Studies of Sequential and Combination Antimetabolite Therapy in Acute Leukemia: 6-Mercaptopurine and Methotrexate

Abstract

The efficacy of three therapeutic programs for acute leukemia were compared. These programs included (1) Methotrexate (Phase I) followed by 6-mercaptopurine (Phase II); (2) 6-mercaptopurine (Phase I) followed by Methotrexate (Phase II); and (3) Combination Therapy, i.e., 6-mercaptopurine given in combination with Methotrexate. In children with acute lymphocytic leukemia the remission rate was 59 per cent for combination therapy, 47 per cent for 6-mercaptopurine, and 29 per cent for Methotrexate. The better remission rate for combination therapy is consistent with that predicted if it is assumed that 6-mercaptopurine and Methotrexate act independently. The median duration of complete remissions for the three treatments was not different (4 to 5 months). However, long lasting remissions were more frequent in patients receiving combination therapy. The median survival from the onset of therapy to death was 9 months. There were no differences between the three treatment programs as regards survival. In adults the remission rate was 15 per cent for combination therapy, 21 per cent for 6-mercaptopurine and 7 per cent for Methotrexate. As regards survival in adults, early deaths were more common in patients who received MTX as initial therapy, whereas after 5 months survival was somewhat better in those patients receiving combination therapy. In both children and adults there was no evidence that prior treatment with one of the antimetabolites altered response to the other antimetabolite. This result differs from those in animal models, and its effect on our concept of the mechanism of resistance is discussed. Responsiveness to the second course of antimetabolite therapy (Phase II) was as good as that to the first course of treatment. This was true for the remission rate, remission duration, and even for survival when appropriate corrections were made. Thus, responsiveness to drug therapy is maintained as the disease progresses temporally. It may be concluded therefore that new agents can be effectively studied in patients with "late" disease. Responsiveness to Phase II therapy was independent of responsiveness to Phase I. The most common and severe toxic manifestations related to the bone marrow and gastrointestinal tract. There were no major differences quantitatively in the toxicity for the three treatment programs in children in spite of the fact that the drugs were given in full dosage in the combination program. Oral ulcers and a generalized erythematous rash occurred significantly more frequently in patients receiving Methotrexate. Jaundice was significantly more frequent in adults and in patients receiving 6-MP.

Antagonism by methotrexate on mercaptopurine disposition in lymphoblasts during up-front treatment of acute lymphoblastic leukemia

“…Whether methotrexate would decrease thiopurine metabolite concentrations in leukemic blasts after highdose intravenous or conventional-dose oral mercaptopurine during continuation therapy (when there is not the more substantial leukemia burden that is present in newly diagnosed cases) is not known. However, there are circumstantial data that methotrexate and mercaptopurine may synergize (or at least avoid antagonism) when combined during continuation therapy; there is a long track record of methotrexate and low-dose oral mercaptopurine having been successfully combined, 34,35 and erythrocyte thioguanine nucleotides correlate with the active metabolites of methotrexate during continuation therapy with methotrexate plus lowdose oral mercaptopurine. 13 Thus it is possible that methotrexate synergizes with low-dose oral mercaptopurine during continuation therapy, a time at which too few blast cells exist in vivo to be readily detected with current techniques.…”

Chemotherapy of acute lymphocytic leukemia of childhood

“…T h e consortium of investigative research No. 6 ALL OF CHILDHOODcenter and collaborating physicians should provide patients with advances in therapy at the earliest possible time, and provide a medium for continuing education.…”

“…Residual tumor size after chemotherapy was estimated by comparing the slope of repopulation (the time to death) with the behavior of control animals with known numbers of injected cells.19 In patients, too, this approach has been of major importance in estimating residual tumor size after chemotherapy. T h e slope of repopulation was determined by serial determinations in the patient himself, where the endpoint was not death but reappearance of leukemia in the marrow (at which time the child was treated with additional chemotherapy).ll Thus, programs of intensive chemotherapy have been undertaken which inclrided deliberate cessa- No. 6 ALL OF CHILDHOODtion of drug administration to determine the effects of the treatment administered.llJ2 This strategy has been reckoned as ethically acceptable since survival experience was not inferior to contemporaneous programs of management involving maintenance chemotherapy.13 T h e long range strategy has been to define the impact of various therapeutic procedures, the better to combine them eventually.…”

High‐dose methotrexate for the remission induction of refractory adult acute lymphocytic leukemia

“…Following the initial report of the effectiveness of folic acid antagonists in the remission induction of ALL [9], subsequent studies with low doses of methotrexate (1-5 mg) have demonstrated a complete remission rate of 20% to 30% in previously untreated children [ 1,21 . Somewhat higher doses of methotrexate (1 -5 mg/kg) have resulted in complete remissions in children previously treated with methotrexate [ 10-121.…”

“…Methotrexate is known to be an active agent in the treatment of acute lymphocytic leukemia (ALL) [ 1,2] . Although it is not currently used alone for the remission induction of patients with ALL, methotrexate is frequently included in maintenance chemotherapy programs or administered intrathecally as central nervous systems (CNS) prophylaxis.…”