Publications by authors named "Jessica A Pollard"

24 Publications

  • Page 1 of 1

Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome.

N Engl J Med 2021 11;385(22):2059-2065

From the Departments of Pediatric Oncology (J.K., K.V.H., J.A.P., C.M.C., A.I., C.B.W., K.A.J., S.G.D.) and Medical Oncology (W.G.K.), Dana-Farber Cancer Institute, Harvard Medical School, the Divisions of Hematology and Oncology (J.K., J.A.P., M.M.H., K.A.J., S.G.D.) and Endocrinology (A.J.W.) and the Departments of Surgery (B.R.W.), Pathology (S.O.V.), and Radiology (S.D.V.), Boston Children's Hospital, Harvard Medical School, and the Manton Center for Orphan Disease Research and the Division of Genetics and Genomics, Boston Children's Hospital (J.A.M., J.L.) - all in Boston; Howard Hughes Medical Institute, Chevy Chase, MD (W.G.K.); and Merck, Kenilworth, NJ (R.F.P., N.J.Z.).

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in . Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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http://dx.doi.org/10.1056/NEJMoa2110051DOI Listing
November 2021

Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2021 Dec 1;68(12):e29281. Epub 2021 Oct 1.

Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Background: High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531.

Methods: Patients on AAML0531 received cytarabine (1600 mg/m )/daunorubicin (150 mg/m )/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48 mg/m )/cytarabine (8000 mg/m ) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE.

Results: MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p = .87; measurable residual disease [MRD]+: 57% vs. 46%, p = .34); or intensification I response (CR: 79% vs. 94%, p = .27; MRD+: 27% vs. 20%, p = 1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p = .63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p = .66). MA was associated with slower neutrophil recovery (median 34 vs. 27 days, p = .007) and platelet recovery (median 29 vs. 24.5 days, p = .04) and longer hospital stay (32 vs. 28 days, p = .01) during induction II.

Conclusion: Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).
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http://dx.doi.org/10.1002/pbc.29281DOI Listing
December 2021

Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric -Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531.

J Clin Oncol 2021 10 28;39(28):3149-3160. Epub 2021 May 28.

Children's Mercy, Kansas City, MO.

Purpose: We investigated the impact of the CD33-targeted agent gemtuzumab ozogamicin (GO) on survival in pediatric patients with -rearranged (-r) acute myeloid leukemia (AML) enrolled in the Children's Oncology Group trial AAML0531 (NCT01407757).

Methods: Patients with -r AML were identified and clinical characteristics described. Five-year overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and relapse risk (RR) were determined overall and for higher-risk versus not high-risk translocation partners. GO's impact on response was determined and outcomes based on consolidation approach (hematopoietic stem cell transplant [HSCT] chemotherapy) described.

Results: Two hundred fifteen (21%) of 1,022 patients enrolled had -r AML. Five-year EFS and OS from study entry were 38% and 58%, respectively. EFS was superior with GO treatment (EFS 48% with GO 29% without, = .003), although OS was comparable (63% 53%, = .054). For patients with -r AML who achieved complete remission, GO was associated with lower RR (40% GO 66% patients who did not receive GO [No-GO], = .001) and improved 5-year DFS (GO 57% No-GO 33%, = .002). GO benefit was observed in both higher-risk and not high-risk -r subsets. For patients who underwent HSCT, prior GO exposure was associated with decreased relapse (5-year RR: 28% GO and HSCT 73% No-GO and HSCT, = .006). In multivariable analysis, GO was independently associated with improved EFS, improved DFS, and reduced RR.

Conclusion: GO added to conventional chemotherapy improved outcomes for -r AML; consolidation with HSCT may further enhance outcomes. Future clinical trials should study CD33-targeted agents in combination with HSCT for pediatric r AML.
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http://dx.doi.org/10.1200/JCO.20.03048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478392PMC
October 2021

Morphologic remission status is limited compared to ΔN flow cytometry: a Children's Oncology Group AAML0531 report.

Blood Adv 2020 10;4(20):5050-5061

Hematologics, Inc, Seattle, WA.

Risk stratification for acute myeloid leukemia (AML) uses molecular and cytogenetic abnormalities identified at diagnosis. Response to therapy informs risk, and morphology continues to be used more frequently than flow cytometry. Herein, the largest cohort of pediatric patients prospectively assessed for measurable residual disease (MRD) by flow cytometry (N = 784) is reported. The "difference from normal" (ΔN) technique was applied: 31% of all patients tested positive (AML range, 0.02% to 91%) after the first course of treatment on Children's Oncology Group study AAML0531. Detection of MRD following initial chemotherapy proved the strongest predicator of overall survival (OS) in univariable and multivariable analyses, and was predictive of relapse risk, disease-free survival, and treatment-related mortality. Clearance of MRD after a second round of chemotherapy did not improve survival. The morphologic definition of persistent disease (>15% AML) failed 27% of the time; those identified as MRD- had superior outcomes. Similarly, for patients not achieving morphologic remission (>5% blasts), 36% of patients were MRD- and had favorable outcomes compared with those who were MRD+ (P < .001); hence an increase in myeloid progenitor cells can be favorable when ΔN classifies them as phenotypically normal. Furthermore, ΔN reclassified 20% of patients in morphologic remission as having detectable MRD with comparable poor outcomes. Retrospective analysis using the relapse phenotype as a template demonstrated that 96% of MRD- patients had <0.02% of the relapse immunophenotype in their end of induction 1 marrow. Thus, the detection of abnormal myeloid progenitor cells by ΔN is both specific and sensitive, with a high predictive signal identifiable early in treatment. This trial was registered at www.clinicaltrials.gov as #NCT00372593.
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http://dx.doi.org/10.1182/bloodadvances.2020002070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594384PMC
October 2020

Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

J Clin Oncol 2020 07 28;38(21):2398-2406. Epub 2020 Apr 28.

Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.

Patients And Methods: This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.

Results: A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% 45.1%; = .534) and OS (65.0% 61.9%; = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% 12.7%; = .068).

Conclusion: Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.
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http://dx.doi.org/10.1200/JCO.19.02856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367546PMC
July 2020

Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study.

Clin Cancer Res 2020 05 22;26(10):2297-2307. Epub 2020 Jan 22.

Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.

Patients And Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial.

Results: The most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia ( = 1); seizure, somnolence, and delirium ( = 1); and pneumonitis, hypoxia, and hyperbilirubinemia ( = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.

Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477726PMC
May 2020

Functional Properties of Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.

Clin Cancer Res 2019 08 10;25(16):5038-5048. Epub 2019 Jun 10.

Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: mutations ( ) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct mutations in CBF pediatric AML.

Experimental Design: Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status [ vs. wild-type ( )] and mutation location (E8 vs. E17).

Results: mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with CBF AML had overall survival similar to those with (78% vs. 81%, = 0.905) but higher relapse rates (RR = 43% vs. 21%; = 0.005). E17 outcomes were inferior to patients [disease-free survival (DFS), 51% vs. 73%, = 0.027; RR = 21% vs. 46%, = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome.

Conclusions: E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754181PMC
August 2019

Improving Time to Antibiotics for Pediatric Oncology Patients With Suspected Infections: An Emergency Department-Based Quality Improvement Intervention.

Pediatr Emerg Care 2018 Jan;34(1):47-52

Objective: Studies in pediatric patients with fever and neutropenia demonstrate that shorter time to antibiotics is associated with a decrease in pediatric intensive care unit admissions and in-hospital mortality. In 2012, a 2-phase quality improvement intervention was implemented in a pediatric emergency department (ED) to improve care for this high-risk patient population.The objective was to determine if the introduction of (1) a rapid absolute neutrophil count (ANC) test and (2) a standardized prearrival process decreased time to antibiotics for febrile hematology/oncology(heme/onc) patients presenting to the ED.

Methods: The rapid ANC test introduced in February 2012 decreased turn-around-times in the laboratory from 60 to 10 minutes. The standardization of the prearrival communication between the heme/onc team and ED was implemented in August 2012 as part of a clinical standard work pathway for heme/onc patients who presented to the ED with fever and possible neutropenia. Time from arrival to the ED to administration of first antibiotic was measured.Data from January 2011 to December 2013 were analyzed using statistical process control.

Results: Seven hundred eighteen encounters for 327 patients were included. After the rapid ANC test, the proportion of patients who received antibiotics within 60 minutes of arrival increased from 47% to 60%. There was further improvement to 69% with implementation of the clinical standard work pathway. Mean time to antibiotics decreased from 83 to 65 minutes (21% decrease).

Conclusion: This 2-phase quality improvement intervention increased the proportion of patients who received antibiotics within 60 minutes of arrival to the ED. Similar processes may be implemented in other pediatric EDs to improve timeliness of antibiotic administration.
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http://dx.doi.org/10.1097/PEC.0000000000001367DOI Listing
January 2018

CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children's Oncology Group Trial AAML0531.

J Clin Oncol 2017 Aug 23;35(23):2674-2682. Epub 2017 Jun 23.

Jatinder K. Lamba, Lata Chauhan, and Miyoung Shin, University of Florida, Gainesville, FL; Michael R. Loken, Hematologics Inc; Rhonda E. Ries, Irwin D. Bernstein, and Soheil Meshinchi, Fred Hutchinson Cancer Research Center; Roland B. Walter and Soheil Meshinchi, University of Washington, Seattle, WA; Jessica A. Pollard, Maine Medical Center, Portland, ME; Jessica A. Pollard, Tufts University, Boston, MA; Yi-Cheng Wang, Children's Oncology Group, Monrovia; Todd A. Alonzo, University of Southern California, Los Angeles, CA; Richard Aplenc, Children's Hospital of Philadelphia, Philadelphia, PA; Betsy A. Hirsch, University of Minnesota, Minneapolis, MN; Susana C. Raimondi, St Jude Children's Research Hospital, Memphis, TN; and Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO.

Purpose Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO-containing chemotherapy. Patients and Methods CD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children's Oncology Group AAML0531 trial. Results The rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript ( P < 1.0E) and with lower diagnostic leukemic cell surface CD33 intensity ( P < 1.0E). Patients with the CC genotype had significantly lower relapse risk in the GO arm than in the No-GO arm (26% v 49%; P < .001). However, in patients with the CT or TT genotype, exposure to GO did not influence relapse risk (39% v 40%; P = .85). Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% v 46%, respectively; P = .004), but this benefit of GO addition was not seen in patients with the CT or TT genotype. Conclusion Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to GO, making this a potential biomarker for the selection of patients with a likelihood of significant response to GO.
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http://dx.doi.org/10.1200/JCO.2016.71.2513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549451PMC
August 2017

A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study.

Clin Cancer Res 2016 Aug 26;22(16):4014-22. Epub 2016 Feb 26.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Purpose: To determine a safe and biologically active dose of quizartinib (AC220), a potent and selective class III receptor tyrosine kinase (RTK) FLT3 inhibitor, in combination with salvage chemotherapy in children with relapsed acute leukemia.

Experimental Design: Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide (AE). A 3+3 dose escalation design was used to identify a safe and biologically active dose. Plasma inhibitory assay (PIA) testing was performed weekly to determine biologic activity.

Results: Toxicities were consistent with intensive relapsed leukemia regimens. One of 6 patients experienced a dose-limiting toxicity (DLT) at 40 mg/m(2)/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60 mg/m(2)/day. Of 17 response evaluable patients, 2 had complete response (CR), 1 complete response without platelet recovery (CRp), 1 complete response with incomplete neutrophil and platelet recovery (CRi), 10 stable disease (SD), and 3 progressive disease (PD). Of 7 FLT3-ITD patients, 1 achieved CR, 1 CRp, 1 Cri, and 4 SD. FLT3-ITD patients, but not FLT3 wild-type (WT) patients, had significantly lower blast counts post-quizartinib. FLT3 phosphorylation was completely inhibited in all patients.

Conclusions: Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m(2)/day with near complete inhibition of FLT3 phosphorylation in all patients. The favorable toxicity profile, pharmacodynamic activity, and encouraging response rates warrant further testing of quizartinib in children with FLT3-ITD AML. Clin Cancer Res; 22(16); 4014-22. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1998DOI Listing
August 2016

Accuracy of Adverse Event Ascertainment in Clinical Trials for Pediatric Acute Myeloid Leukemia.

J Clin Oncol 2016 05 16;34(13):1537-43. Epub 2016 Feb 16.

Tamara P. Miller, Yimei Li, Marko Kavcic, Yuan-Shun V. Huang, Rochelle Bagatell, Alix E. Seif, Brian T. Fisher, Peter C. Adamson, and Richard Aplenc, The Children's Hospital of Philadelphia; Yimei Li, Andrea B. Troxel, Rochelle Bagatell, Alix E. Seif, Brian T. Fisher, Selina Luger, Peter C. Adamson, and Richard Aplenc, University of Pennsylvania School of Medicine, Philadelphia, PA; Lillian Sung, The Hospital for Sick Children, Toronto, Ontario, Canada; Todd A. Alonzo and Michael A. Pulsipher, University of Southern California; Michael A. Pulsipher, Children's Hospital of Los Angeles, Los Angeles; Todd A. Alonzo and Robert Gerbing, Children's Oncology Group, Monrovia, CA; Matt Hall, Children's Hospital Association, Overland Park, Kansas; Marla H. Daves, Children's Healthcare of Atlanta, Atlanta, GA; Terzah M. Horton, Texas Children's Hospital, Houston, TX; Jessica A. Pollard, Seattle Children's Hospital, Seattle, WA; and Alan S. Gamis, Children's Mercy Hospital, Kansas City, MO.

Purpose: Reporting of adverse events (AEs) in clinical trials is critical to understanding treatment safety, but data on AE accuracy are limited. This study sought to determine the accuracy of AE reporting for pediatric acute myeloid leukemia clinical trials and to test whether an external electronic data source can improve reporting.

Methods: Reported AEs were evaluated on two trials, Children's Oncology Group AAML03P1 and AAML0531 arm B, with identical chemotherapy regimens but with different toxicity reporting requirements. Chart review for 12 AEs for patients enrolled in AAML0531 at 14 hospitals was the gold standard. The sensitivity and positive predictive values (PPV) of the AAML0531 AE report and AEs detected by review of Pediatric Health Information System (PHIS) billing and microbiology data were compared with chart data.

Results: Select AE rates from AAML03P1 and AAML0531 arm B differed significantly and correlated with the targeted toxicities of each trial. Chart abstraction was performed on 204 patients (758 courses) on AAML0531. AE report sensitivity was < 50% for eight AEs, but PPV was > 75% for six AEs. AE reports for viridans group streptococcal bacteremia, a targeted toxicity on AAML0531, had a sensitivity of 78.3% and PPV of 98.1%. PHIS billing data had higher sensitivity (> 50% for nine AEs), but lower PPV (< 75% for 10 AEs). Viridans group streptococcal detection using PHIS microbiology data had high sensitivity (92.3%) and PPV (97.3%).

Conclusion: The current system of AE reporting for cooperative oncology group clinical trials in pediatric acute myeloid leukemia underestimates AE rates. The high sensitivity and PPV of PHIS microbiology data suggest that using external data sources may improve the accuracy of AE reporting.
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http://dx.doi.org/10.1200/JCO.2015.65.5860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872308PMC
May 2016

CD33 Expression and Its Association With Gemtuzumab Ozogamicin Response: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531.

J Clin Oncol 2016 Mar 19;34(7):747-55. Epub 2016 Jan 19.

Jessica A. Pollard, Maine Medical Center, Portland, ME; and Tufts University, Boston, MA; Michael Loken, Hematologics; Irwin D. Bernstein and Soheil Meshinchi, Fred Hutchinson Cancer Research Center; Irwin D. Bernstein and Soheil Meshinchi, University of Washington, Seattle, WA; Robert B. Gerbing and Todd A. Alonzo, Children's Oncology Group, Arcadia; Todd A. Alonzo, Keck School of Medicine of University of Southern California, Los Angeles, CA; Susana C. Raimondi, St Jude Children's Research Hospital, Memphis, TN; Betsy Hirsch, University of Minnesota Cancer Center, Minneapolis, MN; Richard Aplenc, Children's Hospital of Philadelphia, Philadelphia, PA; and Alan S. Gamis, Children's Mercy Hospitals and Clinics, Kansas City, MO.

Purpose: CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level.

Patients And Methods: CD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children's Oncology Group AAML0531 and correlated with response to GO.

Results: Patients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, P = .731; event-free survival [EFS]: GO 53% v No-GO 58%, P = .456). However, patients with higher CD33 expression (Q2 to Q4) had significantly reduced RR (GO 32% v No-GO 49%, P < .001) and improved EFS (GO 53% v No-GO 41%, P = .005). This differential effect was observed in all risk groups. Specifically, low-risk (LR), intermediate-risk (IR), and high-risk (HR) patients with low CD33 expression had similar outcomes regardless of GO exposure, whereas the addition of GO to conventional chemotherapy resulted in a significant decrease in RR and disease-free survival (DFS) for patients with higher CD33 expression (LR RR, GO 13% v No-GO 35%, P = .001; LR DFS, GO 79% v No-GO 59%, P = .007; IR RR, GO 44% v No-GO 57%, P = .044; IR DFS, GO 51% v No-GO 40%, P = .078; HR RR, GO 40% v No-GO 73%, P = .016; HR DFS, GO 47% v No-GO 28%, P = .135).

Conclusion: We demonstrate that GO lacks clinical benefit in patients with low CD33 expression but significantly reduces RR and improves EFS in patients with high CD33 expression, which suggests a role for CD33-targeted therapeutics in subsets of pediatric AML.
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http://dx.doi.org/10.1200/JCO.2015.62.6846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872025PMC
March 2016

Gemtuzumab Ozogamicin Reduces Relapse Risk in FLT3/ITD Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

Clin Cancer Res 2016 Apr 7;22(8):1951-7. Epub 2015 Dec 7.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Purpose: Gemtuzumab ozogamicin (GO), a calicheamicin-conjugated mAb against CD33, has been used in the treatment of acute myeloid leukemia (AML). We evaluated the impact of the addition of GO to standard chemotherapy and hematopoietic stem cell transplant (HCT) in patients withFLT3/ITD.

Experimental Design: We analyzed children withFLT3/ITD-positive AML (n= 183) treated on two consecutive Children's Oncology Group AML trials (NCT00070174andNCT00372593). Outcomes were assessed forFLT3/ITD patients receiving standard chemotherapy with or without GO (GO vs. No-GO, respectively), and the impact of consolidation HCT for high-riskFLT3/ITD patients [highFLT3/ITD allelic ratio (ITD-AR)].

Results: For allFLT3/ITD patients, complete remission (CR) rates for the GO versus No-GO cohorts were identical (64% vs. 64%;P= 0.98). Relapse rate (RR) after initial CR was 37% for GO recipients versus 59% for No-GO recipients (P= 0.02), disease-free survival (DFS) was similar (47% vs. 41%;P= 0.45), with higher treatment-related mortality (TRM) in GO recipients (16% vs. 0%;P= 0.008). Among high-riskFLT3/ITD patients with high ITD-AR, those who received HCT in first CR with prior exposure to GO had a significant reduction in RR (15% vs. 53%;P= 0.007), with a corresponding DFS of 65% versus 40% (P= 0.08), and higher TRM (19% vs. 7%;P= 0.08).

Conclusions: CD33 targeting with HCT consolidation may be an important therapeutic strategy in high-riskFLT3/ITD AML and its efficacy and associated toxicity warrant further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834220PMC
April 2016

Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia.

Pediatr Blood Cancer 2015 Jun 8;62(6):1048-54. Epub 2015 Feb 8.

Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Hematology and Oncology, Seattle Children's Hospital, Seattle, Washington.

Background: FLT3/ITD is associated with poor outcomes in adult and pediatric acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) can improve cure rates, however relapse is still common. Recent studies demonstrate the activity of FLT3 inhibitors, including sorafenib, in targeting the underlying mutation.

Procedure: We conducted a retrospective study of 15 pediatric patients with FLT3/ITD+ AML treated with sorafenib within 18 months after receiving HSCT. Sorafenib was administered either as prophylaxis in patients considered at very high risk for relapse (n = 6) or at the time of disease recurrence (n = 9).

Results: Sorafenib was initiated at a median of 100 days post HSCT. Overall, 11/15 (73%) of patients experienced medically significant toxicities. Among patients who experienced toxicity, 6/11 (55%) received treatment at doses above what was later determined to be the maximum tolerated dose of sorafenib for pediatric leukemia. Importantly, sorafenib did not appear to exacerbate graft versus host disease. Our findings suggest that sorafenib may be of particular efficacy in patients with minimal residual disease (MRD); all patients who received sorafenib for MRD immediately prior to transplant or with emergence post-HSCT are alive and remain in complete remission at a median of 48 months post HSCT.

Conclusions: Our case series suggests that sorafenib administration is feasible and tolerable in pediatric FLT3/ITD+ AML patients early post HSCT. Ongoing prospective controlled studies are needed to further define the dosing of sorafenib in the post-HSCT period and to determine the optimal context for this treatment approach.
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http://dx.doi.org/10.1002/pbc.25437DOI Listing
June 2015

Molecular therapeutic approaches for pediatric acute myeloid leukemia.

Front Oncol 2014 18;4:55. Epub 2014 Mar 18.

Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania , Philadelphia, PA , USA.

Approximately two-thirds of children with acute myeloid leukemia (AML) are cured with intensive multi-agent chemotherapy. However, refractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic chemotherapy in pediatric AML is not feasible given the risks of both short-term and long-term organ dysfunction. Substantial emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with the goal of improving remission induction and minimizing relapse. Several promising agents are currently in clinical testing or late preclinical development for AML, including monoclonal antibodies against leukemia cell surface proteins, kinase inhibitors, proteasome inhibitors, epigenetic agents, and chimeric antigen receptor engineered T cell immunotherapies. Many of these therapies have been specifically tested in children with relapsed/refractory AML in Phase 1 and 2 trials with a smaller number of new agents under Phase 3 evaluation for children with de novo AML. Although successful identification and implementation of new drugs for children with AML remain a formidable challenge, enthusiasm for novel molecular therapeutic approaches is great given the potential for significant clinical benefit for children who do not have other curative options.
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http://dx.doi.org/10.3389/fonc.2014.00055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957536PMC
June 2014

The prognostic effect of high diagnostic WT1 gene expression in pediatric AML depends on WT1 SNP rs16754 status: report from the Children's Oncology Group.

Pediatr Blood Cancer 2014 Jan 16;61(1):81-8. Epub 2013 Aug 16.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Pediatric Hematology/Oncology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington; Children's Oncology Group, Arcadia, California.

Background: WT1 is aberrantly over-expressed in most cases of AML. We recently demonstrated that WT1 SNP rs16754 correlates with favorable outcome and high diagnostic WT1 expression in childhood AML. We examined the clinical correlates of diagnostic WT1 expression within a contemporary COG trial and determined whether its prognostic impact differs between SNP+ and SNP- patients.

Procedure: WT1 mRNA expression was measured via qRT-PCR in diagnostic specimens obtained from 225 patients enrolled on COG-AAML03P1. Direct sequencing of WT1 exon 7 was performed to determine SNP rs16754 genotype. WT1 expression was correlated with disease characteristics, SNP status, and outcome.

Results: Patients were categorized into four groups (quartiles: Q1 through Q4) based on diagnostic WT1 expression for analysis. FLT3/ITD (P = 0.017) and WT1 mutations (P < 0.001) both occurred more frequently in patients with the highest WT1 expression. SNP rs16754 frequency did not vary significantly among the quartiles. When all patients were considered, survival outcomes were similar between quartiles. However, when only SNP- patients (n = 150) were analyzed, those with highest WT1 expression (Q4) had the poorest OS (51% vs. 72% for Q1-Q3, P = 0.006) and EFS (35% vs. 54% for Q1-Q3, P = 0.031). Among SNP+ patients (n = 75), survival did not vary significantly between WT1 expression quartiles.

Conclusion: Although WT1 expression was not prognostic when all patients were considered together, stratifying patients by SNP rs16754 genotype revealed significant differences in outcome. In SNP- patients, high WT1 expression predicted decreased survival in univariate, but not multivariate, analysis, due to a preponderance of high-risk cyto/molecular abnormalities in the highest expression quartile.
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http://dx.doi.org/10.1002/pbc.24700DOI Listing
January 2014

High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in paediatric acute myeloid leukaemia: a report from the children's oncology group.

Br J Haematol 2013 Sep 4;162(5):670-7. Epub 2013 Jul 4.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98103, USA.

Ectopic viral integration site-1 (EVI1) is highly expressed in certain cytogenetic subsets of adult acute myeloid leukaemia (AML), and has been associated with inferior survival. We sought to examine the clinical and biological associations of EVI1(high) , defined as expression in excess of normal controls, in paediatric AML. EVI1 mRNA expression was measured via quantitative real-time polymerase chain reaction in diagnostic specimens obtained from 206 patients. Expression levels were correlated with clinical features and outcome. EVI1(high) was present in 58/206 (28%) patients. MLL rearrangements occurred in 40% of EVI1(high) patients as opposed to 12% of the EVI1(low/absent) patients (P < 0·001). No abnormalities of 3q26 were found in EVI1(high) patients by conventional cytogenetic analysis, nor were cryptic 3q26 abnormalities detected in a subset of patients screened by next-generation sequencing. French-American-British class M7 was enriched in the EVI1(high) group, accounting for 24% of these patients. EVI1(high) patients had significantly lower 5-year overall survival from study entry (51% vs. 68%, P = 0·015). However, in multivariate analysis including other established prognostic markers, EVI1 expression did not retain independent prognostic significance. EVI1 expression is currently being studied in a larger cohort of patients enrolled on subsequent Children's Oncology Group trials, to determine if EVI1(high) has prognostic value in MLL-rearranged or intermediate-risk subsets.
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http://dx.doi.org/10.1111/bjh.12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754879PMC
September 2013

Clinical significance of CD33 nonsynonymous single-nucleotide polymorphisms in pediatric patients with acute myeloid leukemia treated with gemtuzumab-ozogamicin-containing chemotherapy.

Clin Cancer Res 2013 Mar 26;19(6):1620-7. Epub 2013 Feb 26.

Department of Hematology, PUMA-Institute of Personalized Medicine, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Purpose: The purpose of this study was to evaluate clinical implications of CD33 single-nucleotide polymorphisms (SNP) in pediatric patients with acute myeloid leukemia (AML) treated with gemtuzumab-ozogamicin (GO)-based therapy.

Experimental Design: We genotyped four CD33 SNPs: rs35112940 (G>A; Arg304Gly), rs12459419 (C>T; Ala14Val), rs2455069 (A>G; Arg69Gly), and rs1803254 (G>C; 3'UTR) in pediatric patients undergoing induction chemotherapy containing GO (COG-AAML03P1 trial; n = 242) or not containing GO (St. Jude AML02 trial; n = 172).

Results: CD33 SNPs were correlated significantly with clinical characteristics and treatment outcome. The coding SNPs, rs35112940 and rs12459419, were significantly associated with clinical endpoints in COG-AAML03P1 but not in the St. Jude AML02 trial. Specifically, among white patients in COG-AAML03P1, the 3-year overall survival (OS) rate from remission was 84% ± 8% for those homozygous (GG) for rs35112940 versus 68% ± 15% for the other genotypes (P = 0.018); these patients also had a lower relapse risk and superior disease-free survival. Likewise, patients homozygous for variant allele (TT) for rs12459419 were more likely to have favorable risk disease than CC and CT genotypes (52% vs. 31%, P = 0.034) and significantly lower diagnostic blast CD33 expression than other genotypes (P < 0.001).

Conclusion: Our data suggest that genetic variations in CD33 could impact clinical outcome of GO-based therapy in pediatric AMLs.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602123PMC
March 2013

Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML.

Blood 2012 Apr 29;119(16):3705-11. Epub 2012 Feb 29.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

CD33 is expressed on the majority of acute myeloid leukemia (AML) leukemic blasts and is the target for gemtuzumab ozogamicin (GO), a toxin-conjugated anti-CD33 mAb. In the present study, we quantified the CD33 mean fluorescent intensity of leukemic blasts prospectively in 619 de novo pediatric AML patients enrolled in Children's Oncology Group GO-containing clinical trials and determined its correlation with disease characteristics and clinical outcome. CD33 expression varied more than 2-log fold; a median mean fluorescent intensity of 129 (range, 3-1550.07) was observed. Patients were divided into 4 quartiles, quartiles 1-4 (Q1-4) based on expression and disease characteristics and clinical response defined across quartiles. High CD33 expression was associated with high-risk FLT3/ITD mutations (P < .001) and was inversely associated with low-risk disease (P < .001). Complete remission (CR) rates were similar, but patients in Q4 had significantly lower overall survival (57% ± 16% vs 77% ± 7%, P = .002) and disease-free survival from CR (44% ± 16% vs 62% ± 8%, P = .022). In a multivariate model, high CD33 expression remained a significant predictor of overall survival (P = .011) and disease-free survival (P = .038) from CR. Our findings suggest that CD33 expression is heterogeneous within de novo pediatric AML. High expression is associated with adverse disease features and is an independent predictor of inferior outcome. The correlation between CD33 expression and GO response is under investigation. These studies are registered at www.clinicaltrials.gov as NCT00070174 and NCT00372593.
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http://dx.doi.org/10.1182/blood-2011-12-398370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335378PMC
April 2012

WT1 synonymous single nucleotide polymorphism rs16754 correlates with higher mRNA expression and predicts significantly improved outcome in favorable-risk pediatric acute myeloid leukemia: a report from the children's oncology group.

J Clin Oncol 2011 Feb 28;29(6):704-11. Epub 2010 Dec 28.

Fred Hutchinson Cancer Research Center, D2-373, 1100 Fairview Ave N, Seattle, WA 98103, USA.

Purpose: To analyze the prevalence and clinical implications of Wilms' tumor 1 (WT1) single nucleotide polymorphism (SNP) rs16754 in the context of other prognostic markers in pediatric acute myeloid leukemia (AML).

Patients And Methods: Available diagnostic marrow specimens (n = 790) from 1,328 patients enrolled in three consecutive Children's Cancer Group/Children's Oncology Group trials were analyzed for the presence of SNP rs16754. SNP status was correlated with disease characteristics, WT1 expression level, and clinical outcome.

Results: SNP rs16754 was present in 229 (29%) of 790 patients. The SNP was significantly more common in Asian and Hispanic patients and less common in white patients (P < .001). SNP rs16754 was also less common in patients with inv(16) (P = .043) and more common in patients with -5/del(5q) (P = .047). WT1 expression levels were significantly higher in patients with rs16754 or with WT1 mutations compared with WT1 wild-type patients (P = .021). Five-year overall survival (OS) for patients with and without the SNP was 60% and 50%, respectively (P = .031). Prognostic assessment by risk group demonstrated that in patients with low-risk disease, OS for those with and without SNP rs16754 was 90% versus 64% (P < .001) with a corresponding disease-free survival of 72% versus 53% (P = .041).

Conclusion: The presence of SNP rs16754 was an independent predictor of improved OS; outcome differences were most pronounced in the low-risk subgroup. The high prevalence of WT1 SNP rs16754, and its correlation with improved outcome, identifies WT1 SNP rs16754 as a potentially important molecular marker of prognosis in pediatric AML.
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http://dx.doi.org/10.1200/JCO.2010.31.9327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3056655PMC
February 2011

The role of competition in word learning via referent selection.

Dev Sci 2010 Sep;13(5):706-13

Department of Psychology, University of Sussex, UK.

Previous research suggests that competition among the objects present during referent selection influences young children's ability to learn words in fast mapping tasks. The present study systematically explored this issue with 30-month-old children. Children first received referent selection trials with a target object and either two, three or four competitor objects. Then, after a short delay, children were tested on their ability to retain the newly fast-mapped names. Overall, the number of competitors did not affect children's ability to form the initial name-object mappings. However, only children who encountered few competitors during referent selection demonstrated significant levels of retention. Results and implications are discussed in terms of the role of competition in studies of children's fast mapping. The relationship between referent selection and full word learning is also discussed.
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http://dx.doi.org/10.1111/j.1467-7687.2009.00926.xDOI Listing
September 2010

Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group.

Blood 2010 Aug 22;116(5):702-10. Epub 2010 Apr 22.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Recent studies of WT1 mutations in acute myeloid leukemia (AML) mostly report an association with unfavorable clinical outcome. We screened 842 patients treated on 3 consecutive pediatric AML trials for WT1 zinc-finger mutations. Eighty-five mutations were detected in 70 of 842 patients (8.3%). Mutations occurred predominantly in exon 7 (n = 74) but were also found in exons 8 (n = 5) and 9 (n = 6). Normal karyotype was observed in 35.3% of WT1(mut) patients, whereas 27.5% WT1(mut) patients harbored favorable risk cytogenetics. Patients with or without mutations had similar rates of complete remission after one course of induction chemotherapy. Overall survival (OS) for patients with WT1 mutations was 41% versus 54% for those without mutations (P = .016). Corresponding event-free survival (EFS) was also significantly worse for those with WT1 mutations (28% vs 42%; P = .01). However, FLT3/ITD was present in 36% of the WT1(mut) cohort; WT1(mut) patients without FLT3/ITD had similar OS (56% vs 56%, respectively; P = .8) and EFS (35% and 44%, respectively; P = .34) to patients who were wild type for both mutations. In current risk stratification schemes incorporating cytogenetics and FLT3/ITD status, the presence of WT1 mutations has no independent prognostic significance in predicting outcome in pediatric AML. The clinical trials are registered at www.clinicaltrials.gov as #NCT00002798 and #NCT00070174.
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http://dx.doi.org/10.1182/blood-2010-02-268953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918327PMC
August 2010

Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML.

Blood 2010 Mar 7;115(12):2372-9. Epub 2010 Jan 7.

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML). However, their prevalence and prognostic significance in pediatric CBF AML is not well established. We performed KIT mutational analysis (exon 8 and exon 17) on diagnostic specimens from 203 pediatric patients with CBF AML enrolled on 4 pediatric AML protocols. KIT mutations were detected in 38 (19%) of 203 (95% CI, 14%-25%) patient samples of which 20 (52.5%) of 38 (95% CI, 36%-69%) involved exon 8, 17 (45%) of 38 (95% CI, 29%-62%) involved exon 17, and 1 (2.5%; 95% CI, 0%-14%) involved both locations. Patients with KIT mutations had a 5-year event-free survival of 55% (+/- 17%) compared with 59% (+/- 9%) for patients with wild-type KIT (P = .86). Rates of complete remission, overall survival, disease-free survival, or relapse were not significantly different for patients with or without KIT mutations. Location of the KIT mutation and analysis by cytogenetic subtype [t(8;21) vs inv(16)] also lacked prognostic significance. Our study shows that KIT mutations lack prognostic significance in a large series of pediatric patients with CBF AML. This finding, which differs from adult series and a previously published pediatric study, may reflect variations in therapeutic approaches and/or biologic heterogeneity within CBF AML. Two of 4 studies included in this analysis are registered at http://clinicaltrials.gov as NCT00002798 (CCG-2961) and NCT00070174 (COG AAML03P1).
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http://dx.doi.org/10.1182/blood-2009-09-241075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845895PMC
March 2010

FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia.

Blood 2006 Oct 29;108(8):2764-9. Epub 2006 Jun 29.

Fred Hutchinson Cancer Research Center, Clinical Research Division, D2-373, 1100 Fairview Ave N, Seattle, WA 98109, USA.

Acute myeloid leukemia (AML) is a clonal disease characterized by heterogeneous involvement of hematopoietic stem cell/progenitor cell populations. Using FLT3 internal tandem duplication (FLT3/ITD) as a molecular marker, we tested the hypothesis that clinical outcome in AML correlates with disease involvement of CD34(+)/CD33(-) precursors. Diagnostic specimens from 24 children with FLT3/ITD-positive AML were sorted by fluorescence-activated cell sorting (FACS), and resultant CD34(+)/CD33(-) and CD34(+)/CD33(+) progenitors were analyzed directly and after colony-forming cell (CFC) assay for the presence of FLT3/ITD. FLT3/ITD was present in all CD34(+)/CD33(+) patient samples. In contrast, FLT3/ITD was detected in CD34(+)/CD33(-) progenitors in only 19 of 24 samples. A bipotent progenitor was affected in a subset of patients, as evidenced by the presence of FLT3/ITD in both granulocyte-macrophage colony-forming unit (CFU-GM) and erythroid burst-forming unit (BFU-E) colonies. Those patients in whom CD34(+)/CD33(-) precursors harbored the FLT3/ITD had worse clinical outcome; actuarial event-free survival (EFS) at 4 years from study entry for those patients with and without FLT3/ITD detection in CD34(+)/CD33(-) progenitors was 11% +/- 14% versus 100% +/- 0%, respectively (P = .002). This study suggests that FLT3/ITD involvement in CD34(+)/CD33(-) precursors is heterogeneous and that detection of the mutation in the less-mature progenitor population may be associated with disease resistance.
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http://dx.doi.org/10.1182/blood-2006-04-012260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895585PMC
October 2006
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