Methotrexate and asparaginase combination chemotherapy in refractory acute lymphoblastic leukemia of childhood

Abstract

Two groups of children with refractory acute lymphoblastic leukemia were treated with a regimen of methotrexate (MTX) and asparaginase (Asn'ase) based on studies of the effect of MTX in vitro on human lymphoblasts exposed to Asn'ase. Induction therapy in 12 children produced 4 complete remissions, 3 partial remissions, and 5 failures. Responsiveness to Asn'ase seemed necessary for successful induction with the drug combination. Maintenance therapy in 18 children produced a median hematologic remission of 31 weeks (range 3-85 weeks). During remission, 2 children developed central nervous system leukemia and 2 died of infection. The mean maximally tolerated dose of MTX was 361 mg/m2. The results of this trial suggest therapeutic synergy in maintenance therapy and the capability of Asn'ase to attenuate MTX toxicity.Cancer 43:1089-1094, 1979. H E USE OF MULTIPLE CHEMOTHERAPEUTICT AGENTS is superior to single agent therapy in the management of acute lymphoblastic leukemia (ALL) of childhood, and has contributed significantly to the improved prognosis in that disease Certain pharmacologic considerations make methotrexate (MTX) and asparaginase (Asn'ase) attractive for such combination chemotherapy. Asn'ase seems to lack crossresistance with other antileukemic drugs, and has a rather unique spectrum of toxicity." Response to MTX varies significantly with manipulation of dosage and ~chedule,'~-'~~*' allowing comparison of multiple regimens of MTX plus another chemotherapeutic agent. In addition, the mechanisms of action of MTX and Asn'ase may interact. Although MTX is a known folate antagonist, its final mechanism of cell death is ~n c l e a r .~ One factor appears to be continued synthesis of RNA and protein with concomitant inhibition of nuclear DNA replication, a phenomenon termed "unbalanced g r~w t h . "~ When the drugs are used together, Asn'ase may attenuate MTX effect through inhibition of protein synthesis, thus altering the unbalanced growth induced by MTX.8 Asn'ase can also have an inhibitory effect on MTX membrane transport.23,32 A goal of combined therapy with these two drugs then becomes an additive or synergistic cytotoxic effect on leukemic cells, with an accompanying attenuation of, or "rescue" from, the usual toxic manifestations of MTX on bone marrow and mucosal surfaces.This schedule-dependent synergistic cytotoxic effect with MTX and Asn'ase has been demonstrated on murine leukemia cells both in vitro and in vivo,6*8,12,31 and in human leukemia cells in v i t r~. ' ,~ Capizzi studied the effect of MTX on the rate of DNA synthesis in vztro in human lymphoblasts obtained from peripheral blood and bone marrow, before and after a single intravenous dose of A s n ' a~e .~-~ He showed that within 24 hours of an exposure to Asn'ase the rate of DNA synthesis

Asparagine Synthetase Chemotherapy

“…The molecular basis of ASNase resistance, which is a major clinical problem, remains poorly understood despite a significant amount of ongoing research (8,18). Because ASNase sensitivity in tumors cannot yet be predicted reliably, the major use of this enzyme remains confined to the treatment of childhood ALL, despite estimates that 5-10% of all solid tumors may be sensitive to therapies based upon the depletion of blood asparagine (16).…”

“…First, the treatment produces a wide variety of side effects, including immunosuppression and pancreatitis (13,14). Second, 10% to 12% of patients who achieve remission suffer a relapse with tumors that are resistant to further ASNase therapy (5,(14)(15)(16). Finally, ASNase administration may enhance the growth of resistant tumors and increase their metastatic activity (10,17).…”

Comparison of the L10M consolidation regimen to an alternative regimen including escalating methotrexate/L-asparaginase for adult acute lymphoblastic leukemia: a Southwest Oncology Group Study

“…Several studies employed this approach and suggested a positive correlation between the methotrexate dose delivered and remission duration. 11,12 Accordingly, the Southwest Oncology Group conducted a study, SWOG 8417/8419, to evaluate a consolidation regimen combining the brief, intensive DAT regimen from the L17M regimen with the Capizzi program of escalating methotrexate and L-asparaginase. The objective of this phase III study was to compare this consolidation regimen to the standard L10M consolidation in terms of disease-free survival, overall survival, and toxicity.…”

Pretreatment Plasma Folate Modulates the Pharmacodynamic Effect of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: “Folate Overrescue” Concept Revisited

“…Evidence supporting the importance of MTX dosing and scheduling can be found in the literature over decades of clinical use (1,13,14 ). The pediatric ALL community remains divided concerning the use of either "industrial" MTX doses with leucovorin rescue [BerlinFrankfurt-Munster Cooperative Group (BFM) (15 ), United Kingdom ALL Cooperative Group (UKALL) (1 ), and Nordic (10 ) studies] or repeated, escalating low doses of systemic MTX administered with absolutely no leucovorin rescue, the so-called Capizzi methotrexate (5,16 ), which also has apparent clinical efficacy (17,18 ). To gain more insight into this unresolved issue, the Children's Oncology Group (COG) has recently initiated a randomized study evaluating HDMTX with leucovorin rescue, as specified by the BFM trial group, compared with the Capizzi methotrexate protocol (19 ).…”