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The clinical course and other distinctive features of five children who developed a testicular relapse 4 months to 25 months after the diagnosis of acute nonlymphoblastic leukemia (ANLL) are described. The chief presenting feature at relapse was painless testicular enlargement, as is also seen in children with acute lymphoblastic leukemia who relapse in the testes. By French-American-British convention, the malignant cells were classified as M4 (myelomonoblastic) in four cases and M2 (myeloblastic) in one. All children received a course of multiagent reinduction chemotherapy and all but one received local irradiation to the testes. Only one of these children, whose relapse was a late event after elective cessation of therapy, is a long-term survivor. A comparison with six previously published cases shows similar clinical characteristics and outcome. Given the poor responses of such patients to conventional treatment, it seems worthwhile to consider the use of intensive reinduction chemotherapy with concomitant bilateral testicular irradiation followed by remission intensification and an autologous or allogenic marrow transplant.

Forty-one children with refractory acute nonlymphocytic leukemia (ANLL) were treated from March 1975 to February 1979 with a schedule-dependent combination of methotrexate (MTX) and L-asparaginase. Intravenous (IV) MTX was followed 24 hours later by IV L-asparaginase (10,000 units [U]/m2). The MTX dose was started at 60 to 100 mg/m2 and was escalated by 20 to 40 mg/m2 as tolerated. This sequence was repeated every 7 to 10 days. Eight patients (20%) achieved a complete remission (CR) and six others had a partial response (PR), with clearance of blasts from the peripheral blood and reduction of bone marrow blasts to less than 25% of nucleated marrow cells. Responding patients received a median maximum MTX dose of 120 mg/m2 (range, 60 to 220 mg/m2). The median number of courses required to achieve a CR was 6 (range, 2 to 13 courses). Toxicity consisted of allergic reactions to L-asparaginase (n = 12), stomatitis (n = 6), minimal elevation of hepatic enzymes (n = 2), and hyperglycemia (n = 1). Treatment was given on an outpatient basis in 95% of all courses. The data indicate that this combination therapy has antileukemic activity and is relatively nontoxic in childhood ANLL.

In this study of children with acute nonlymphocytic leukemia an attempt was made to prevent central nervous system relapse and to determine whether this therapy, coupled with multiagent chemotherapy, would be successful in prolonging durations of complete remission. Central nervous system relapses were prevented by irradiation, although patients who received this therapy did no better than those who did not receive irradiation. A small group of patients received irradiation to the liver and spleen, but this modality also failed to improve the duration of remission. Control of extramedullary leukemia, in this study, failed to improve remission duration because bone marrow relapse was not prevented or delayed. It is unlikely that focal therapy will have a significant impact in acute nonlymphocytic leukemia until longer marrow remissions are achieved.

On the basis of previous findings at this institution, VM-26 and Cytosine Arabinoside (ara-C) were used in combination to treat 33 children with refractory acute lymphocytic leukemia (ALL). Chemotherapy was given by vein twice a week for four weeks at dosage of 300 mg/m2 for ara-C and 50, 75, 110, 165, or 200 mg/m2 for VM-26. Ten marrow remissions (nine complete and one partial) were induced, with hypotension (2/33) and bone marrow hypoplasia (20/33) the most significant side effects observed. Therapeutic responses were obtained with each dosage of VM-26 except 75 mg/m2; myelosuppression developed at all dosages, being most prolonged at 200 mg/m2. Ten of the 23 non-responders did not complete their planned courses of therapy. The significance of this information is that combinations of VM-26 and ara-C were effective in patients who were either in late stages of their leukemia or had never achieved an initial remission. All had been previously treated with prednisone, vincristine, daunomycin and L-asparaginase. In addition, seven of the 10 responders had previously received ara-C in other drug combinations. The use of VM-26 and ara-C in combination may be warranted for newly diagnosed patients who are at high risk for treatment failure with first-line drugs.

Combination chemotherapy with VM-26 and ara-C was given to 14 children with acute lymphocytic leukemia who had not responded to initial treatment with prednisone, vincristine, daunomycin, and asparaginase. Nine of these patients had also received ara-C. At diagnosis, five children were classified as having standard prognostic features and nine as being at high risk for treatment failure. The drug combination was administered by vein twice a week for four weeks at dosages of 165 mg/m2 for VM-26 and 300 mg/m2 for araC. Nine complete remissions, five in patients with high-risk leukemia, were induced with acceptable toxicity; all 9 subsequently were given continuation therapy with oral mercaptopurine and methotrexate. Four of the 9 patients have relapsed at 2--21 months. All treatment was stopped in 2 patients after 30 months of complete remission. Combinations of VM-26 and ara-C represent an alternative remission induction treatment for patients who fail to attain initial remission with agents of established effectiveness. These agents may especially benefit patients with prognostic features indicating a high risk of treatment failure.

The incidence and clinical characteristics of anaphylactoid reactions to intravenous asparaginase were assessed in 196 patients given E. coli asparaginase and 49 patients given Erwinia asparaginase. All patients were given a 50 IU intravenous test dose followed in 30 min by the full dosage (10,000 IU/m2), if no reaction occurred to the test dose. Twenty-nine of 196 patients (14.8%) given E. coli asparaginase had an anaphylactoid reaction, occurring after their first through 12th doses. The probability of an anaphylactoid reaction was significantly greater in those patients not receiving concomitant prednisone-vincristine and patients with a hiatus between courses of asparaginase therapy. By logistic regression analysis, other variables such as age, sex, race, diagnosis, total number of doses and concurrent methotrexate or arabinosylcytosine did not contribute significantly to the probability of a reaction. Twenty-three of the patients who had reacted to E. coli asparaginase and 26 patients who had not reacted to E. coli asparaginase were subsequently given Erwinia asparaginase. Seven of these 49 patients (14%) had an anaphylactoid reaction. The probability of a reaction to Erwinia asparaginase was significantly related to a prior reaction to E. coli asparaginase, concomitant prednisone-vincristine therapy, total number of asparaginase doses, number of prior E. coli asparaginase doses, and diagnosis, when assessed by a logistic regression model. However, after adjusting for prior reaction to E. coli asparaginase and the total number of asparaginase doses given, the other variables did not contribute significantly to the probability of a reaction. Only 5/29 patients reacting to E. coli asparaginase and 1/7 reacting to Erwinia asparaginase had a reaction to the test dose. None of the reactions were fatal.

This controlled study of children with ALL was designed to test the efficacy and toxicity of one-, two-, three- and four-drug therapy during remission and whether more aggressive therapy in the first eight weeks prolongs remission in patients with features associated with a particularly poor prognosis. After inducing remission with prednisone, vincristine and asparaginase, patients received cranial irradiation and IT methotrexate and were randomized to receive: 1--methotrexate alone; 2--methotrexate plus mercaptopurine; 3--same as in group 2 plus cyclophosphamide; and 4--same as in group 3 plus arabinosyl cytosine. Patients with CNS leukemia at diagnosis received IT methotrexate weekly during the induction period and a higher dose of CNS irradiation. Patients with anterior mediastinal enlargement at diagnosis received radiotherapy to the mass during the induction period. Patients who failed to attain bone marrow remission after four weeks of therapy were given daunorubicin and prednisone for 2--4 additional weeks. Of the 282 patients entering this study between January 1972 and November 1975, 268 (95%) attained complete remission and 228 (85%) were randomized to receive continuation chemotherapy with 1, 2, 3 or 4 drugs. In Group 1 (methotrexate alone), 14 of 20 patients relapsed and 9 developed leukoencephalopathy without antecedent CNS leukemia apparently due to higher doses of intravenous methotrexate; in Groups 2, 3 and 4 the results were equivalent, but without leukoencephalopathy in initial CR. The addition of cyclophosphamide and arabinosyl cytosine increased toxicity and complications without demonstrably increasing the leukemocidal effect. In the 40 patients given additional early therapy, the modalties employed in this study did not prolong remission.