Irma Ramirez

Curability of Burkitt's lymphoma with high-dose cyclophosphamide-high-dose methotrexate therapy and intrathecal chemoprophylaxis.

Twenty-four children with Burkitts lymphoma were treated beginning May 1976 with a regimen alternating high doses of cyclophosphamide and methotrexate in induction and consolidation; only high doses of methotrexate were used in the maintenance phase. Throughout therapy, which was planned for 54 weeks, intrathecal chemoprophylaxis using methotrexate, cytosine arabinoside, and hydrocortisone was coordinated with the high-dose methotrexate infusion therapy to provide CNS chemoprophylaxis that maintained therapeutic methotrexate spinal fluid levels (greater than 10(-6) mol/L) for approximately 60 hours. Twenty-two (92%) of the 24 children attained complete remission; two (8.3%) patients attained only partial remission, failing therapy. Two children died of infection while in complete remission; two children relapsed on therapy. Actual survival is 75%; the median follow-up time is 38+ months (range, 1 1/2+ to 84+ months). Relapses correlated with Murphy disease stage as follows: stage I--0/3, stage II--2/7, stage III--2/10, and stage IV--0/2. Serious side effects and toxicities of chemotherapy occurred in ten patients (metabolic disturbances after rapid tumor lysis, two; infectious and/or febrile episodes following cyclophosphamide therapy, three; methotrexate side effects, four; and complications of intrathecal therapy, one). Results of this therapy are similar to those of the best regimens that have been reported. Treatment has been adapted for use in Burkitts lymphoma by the Pediatric Oncology Group; the responsiveness of other B cell lymphomas of childhood to this treatment is also being determined.

High-dose mercaptopurine followed by intermediate-dose cytarabine in relapsed acute leukemia.

PURPOSEnThis phase I/II study was designed to explore the feasibility, toxicity, and potential efficacy of administering high-dose continuous intravenous mercaptopurine (6MP) followed by intermediate-dose continuous intravenous cytarabine (Ara-C) to children with relapsed or unresponsive acute leukemia.nnnPATIENTS AND METHODSnTwenty-three children with relapsed or unresponsive acute leukemia (13 myeloid, 10 lymphoid) were entered onto the study. After initial hydration and alkalinization, 1,000 or 1,250 mg/m2 of 6MP was administered by continuous intravenous infusion over 24 hours. Following another period of hydration, 500 mg/m2 of Ara-C was administered by continuous intravenous infusion daily for 4 days. In 17 children, plasma concentrations of 6MP were measured at hours 4, 24, and 27 of the 6MP infusions. Plasma concentrations of Ara-C were measured at hours 8, 24, 48, 72, and 96 of the Ara-C infusions. Intracellular Ara-C triphosphate (Ara-CTP) concentrations were measured in peripheral-blood leukemia cells of the five patients with sufficient cells for measurement. Children who developed remission received repeated courses of this regimen every 3 to 4 weeks until relapse or completion of 12 courses.nnnRESULTSnOf 13 children with acute myeloid leukemia (AML), six developed complete remissions (CRs) lasting 7 months to nearly 4 years. Two children remain in CR with normal growth, development, and health 3 years after cessation of treatment. Of 10 children with acute lymphoid leukemia (ALL), one had a CR of 2 months duration. Dose-limiting toxicity consisted of severe hematosuppression with fever, neutropenia, and serious infection. There were two toxic deaths. The mean steady-state plasma concentrations of 6MP were approximately 4 mumol/L and of Ara-C approximately 3 mumol/L. The median Ara-CTP concentration in peripheral-blood leukemia cells was 308 mumol/L at hour 8 of the Ara-C infusion.nnnCONCLUSIONnHigh-dose continuous intravenous 6MP followed by intermediate-dose intravenous Ara-C produced CRs of longer than 6 months in approximately half of children with relapsed or unresponsive AML. Further study of this drug regimen is justified.

High-dose cyclophosphamide-high-dose methotrexate with coordinated intrathecal therapy for advanced nonlymphoblastic lymphoma of childhood: results of a Pediatric Oncology Group study.

The Pediatric Oncology Group (POG) investigated a high-dose cyclophosphamide (CPM) high-dose methotrexate (MTX) regimen to determine therapeutic efficacy in confirmed advanced nonlymphoblastic non-Hodgkins lymphoma (NHL) (stages III and IV) and B-cell acute lymphatic leukemia (B-ALL) in children. Another goal was to determine the comparative effectiveness of shortened maintenance treatment (2 versus 6 courses) in the study population. Systemic induction therapy included vincristine, prednisone, cyclophosphamide, and intermediate-dose MTX with leucovorin rescue. Superimposed intrathecal (IT) therapy included cytosine arabinoside for 2 successive days followed on day 3 by MTX. Intrathecal MTX was given 3 times during induction. At the end of induction, 2 days of triple (hydrocortisone, MTX, and cytosine arabinoside) therapy were given intrathecally (TIT). All patients then received a consolidation course of 4 doses of TIT, 2 doses of cyclophosphamide, and 4 more courses of vincristine and MTX with leucovorin rescue. Patients were then randomized to receive either 2 or 6 cycles of vincristine plus MTX with leucovorin rescue. The TIT was given with each cycle. Complete response rates by histology and Murphy stage (1) were as follows: undifferentiated lymphoma (DUL) stage III, 84/105 (80%): stage IV, 5/12 (42%); and other NHL [primarily large cell lymphoma (LCL)] stage III, 21/28 (75%); stage IV, 2/3 (67%). Event-free survival (EFS) at greater than 2 years was similar for patients with DUL and LCL, i.e., 65 and 61%, respectively. No significant difference in outcome was noted between patient groups receiving 2 or 6 maintenance treatments (p = .76). Treatment was notable for its modest toxicity following the early change to single-dose CPM therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

High-Dose Mercaptopurine and Intermediate-Dose Cytarabine During First Remission of Acute Myeloid Leukemia

High-dose, continuous infusion of intravenous mercaptopurine (HD 6MP) followed by intermediate-dose continuous cytarabine (ID Ara-C) has been shown to produce remissions in children with relapsed acute myeloid leukemia (AML). The purpose of this pilot study was to explore the feasibility of using this drug regimen as a component of treatment during the first remission of AML. Of 17 children with newly diagnosed AML registered in the study, 14 developed complete remission on conventional induction therapy and subsequently received the HD 6MP and ID Ara-C combination. The dosages of HD 6MP were escalated from 500 mg/m2 to 1250 mg/m2 in 24-hr infusions. The initial dosages of ID Ara-C were escalated from 250 mg/m2 to 650 mg/m2/24 hr and from 1 day to 4 days. Conventional treatment for AML was administered simultaneously. Seven of the 14 children remain in initial complete remission for 15 to 46 months and have completed treatment. Severe pancytopenia was observed in all patients, but there were no toxic deaths and no deaths during remission. The inclusion of HD 6MP and ID Ara-C in the treatment of AML in first remission appears to be feasible. Evaluation of its efficacy will require a comparative clinical trial.