Publications by authors named "Elly Barry"

15 Publications

  • Page 1 of 1

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

Eur J Cancer 2021 Nov 15;157:198-213. Epub 2021 Sep 15.

Hospital for Sick Children, Toronto, Canada.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.
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http://dx.doi.org/10.1016/j.ejca.2021.08.022DOI Listing
November 2021

Navigating the Regulatory Landscape to Develop Pediatric Oncology Drugs: Expert Opinion Recommendations.

Paediatr Drugs 2021 Jul 26;23(4):381-394. Epub 2021 Jun 26.

Pfizer Inc, New York, NY, USA.

Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials.
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http://dx.doi.org/10.1007/s40272-021-00455-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275539PMC
July 2021

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Eur J Cancer 2020 09 17;136:116-129. Epub 2020 Jul 17.

FORMA Therapeutics, USA.

Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives.

Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents.

Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field.

Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.
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http://dx.doi.org/10.1016/j.ejca.2020.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789799PMC
September 2020

ACCELERATE and European Medicines Agency Paediatric Strategy Forum for medicinal product development of checkpoint inhibitors for use in combination therapy in paediatric patients.

Eur J Cancer 2020 03 24;127:52-66. Epub 2020 Jan 24.

BMS, USA.

The third multistakeholder Paediatric Strategy Forum organised by ACCELERATE and the European Medicines Agency focused on immune checkpoint inhibitors for use in combination therapy in children and adolescents. As immune checkpoint inhibitors, both as monotherapy and in combinations have shown impressive success in some adult malignancies and early phase trials in children of single agent checkpoint inhibitors have now been completed, it seemed an appropriate time to consider opportunities for paediatric studies of checkpoint inhibitors used in combination. Among paediatric patients, early clinical studies of checkpoint inhibitors used as monotherapy have demonstrated a high rate of activity, including complete responses, in Hodgkin lymphoma and hypermutant paediatric tumours. Activity has been very limited, however, in more common malignancies of childhood and adolescence. Furthermore, apart from tumour mutational burden, no other predictive biomarker for monotherapy activity in paediatric tumours has been identified. Based on these observations, there is collective agreement that there is no scientific rationale for children to be enrolled in new monotherapy trials of additional checkpoint inhibitors with the same mechanism of action of agents already studied (e.g. anti-PD1, anti-PDL1 anti-CTLA-4) unless additional scientific knowledge supporting a different approach becomes available. This shared perspective, based on scientific evidence and supported by paediatric oncology cooperative groups, should inform companies on whether a paediatric development plan is justified. This could then be proposed to regulators through the available regulatory tools. Generally, an academic-industry consensus on the scientific merits of a proposal before submission of a paediatric investigational plan would be of great benefit to determine which studies have the highest probability of generating new insights. There is already a rationale for the evaluation of combinations of checkpoint inhibitors with other agents in paediatric Hodgkin lymphoma and hypermutated tumours in view of the activity shown as single agents. In paediatric tumours where no single agent activity has been observed in multiple clinical trials of anti-PD1, anti-PDL1 and anti-CTLA-4 agents as monotherapy, combinations of checkpoint inhibitors with other treatment modalities should be explored when a scientific rationale indicates that they could be efficacious in paediatric cancers and not because these combinations are being evaluated in adults. Immunotherapy in the form of engineered proteins (e.g. monoclonal antibodies and T cell engaging agents) and cellular products (e.g. CAR T cells) has great therapeutic potential for benefit in paediatric cancer. The major challenge for developing checkpoint inhibitors for paediatric cancers is the lack of neoantigens (based on mutations) and corresponding antigen-specific T cells. Progress critically depends on understanding the immune macroenvironment and microenvironment and the ability of the adaptive immune system to recognise paediatric cancers in the absence of high neoantigen burden. Future clinical studies of checkpoint inhibitors in children need to build upon strong biological hypotheses that take into account the distinctive immunobiology of childhood cancers in comparison to that of checkpoint inhibitor responsive adult cancers.
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http://dx.doi.org/10.1016/j.ejca.2019.12.029DOI Listing
March 2020

Population Pharmacokinetics of Gemtuzumab Ozogamicin in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia.

Clin Pharmacokinet 2019 02;58(2):271-282

Clinical Pharmacology, Oncology, Global Product Development, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA.

Background And Objective: To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study.

Methods: The pharmacokinetics (PK) of GO, as represented by total hP67.6 antibody, were described by a two-compartment model with two clearance components: a linear clearance (CL) and time-dependent clearance that includes a decay coefficient. The PK of unconjugated calicheamicin (UC; payload) were described by a two-compartment model with CL and an input rate of formation based on antibody rate of elimination. Allometric scaling was included in both models, with baseline body weight as a fixed effect on CL and central volume.

Results And Conclusions: PK parameters for hP67.6 and UC were not significantly affected by any of the available demographic factors and safety laboratory values tested as covariates (except baseline body weight). Simulations to compare GO dosing regimens (6, 7.5, and 9 mg/m on days 1 and 15 versus, 3 mg/m fractionated dosing on days 1, 4, and 7) were performed, showing that total antibody and UC trough concentrations were maintained at higher concentrations during treatment following the more frequent dosing than following the original regimen.

Study Identifier: 0903A1-102-US.
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http://dx.doi.org/10.1007/s40262-018-0694-xDOI Listing
February 2019

Effects of Bosutinib Treatment on Renal Function in Patients With Philadelphia Chromosome-Positive Leukemias.

Clin Lymphoma Myeloma Leuk 2017 10 17;17(10):684-695.e6. Epub 2017 Jun 17.

Winship Cancer Institute of Emory University, Atlanta, GA.

Background: The purpose of the study was to assess renal function in patients with Philadelphia chromosome-positive leukemias receiving bosutinib or imatinib.

Patients And Methods: Patients received first-line bosutinib (n = 248) or imatinib (n = 251; phase III trial), or second-line or later bosutinib (phase I/II trial; n = 570). Adverse events (AEs) and changes from baseline in estimated glomerular filtration rate (eGFR) and serum creatinine were assessed.

Results: Time from the last patient's first dose to data cutoff was ≥ 48 months. Renal AEs were reported in 73/570 patients (13%) receiving second-line or later bosutinib, and in 22/248 (9%) and 16/251 (6%) receiving first-line bosutinib and imatinib, respectively. eGFR in patients receiving bosutinib declined over time with more patients developing Grade ≥ 3b eGFR (< 45 mL/min/1.73 m according to the Modification of Diet in Renal Disease method) with second-line or later bosutinib (139/570, 24%) compared with first-line bosutinib (26/248, 10%) and imatinib (25/251, 10%); time to Grade ≥ 3b eGFR was shortest with second-line or later bosutinib. Similar proportions of patients receiving second-line or later bosutinib (74/139, 53%), first-line bosutinib (15/26, 58%), and first-line imatinib (15/25, 60%) improved to ≥ 45 mL/min/1.73 m eGFR as of the last follow-up. In a regression analysis, first-line treatment with bosutinib versus imatinib was not a significant predictor of Grade ≥ 3b eGFR.

Conclusion: Long-term bosutinib treatment is associated with an apparently reversible decline in renal function with frequency and characteristics similar to renal decline observed with long-term imatinib treatment. Patients with risk factors for Grade ≥ 3b eGFR should be monitored closely.
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http://dx.doi.org/10.1016/j.clml.2017.06.001DOI Listing
October 2017

Clofarabine in pediatric acute leukemia: current findings and issues.

Pediatr Blood Cancer 2012 Sep 21;59(3):417-22. Epub 2012 Feb 21.

Northwestern University Feinberg School of Medicine and Division of Pediatric Hematology-Oncology, Children's Memorial Hospital, Chicago, Illinois 60614-3394, USA.

Clofarabine is a second-generation purine nucleoside analog and has significant anti-leukemic activity as a single agent. It is approved by the United States Food and Drug Administration (FDA) for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children. Combinations of clofarabine with purine nucleoside analogs or DNA-damaging agents have been investigated utilizing synergistic effects and now tested in a number of studies including a frontline study. In this article, we review the development of clofarabine, rationale and history of combination regimens, and their potential roles and toxicities in the treatment of pediatric ALL that are important to treating clinicians.
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http://dx.doi.org/10.1002/pbc.24112DOI Listing
September 2012

Phase 2 trial of clofarabine in combination with etoposide and cyclophosphamide in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.

Blood 2011 Dec 3;118(23):6043-9. Epub 2011 Oct 3.

Department of Pediatric Hematology-Oncology, Children's Memorial Hospital and Northwestern University Feinberg School of Medicine, Chicago, IL 60614-3394, USA.

The outcomes in children with refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) are dismal. The efficacy and safety of intravenous clofarabine 40 mg/m(2) per day, cyclophosphamide 440 mg/m(2) per day, and etoposide 100 mg/m(2) per day for 5 consecutive days in pediatric patients with R/R ALL was evaluated in this phase 2 study. The primary endpoint was overall response rate (complete remission [CR] plus CR without platelet recovery [CRp]). Among the 25 patients (median age, 14 years; pre-B cell ALL, 84%; ≥ 2 prior regimens: 84%; refractory to previous regimen: 60%), the overall response rate was 44% (7 CR, 4 CRp) with a 67.3-week median duration or remission censored at last follow-up. Most patients proceeded to alternative therapy, and 10 patients (40%) received hematopoietic stem cell transplantation. Six patients (24%) died because of treatment-related adverse events associated with infection, hepatotoxicity, and/or multiorgan failure. The study protocol was amended to exclude patients with prior hematopoietic stem cell transplantation after 4 of the first 8 patients developed severe hepatotoxicity suggestive of veno-occlusive disease. No additional cases of veno-occlusive disease occurred. The regimen offered encouraging response rates and sustained remission in R/R patients. Future investigation should include exploration of patient selection, dosing, and supportive care. This trial was registered at www.clinicaltrials.gov as #NCT00315705.
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http://dx.doi.org/10.1182/blood-2011-08-374710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731655PMC
December 2011

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.

Lancet Oncol 2010 Oct 16;11(10):950-61. Epub 2010 Sep 16.

University of Miami, Leonard M Miller School of Medicine, Miami, FL, USA.

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, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(10)70204-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756093PMC
October 2010

Tolerability of pravastatin in pediatric hematopoietic stem cell transplant patients with bronchiolitis obliterans.

J Pediatr Hematol Oncol 2010 Apr;32(3):185-8

Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Pravachol and other statins have immune modulatory effects and have been shown to decrease the incidence of bronchiolitis obliterans (BrOb) in lung transplant recipients. It may also be useful in the treatment or prevention of hematopoietic stem cell transplant (HSCT) associated bronchiolitis obliterans. However, the safety of pravachol has not been shown in pediatric patients with BrOb after HSCT. We report on the safety and tolerability in 5 pediatric HSCT patients with established BrOb. All participants tolerated the drug without difficulty and there were no pravachol-associated adverse effects. Changes in creatine kinase (CK) and transaminases were minimal in 4 patients. One patient experienced increased CK and alanine aminotransferase, and a decrease in platelet count in the setting of severe systemic illness. No other patient had a clinically relevant change in white blood cell count, platelet count, or hemoglobin. Pravachol was well tolerated and safe in this group of patients, and merits further study in this patient population.
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http://dx.doi.org/10.1097/MPH.0b013e3181d32184DOI Listing
April 2010

Acute lymphoblastic leukemia in adolescents and young adults.

Curr Hematol Malig Rep 2008 Jul;3(3):161-6

Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

Age at diagnosis remains one of the strongest prognostic factors in acute lymphoblastic leukemia (ALL), with older patients having inferior outcomes compared with younger patients. Adolescents and young adults (AYAs) with ALL (age 15-30 years) represent a patient subgroup with distinctive biology whose optimal therapy has yet to be determined. Compared with younger children with ALL, AYAs are more likely to present with unfavorable presenting characteristics (such as high presenting leukocyte counts, T-cell phenotype, and the Philadelphia chromosome). Additionally, AYAs with ALL experience more regimen-related toxicity than younger patients. Recent retrospective studies suggest that patients age 15 to 21 years treated on pediatric ALL regimens have better outcomes than similarly aged patients treated on adult ALL regimens. Pilot prospective studies are under way to test the feasibility of administering pediatric ALL regimens to AYAs with ALL, with promising preliminary results.
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http://dx.doi.org/10.1007/s11899-008-0023-9DOI Listing
July 2008

Absence of secondary malignant neoplasms in children with high-risk acute lymphoblastic leukemia treated with dexrazoxane.

J Clin Oncol 2008 Mar;26(7):1106-11

Departments of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA.

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 Hodgkin's 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.
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http://dx.doi.org/10.1200/JCO.2007.12.2481DOI Listing
March 2008

Uniform sensitivity of FLT3 activation loop mutants to the tyrosine kinase inhibitor midostaurin.

Blood 2007 Dec 7;110(13):4476-9. Epub 2007 Sep 7.

Dana-Farber Cancer Institute, Department of Pediatric Oncology, Boston, MA 02115, USA.

Small molecule inhibitors that target fms-like tyrosine kinase 3 (FLT3)-activating mutations have potential in the treatment of leukemias. However, certain mutations can simultaneously activate the tyrosine kinase, and confer resistance to small molecule inhibitors. We therefore tested the sensitivity of 8 FLT3 activation loop mutants to midostaurin. Each mutant conferred IL-3 factor-independent proliferation to Ba/F3 cells, and each resulted in the constitutive activation of FLT3 and its targets, signal transducer and activator of transcription 5 (STAT5) and extracellular stimuli-responsive kinase (ERK). For each mutant tested, midostaurin inhibited cell growth and phosphorylation of FLT3, STAT5, and ERK. In contrast, midostaruin did not inhibit Ba/F3 cells stably transduced with FLT3-internal tandem duplications containing a G697R mutation that confers resistance to midostaurin, demonstrating that midostaurin inhibition of FLT3 activation loop mutants was not due to off-target effects. We conclude that midostaurin is a potent inhibitor of a spectrum of FLT3 activation loop mutations, and that acute myeloid leukemia patients with such mutations are potential candidates for clinical trials involving midostaurin.
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http://dx.doi.org/10.1182/blood-2007-07-101238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2234789PMC
December 2007

Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management.

Expert Opin Pharmacother 2007 Jun;8(8):1039-58

Department of Pediatric Oncology, Dana-Farber Cancer Institute/Children's Hospital, Boston/Harvard Medical School, 44 Binney Street, 3rd Floor, Boston, MA 02115, USA.

Although effective anti-neoplastic agents, anthracyclines are limited by their well recognized and pervasive cardiotoxic effects. The incidence of late progressive cardiovascular disease in long-term survivors of cancer is established and may contribute to heart failure and death. To maximize the benefits of these drugs, a high-risk population has been identified and new strategies have been investigated to minimize toxic effects, including limiting the cumulative dose, controlling the rate of administration and using liposomal preparations and novel anthracycline analogues. Dexrazoxane also shows promise as a cardioprotectant during treatment. This paper reviews these strategies, as well as medications used to manage anthracycline-induced cardiotoxicity, and functional and biochemical means of monitoring cardiotoxicity, including echocardiography, radionuclide scans and biomarker analysis. The treatment of adult cancer survivors who have had anthracycline-related cardiotoxicity has not been systematically studied. Empirically, anthracycline-associated cardiac dysfunction is treated very similarly to other forms of heart failure. These treatments include avoiding additional cardiotoxic regimens, controlling hypertension, lifestyle changes, medications and heart transplantation.
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http://dx.doi.org/10.1517/14656566.8.8.1039DOI Listing
June 2007

Favorable outcome for adolescents with acute lymphoblastic leukemia treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium Protocols.

J Clin Oncol 2007 Mar;25(7):813-9

Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Purpose: Historically, adolescents with acute lymphoblastic leukemia (ALL) have had inferior outcomes when compared with younger children. We report the outcome of adolescents treated on Dana-Farber Cancer Institute (DFCI; Boston, MA) ALL Consortium Protocols conducted between 1991 and 2000.

Patients And Methods: A total of 844 patients aged 1 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI-ALL Consortium Protocols. We compared outcomes in three age groups: children aged 1 to 10 years (n = 685), young adolescents aged 10 to 15 years (n = 108), and older adolescents aged 15 to 18 years (n = 51).

Results: With a median follow-up of 6.5 years, the 5-year event-free survival (EFS) for those aged 1 to 10 years was 85% (SE, 1%), compared with 77% (SE, 4%) for those aged 10 to 15 years, and 78% (SE, 6%) for those aged 15 to 18 years (P = .09). Adolescents were more likely to present with T-cell phenotype (P < .001) and less likely to have the TEL-AML1 fusion (P = .05). The incidence of pancreatitis and thromboembolic complications, but not asparaginase allergy, was higher in patients 10 years of age compared with those younger than 10 years. However, there was no difference in the rate of treatment-related complications between the 10- to 15-year and 15- to 18-year age groups.

Conclusion: Adolescents were more likely to present at diagnosis with biologically higher risk disease (T-cell phenotype and absence of the TEL-AML1 fusion) and more likely to experience treatment-related complications than younger children. However, the 5-year EFS for older adolescents was 78% +/- 6%, which is superior to published outcomes for similarly aged patients treated with other pediatric and adult ALL regimens. Based on this experience, we currently are piloting our regimen in patients aged 18 to 50 years.
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http://dx.doi.org/10.1200/JCO.2006.08.6397DOI Listing
March 2007
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