Treatment of childhood acute lymphoblastic leukemia: results of Dana-Farber ALL Consortium Protocol 87-01

To improve efficacy and reduce toxicity of treatment for children with acute lymphoblastic leukemia. Patients from all risk groups, including infants and those with T-cell disease, were treated between 1987 and 1991. Standard-risk (SR) patients did not receive cranial irradiation, whereas high-risk (HR) and very high-risk (VHR) patients participated in a randomized comparison of 18 Gy of cranial irradiation conventionally fractionated versus two fractions per day (hyperfractionated). At a median follow-up of 9.2 years, the 9-year event-free survival (EFS +/- SE) was 75% +/- 2% for all 369 patients, 77% +/- 4% for the 142 SR patients, and 73% +/- 3% for the 227 HR/VHR patients (P =.37 comparing SR and HR/VHR). The CNS, with or without concomitant bone marrow involvement, was the first site of relapse in 19 (13%) of the 142 SR patients: 16 (20%) of 79 SR boys and three (5%) of 63 SR girls. This high incidence of relapses necessitated a recall of SR boys for additional therapy. CNS relapse occurred in only two (1%) of 227 HR and VHR patients. There were no outcome differences found among randomized treatment groups. Nine-year overall survival was 84% +/- 2% for the entire population, 93% +/- 2% for SR children, and 79% +/- 3% for HR and VHR children (P <.01 comparing SR and HR/VHR). A high overall survival outcome was obtained for SR patients despite the high risk of CNS relapse for SR boys, which was presumed to be associated with eliminating cranial radiation without intensifying systemic or intrathecal chemotherapy. For HR/VHR patients, inability to salvage after relapse (nearly all of which were in the bone marrow) remains a significant clinical problem

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

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. 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/m2/dose, cumulative dose 300mg/m2) preceded by dexrazoxane (300mg/m2/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. 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%. 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

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/m(2) of doxorubicin in 30 mg/m(2) 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 \u3e/=1 echocardiogram \u3e/=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