patients were standard risk. The median age of the children was 8 years, and 32 had Murphy stage III and five had stage IV disease. Twelve of the patients were diagnosed with large cell lymphoma, and 27 with small noncleaved lymphoma.

In contrast to previous CCG research on similar regimens, older age was a poor prognostic factor in this study. Those 15 years or older had a 5-year EFS of 50% vs an 82% EFS for younger children.

The "Orange" regimen produced significant hematologic toxicity, according to Dr. Cairo. Depending on whether the patients were standard or high risk, 14% to 44% had platelet counts of less than 25,000. Hemoglobin counts were less than 6.5 in 10% to 35% of patients.

One toxic death resulted from the intense regimen, and two toxic deaths occurred through sepsis. Two patients developed secondary acute myelogenous leukemia. Out of 34 patients available for long-term follow-up, one showed long-term cardiac effects.

"This regimen needs to be proven in larger numbers, but the study suggests that it can be as effective as regimens with high-dose methotrexate in patients with advanced standard-risk lymphoma," Dr. Cairo said. "However, it’s significantly inferior for those with high-risk disease."

"Since age is a poor prognostic factor, clinicians would need to consider alternative treatments and strategies for older patients," he added.