Cardiotoxicity of CPX-351 in children and adolescents with relapsed AML: a Children's Oncology Group report.

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/m2/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/m2 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).

Pineal gland hypermetabolic involvement without central nervous system symptoms in a pediatric patient with primary nodular sclerosis subtype classical Hodgkin Lymphoma.

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.

Prognostic significance of chromosomal abnormalities at relapse in children with relapsed acute myeloid leukemia: A retrospective cohort study of the Relapsed AML 2001/01 Study.

BACKGROUND: In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. METHODS: This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. RESULTS: Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. CONCLUSION: The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.

Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

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/m2/dose on days 1-5; cytarabine 2,000 mg/m2/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/m2 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/m2/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.

The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01.

The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6-10%, 11-20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677.

AAML0523: a report from the Children's Oncology Group on the efficacy of clofarabine in combination with cytarabine in pediatric patients with recurrent acute myeloid leukemia.

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.

Phase I/II trial of clofarabine and cytarabine in children with relapsed/refractory acute lymphoblastic leukemia (AAML0523): a report from the Children's Oncology Group.

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.

Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group.

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.

Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections.

BACKGROUND: Despite recent studies failing to demonstrate the value of routine chest radiography (CXR) in the initial evaluation of the febrile neutropenic patient with cancer, this screening test is advocated by some experts. We evaluated the benefits of CXR for early diagnosis of pulmonary infection at St. Jude Children's Research Hospital (SJCRH) with emphasis on early recognition of mould infections. PATIENTS AND METHODS: We reviewed the courses of 200 consecutive febrile neutropenic pediatric patients to determine if routine CXR at initial evaluation was useful in the identification of clinically occult pneumonia. We also reviewed all cases of proven or probable mould infections from the opening of SJCRH in 1962 until 1998 when routine CXR was no longer practiced in our institution to identify cases that were first recognized by routine CXR. RESULTS: Of 200 febrile neutropenic patients, pulmonary abnormalities consistent with pneumonia were detected by routine CXR in only five patients without pulmonary signs or symptoms. In only one case was a change in management considered. Of the 70 patients with pulmonary mould infection identified from 1962 to 1998, routine CXR was performed in 45 patients at the onset of a febrile, neutropenic episode in which a mould infection was diagnosed. Routine CXR was pivotal in the recognition of the mould infection in only two cases over this 36-year period. CONCLUSION: CXR is warranted in the evaluation of the newly febrile neutropenic pediatric oncology patient only when respiratory signs or symptoms are present.

Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes.

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.

Randomized trial of 2 dosages of prophylactic granulocyte-colony-stimulating factor after induction chemotherapy in pediatric acute myeloid leukemia.

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.

Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer.

Clofarabine for injection is a second-generation nucleoside analog approved in the United States (Clolar(®)) and Europe (Evoltra(®)) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. This report describes the population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with hematologic malignancies or solid tumors. Clofarabine pharmacokinetics were best described by a 2-compartment model with linear elimination and first-order absorption after oral administration. Clofarabine was rapidly absorbed following oral administration with a mean absorption time of less than 2 h and bioavailability of 57.5%. The important covariates affecting clofarabine pharmacokinetics were age, weight, and estimated creatinine clearance (eCrCL). No difference in pharmacokinetics was observed between sexes, races, or disease type. The elimination half-life was dependent on all the covariates but was generally less than 7 h in all cases. A difference in clofarabine pharmacokinetics was observed between adults and children. For a pediatric patient 3 years old weighing 16 kg with an eCrCL of 138 mL/min/1.73 m(2), the population estimates for total systemic clearance and volume of distribution at steady-state were 18.3 L/h (1.14 L/h/kg) and 92.9 L (5.81 L/kg), respectively. α- and ß-half-life were 0.9 and 4.4 h, respectively. For an elderly patient 82 years old weighing 96 kg with an eCrCL of 46 mL/min/1.73 m(2), the population estimates for CL and Vdss were 21.5 L/h (0.22 L/h/kg) and 257.4 L (268 L/kg), respectively. α- and ß-half-life were 0.5 and 10.6 h, respectively. Because of the difference in pharmacokinetics, adults have higher exposure than children given a similar dose standardized to body surface area. The exact mechanism of this difference is not understood. As eCrCL decreased, exposure increased due to reduced total systemic clearance. In the case of moderate (eCrCL 30 to 60 mL/min/1.73 m(2)) and severe (eCrCL <30 mL/min/1.73 m(2)) renal impairment, dose reduction may be needed to maintain similar exposure in an equivalent patient of the same age, weight, and normal renal function after both oral and intravenous administration. 6-Ketoclofarabine was a minor metabolite with peak plasma concentrations occurring about 1 h after the start of the infusion and having a metabolite ratio averaging less than 5% and not more than 8% for any particular individual. 6-Ketoclofarabine was rapidly cleared from plasma with an average apparent half-life of 4.9 h (range 3.9 to 6.2 h). No accumulation of 6-ketoclofarabine was observed with predose samples all below the limit of quantification on Days 8 and 15. Further monitoring of 6-ketoclofarabine is not required in future studies.

Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial.

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).

Combination of cladribine plus topotecan for recurrent or refractory pediatric acute myeloid leukemia.

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.

Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia.

PURPOSE: To determine the efficacy and safety of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia (AML). PATIENTS AND METHODS: A phase II, open-label, multicenter study was conducted with single-agent clofarabine in pediatric patients with refractory or relapsed AML. Clofarabine was administered intravenously over 2 hours at the pediatric maximum-tolerated dose (MTD) of 52 mg/m(2) daily for 5 consecutive days. Cycles were repeated every 2 to 6 weeks. Responses determined by an independent response review panel. RESULTS: The 42 patients treated on the study had a median age of 13 years (range, 2 to 22 years) and had received a median number of two (range, one to five) prior regimens. The response rate was 26% and included one complete response without platelet recovery and 10 partial responses. The median duration of response was 20 weeks (range, 2 to >or= 156 weeks). Six of 28 patients who were refractory to the immediately preceding therapy achieved response. Thirteen patients (31%), including seven responders, proceeded to hematopoietic stem-cell transplantation (HSCT) after treatment with clofarabine and survived between 24 to >or= 160 weeks. Five patients (12%) remain alive post-transplantation at >or= 63, >or= 71, >or= 86, >or= 114, and >or= 130 weeks. The most common grade 3 or greater adverse events without regard to causality were febrile neutropenia, catheter-related infection, epistaxis, hypotension, nausea, and fever. Transient elevation of liver enzymes and hypokalemia occurred frequently. Five patients died within 30 days of clofarabine administration secondary to progressive disease, and another five died as a result of an adverse event. CONCLUSION: Clofarabine is active in pediatric patients with multiply relapsed or refractory AML. Responses allowed several refractory patients to proceed to HSCT. The toxicity profile was expected in this patient population.

Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital.

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.

Limb salvage surgery for children and adolescents with malignant bone tumors in a developing country.

PURPOSE: To describe the 5-year experience of a multidisciplinary limb salvage program for children and adolescents with malignant bone tumors in Lebanon. PATIENTS AND METHODS: Between January 2002 to February 2007, 30 children and adolescents (2 with Ewing sarcoma and 28 with osteosarcoma) underwent Limb Salvage Surgeries (LSS) at the American University of Beirut Medical Center after partnering with the multidisciplinary team at St. Judes Children's Research Hospital (SJCRH). Procedures performed included 12 Repiphysis, noninvasively expandable, prostheses inserted in skeletally immature children, 15 modular prostheses, 2 allografts and 1 rotationplasty. All patients received pre- and postoperative chemotherapy. RESULTS: With a mean follow-up of 31 months, 20 patients are now off therapy, 4 died, and 6 are receiving chemotherapy (3 due to pulmonary recurrence). Complications of surgery included infections in three cases, failure of the expansion mechanism in two, femoral stem fracture in one, prostheses femoral stem loosening in one and wound dehiscence in one. Lengthening of Repiphysis prostheses was achieved by subjecting the limb to an electromagnetic field that would allow controlled release of the Repiphysis expansion mechanism. Ten patients underwent a total of 42 lengthening procedures with an average of 9 mm lengthened per procedure (range 2-15 mm). All patients have good function of the affected limb. CONCLUSION: Our LSS results are comparable to those reported in the literature. Collaboration with SJCRH and fund raising were critical to the program's success. This endeavor could serve as a model for establishing LSS programs in developing countries.

Clinical and biologic features and treatment outcome of children with newly diagnosed acute myeloid leukemia and hyperleukocytosis.

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.

Prophylactic antibiotics reduce morbidity due to septicemia during intensive treatment for pediatric acute myeloid leukemia.

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.

Team management, twinning, and telemedicine in retinoblastoma: a 3-tier approach implemented in the first eye salvage program in Jordan.

BACKGROUND: This study evaluated the outcome of retinoblastoma patients, when employing a telemedicine-based twinning program in Jordan. PROCEDURE: This cohort study included patients at the King Hussein Cancer Centre (KHCC; Amman, Jordan) who received consultations for retinoblastoma from March 2003 to September 2006. A collaborative program was established with the International Outreach Program at St. Jude Children's Research Hospital in Memphis, Tennessee. Cases were discussed using an Internet consultation service where fundus images, clinical history, and proposed treatment were reviewed. Selected cases were further discussed via videoconferencing and electronic mail. RESULTS: Thirty-three children with retinoblastoma (20 bilateral) were treated at KHCC. The median age at diagnosis was 7 months for patients with bilateral retinoblastoma and 35 months for patients with unilateral retinoblastoma. Of the 20 patients with bilateral disease, 12 were newly diagnosed and 8 had received prior treatment. Our success in the bilateral cases was most evident in the previously untreated group, in which only six eyes (25%) were enucleated and four eyes (17%) were irradiated. Of the 13 patients with unilateral retinoblastoma, 12 underwent enucleation, and 6 required radiation. Neither group experienced mortality. CONCLUSIONS: Twinning has positively impacted survival and ocular salvage in Jordan. By partnering a team of professionals with mentors willing to provide close supervision, the highly specialized management of retinoblastoma can be successfully implemented in a developing country.