C. Philip Steuber

X-Linked Lymphoproliferative Syndrome Registry report

Immune deficiency, especially to the Epstein-Barr virus, and increased susceptibility to fatal infectious mononucleosis, acquired agammoglobulinemia, and lymphoma are the cardinal features of the X-linked lymphoproliferative syndrome. Since the establishment of the XLP Registry in September, 1978, 59 affected males in seven unrelated kindreds were comprehensively studied. A spectrum of lymphoproliferative phenotypes was observed. Thirty-four patients (57%) died from infectious mononucleosis, eight (14%) had fatal infectious mononucleosis with lymphoma (immunoblastic sarcoma), nine (15%) had depressed immunity following EBV infection, and eight (14%) developed lymphoma. Several patients with XLP lacked EBV antibodies despite infection by EBV. The results of this study suggest that EBV can be an oncogenic agent in patients who are immune deficient with XLP.

Pediatric oncology group experience with modified LSA2-L2 therapy in 107 children with non-Hodgkin's lymphoma (Burkitt's lymphoma excluded)

From September 1976 to August 1979 the Pediatric Oncology Group accessed 145 children to study the effectiveness of modified LSA2‐L2 therapy for the treatment of non‐Hodgkins lymphoma (NHL). Burkitts lymphoma patients were ineligible; E‐rosette‐positive patients with ≥ 25% blasts in the marrow entered after February 1977 were reported separately. Radiotherapy could be used to treat patients with compressive mediastinal disease at diagnosis and was prescribed for those with residual abdominal disease as demonstrated by second‐look surgery on completion of induction chemotherapy. Confirmation of diagnosis by the Pathology Panel and Repository Center for Lymphoma Clinical Trials was mandatory. Diagnostic tissues of 131 patients were reviewed. Among 107 evaluable patients, 91 (85%) achieved complete remission. Differences in response rates among the three major histologic groups (lymphoblastic, undifferentiated, and large cell) were of statistical significance, with response being poorest for diffuse undifferentiated lymphoma (P = 0.03). Failure‐free survival did not differ significantly for the three major histologic diagnoses. While response rate was lowest for Murphy Stage III patients (79%), the differences among the stages were not significant. Stage was not a significant prognostic factor for failure‐free survival (P = 0.08). The number of patients still at risk and the Kaplan‐Meier estimate of percentage of patients remaining at risk after 3 years is: Stage I, 8 (100%); Stage II, 10 (67%); Stage III, 28 (57%); Stage IV, 6 (39%); and > 25% blasts, 1 (13%). Stage III failure curves for lymphoblastic disease show continuing stepwise failure through 3 years. Among patients with diffuse large cell and undifferentiated disease, most failures occurred by 8 months. M1 and M2 levels of marrow involvement were not prognostic among children with lymphoblastic disease. The presence of a mediastinal mass was a significant factor contributing to failure in children with lymphoblastic disease without marrow involvement. Leucocytosis > 10,000/1, was a significant (P = <0.001) factor predicting failure‐free survival for patients with large cell lymphoma. The delivery of radiotherapy was not a significant factor in achieving remission. No consistent benefit resulted from using radiotherapy to treat postinduction residual disease demonstrated on second‐look exploration. The LSA2‐L2 regimen was associated with considerable toxicity, severe or worse in 77% and life‐threatening to 40% of these patients. Four died of toxicity. However, therapy was given more easily and safely as investigator experience increased. Maintenance therapy was delivered on an out patient basis without complications in most instances. This study demonstrates the ability of the LSA2‐L2 regimen to produce long‐term remissions, or to “cure” 60% to 70% of children among the major histologic categories of childhood NHL, excepting Burkitts lymphoma. Long‐term survival, or “cure”, occurs in 90% with Stages I and II disease and some 50% of those with Stages III and IV disease. Neither radiotherapy nor second‐look surgical procedures appear to influence outcome. The continuous relapse pattern seen in lymphoblastic disease involving the mediastinum suggests the need for more intensive repetitive therapy “up‐front”. The relapse pattern of non‐lymphoblastic disease suggests the discontinuation of therapy after 1 year.

Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study

PURPOSE To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia. PATIENTS AND METHODS Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m(2)/d for 5 days and 2.4 mg/m(2)/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days). RESULTS Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m(2)/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m(2) (range, 9.4 to 45.9 L/h/m(2)) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days. CONCLUSION The MTD was 2.4 mg/m(2)/d for 9 days. Further testing is warranted of TPTs schedule dependence in children with leukemia.

Intensification With Intermediate-Dose Intravenous Methotrexate Is Effective Therapy for Children With Lower-Risk B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study

PURPOSE To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m(2) plus IV MP 1,000 mg/m(2) (regimen A) or IV MTX 1,000 mg/m(2) alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years. RESULTS Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P =.5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. CONCLUSION Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.

Treatment of essential thrombocythemia with anagrelide

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by persistent elevation in platelet count. It is a rare disorder in children, and children who have symptoms require treatment. We report the successful use of anagrelide, with few toxic effects, in the treatment of three children with ET.

Repetitive low dose oral methotrexate and intravenous mercaptopurine treatment for patients with lower risk B—lineage acute lymphoblastic leukemia. A pediatric oncology group pilot study

Background. This trial evaluated the toxicity and preliminary efficacy of a repeated oral low dose (LD) methotrexate schedule with intravenous mercaptopurine infusions as intensification therapy for children with lower risk B‐lineage acute lymphoblastic leukemia (ALL).

Idarubicin and cytosine arabinoside reinduction therapy for children with multiple recurrent or refractory acute lymphoblastic leukemia: a Pediatric Oncology Group study.

PURPOSE This study was designed to determine the toxicity of and response to idarubicin and cytosine arabinoside in children and adolescents with acute lymphoblastic leukemia (ALL) who had refractory or recurrent bone marrow disease. PATIENTS AND METHODS Patients <21 years of age with ALL in second or later bone marrow relapse or refractory to induction therapy were eligible. Some patients also had concurrent central nervous system (CNS) relapse. Therapy consisted of cytosine arabinoside, 1 g/m2/day given as a 6-h infusion, followed by bolus idarubicin, 5 mg/m2/day, both daily for 6 days. Children achieving remission received maintenance therapy with 3 days of etoposide, 100 mg/m2/day, followed by ifosfamide, 2.8 g/m2/day, alternating every 3 weeks with 3 days of cytosine arabinoside and idarubicin in the dosages described earlier. All courses of therapy were followed by granulocyte colony-stimulating factor (G-CSF). Removal from study to undergo bone marrow transplantation (BMT) was encouraged. RESULTS Eighty-two patients were entered. There were 14 deaths (nine early), mostly from documented or presumed bacterial or fungal sepsis. Overall, 30 patients achieved complete remission (37%). These were mostly of brief duration--only one patient was still alive at 600+ days after BMT. CONCLUSIONS Cytosine arabinoside and idarubicin showed moderate activity in heavily pretreated children with ALL.

Intensive alternating drug pairs for treatment of high‐risk childhood acute lymphoblastic leukemia. A pediatric oncology group pilot study

Background. To prevent drug resistance, the authors designed a protocol that featured early intensive rotating drug pairs as part of the therapy for acute lymphoblastic leukemia (ALL).

Toxicity trials of amsacrine (AMSA) and etoposide +/- azacitidine (AZ) in childhood acute non-lymphocytic leukemia (ANLL) : a pilot study

Recurrent or induction therapy-resistant ANLL carries a grave prognosis. The combination of AMSA at 100 mg/M2 daily for 5 days and etoposide at 200 mg/M2 daily for the first 3 days of therapy was given to 40 patients with refractory ANLL. An additional 17 patients received those two agents plus azacitidine at a dosage of 250 mg/M2 on days 4 and 5. All three drugs were given as one-hour infusions. All patients had normal electrolyte determinations daily and were on cardiac monitors during the period of drug administration. No arrhythmias were detected in 522 doses of AMSA. Toxicities observed were primarily related to myelosuppression. Forty-nine of the 57 patients required hospitalization for suspected or proven infection. Nausea/vomiting and mucositis were the next most commonly occurring toxicities. Responses were seen in 22 patients.

Human leukocyte alpha interferon-induced transient neurotoxicity in children

SummaryNeuropsychiatric complications with recombinant alpha interferon (rIFN-α) have been described in adults. Little documentation of similar toxicity in pediatric phase I and phase II trials exists. Two children, treated with rIFN-α, experienced confusion, somnolence and syncope, associated with transient electroencephalographic abnormalities. Symptoms abated and electroencephalographic findings improved with termination of therapy. Readministration at lower dosages has not been associated with recurrence of neurotoxicity.