Uma H. Athale

Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial

BACKGROUND Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. METHODS Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. FINDINGS 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99). INTERPRETATION Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. FUNDING US National Institutes of Health, Childrens Cardiomyopathy Foundation, University of Miami Womens Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.

Changes in Cardiac Biomarkers During Doxorubicin Treatment of Pediatric Patients With High-Risk Acute Lymphoblastic Leukemia: Associations With Long-Term Echocardiographic Outcomes

PURPOSE Doxorubicin causes cardiac injury and cardiomyopathy in children with acute lymphoblastic leukemia (ALL). Measuring biomarkers during therapy might help individualize treatment by immediately identifying cardiac injury and cardiomyopathy. PATIENTS AND METHODS Children with high-risk ALL were randomly assigned to receive doxorubicin alone (n = 100; 75 analyzed) or doxorubicin with dexrazoxane (n = 105; 81 analyzed). Echocardiograms and serial serum measurements of cardiac troponin T (cTnT; cardiac injury biomarker), N-terminal pro-brain natriuretic peptide (NT-proBNP; cardiomyopathy biomarker), and high-sensitivity C-reactive protein (hsCRP; inflammatory biomarker) were obtained before, during, and after treatment. RESULTS cTnT levels were increased in 12% of children in the doxorubicin group and in 13% of the doxorubicin-dexrazoxane group before treatment but in 47% and 13%, respectively, after treatment (P = .005). NT-proBNP levels were increased in 89% of children in the doxorubicin group and in 92% of children in the doxorubicin-dexrazoxane group before treatment but in only 48% and 20%, respectively, after treatment (P = .07). The percentage of children with increased hsCRP levels did not differ between groups at any time. In the first 90 days of treatment, detectable increases in cTnT were associated with abnormally reduced left ventricular (LV) mass and LV end-diastolic posterior wall thickness 4 years later (P < .01); increases in NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling, 4 years later (P = .01). Increases in hsCRP were not associated with any echocardiographic variables. CONCLUSION cTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL. Definitive validation studies are required to fully establish their range of clinical utility.

Absence of Secondary Malignant Neoplasms in Children With High-Risk Acute Lymphoblastic Leukemia Treated With Dexrazoxane

PURPOSE Dexrazoxane is a drug used to prevent anthracycline-induced cardiotoxicity. A recent report found an association between the use of dexrazoxane and the risk of developing secondary malignant neoplasms (SMNs) in children with Hodgkins disease. We report the absence of an association of SMNs in children with acute lymphoblastic leukemia (ALL) treated on Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. PATIENTS AND METHODS Two hundred five children with high-risk (HR) ALL were randomly assigned to receive doxorubicin alone (n = 100) or doxorubicin with dexrazoxane (n = 105) during the induction and intensification phases of multiagent chemotherapy. We compared incidence of SMNs in these two groups. RESULTS With a median follow-up of 6.2 years, no differences in the incidence of SMNs were noted between the group that received dexrazoxane and the group that did not (P = .66). One SMN (a melanoma located outside of the cranial radiation field) occurred in a patient who was randomly assigned to doxorubicin alone. No SMNs were observed in patients randomly assigned to receive dexrazoxane. CONCLUSION Dexrazoxane was not associated with an increased risk of SMNs in children treated for HR ALL. Given the potential importance of dexrazoxane as a cardioprotectant, we recommend that dexrazoxane continue to be used and studied in doxorubicin-containing pediatric regimens.

Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia.

Escherichia coli asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity develops in up to 30% of patients. We assessed the nadir enzyme activity and tolerability of Erwinia asparaginase, an alternative preparation, in E. coli asparaginase‐allergic patients.

Continuous Versus Bolus Infusion of Doxorubicin in Children With ALL: Long-term Cardiac Outcomes

BACKGROUND AND OBJECTIVES: Doxorubicin, effective against many malignancies, is limited by cardiotoxicity. Continuous-infusion doxorubicin, compared with bolus-infusion, reduces early cardiotoxicity in adults. Its effectiveness in reducing late cardiotoxicity in children remains uncertain. We determined continuous-infusion doxorubicin cardioprotective efficacy in long-term survivors of childhood acute lymphoblastic leukemia (ALL). METHODS: The Dana-Farber Cancer Institute ALL Consortium Protocol 91-01 enrolled pediatric patients between 1991 and 1995. Newly diagnosed high-risk patients were randomly assigned to receive a total of 360 mg/m2 of doxorubicin in 30 mg/m2 doses every 3 weeks, by either continuous (over 48 hours) or bolus-infusion (within 15 minutes). Echocardiograms at baseline, during, and after doxorubicin therapy were blindly remeasured centrally. Primary outcomes were late left ventricular (LV) structure and function. RESULTS: A total of 102 children were randomized to each treatment group. We analyzed 484 serial echocardiograms from 92 patients (n = 49 continuous; n = 43 bolus) with ≥1 echocardiogram ≥3 years after assignment. Both groups had similar demographics and normal baseline LV characteristics. Cardiac follow-up after randomization (median, 8 years) showed changes from baseline within the randomized groups (depressed systolic function, systolic dilation, reduced wall thickness, and reduced mass) at 3, 6, and 8 years; there were no statistically significant differences between randomized groups. Ten-year ALL event-free survival rates did not differ between the 2 groups (continuous-infusion, 83% versus bolus-infusion, 78%; P = .24). CONCLUSIONS: In survivors of childhood high-risk ALL, continuous-infusion doxorubicin, compared with bolus-infusion, provided no long-term cardioprotection or improvement in ALL event-free survival, hence provided no benefit over bolus-infusion.

The low incidence of secondary acute myelogenous leukaemia in children and adolescents treated with dexrazoxane for acute lymphoblastic leukaemia: A report from the Dana-Farber Cancer Institute ALL Consortium

BACKGROUND Dexrazoxane reduces the risk of anthracycline-related cardiotoxicity. In a study of children with Hodgkin lymphoma, the addition of dexrazoxane may have been associated with a higher risk for developing second malignant neoplasms (SMNs) including acute myelogenous leukaemia (AML) and myelodysplastic syndrome (MDS). We determined the incidence of SMNs in children and adolescents with acute lymphoblastic leukaemia (ALL) who were treated with dexrazoxane. METHODS Between 1996 and 2010, the Dana-Faber Cancer Institute ALL Consortium conducted three consecutive multicentre trials for children with newly diagnosed ALL. In the first (1996-2000), high risk patients were randomly assigned to receive doxorubicin (30mg/m(2)/dose, cumulative dose 300mg/m(2)) preceded by dexrazoxane (300mg/m(2)/dose, 10 doses), or the same dose of doxorubicin without dexrazoxane, during induction and intensification phases. In subsequent trials (2000-2005 and 2005-2010), all high risk and very high risk patients received doxorubicin preceded by dexrazoxane. Cases of SMNs were collected prospectively and were pooled for analysis. The frequency and 5-year cumulative incidence (CI) of SMNs were determined for patients who had received dexrazoxane. FINDINGS Among 553 patients treated with dexrazoxane (1996-2000, N=101; 2000-2005, N=196; and 2005-2010, N=256), the number of SMNs observed by protocol was 0 (median follow-up 9.6years), 0 (median follow-up 5.2years), and 1 (median follow-up 2.1years). The only SMN was a case of AML, which developed in a patient with MLL-rearranged ALL 2.14years after initial diagnosis. The overall 5-year CI of SMNs for all 553 patients was 0.24±0.24%. INTERPRETATION In a large population of children with high risk ALL who received dexrazoxane as a cardioprotectant drug, the occurrence of secondary AML was a rare event.

Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia

Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin‐iron complexes leading to free‐radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin‐associated cardiotoxicity in survivors of childhood high‐risk acute lymphoblastic leukemia.

Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer

The prevalence and risk factors for thromboembolism (TE) in children with cancer are largely unknown. This retrospective cohort study aims to determine the epidemiology of TE and to identify potential risk factors for TE in children with cancer.

Use of Reverse Transcriptase Polymerase Chain Reaction for Diagnosis and Staging of Alveolar Rhabdomyosarcoma, Ewing Sarcoma Family of Tumors, and Desmoplastic Small Round Cell Tumor

Purpose To compare the use of reverse transcriptase polymerase chain reaction (RT-PCR) with that of morphology-based methods for diagnosis, staging, and detection of metastatic disease in pediatric alveolar rhabdomyosarcoma (ARMS), Ewing sarcoma family of tumors (ESFT), and desmoplastic small round cell tumors (DSRCT). Materials and Methods RT-PCR assays for the EWS-FLI1, EWS-ERG, PAX3-FKHR, PAX7-FKHR, and EWS-WT1 fusion transcripts were performed on RNA extracted from the primary tumor tissue, bone marrow, and body fluids obtained at initial presentation and relapse. Molecular findings were compared with original histologic diagnoses and results of staging procedures. Results Eighty-eight samples from 47 patients with ARMS (n = 13), ESFT (n = 31), or DSRCT (n = 3) were analyzed. The detection rate of metastatic disease was significantly higher with RT-PCR (95%) as compared with the morphologic methods (70%) for the three pediatric sarcomas studied. In primary tumors with characteristic fusion transcript, RT-PCR was positive in all cases with morphologic evidence of metastatic disease. Moreover, in six patients (3 with ARMS, 2 with DSRCT, and 1 with ESFT) with metastatic disease, micrometastases in bone marrow (4) and other sites (2) were detected by RT-PCR alone. Importantly, none of the patients with localized disease diagnosed had micrometastases detected by RT-PCR in bone marrow. Conclusions The high sensitivity and specificity of RT-PCR for the characteristic fusion transcripts of pediatric sarcomas make it an ideal method to aid in the routine staging of these patients. In addition, the 100% sensitivity of RT-PCR in detection of micrometastasis makes it useful for follow-up and detection of minimal residual disease. However, the clinical significance of molecularly-detectable disease remains unknown. Further studies should aim to elucidate the therapeutic and prognostic implications of micrometastases detected by RT-PCR alone.

Thromboembolism in children with acute lymphoblastic leukaemia treated on Dana‐Farber Cancer Institute protocols: effect of age and risk stratification of disease

Children with acute lymphoblastic leukaemia (ALL) are at increased risk for thromboembolism (TE). Identification of a susceptible population is crucial for effective thromboprophylaxis. However, the risk factors for ALL‐associated TE are unclear. Concomitant asparaginase (ASP) and steroid therapy has been shown to increase the incidence of TE. Dana‐Farber Cancer Institute (DFCI)‐ALL protocols use a combination of ASP and steroids during the postinduction intensification phase when high‐risk (HR) patients receive thrice the steroid‐dose given to standard‐risk (SR) patients. We studied prospectively assembled cohorts of children treated on two consecutive DFCI‐ALL protocols to define the risk factors for symptomatic TE. Ten (11%) of 91 patients developed symptomatic TE; eight (seven HR) during intensification. Seven (44%) of 16 older patients (≥10 years) compared with three of 75 (4%) younger patients developed TE (P < 0·0001). Nine of 35 (26%) HR and one of 56 (2%) SR patients developed TE (P = 0·0006). Gender, ALL‐immunophenotype, steroid‐type or ASP dosing schedule did not alter the risk but older age and HR‐disease were factors predisposing to TE associated with DFCI‐ALL protocols. Age‐related risk may partly reflect the effect of ALL‐risk stratification. Higher dose steroids combined with ASP may lead to an increased risk of TE in HR patients.