There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Intensification with repeated i.v. MTX in the setting of low-dose LCV rescue was associated with a higher risk for acute NT and LE, especially in patients who received concomitant TIT. The long-term consequences for affected patients remain unknown.

Children with Down syndrome and ALL had a low frequency of adverse clinicobiologic features at diagnosis. However, these findings did not translate into a superior outcome, apparently because of treatment-related toxicity in this group. Future trials should focus on pharmacokinetics and other strategies to reduce toxicity in these compromised patients.

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3 þ 7 þ 7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P ¼ 0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2 þ 5) during the second induction course (5 year EFS estimates, 22 vs 27%; P ¼ 0.33). Age o2 years and leukocyte count o100 000/mm 3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (3674.7%) and for the group that received only intensive chemotherapy (3574.5%) (P ¼ 0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 6375.4%) and of children with Down's syndrome (5-year EFS estimate, 6678.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both highdose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 4278.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.

Two children with congenital chronic relapsing thrombotic thrombocytopenic purpura (TTP) have episodes every 3 weeks. These relapses can be prevented by the infusion of normal fresh-frozen plasma (FFP) without concurrent plasmapheresis. We conducted a study to determine whether the exposure of normal plasma to agents that inactivate human immunodeficiency virus and other viruses destroys the component necessary for the effective treatment of this type of TTP that requires only plasma infusion to prevent or reverse relapses. Clinical responsiveness and von Willebrand factor (vWF)-mediated fluid shear stress-induced platelet aggregation were evaluated before and after the infusion of 10 mL/kg FFP or solvent [tri(n- butyl)phosphate]/detergent (Triton X-100)-treated plasma (S/D plasma). Platelet aggregation at shear stresses of 90 to 180 dyne/cm2 (similar to those in the partially occluded microcirculation) imposed for 30 seconds was excessive using the citrated platelet-rich plasma of both patients, and was associated with the presence of unusually large vWF forms in patient platelet-poor plasma. Infusion with either FFP or S/D plasma at 3-week intervals caused the platelet count to increase to (or above) normal within 1 week (on 12 of 12 occasions); the disappearance or diminution of unusually large vWF forms within 1 hour (on 6 of 10 occasions studied); and the reversal within 1 to 4 hours of excessive shear-induced platelet aggregation (on 8 of 9 occasions studied). We conclude that a component in normal plasma resistant to S/D treatment is responsible for preventing thrombocytopenia and TTP episodes, and for controlling excessive shear-induced aggregation in these patients. Our results suggest that excessive in vivo platelet aggregation in chronic relapsing TTP and excessive in vitro vWF-mediated shear-induced aggregation may be similar phenomena.

In June 1984, the Pediatric Oncology Group (POG) initiated a pilot study (8498) using high-dose cytarabine (HdA; 3 g/m2) for intensification of early therapy in childhood acute myelogenous leukemia (AML) (group I). Remission induction therapy consisted of two courses of daunorubicin, cytarabine (Ara-C), and thioguanine (DAT). Postremission therapy consisted of four sequential courses, each consisting of (1) four doses of HdA (HdA4) followed by asparaginase (L-Asp), (2) etoposide (VP) plus azacytidine (Az), (3) prednisone, vincristine, methotrexate, and mercaptopurine (POMP), and (4) Ara-C daily for 5 days by continuous infusion. Six doses of intrathecal Ara-C were given for CNS prophylaxis. In December 1986, the protocol was amended (group II) to substitute six doses of HdA (HdA6) for the second DAT (two + five) induction course; postinduction, a single course of HdA6 was given instead of four HdA/L-Asp courses, and the remainder of the therapy was unchanged. One hundred forty group I patients and 145 group II patients were assessable. The two groups were similar with regard to clinical prognostic groups. No significant differences were noted in the two groups with regard to remission induction (85% [SE = 2%] in each group), induction deaths (6.5% v 7.0%), or deaths in remission (one in each group). Cerebellar toxicity was reported in three patients in group II (with HdA6) but none in group I (HdA4). At present, patients who received HdA6 (group II) had higher event-free survival than patients in group I (EFS at 3 years, 34% [SE = 11%] v 29% [SE = 4%]), and disease-free survival (DFS at 3 years, 42% [SE = 14%] v 34% [SE = 4%]), but the differences were not statistically significant. In both groups, children less than 2 years and those with WBCs less than 100,000/microL had significantly better outcome (EFS of 55% [SE = 10%] and 36% [SE = 5%] at 3 years, respectively) than children greater than or equal to 2 years and those with WBCs greater than or equal to 100,000/microL (EFS of 27% [SE = 5%] and 20% [SE = 9%] at 3 years, respectively.

The purpose of the paper was to define clinical or biological features associated with the risk for treatment failure for children with acute myeloid leukemia. Data from 560 children and adolescents with newly diagnosed acute myeloid leukemia who entered the Pediatric Oncology Group Study 8821 from June 1988 to March 1993 were analyzed by univariate and recursive partitioning methods. Children with Down syndrome or acute promyelocytic leukemia were excluded from the study. Factors examined included age, number of leukocytes, sex, FAB morphologic subtype, cytogenetic findings, and extramedullary disease at the time of diagnosis. The overall event-free survival (EFS) rate at 4 years was 32.7% (s.e. = 2.2%). Age у2 years, fewer than 50 × 10 9 /l leukocytes, and t(8;21) or inv(16), and normal chromosomes were associated with higher rates of EFS (P value = 0.003, 0.049, 0.0003, 0.031, respectively), whereas the M5 subtype of AML (P value = 0.0003) and chromosome abnormalities other than t(8;21) and inv(16) were associated with lower rates of EFS (P value = 0.0001). Recursive partitioning analysis defined three groups of patients with widely varied prognoses: female patients with t(8;21), inv(16), or a normal karyotype (n = 89) had the best prognosis (4-year EFS = 55.1%, s.e. = 5.7%); male patients with t(8;21), inv(16) or normal chromosomes (n = 106) had an intermediate prognosis (4-year EFS = 38.1%, s.e. = 5.3%); patients with chromosome abnormalities other than t(8;21) and inv(16) (n = 233) had the worst prognosis (4-year EFS = 27.0%, s.e. = 3.2%). One hundred and thirty-two patients (24%) could not be grouped because of missing cytogenetic data, mainly due to inadequate marrow samples. The results suggest that pediatric patients with acute myeloid leukemia can be categorized into three potential risk groups for prognosis and that differences in sex and chromosomal abnormalities are associated with differences in estimates of EFS. These results are tentative and must be confirmed by a large prospective clinical trial.

This study represents a modest outcome improvement in comparison to previous experience with ALL for infants treated on POG trials. More effective therapy is still needed for infants with ALL.