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Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421., Methods: Subjects received 135 units/m 2 /dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%., Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m 2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p  = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF., Discussion: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562)., Competing Interests: KL declares: Jazz pharmaceuticals (consulting, advisory board participation); moderate conflict (annual payments $6 k); Abbott Diagnostics (research funding). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that the clinical trial within which these cardiac studies were conducted received drug supply and funding from Jazz Pharmaceuticals. The funder was involved in the review and approval of the clinical trial protocol., (© 2024 Leger, Absalon, Demissei, Smith, Gerbing, Alonzo, Narayan, Hirsch, Pollard, Razzouk, Getz, Aplenc, Kolb, Ky and Cooper.)

This case report presents the first reported pediatric case of primary classical nodular sclerosing Hodgkin Lymphoma (HL) with pineal gland involvement, presenting without CNS symptoms, which completely resolved after 2 cycles of chemotherapy. The 12 year-old male first presented with a right inguinal mass and external iliac lymphadenopathy accompanied by B symptoms. He was diagnosed with stage IV B classical HL, and as part of the staging work-up, a full-body PET/CT scan was performed. In addition to the right inguinal mass, the PET/CT demonstrated increased FDG uptake at the pineal gland along with level II lymph nodes. The patient was treated with ABVE-PC chemotherapy (Doxorubicin, Bleomycin, Vincristine, Etoposide, Prednisone, and Cyclophosphamide) as per standard arm of AHOD1331 COG protocol for newly diagnosed high-risk HL patients, which resolved the pineal mass after 2 cycles without requiring radiation therapy. Following 5 cycles, a full-body PET/CT showed no brain or neck activity, along with decreased size and activity of the right groin mass. To our knowledge, there are no other documented cases of primary HL with specific pineal involvement, and no cases that lack CNS symptoms altogether like this one did. Additionally, this is the third published pediatric case of primary CNS-HL, both of the previous cases were treated with radiotherapy and presented with CNS symptoms. Thus, this case demonstrates the importance of ordering a full-body PET/CT as part of the initial HL work-up and provides evidence that chemotherapy alone is a treatment option for some patients with primary intracranial HL.

Purpose: Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy., Patients and Methods: Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m 2 /dose on days 1-5; cytarabine 2,000 mg/m 2 /dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count > 500/µL]). Response was assessed after each cycle., Results: Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m 2 on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT., Conclusion: The RP2D of CPX-351 is 135 units/m 2 /dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.

Background: The discovery of new, effective non-anthracycline-based reinduction regimens for children with recurrent acute myeloid leukemia (AML) is critical. In this phase 1/2 study, the tolerability and overall response rate of clofarabine in combination with cytarabine was investigated in children with recurrent/refractory AML., Methods: AAML0523 enrolled 49 children with AML in first recurrence or who were refractory to induction therapy. The study consisted of a dose-finding phase (9 patients) and an efficacy phase (40 patients). Two children received clofarabine at a dose of 40 mg/m(2)/day and 47 children at a dose of 52 mg/m(2)/day., Results: Toxicities typical for intensive chemotherapy regimens were observed at all doses of clofarabine. The recommended pediatric phase 2 dose of clofarabine in combination with cytarabine was 52 mg/m(2)/day for 5 days. Of 48 evaluable patients, the overall response rate (complete remission plus complete remission with partial platelet recovery) was 48%. Four patients met conventional criteria for complete remission with incomplete count recovery. Twenty-one of 23 responders subsequently underwent hematopoietic stem cell transplantation. The overall survival rate at 3 years was 46% for responders compared with 16% for nonresponders (P < .001). Patients found to have no minimal residual disease at the end of the first cycle by flow cytometric analysis had superior overall survival after 1 year (100% vs 38%; P = .01)., Conclusions: The combination of clofarabine and cytarabine yielded an acceptable response rate without excess toxicity in children with recurrent AML. The nearly 50% survival rate reported in responders is highly encouraging in these high-risk patients and suggests that this combination is an effective bridge to hematopoietic stem cell transplantation., (© 2014 American Cancer Society.)

Background: The discovery of effective re-induction regimens for children with more than one relapse of acute lymphoblastic leukemia (ALL) remains elusive. The novel nucleoside analog clofarabine exhibits modest single agent efficacy in relapsed ALL, though optimal combinations of this agent with other active chemotherapy drugs have not yet been defined. Herein we report the response rates of relapsed ALL patients treated on Children's Oncology Group study AAML0523, a Phase I/II study of the combination of clofarabine and cytarabine., Procedure: AAML0523 enrolled 21 children with ALL in second or third relapse, or those refractory to re-induction therapy. The study consisted of two phases: a dose finding phase and an efficacy phase. The dose finding portion consisted of a single dose escalation/de-escalation of clofarabine for 5 days in combination with a fixed dose of cytarabine (1 g/m(2)/day for 5 days). Eight patients received clofarabine at 40 mg/m(2)/day and 13 patients at 52 mg/m(2)/day., Results: Toxicities observed at all doses of clofarabine were typical of intensive chemotherapy regimens for leukemia, with infection being the most common. We did not observe significant hepatotoxicity as reported in other clofarabine combination regimens. The recommended pediatric Phase II dose of clofarabine in combination with cytarabine for the efficacy portion of AAML0523 was 52 mg/m(2). Of 21 patients with ALL, 3 (14%) achieved a complete response (CR). Based on the two-stage design definition of first-stage inactivity, the therapy was deemed ineffective., Conclusion: The combination of clofarabine and cytarabine in relapsed/refractory childhood ALL does not warrant further clinical investigation., (Copyright © 2013 Wiley Periodicals, Inc.)

Purpose: In pediatric relapsed acute myeloid leukemia (AML), optimal reinduction therapy is unknown. Studies suggest that liposomal daunorubicin (DNX; DaunoXome; Galen, Craigavon, United Kingdom) is effective and less cardiotoxic, which is important in this setting. These considerations led to a randomized phase III study by the International Berlin-Frankfurt-Münster Study Group., Patients and Methods: Patients with relapsed or primary refractory non-French-American-British type M3 AML who were younger than 21 years of age were eligible. Patients were randomly assigned to fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) or to FLAG plus DNX in the first reinduction course. The primary end point was status of the bone marrow (BM) sampled shortly before the second course of chemotherapy (the day 28 BM). Data are presented according to intention-to-treat for all 394 randomly assigned patients (median follow-up, 4.0 years)., Results: The complete remission (CR) rate was 64%, and the 4-year probability of survival (pOS) was 38% (SE, 3%). The day 28 BM status (available in 359 patients) was good (≤ 20% leukemic blasts) in 80% of patients randomly assigned to FLAG/DNX and 70% for patients randomly assigned to FLAG (P = .04). Concerning secondary end points, the CR rate was 69% with FLAG/DNX and 59% with FLAG (P = .07), but overall survival was similar. However, core-binding factor (CBF) AML treated with FLAG/DNX resulted in pOS of 82% versus 58% with FLAG (P = .04). Grade 3 to 4 toxicity was essentially similar in both groups., Conclusion: DNX added to FLAG improves early treatment response in pediatric relapsed AML. Overall long-term survival was similar, but CBF-AML showed an improved survival with FLAG/DNX. International collaboration proved feasible and resulted in the best outcome for pediatric relapsed AML reported thus far.

Background: Granulocyte-colony-stimulating factor (G-CSF) is effective in accelerating neutrophil recovery after intensive chemotherapy for acute myeloid leukemia (AML). However, the optimal G-CSF dosage for patients with AML has not been determined. To the authors' knowledge, G-CSF dosages have not been compared in a randomized AML study., Methods: Patients who were enrolled on the St. Jude AML97 protocol and remained on study after window therapy were eligible to participate. The effect of the dosage of G-CSF given after induction chemotherapy Courses 1 and 2 was analyzed in 46 patients who were assigned randomly in a double-blinded manner to receive either 5 μg/kg daily or 10 μg/kg daily of G-CSF. The number of days of G-CSF treatment, neutropenia (an absolute neutrophil count <0.5 × 10(9) /L), and hospitalization; the number of episodes of febrile neutropenia, grade 2 through 4 infection, and antimicrobial therapy; transfusion requirements; the cost of supportive care; and survival were compared between the 2 study arms., Results: No statistically significant differences were observed between the 2 arms in any of the endpoints measured., Conclusions: The higher G-CSF dosage (10 μg/kg daily) offered no greater benefit than the lower dosage (5 μg/kg daily) in patients who were receiving intensive chemotherapy for AML., (Copyright © 2010 American Cancer Society.)

Aim: To identify gene-expression signatures predicting cytarabine response by an integrative analysis of multiple clinical and pharmacological end points in acute myeloid leukemia (AML) patients., Materials & Methods: We performed an integrated analysis to associate the gene expression of diagnostic bone marrow blasts from acute myeloid leukemia (AML) patients treated in the discovery set (AML97; n = 42) and in the independent validation set (AML02; n = 46) with multiple clinical and pharmacological end points. Based on prior biological knowledge, we defined a gene to show a therapeutically beneficial (detrimental) pattern of association of its expression positively (negatively) correlated with favorable phenotypes such as intracellular cytarabine 5´-triphosphate levels, morphological response and event-free survival, and negatively (positively) correlated with unfavorable end points such as post-cytarabine DNA synthesis levels, minimal residual disease and cytarabine LC(50)., Results: We identified 240 probe sets predicting a therapeutically beneficial pattern and 97 predicting detrimental pattern (p ≤ 0.005) in the discovery set. Of these, 60 were confirmed in the independent validation set. The validated probe sets correspond to genes involved in PIK3/PTEN/AKT/mTOR signaling, G-protein-coupled receptor signaling and leukemogenesis. This suggests that targeting these pathways as potential pharmacogenomic and therapeutic candidates could be useful for improving treatment outcomes in AML., Conclusion: This study illustrates the power of integrated data analysis of genomic data as well as multiple clinical and pharmacologic end points in the identification of genes and pathways of biological relevance.

Background: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients., Patients and Methods: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered., Results: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths., Conclusions: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Background: We sought to improve outcome in patients with childhood acute myeloid leukaemia (AML) by applying risk-directed therapy that was based on genetic abnormalities of the leukaemic cells and measurements of minimal residual disease (MRD) done by flow cytometry during treatment., Methods: From Oct 13, 2002, to June 19, 2008, 232 patients with de-novo AML (n=206), therapy-related or myelodysplasia-related AML (n=12), or mixed-lineage leukaemia (n=14) were enrolled at eight centres. 230 patients were assigned by block, non-blinded randomisation, stratified by cytogenetic or morphological subtype, to high-dose (18 g/m(2), n=113) or low-dose (2 g/m(2), n=117) cytarabine given with daunorubicin and etoposide (ADE; induction 1). The primary aim of the study was to compare the incidence of MRD positivity of the high-dose group and the low-dose group at day 22 of induction 1. Induction 2 consisted of ADE with or without gemtuzumab ozogamicin (GO anti-CD33 monoclonal antibody); consolidation therapy included three additional courses of chemotherapy or haematopoietic stem-cell transplantation (HSCT). Levels of MRD were used to allocate GO and to determine the timing of induction 2. Both MRD and genetic abnormalities at diagnosis were used to determine the final risk classification. Low-risk patients (n=68) received five courses of chemotherapy, whereas high-risk patients (n=79), and standard-risk patients (n=69) with matched sibling donors, were eligible for HSCT (done for 48 high-risk and eight standard-risk patients). All 230 randomised patients were analysed for the primary endpoint. Other analyses were limited to the 216 patients with AML, excluding those with mixed-lineage leukaemia. This trial is closed to accrual and is registered with ClinicalTrials.gov, number NCT00136084., Findings: Complete remission was achieved in 80% (173 of 216 patients) after induction 1 and 94% (203 of 216) after induction 2. Induction failures included two deaths from toxic effects and ten cases of resistant leukaemia. The introduction of high-dose versus low-dose cytarabine did not significantly lower the rate of MRD-positivity after induction 1 (34%vs 42%, p=0.17). The 6-month cumulative incidence of grade 3 or higher infection was 79.3% (SE 4.0) for patients in the high-dose group and 75.5% (4.2) for the low-dose group. 3-year event-free survival and overall survival were 63.0% (SE 4.1) and 71.1% (3.8), respectively. 80% (155 of 193) of patients achieved MRD of less than 0.1% after induction 2, and the cumulative incidence of relapse for this group was 17% (SE 3). MRD of 1% or higher after induction 1 was the only significant independent adverse prognostic factor for both event-free (hazard ratio 2.41, 95% CI 1.36-4.26; p=0.003) and overall survival (2.11, 1.09-4.11; p=0.028)., Interpretation: Our findings suggest that the use of targeted chemotherapy and HSCT, in the context of a comprehensive risk-stratification strategy based on genetic features and MRD findings, can improve outcome in patients with childhood AML., Funding: National Institutes of Health and American Lebanese Syrian Associated Charities (ALSAC)., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: The prognosis after recurrence of pediatric acute myeloid leukemia (AML) is poor, and effective salvage regimens are urgently needed., Methods: In phase 1 and pilot studies, the authors evaluated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of a 5-day course of cladribine followed by topotecan in pediatric patients with recurrent/refractory AML. The cladribine dose was escalated as follows: 9.1, 13.6, 16.3, and 19.5 mg/m(2) per day (8.9 mg/m(2) per day in the pilot study). Outcome was analyzed according to the absence (Stratum 1) versus presence (Stratum 2) of previous allogeneic hematopoietic stem cell transplantation. Twenty-six patients (20 in Stratum 1 and 6 in Stratum 2) were treated., Results: The MTD was not reached in Stratum 1, but a DLT occurred at the lowest cladribine dosage (9.1 mg/m(2) per day) in Stratum 2. Febrile neutropenia was common in both strata. Nine (34.6%) of 26 patients experienced a complete response, and 7 (30.4%) achieved a partial response; 5 (19.2%) were long-term survivors at the time of last follow-up. Clinical outcome was not associated with cladribine or topotecan systemic exposure., Conclusions: The combination was well tolerated in Sratum 1, and the response rate was encouraging. This regimen offers a postrecurrence treatment alternative for patients, especially those who have received anthracycline-containing chemotherapy., (Copyright 2010 American Cancer Society.)

Because cladribine can increase cytarabine triphosphate levels, we tested a cladribine-cytarabine combination in the St Jude AML97, trial in which this combination was administered before standard chemotherapy to 96 children with acute myeloid leukemia (AML) or myelodysplastic syndrome. Patients received a 5-day course of cladribine (9 mg/m(2) per dose) and cytarabine either as daily 2-h infusions (500 mg/m(2) per dose) (arm A) or a continuous infusion (500 mg/m(2) per day) (arm B). Ara-CTP levels and inhibition of DNA synthesis increased from day 1 to day 2, but were not different between the two arms. In addition, the median blast percentages at day 15 did not differ between arms A and B, but patients treated in arm A had shorter intervals between the initiation of the first and second courses of therapy. Thus, although there were trends toward better complete remission rates and overall survival for patients treated in arm B, the reduced efficacy of arm A may have been partially compensated by more intense timing of therapy for that group. For all patients, 5-year event-free survival and overall survival estimates were 44.1+/-5.4 and 50.0+/-5.5%. Our results suggest that cladribine in combination with continuous-infusion cytarabine is effective therapy for childhood AML.

There has been a steady improvement in cure rates for children with advanced-stage lymphoblastic non-Hodgkin's lymphoma. To further improve cure rates whereas minimizing long-term toxicity, we designed a protocol (NHL13) based on a regimen for childhood T-cell acute lymphoblastic leukemia, which features intensive intrathecal chemotherapy for central -nervous system-directed therapy and excludes prophylactic cranial irradiation. From 1992 to 2002, 41 patients with advanced-stage lymphoblastic lymphoma were enrolled on the protocol. Thirty patients had stage III and 11 had stage IV disease. Thirty-three cases had a precursor T-cell immunophenotype, five had precursor B-cell immunophenotype and in three immunophenotype was not determined. Out of the 41 patients, 39 (95%) achieved a complete remission. The 5-year event-free rate was 82.9+/-6.3% (s.e.), and 5-year overall survival rate was 90.2+/-4.8% (median follow-up 9.3 years (range 4.62-13.49 years)). Adverse events included two induction failures, one death from typhlitis during remission, three relapses and one secondary acute myeloid leukemia. The treatment described here produces high cure rates in children with lymphoblastic lymphoma without the use of prophylactic cranial irradiation.

To characterize the biology and optimal therapy of acute mixed-lineage leukemia in children, we reviewed the pathologic and clinical features, including response to therapy, of 35 patients with mixed-lineage leukemia. The majority of cases (91%) had blasts cells that simultaneously expressed either T-lineage plus myeloid markers (T/myeloid, n = 20) or B-lineage plus myeloid markers (B/myeloid, n = 12). Overall survival rates for the B/myeloid and T/myeloid subgroups were not significantly different from each other or from the rate for acute myeloid leukemia (AML) but were inferior to the outcome in children with acute lymphoblastic leukemia (ALL). Patients who failed to achieve complete remission with AML-directed therapy could often be induced with a regimen of prednisone, vincristine, and L-asparaginase. Analysis of gene-expression patterns identified a subset of biphenotypic leukemias that did not cluster with T-cell ALL, B-progenitor ALL, or AML. We propose that treatment for biphenotypic leukemia begin with one course of AML-type induction therapy, with a provision for a switch to lymphoid-type induction therapy with a glucocorticoid, vincristine, and L-asparaginase if the patient responds poorly. We also suggest that hematopoietic stem cell transplantation is often not required for cure of these patients.

Background: Acute myeloid leukemia (AML) with hyperleukocytosis often is associated with early complications. To the authors' knowledge, no recently published study has evaluated the management and clinical course in this regard, especially in relation to pediatric patients., Methods: The authors reviewed 579 patients with newly diagnosed pediatric AML who were treated at St. Jude Children's Research Hospital from 1968 to 2002 and carefully examined 106 patients with initial leukocyte counts > or = 100 x 10(9)/L and French-American-British (FAB) AML subtypes other than M3. These patients with hyperleukocytosis were divided into 2 groups-'before' (early period; 70 patients) and 'after' (late period; 36 patients) the initiation of the AML-83 protocol-to address potential differences in supportive measures (including leukoreduction)., Results: Forty-five patients (42.5%) had early complications that were associated strongly with M4 and M5 FAB subtypes and had higher initial leukocyte counts than the patients without complications. Early deaths were less common in the late period (2.8%) than in the early period (22.9%; P = .01), although the incidence of early complications was similar. The late period was associated with a shorter time for referral (P = .0018), a longer time from admission to chemotherapy initiation (P < .0001), and lower white blood cell counts at chemotherapy initiation (P < .0001). In the late period, patients with or without hyperleukocytosis had similar complete remission rates. However, those with hyperleukocytosis had a lower postremission 10-year event-free survival rate (21.2% vs 41.7%; P = .0228)., Conclusions: With improved management, including supportive care, early mortality in patients with AML and hyperleukocytosis decreased remarkably in the more recent period. However, better postremission treatment is required to improve long-term survival., ((c) 2008 American Cancer Society)

Background: The aim of this study was to determine whether antibiotic prophylaxis during periods of neutropenia reduced streptococcal (S. viridans) sepsis and overall bacterial sepsis., Methods: The authors reviewed outcomes of 78 evaluable patients who were consecutively treated for acute myeloid leukemia (AML) from October 2002 through January 2007. Several successive prophylactic antibiotic regimens were used. All patients received antifungal prophylaxis with oral voriconazole., Results: Oral cephalosporins did not significantly reduce the odds of bacterial sepsis (P = .81) or streptococcal (S. viridans) sepsis (P = .90) relative to no prophylaxis. Intravenous (iv) cefepime completely prevented streptococcal (S. viridans) sepsis and reduced the odds of bacterial sepsis 91% (P < .0001) relative to no prophylaxis, but resistant gram-negative bacteria emerged in 2 patients. Vancomycin with oral ciprofloxacin or a cephalosporin reduced the odds of bacterial sepsis by 93% (P < .0001) and streptococcal (S. viridans) sepsis by 99% (P < .0001). The fungal infection rate did not differ significantly between patients who did and did not receive antibiotic prophylaxis (1.0 per 1000 patient-days for both groups). The observed reduction in average hospital days per chemotherapy course for patients given vancomycin regimens or cefepime was 5.7 (P < .0001) and 4.1 (P = .0039) days, respectively. No reduction was observed with oral cephalosporins (P = .10). Furthermore, vancomycin regimens or cefepime were associated with a 20% reduction in healthcare charges (P = .0015) relative to using no antibiotics. One patient, who was on oral cefuroxime alone, died of septicemia., Conclusions: Prophylaxis with intravenous cefepime or a vancomycin regimen, and voriconazole, reduced morbidity in children with AML, and resulted in dramatic decreases in the incidence of septicemia and hospitalization days.

Background: The percentage of myeloperoxidase (MPO)-positive blast cells is associated with prognosis in adult acute myeloid leukemia (AML), but this association is unsubstantiated in pediatric AML., Procedure: We retrospectively compared cytochemical MPO results with outcome in 154 patients younger than 21 years treated on three consecutive institutional protocols for newly diagnosed AML (1987-2001). Patients with FAB M0 and M7 AML (no MPO expression) or M3 AML (100% MPO expression) and Down's syndrome were excluded., Results: Median MPO expression was higher in FAB M2 subtype than in other subtypes (P < 0.0001) and differed significantly across cytogenetic risk groups (P = 0.002) with highest MPO expression among those with favorable karyotypes. The percentage of MPO-positive blasts was not significantly associated with the probability of complete remission (P = 0.97), event-free survival (P = 0.72), or survival (P = 0.76) in multivariate analyses that accounted for age, FAB subtype, presenting WBC count, cytogenetic and protocol treatment risk group. In analysis limited to patients with intermediate-risk cytogenetics, higher MPO expression appeared to be associated with improved EFS (P = 0.06) but was not associated with remission induction rate (P = 0.16) or overall survival (P = 0.38)., Conclusions: The percentage of MPO-positive blast cells is related to FAB subtype in pediatric AML but has limited prognostic relevance., ((c) 2007 Wiley-Liss, Inc.)

Arsenic trioxide (ATO) induces remission in 85% of adults with refractory acute promyelocytic leukemia (APL). We conducted a phase 1 trial of ATO in children (median age 13 y, range, 2-19) with refractory leukemia. ATO was administered intravenously over 2 hours, 5 d/wk for 20 doses/cycle. Patients with APL (n=13) received 0.15 mg/kg per day, and patients with other types of leukemia received 0.15 mg/kg per day (n=2) or 0.2 mg/kg per day (n=4). Nineteen of the 24 enrolled patients were fully evaluable for toxicity. At 0.15 mg/kg per day, 2 of 15 patients experienced dose-limiting corrected QT interval (QTc) prolongation, pneumonitis, or neuropathic pain. At 0.2 mg/kg per day, 2 of 4 patients had dose-limiting QTc prolongation or pancreatitis. Non-dose-limiting toxicities included elevated serum transaminases, nausea, vomiting, abdominal pain, constipation, electrolyte imbalance, hyperglycemia, dermatitis, and headache. At 0.15 mg/kg per day, the median (range) plasma arsenic maximum concentration (Cmax) was 0.28 microM (0.11-0.37 microM) and at 0.2 mg/kg per day, Cmax was 0.40 and 0.46 microM; area under the concentration times time curve (AUC0-24) was 2.50 microM-hr (1.28-3.85 microM-hr) and 4.37 microM-hr and 4.69 microM-hr, respectively. Morphologic complete response (CR) was achieved in 85% of patients with APL; no responses were observed in non-APL patients. ATO is well-tolerated in children at the recommended dose of 0.15 mg/kg per day. The response rate in children with relapsed APL is similar to the response rate in adults. This trial was registered as #NCT00020111 at www.ClinicalTrials.gov.

Children living with and dying of advanced-stage cancer suffer physically, emotionally, and spiritually. Relief of their suffering requires comprehensive, compassionate palliative and end-of-life (EoL) care.However, an EoL care program might appear inconsistent with the mission of a pediatric oncology research center committed to seeking cures. Here the authors describe the methods used to achieve full institutional commitment to their EoL care program and those used to build the program's philosophical, research, and educational foundations after they received approval. The authors convened 10 focus groups to solicit staff perceptions of the hospital's current palliative and EoL care. They also completed baseline medical record reviews of 145 patient records to identify key EoL characteristics. The authors then crafted a vision statement and a strategic plan, implemented new research protocols,and established publication and funding trajectories. They conclude that establishing a state-of-the-art palliative and EoL program in a cure-oriented pediatric setting is achievable via consensus building and recruitment of diverse institutional resources.

We report a case of BK virus-induced tubulointerstitial nephritis in a child with acute lymphoblastic leukemia. Primary BK virus infection was exacerbated by chemotherapy-induced immunodeficiency. Careful administration of chemotherapy and anti-viral therapy prevented further damage. This diagnosis should be considered in children who experience renal dysfunction during cancer treatment.

This prospective, two-site, randomized, controlled pilot study assessed the feasibility of an enhanced physical activity (EPA) intervention in hospitalized children and adolescents receiving treatment for a solid tumor or for acute myeloid leukemia (AML), and assessed different statistical techniques to detect the intervention's sleep and fatigue outcomes. Twenty-nine patients (25 with a solid tumor and 4 with AML) participated. Data were collected from actigraph; patient, parent, and staff nurse reports of patient fatigue; parent sleep diaries; and patient charts. The intervention was successfully implemented 85.4% of the scheduled times. We used two different statistical methods to analyze the longitudinal data. Using an ANOVA model, sleep was significantly more efficient in the experimental arm than in the control arm when daily differences from baseline sleep efficiency values were averaged and compared (F=4.17, P=0.053). However, in a mixed model (repeated measures) analysis, sleep duration (F=0.54, P=0.47) and sleep efficiency (F=0.04, P=0.85) were not seen to differ between study arms. We conclude that an inpatient intervention of EPA can be delivered to children and adolescents receiving chemotherapy. Our findings identify design and statistical considerations for a future effectiveness study of the EPA intervention in hospitalized pediatric oncology patients.

While the disease-free survival of acute promyelocytic leukemia (APML) now approaches 75%, some children continue to experience relapses, and questions remain as to the optimal management of these patients. We describe two young children who experienced combined relapses in the bone marrow and extramedullary locations following hematopoietic stem cell transplantation (HSCT). An induction regimen, consisting of all-trans retinoic acid (ATRA), methotrexate, and 6-mercaptopurine (6MP), successfully and safely achieved hematologic remission in one patient and molecular remission in the other. These cases demonstrate that there is a role for ATRA plus differentiating chemotherapy other than arsenic trioxide in the treatment of relapsed APML.

Context: Little is known about the incidence of secondary neoplasms after 15 to 20 years in children and adolescents who were treated for acute lymphoblastic leukemia., Objectives: To investigate the cumulative incidence of secondary neoplasms in pediatric patients treated for acute lymphoblastic leukemia over 30 years and to characterize late-occurring tumors., Design, Setting, and Patients: Retrospective study of 2169 patients with acute lymphoblastic leukemia treated between 1962 and 1998 at St Jude Children's Research Hospital, Memphis, Tenn, who achieved complete remission and had a median follow-up time of 18.7 years (range, 2.4-41.3 years)., Main Outcome Measures: Cumulative incidences of secondary neoplasms in first remission and standard incidence ratios of observed rates compared with rates of cancer development in the general US population., Results: Secondary neoplasms developed as the first event in 123 patients and comprised 46 myeloid malignancies, 3 lymphomas, 14 basal cell carcinomas, 16 other carcinomas, 6 sarcomas, 16 meningiomas, and 22 other brain tumors. The cumulative incidence of secondary neoplasm was 4.17% (SE, 0.46%) at 15 years and increased substantially after 20 years, reaching 10.85% (SE, 1.27%) at 30 years. When meningiomas and basal cell carcinomas were excluded, the overall cumulative incidence was 3.99% (SE, 0.44%) at 15 years and 6.27% (SE, 0.83%) at 30 years, representing a 13.5-fold increase in overall risk compared with the general population. The cumulative incidence of each tumor type at 30 years was 2.19% (SE, 0.32%) for myeloid malignancy, 0.17% (SE, 0.10%) for lymphoma, 3.00% (SE, 0.59%) for brain tumor, 4.91% (SE, 1.04%) for carcinoma, and 0.57% (SE, 0.37%) for sarcoma., Conclusions: The cumulative incidence of secondary neoplasms increases steadily over 30 years after treatment of acute lymphoblastic leukemia. Although the majority of the late-occurring secondary neoplasms are low-grade tumors, the increase in incidence of more aggressive malignant neoplasms is significantly higher than expected in the general population. These results suggest that lifelong follow-up of acute lymphoblastic leukemia survivors is needed to ascertain the full impact of treatment and other leukemia-related factors on secondary neoplasm development.

Purpose/objectives: To describe nocturnal awakenings and sleep environment interruptions experienced by children and adolescents hospitalized for two to four days to receive chemotherapy and to assess the relationships among nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue., Design: Longitudinal, descriptive design., Setting: St. Jude Children's Research Hospital and Texas Children's Cancer Center., Sample: 25 patients with solid tumors and 4 with acute myeloid leukemia., Methods: Actigraphy, fatigue instruments, sleep diary, room entry and exit checklists, and blood samples., Main Research Variables: Nocturnal awakenings, sleep environment interruptions, sleep duration, and fatigue., Findings: The number of nocturnal awakenings per night as measured by actigraphy ranged from 0-40. The number of room entries and exits by a staff member or parent was 3-22 times per eight-hour night shift. The number of nocturnal awakenings was related to fatigue by patient report; patients who experienced 20 or more awakenings had significantly higher fatigue scores than those with fewer awakenings. Nocturnal awakenings also were significantly associated with sleep duration by patient and parent report., Conclusions: Hospitalized pediatric patients with cancer who experience more nocturnal awakenings are more fatigued and sleep longer., Implications for Nursing: Nurses may be able to control some of the factors that contribute to nocturnal awakenings and sleep environment interruptions that affect fatigue and sleep duration in hospitalized pediatric patients with cancer.

Background: Outcome after recurrence of childhood acute myeloid leukemia (AML) is poor. We performed this study to identify prognostic factors for recurrence and for survival after recurrence of AML., Methods: The clinical characteristics, biological features, treatment modalities, and outcomes of children with de novo AML who were enrolled on 3 consecutive clinical protocols from 1987 to 2002 at St. Jude Children's Research Hospital were studied. Regression modeling was used to identify prognostic factors for recurrence and for survival after recurrence., Results: The outcome after recurrence was poor, with a 5-year survival estimate of only 23.3% +/- 5.7%. Multivariable analysis indicated that male sex (P = .005), autologous stem cell transplant before recurrence (P = .097), each additional month from diagnosis to recurrence (P = .041), and stem cell transplant after recurrence (P < .001) were associated with a better survival after recurrence, whereas M5 or M7 morphology (P = .001) were significantly predictive of a lower survival estimate after recurrence., Conclusions: Survival after recurrence was poor in children with AML. Novel therapies are urgently needed to prevent or to treat recurring AML., ((c) 2006 American Cancer Society.)

Background: The association between race and outcome of treatment for childhood acute myeloid leukemia (AML) has not been adequately studied., Procedure: We compared the clinical characteristics, biological features, and outcomes between white and black children with AML who were treated on five consecutive clinical protocols (1980-2002) at St. Jude Children's Research Hospital. We used proportional hazards modeling to investigate the relation between race and outcome., Results: We observed no statistically significant differences between the 229 white and 58 black patients in clinical characteristics, FAB subtype, cytogenetic features, or outcome. There were no significant differences in event-free survival (EFS) or overall survival (OS) between the two race groups in individual clinical trials or in all studies combined. For the study group as a whole, the 5-year survival estimate was 39.2% +/- 3.6% for white patients and 33.8% +/- 6.5% for black patients. However, on our most recent trial (AML-97), there was a trend towards inferior outcome among black patients: the 5-year survival estimates were 55.6% +/- 12.3% and 27.3% +/- 13.5% for whites and blacks, respectively., Conclusions: Although we detected no differences in treatment outcome between white and black children with AML over the entire study period, black children appear to have worse outcomes than white children during more recent studies. Improved treatment is needed for all children with AML., ((c) 2006 Wiley-Liss, Inc.)

There is conflicting information about the influence of body mass index (BMI) on the pharmacokinetics, toxicity, and outcome of chemotherapy. We compared pharmacokinetics, outcome, and toxicity data across 4 BMI groups (underweight, BMI < or = 10th percentile; normal; at risk of overweight, BMI > or = 85th and < 95th percentile; overweight, BMI > or = 95th percentile) in 621 children with acute lymphoblastic leukemia (ALL) treated on 4 consecutive St Jude Total Therapy studies. Chemotherapy doses were not adjusted to ideal BMI. Estimates of overall survival (86.1% +/- 3.4%, 86.0% +/- 1.7%, 85.9% +/- 4.3%, and 78.2% +/- 5.5%, respectively; P = .533), event-free survival (76.2% +/- 4.2%, 78.7% +/- 2.1%, 73.4% +/- 5.5%, and 72.7% +/- 5.9%, respectively; P = .722), and cumulative incidence of relapse (16.0% +/- 3.7%, 14.4% +/- 1.8%, 20.6% +/- 5.1%, and 16.7% +/- 5.1%, respectively; P = .862) did not differ across the 4 groups. In addition, the intracellular levels of thioguanine nucleotides and methotrexate polyglutamates did not differ between the 4 BMI groups (P = .73 and P = .74, respectively). The 4 groups also did not differ in the overall incidence of grade 3 or 4 toxicity during the induction or postinduction periods. Further, the systemic clearance of methotrexate, teniposide, etoposide, and cytarabine did not differ with BMI (P > .3). We conclude that BMI does not affect the outcome or toxicity of chemotherapy in this patient population with ALL.

CD20 expression is associated with inferior survival in adults with acute lymphoblastic leukemia (ALL). We analyzed the prognostic impact of CD20 expression in 353 children with B-cell precursor ALL treated in 3 consecutive St Jude Total Therapy studies. CD20 expression (> 20%) was found in 169 patients (48%) and was more frequent in patients between 1 and 10 years of age than in those younger than 1 or older than 10 years (P = .001). None of 14 patients with MLL-AF4 expressed CD20. There was no association between CD20 expression and E2A-PBX, TEL-AML1, ploidy, white blood cell count at diagnosis, or sex. In contrast to the experience in adult ALL, our patients with CD20 expression tended to have a better treatment outcome than those without the expression: 5-year event-free survival 84% +/- 2.9% versus 78% +/- 3.1% (P = .08). These data suggest that CD20 expression is not associated with inferior outcome in pediatric patients treated with contemporary regimens.

Background: Epoetin alfa (EPO, PROCRIT) pharmacokinetics and pharmacodynamics were evaluated in children with malignant solid tumors receiving chemotherapy., Procedure: Children initially received IV EPO 600 IU/kg (max dose 40,000 IU) or placebo once weekly for 16 weeks. Dose was increased to 900 IU/kg (max dose 60,000 IU) for patients not achieving a 1 g/dl increase in hemoglobin by study week 3 or 4. Serial PK samples were collected for 24 hr after the first study dose, and after the 10th or 11th dose. Serum EPO concentrations were analyzed using an ELISA assay, and pharmacokinetics were evaluated using compartmental methods., Results: Twelve children participated; six (median age 15.2 years; range 9.3-18.6 years) were randomized to receive EPO. All children required dosage increases to 900 IU/kg due to no response. The median (range) apparent EPO AUC0-24 and clearance (CL) were 67.1 IU/ml.hr (13.8-102.6) and 0.26 L/hr/m2 (0.19-1.08), respectively. After the 10th or 11th EPO dose in four of these six EPO patients, the median (range) apparent AUC0-24 and CL of EPO was 126.5 IU/ml.hr (107.3-161.1) and 0.21 L/hr/m2 (0.15-0.25), respectively. No significant correlations were observed between pharmacokinetic parameters and pharmacodynamic effects., Conclusions: EPO disposition in our patients was similar to other pediatric patient populations or adults receiving IV EPO. Interesting but insignificant trends were noted in pharmacodynamic effects., (Copyright (c) 2005 Wiley-Liss, Inc.)

Purpose: To evaluate the effects of once-weekly epoetin alfa (EPO) on health-related quality of life (HRQOL), hemoglobin (Hb), transfusions, and tolerability in children with cancer., Methods: Anemic patients 5 years to 18 years of age receiving myelosuppressive chemotherapy for nonmyeloid malignancies, excluding brain tumors, received intravenous EPO 600 units/kg to 900 units/kg or placebo once-weekly for 16 weeks. Patients and parents completed the pediatric health-related quality-of-life generic scales (GS) and cancer-specific scales (CS)., Results: One hundred eleven patients received EPO and 111 patients received placebo. Mean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P > or = .238; P > or = .081, respectively) were not significantly different between treatment groups. EPO-treated patients had greater increases in Hb overall (P = .002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P = .010). Change in Hb was correlated with change in PedsQL-GCS total score in the EPO group (r = 0.242; P = .018), but was not in the placebo group (r = 0.086; P = .430). Adverse events were comparable between treatment groups., Conclusion: This study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL was detected between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group. Additional studies are warranted to assess HRQOL when anemia is managed optimally in children with cancer.

Background: The prognostic significance of age among pediatric patients with acute myeloid leukemia (AML) was investigated., Methods: The authors reviewed the outcome of 424 patients who were

Purpose: To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL)., Patients and Methods: In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens)., Results: The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade > or = 3 were febrile neutropenia, anorexia, hypotension, and nausea., Conclusion: Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

Despite substantial progress in the management of childhood acute myeloid leukemia (AML), only about 50% of patients are cured by intensive chemotherapy. The long-term results of clinical trials may reveal principles that can guide the development of future therapy. From 1980 to 2000, 251 patients <15 years of age with newly diagnosed AML were enrolled on one of the five consecutive St Jude AML studies. The median age of the 128 boys and 123 girls was 6.2 years; 193 were white, 45 black, and 13 of other racial groups. With the exception of one protocol (AML-83), outcomes improved in general over the two decades. The estimated 5-year event-free survival (+/-s.e.) was 30.8+/-5.6% for AML-80; 11.1+/-4.3% for AML-83; 35.9+/-7.4% for AML-87; 43.5+/-6.2% for AML-91; and 45.0+/-11.1% for AML-97. Resistant or relapsed AML caused the great majority of treatment failures. Increasing the intensity of chemotherapy (AML-87) did not improve outcome, partially because of toxicity, nor did prolonging postremission therapy by adding sequential myeloablative (AML-80) or nonmyeloablative (AML-83) chemotherapy cycles. We conclude that subtype-specific therapies are needed to replace the 'one size fits all' strategy of the past two decades.

Purpose: We studied the frequency, causes, and predictors of adverse events in children with acute lymphoblastic leukemia (ALL) who had completed treatment on contemporary clinical protocols between 1984 and 1999. Our goal was to use the information to further refine therapy and advance cure rates., Methods: Cumulative incidence functions of any post-treatment failure or any post-treatment relapse were estimated by the method of Kalbfleisch and Prentice and compared with Gray's test. The Cox proportional hazards model was used to identify independent prognostic factors., Results: Of the 827 patients who completed all treatment while in initial complete remission, 134 patients subsequently had major adverse events, including 90 leukemic relapses, 40 second malignancies, and four deaths in remission. The cumulative incidence of any adverse event was 14.0% +/- 1.2% (SE) at 5 years and 16.9% +/- 1.4% at 10 years. The risk of any leukemic relapse was 10.0% +/- 1.1% at 5 years and 11.4% +/- 1.2% at 10 years. Male sex was the only independent predictor of relapse (hazard ratio, 1.74; 95% CI, 1.11 to 2.74; P = .02)., Conclusion: Further treatment refinements for children with ALL should aim not only to decrease the leukemic relapse rate, but also to reduce the risk of development of second malignancies.

To assess the prognosis of overt testicular disease at diagnosis of acute lymphoblastic leukemia, and any therapeutic role of irradiation for this involvement, we reviewed the data of 811 boys treated on St Jude studies Total X--XI (early period) and Total XII-XIV (recent period). In all, 19 boys (2.3%) had testicular disease at diagnosis. In the early period, patients with testicular leukemia had a poorer overall survival (OS) (P=0.003), event-free survival (EFS) (P=0.064), and higher cumulative incidence of relapse (P=0.041) than did other patients. During the recent period, patients with and without overt testicular leukemia did not differ in OS (P=0.257), EFS (P=0.102), or cumulative incidence of relapse (P=0.51). In a multivariate analysis, OS was lower for patients with testicular disease than for those without the involvement in the early period (P=0.047) but not in the recent one (P=0.75). Both patients who received irradiation for residual testicular disease at the end of induction subsequently died of leukemia. Of the other 17 patients who did not receive irradiation, only one developed testicular relapse in combination with bone marrow relapse. In conclusion, the prognostic impact of overt testicular disease has diminished. Irradiation appears to provide no survival advantage to this patient population., (Leukemia (2005) 19, 1399-1403.)

Background: Typhlitis is increasingly recognized in children undergoing chemotherapy but is poorly characterized. The authors investigated the demographic, clinical, and imaging (ultrasonography and computed tomography [CT] scans) variables related to the diagnosis, risk, and outcome of typhlitis., Methods: The authors reviewed the records of patients who had typhlitis (bowel wall thickness > or = 0.3 cm plus clinical findings) during treatment at St. Jude Children's Research Hospital (Memphis, TN) between 1990 and 2001. They assessed whether duration of typhlitis was related to bowel wall thickness, extent of colonic involvement, ascites, demographics, primary diagnosis, symptoms of typhlitis, or duration of neutropenia. To identify risk factors for typhlitis, the authors compared the demographic data and previous drug therapy of 78 patients who had typhlitis and 1231 identically treated children who did not., Results: Of 3171 children, 83 (2.6%) developed typhlitis. Frequent symptoms were abdominal pain (91%), fever (84%), abdominal tenderness (82%), and diarrhea (72%). Twelve percent of the patients were not neutropenic. Duration of typhlitis was associated with bowel wall thickness measured by ultrasonography (n = 68; P = 0.05) but not CT scan (n = 48; P = 0.67) and was associated with duration of neutropenia (P = 0.02), fever (P = 0.01), and abdominal tenderness (P = 0.04). Age >16 years at cancer diagnosis was the only demographic factor associated with typhlitis (P = 0.03). Two patients died of typhlitis., Conclusions: Ultrasonography was a useful imaging modality for children with suspected typhlitis. The classic triad of abdominal pain, fever, and neutropenia may be absent. The severity of typhlitis was related to the duration of neutropenia and the presence of fever or abdominal tenderness.

Background: To add to the data regarding the quality of care given to dying children and their families., Objective: To develop baseline of end-of-life care at a single pediatric facility to evaluate institution-wide palliative care initiative., Design: Retrospective chart review of all known deaths during an 18-month time period., Setting/subjects: One hundred forty-five charts of patients from a single pediatric cancer facility who died during designated time period., Measurements: Variables included: cause and place of death; CPR/DNR status prior to death; length of end of life care prior to death; sibling counseling and bereavement counseling offered to family after death; and wishes or preferences of patient/family regarding the death experience., Results: Results included: solid tumor patients more likely to die of progressive disease than leukemia or bone marrow transplant patients; bone marrow transplant patients 2-3 times more likely to die of cardiopulmonary or cardiovascular complications; solid tumor patients were more likely to die at home than leukemia patients; solid tumor/brain tumor patients had a median time in end of life or palliative care of 29 days compared to leukemia patients' median of 11 days; 48% of DNRs completed 11 days prior to death., Conclusions: Relationship exists between diagnosis, cause and place of death in this population; findings replicate findings of 4 similar studies; accurate and consistent quality standards of care need to be established for this population as well as methods of documentation before reviewing/accrediting agencies impose standards that are not evidence based.

Background: Life-threatening pulmonary complications that coincide with cell lysis during early chemotherapy and that mimic systemic inflammatory response syndrome (SIRS) have been reported in patients with acute myeloid leukemia (AML)., Methods: We reviewed the records of patients with de novo AML, excluding M3 and Down syndrome, treated at our institution between 1991 and 2002 to determine the prevalence of severe SIRS with grade 3/4 pulmonary complications and to identify AML subtypes associated with severe SIRS. To examine the role of cell lysis, we compared leukocyte reduction in AML subtypes affected by severe SIRS with that in unaffected subtypes., Results: Of 155 patients, 5 (3 with M4eo and 2 with M5) experienced severe pulmonary complications attributed to tumor lysis, met the criteria for severe SIRS, and showed no clear evidence of infection. Four required pressor support for severe hypotension. Severe SIRS was significantly more common in myelomonocytic or monocytic AML (M4/M4eo/M5) than in other subtypes (P = 0.010) and significantly more common in M4eo than in M4/M5 (P = 0.008). Among 112 cases for which information was available, leukocyte reduction was significantly greater in patients with M4/M4eo/M5 than among others during the first 4 days of chemotherapy (P = 0.015). Leukocyte reduction was significantly more rapid among patients who had severe SIRS than among others (P = 0.008)., Conclusions: Patients with M4/M4eo/M5 AML, especially M4eo, experience life-threatening cardiopulmonary complications of tumor lysis that meet the criteria for severe SIRS. This observation may reflect more rapid cell reduction and the unique biology of this subtype., ((c) 2004 Wiley-Liss, Inc.)

St Jude Total Therapy Study XIIIB for childhood acute lymphoblastic leukemia (ALL) incorporated more stringent risk classification, early intensification of intrathecal chemotherapy, reinduction treatment, and the addition of dexamethasone to postremission therapy to increase the proportion of event-free survivors without jeopardizing their quality of life. Cranial irradiation was reserved for the 12% of patients who had T-cell ALL and a presenting leukocyte count of 100 x 10(9)/L or more, or CNS-3 (5 or more leukocytes/microL with identifiable blast cells in an atraumatic sample or the presence of cranial nerve palsy) status. Among the 247 consecutive patients enrolled in the study, 117 were classified as having lower-risk leukemia and received mainly antimetabolite-based continuation therapy; the 130 cases with higher-risk leukemia received more intensive continuation chemotherapy with multiple drug pairs administered in weekly rotation. The 5-year event-free survival estimate was 80.8% +/- 2.6% (SE); the 8-year rate was 78.6% +/- 5.8%. The 5-year cumulative risk of an isolated central nervous system (CNS) relapse was 1.7% +/- 0.8%, and that of isolated plus combined CNS relapse was 3.0% +/- 1.1%. The 5-year cumulative risks of etoposide-related myeloid malignancies were 1.8% +/- 1.3% in the lower-risk patients who received a cumulative dose of 1.2 g/m(2) and 5.0% +/- 2.0% in the higher-risk patients who received a cumulative dose of up to 14.4 g/m(2) (P = .18). Independent adverse prognostic features included the presence of MLL-AF4 or BCR-ABL fusion gene and minimal residual leukemia of 0.01% or more at the end of the 6-week remission induction phase. Our results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether.

The authors reviewed the medical records of 42 children younger than 13 years of age diagnosed with Burkitt lymphoma at the American University of Beirut Medical Center between 1983 and 1993. The male:female ratio was 3.9. The abdomen was the most common site of disease (86%). Jaw, central nervous system, and bone marrow involvement occurred in 16.6%, 16.6%, and 9.5%, respectively. The mean LDH level was 447 U/L. The mean age at diagnosis was 6.9 years. Thirty-nine patients received a variation of the COMP protocol. The total duration of treatment ranged from 6 to 18 months. At a median follow-up of 5 years the event-free survival was 100% for children with stages I and II disease, 77.4% (+/- 2 SE) for stage III, and 0% for stage IV. Failures in stage III patients were due to tumor lysis (3/24) and progressive disease (2/24). Aggressive therapy with high doses of methotrexate and anthracyclines may not be necessary for the treatment of children with extensive abdominal disease (stage III) in Lebanon. If confirmed in a larger series of patients, this study could have a major impact on the treatment of Burkitt lymphoma in Lebanon and other countries with limited resources.

Background: Despite improvements in supportive care, death due to treatment toxicity remains a significant problem for children treated for acute leukemia., Methods: To determine the causes of and risk factors for death unrelated to refractory leukemia, to disease recurrence, or to second malignancy, the authors reviewed the records of 1011 patients with acute lymphoblastic leukemia (ALL) and 260 patients with acute myeloid leukemia (AML) treated between 1984 and 1999 and between 1983 and 2002, respectively, at St. Jude Children's Research Hospital (Memphis, TN). Data for patients who underwent stem cell transplantation were censored at the time of transplantation., Results: For patients with ALL, the estimated 10-year cumulative incidence of death was 2.9% +/- 5.3%. Age was the only predictor of death. Patients with ALL 1-9 years old had a significantly lower risk of death than did younger or older patients (P = 0.002). For patients with AML, the estimated 5-year cumulative incidence of death was 7.6% +/- 1.9%. Increasing age and increasing leukocyte count were significantly associated with increased risk of death. For patients with ALL and with AML, the incidence of death remained relatively constant during the time periods studied. Infection was the most common cause of death., Conclusions: In the current study, the authors determined that children > or = 10 years of age are at increased risk of death during therapy for ALL and AML., ((c) 2004 American Cancer Society.)

To evaluate the efficacy of cladribine and cytarabine in children with relapsed or refractory myeloid malignancies, we administered cytarabine (200 mg/m2 per day) by continuous subcutaneous infusion and cladribine (8.9 mg/m2 per day) by continuous intravenous infusion concomitantly for 5 days to nine patients younger than 21 years. After one course, five patients had no response, two patients had partial responses, one had stable disease, and one had progressive disease. Two patients received a second course: one patient had stable disease after one course and progressive disease after the second; another patient had a partial response after one course and no response after the second. Despite the efficacy of the cladribine and cytarabine regimen in treating newly diagnosed acute myeloid leukemia (AML) in a previously reported study, the combination was not effective for relapsed or refractory childhood AML.

Using flow cytometric techniques capable of detecting 0.01% leukemic cells, we prospectively studied minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) after first relapse. At the end of remission reinduction, 41 patients had a bone marrow sample adequate for MRD studies; 35 of these were in morphologic remission. Of the 35 patients, 19 (54%) had MRD >/=0.01%, a finding that was associated with subsequent leukemia relapse. The 2-year cumulative incidence of second leukemia relapse was 70.2+/-12.3% for the 19 MRD-positive patients and 27.9+/-12.4% for the 16 MRD-negative patients (P=0.008). Among patients with a first relapse off therapy, 2-year second relapse rates were 49.1+/-17.8% in the 12 MRD-positive and 0% in the 11 MRD-negative patients (P=0.014); among those who received only chemotherapy after first relapse, the 2-year second relapse rates were 81.5+/-14.4% (n=12) and 25.0+/-13.1% (n=13), respectively (P=0.004). Time of first relapse and MRD were the only two significant predictors of outcome in a multivariate analysis. We conclude that MRD assays should be used to guide the selection of postremission therapy in patients with ALL in first relapse.

To determine the clinical significance of central nervous system (CNS) involvement at the time of diagnosis of pediatric acute myeloid leukemia (AML), we analyzed clinical features and outcomes of 290 patients treated consecutively on four institutional trials (AML80, AML83, AML87, and AML91). CNS status was classified as CNS1 (no blast cells in CSF; n=205), CNS2 (<5 WBC/mul CSF with blast cells; n=37), or CNS3 (>/=5 WBC/mul CSF with blast cells, or signs of CNS involvement; n=48). Patients with CNS3 status were significantly younger than others (P=0.016) and significantly more likely to have the favorable cytogenetic features t(9;11), t(8;21), or inv(16) (P<0.001). The CNS3 group had a significantly greater probability (+/-s.e.) of 5-year event-free survival (43.7+/-7.0%) than did the CNS1 (27.8+/-3.2%, P=0.015) and CNS2 (24.3+/-7.5%, P=0.032) groups. However, after adjustment for favorable genetic features, there was no significant difference in EFS between the CNS3 and the combined CNS1+CNS2 groups (P=0.075). In all, 10 of 151 patients treated on AML80 and AML83, but none of 139 treated on AML87 and AML91, had primary CNS relapse. CNS involvement had no adverse prognostic significance, and patients with CNS2 status had similar outcome to CNS1 patients in this large group of pediatric patients with AML, treated at a single institution.

Context: Treatment results for acute lymphoblastic leukemia (ALL) clearly have improved over the past decade, but black children have not fared as well as white children in large national trials., Objective: To compare the clinical outcomes of therapy for black and white children with ALL treated at a single institution., Design, Setting, and Patients: A retrospective analysis of 412 children and adolescents (68 black, 338 white, and 6 other race) with newly diagnosed ALL who were treated consecutively at a pediatric cancer center in Memphis, Tenn. Patients were enrolled from December 1991 to July 1998 in successive Total Therapy studies regardless of race, ethnicity, or ability to pay and received risk-directed therapy according to stringent criteria., Interventions: All patients received the same intensive, remission-induction therapy followed by 120 weeks of risk-assigned postremission therapy that included reinduction treatment, pulses of high-dose methotrexate, and early intensification of intrathecal chemotherapy., Main Outcome Measures: Event-free and overall survival rates for black and white children were estimated by the method of Kaplan and Meier and compared with the Mantel-Haenszel test and by Cox proportional hazards regression analysis, adjusting for known prognostic factors., Results: The 68 black children were significantly more likely than the 338 white children to have higher-risk prognostic features, including an initial leukocyte count greater than 100 x 10(3)/ microL, a T-cell immunophenotype, and the t(1;19) chromosomal translocation with E2A-PBX1 fusion, and were less likely to have hyperdiploid blast cells, a favorable prognostic factor in childhood ALL. However, the clinical outcomes for these 2 cohorts were not significantly different: 5-year event-free and overall survival rates were 80.7% (95% confidence interval [CI], 70.3%-91.1%) and 86.2% (95% CI, 77.2%-95.2%) for black children vs 79.4% (95% CI, 74.7%-84.1%) and 85.0% (95% CI, 80.9%-89.1%) for white children. Ten-year results also were comparable, but the CIs were wide because of the small numbers of patients who had been followed up for 10 years or more. The lack of a racial effect on the long-term outcome of therapy was still apparent in a multivariate Cox regression analysis, adjusting for sex, age, presenting leukocyte count, leukemic cell DNA index, immunophenotype, and central nervous system status., Conclusion: With equal access to effective antileukemic therapy, black and white children with ALL can expect the same high rate of cure.