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West Scarborough, MN, United States

Chaleff S.,Maine Childrens Cancer Program | Hurwitz C.A.,Maine Childrens Cancer Program | Chang M.,University of Florida | Dahl G.,Stanford University | And 2 more authors.
British Journal of Haematology | Year: 2012

Relapse remains the leading cause of death in patients with acute myeloid leukaemia (AML). Relatively few new chemotherapy agents have been proven to be effective in this population. We report on a Phase 2 clinical trial using the novel combination of 2-chlorodeoxyadenosine (2-CDA) (8mg/m 2 per d×5d) plus idarubicin (Ida) (10mg/m 2 per d×3d). The study involved 109 paediatric patients with AML at first relapse, of whom 104 were available for analysis. The overall response rate was 51% (complete response [CR]+partial response) with a CR rate of 46%. 2-year event-free survival (EFS) and overall survival (OS) were 20% and 26%. The only significant variable in determining response, EFS and OS was duration of initial remission, with patients who had an initial remission >1year having much worse outcomes overall (response rate 74% vs. 25%, EFS 8% vs. 37% and OS of 16% vs. 39%, P<0·01 for all). There was an acceptable toxicity profile with one neurological event and no cardiac events observed. The most common grade 3-4 toxicities observed were neutropenia (59%) and thrombocytopenia (68%). This study demonstrated that the novel combination of 2-CDA/Ida was effective and should be considered for incorporation in front line therapy for children with AML. © 2011 Blackwell Publishing Ltd.

Bowman W.P.,Cook Childrens Hospital | Larsen E.L.,Maine Childrens Cancer Program | Devidas M.,University of Florida | Linda S.B.,University of Florida | And 9 more authors.
Pediatric Blood and Cancer | Year: 2011

Background: The augmented BFM regimen improves outcome for children with NCI high acute lymphoblastic leukemia (ALL). Patient age, sex, and presenting white blood cell count (WBC) can be used to identify a subset of approximately 12% of children with B-precursor ALL that had a 5-year continuous complete remission (CCR) rate of only about 50% on earlier Pediatric Oncology Group (POG) trials. Procedures: Children's Oncology Group trial P9906 evaluated a modified augmented BFM regimen in 267 patients with particularly high risk B-precursor ALL. Minimal residual disease (MRD) was assessed in blood at day 8 and in marrow at day 29 of induction and correlated with outcome. Results: The 5-year CCR probability for patients in P9906 was significantly better than that observed for similar patients on POG trials 8602/9006 (62.2±3.7% vs. 50.6±2.4%; P=0.0007) but similar to POG 9406 (63.5±2.4%; P=0.81). Interim analysis showed poor central nervous system (CNS) control, especially in patients with initial WBC ≥100,000/microliter. Day 29 marrow MRD positive (≥0.01%) vs. negative patients had 5 year CCR rates of 37.1±7.4% vs. 72.6±4.3%; day 8 blood MRD positive vs. negative patients had 5 year CCR rates of 57.1±4.6% vs.83.6±6.3%. End induction marrow MRD predicted marrow but not CNS relapse. In multivariate analysis, day 29 MRD>0.01%, initial WBC≥100,000/μl, male gender, and day 8 blood MRD>0.01% were significant prognostic factors. Conclusions: Augmented BFM therapy improved outcome for children with higher risk ALL. Day 8 blood and day 29 marrow MRD were strong prognostic factors in these patients. © 2011 Wiley-Liss, Inc.

Loh M.L.,University of California at San Francisco | Zhang J.,St Jude Childrens Research Hospital | Harvey R.C.,University of New Mexico | Roberts K.,St Jude Childrens Research Hospital | And 22 more authors.
Blood | Year: 2013

One recently identified subtype of pediatric B-precursor acute lymphoblastic leukemia (ALL) has been termed BCR-ABL1-like or Ph-like because of similarity of the gene expression profile to BCR-ABL1 positive ALL suggesting the presence of lesions activating tyrosine kinases, frequent alteration of IKZF1, and poor outcome. Prior studies demonstrated that approximately half of these patients had genomic lesions leading to CRLF2 overexpression, with half of such cases harboring somatic mutations in the Janus kinases JAK1 and JAK2. To determine whether mutations in other tyrosine kinases might also occur in ALL, we sequenced the tyrosine kinome and downstream signaling genes in 45 high-risk pediatric ALL cases with either a Ph-like gene expression profile or other alterations suggestive of activated kinase signaling. Aside from JAK mutations and 1 FLT3 mutation, no somatic mutations were found in any other tyrosine kinases, suggesting that alternative mechanisms are responsible for activated kinase signaling in high-risk ALL. Copyright 2011 by The American Society of Hematology; all rights reserved. © Copyright 2011 by The American Society of Hematology; all rights reserved.

Roberts K.,St Jude Childrens Research Hospital | Morin R.,BC Cancer Agency | Zhang J.,St Jude Childrens Research Hospital | Hirst M.,BC Cancer Agency | And 46 more authors.
Cancer Cell | Year: 2012

Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2, and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2-negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy. © 2012 Elsevier Inc.

Lipshultz S.E.,University of Miami | Miller T.L.,University of Miami | Lipsitz S.R.,Brigham and Womens Hospital | Neuberg D.S.,Dana-Farber Cancer Institute | And 15 more authors.
Pediatrics | Year: 2012

BACKGROUND AND OBJECTIVES: Doxorubicin, effective against manymalignancies, 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/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 ≥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 (continuousinfusion, 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. Copyright © 2012 by the American Academy of Pediatrics.

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