NEW YORKShort-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 patients96% 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."
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
patients78% 5-year EFSthan 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
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
"Since age is a poor prognostic factor, clinicians would
need to consider alternative treatments and strategies for older
patients," he added.