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  • 1
    Language: English
    In: Clinical cancer research, 2017-02-15, Vol.23 (4), p.1012-1024
    Description: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease. We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity. We first determined that both -mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice. We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. .
    Subject(s): Aminopyridines - administration & dosage ; Dexamethasone - administration & dosage ; Cyclin-Dependent Kinase 4 - genetics ; Humans ; Everolimus - administration & dosage ; Purines - administration & dosage ; Drug Synergism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; Xenograft Model Antitumor Assays ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Animals ; TOR Serine-Threonine Kinases - genetics ; T-Lymphocytes - drug effects ; Cell Line, Tumor ; Mice ; T-Lymphocytes - pathology ; Cyclin-Dependent Kinase 4 - antagonists & inhibitors ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Index Medicus
    ISSN: 1078-0432
    E-ISSN: 1557-3265
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 2
    Language: English
    In: The lancet oncology, 2015, Vol.16 (16), p.1677-1690
    Description: Summary Background l -asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli ( E coli ) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E coli l -asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. Methods DFCI 05-001 enrolled patients aged 1–18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m2 every 2 weeks) or intramuscular native E coli l -asparaginase (30 doses of 25 000 IU/m2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00400946. Findings Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E coli l -asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E coli l -asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0–7·1). 5-year disease-free survival was 90% (95% CI 86–94) for patients assigned to intravenous PEG-asparaginase and 89% (85–93) for those assigned to intramuscular native E coli l -asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E coli l -asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E coli l -asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E coli l -asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Interpretation Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E coli l -asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. Funding National Cancer Institute and Enzon Pharmaceuticals.
    Subject(s): Hematology, Oncology and Palliative Medicine ; Age Factors ; United States ; Humans ; Child, Preschool ; Polyethylene Glycols - adverse effects ; Infant ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - mortality ; Antineoplastic Agents - administration & dosage ; Escherichia coli Proteins - adverse effects ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Asparaginase - adverse effects ; Escherichia coli Proteins - administration & dosage ; Time Factors ; Antineoplastic Agents - adverse effects ; Female ; Surveys and Questionnaires ; Child ; Escherichia coli - enzymology ; Risk Factors ; Kaplan-Meier Estimate ; Proportional Hazards Models ; Treatment Outcome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis ; Injections, Intramuscular ; Polyethylene Glycols - administration & dosage ; Asparaginase - administration & dosage ; Canada ; Disease-Free Survival ; Administration, Intravenous ; Adolescent ; Intention to Treat Analysis ; Quality of Life ; Medical colleges ; Escherichia coli ; Index Medicus
    ISSN: 1470-2045
    E-ISSN: 1474-5488
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 3
    Language: English
    In: Journal of clinical oncology, 2013-05-20, Vol.31 (15), p.1893-1903
    Description: The somatic genomic alterations in pediatric cancers to some extent overlap with those seen in adult cancers, but the exact distribution throughout the genome and the types and frequency of alterations differ. The ultimate goal of genomic research in children, as with adults, is translation to the clinic to achieve more accurate diagnosis, more precise risk stratification, and more effective, less toxic therapy. The genomic features of pediatric malignancies and pediatric-specific issues in clinical investigation may make translating genomic discoveries to the clinic more difficult. However, through large-scale molecular profiling of pediatric tumors, continued coordinated efforts to evaluate novel therapies in the pediatric population, thoughtful phase II and III trial design, and continued drug development, genomically based therapies will become more common in the pediatric oncology clinic in the future.
    Subject(s): Pediatrics - trends ; Medical Oncology - methods ; Humans ; Neoplasms - diagnosis ; Translational Medical Research - trends ; Forecasting ; Neoplasms - therapy ; Clinical Trials as Topic - trends ; Neoplasms - genetics ; Medical Oncology - trends ; Pediatrics - methods ; Clinical Trials as Topic - methods ; Research Design - trends ; Genomics - methods ; Translational Medical Research - methods ; Child ; Genomics - trends
    ISSN: 0732-183X
    E-ISSN: 1527-7755
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 4
    Language: English
    In: Leukemia, 2018-11, Vol.32 (11), p.2316-2325
    Description: The survival of pediatric patients with multiply relapsed and/or refractory (R/R) B-cell acute lymphoblastic leukemia has historically been very poor; however, data are limited in the current era. We conducted a retrospective study to determine the outcome of multiply R/R childhood B-ALL treated at 24 TACL institutions between 2005 and 2013. Patient information, treatment, and response were collected. Prognostic factors influencing the complete remission (CR) rate and event-free survival (EFS) were analyzed. The analytic set included 578 salvage treatment attempts among 325 patients. CR rates (mean ± SE) were 51 ± 4% for patients with bone marrow R/R B-ALL who underwent a second salvage attempt, 37 ± 6% for a third attempt, and 31 ± 6% for the fourth through eighth attempts combined. For patients achieving a CR after their second, third, and fourth through eighth attempts, the 2 year EFS was 41 ± 6%, 13 ± 7%, and 27 ± 13% respectively. Our results showed slight improvement when compared to previous studies. This is the largest and most recent study to date that evaluates the outcome of this patient population. Our data will provide detailed reference for the evaluation of new agents being developed for childhood B-ALL.
    ISSN: 0887-6924
    E-ISSN: 1476-5551
    Source: Nature Open Access
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 5
    Language: English
    In: Pediatric blood & cancer, 2019-04, Vol.66 (4), p.e27568-n/a
    Description: Background Bacillus species are known to cause severe infection in immunocompromised hosts. The incidence of Bacillus bloodstream infections and characteristics of infection among children with cancer or indication for hematopoietic cell transplant (HCT) is unknown. Methods We performed a retrospective medical record review of all cases of Bacillus bacteremia between January 1, 2005, and December 31, 2014, at Boston Children's Hospital. We report average incidences from 2012 to 2014. We performed a detailed review of infections among children with cancer or undergoing HCT and a case–control study to evaluate whether neutropenia at diagnosis caries higher risk of Bacillus infection for children with acute lymphoblastic leukemia (ALL). Results One hundred fourteen children developed Bacillus bacteremia during the study period, with an estimated incidence of 0.27/1,000 patients. Among children treated for cancer or undergoing HCT, there were 37 bloodstream infections (2.0/1,000 patients). Of the 37 oncology/HCT patients, oncologic diagnoses included ALL (18), acute myeloid leukemia (3), myelodysplastic syndrome (1), solid tumors (8), and 7 children were undergoing HCT. The incidence of infection among children with ALL was 34/1,000 patients and all central nervous system (CNS) infections (6) and deaths (3) occurred in this population. Neutropenia at time of diagnosis in children with ALL was not associated with risk of infection (P = 0.17). Discussion We report the first hospital‐wide analysis of Bacillus infection and found that immunocompromised children experience a significant proportion of Bacillus infections. Children with ALL have a high incidence of infection and are at higher risk of CNS involvement and death.
    Subject(s): tumors ; leukemias ; solid ; Acute lymphoblastic leukemia ; infectious diseases ; BMT ; bacillus ; oncology ; Hematologic Neoplasms - therapy ; Neutropenia - epidemiology ; Humans ; Child, Preschool ; Hematopoietic Stem Cell Transplantation ; Infant ; Male ; Hematologic Neoplasms - epidemiology ; Incidence ; Neutropenia - etiology ; Adolescent ; Bacillus ; Adult ; Bacteremia - epidemiology ; Female ; Retrospective Studies ; Child ; Pediatrics ; Communicable diseases ; Analysis ; Leukemia ; Oncology, Experimental ; Medical records ; Transplantation ; Children ; Research ; Hematopoietic stem cells ; Cancer ; Index Medicus
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    Source: Alma/SFX Local Collection
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 6
    Language: English
    In: Pediatric blood & cancer, 2018-07, Vol.65 (7), p.e27062-n/a
    Description: Background We sought to determine the feasibility of co‐administering everolimus with a four‐drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. Procedure This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring 〉18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2/day). Additional patients were enrolled at the 3‐ and 5 mg/m2/day DLs to further evaluate toxicity (dose expansion). Results Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose‐limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2/day). The most common grade ≥3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end‐reinduction minimal residual disease (MRD) level (≤10−3 by polymerase chain reaction–based assay). The CR2 rate for patients with B‐cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. Conclusions Everolimus combined with four‐drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end‐reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four‐drug reinduction is 5 mg/m2/day. This promising combination should be further evaluated in a larger patient cohort.
    Subject(s): relapsed acute lymphoblastic leukemia ; mTOR inhibitor ; developmental therapeutics ; Anthracyclines ; Relapse ; Chemotherapy ; Corticosteroids ; Clinical trials ; Product development ; Acute lymphocytic leukemia ; Diseases ; Cancer
    ISSN: 1545-5009
    E-ISSN: 1545-5017
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: The lancet oncology, 2015-12, Vol.16 (16), p.1677-1690
    Description: l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. DFCI 05-001 enrolled patients aged 1–18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m2 every 2 weeks) or intramuscular native E colil-asparaginase (30 doses of 25 000 IU/m2 weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E colil-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E colil-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0–7·1). 5-year disease-free survival was 90% (95% CI 86–94) for patients assigned to intravenous PEG-asparaginase and 89% (85–93) for those assigned to intramuscular native E colil-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E colil-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. National Cancer Institute and Enzon Pharmaceuticals.
    ISSN: 1470-2045
    E-ISSN: 1474-5488
    Source: Alma/SFX Local Collection
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  • 8
    Language: English
    In: Cancer medicine (Malden, MA), 2021-04, Vol.10 (7), p.2310-2318
    Description: Background Single patient Investigational New Drug (IND) applications are one mechanism through which experimental therapies are accessed for children with cancer. The landscape of use, outcomes, and toxicity from single patient INDs remains unknown in pediatric oncology. Methods We performed a retrospective analysis of all single patient INDs requested and prescribed at a single institution between 1/1/2007 and 5/1/2019. We report aggregate data from the US Food and Drug Administration (FDA) on single patient IND applications over the final two years of the study (2017–2019). We report an overview of all IND applications, as well as clinical descriptions of patients, treatments, outcomes, and toxicity. Results Over the 2‐year period, the FDA approved all 171 submitted single patient IND requests for pediatric oncology. We identified 56 requests from our center during the 12‐year study period, and all were approved (median time from FDA submission to approval: 1 day (range 0–12)). 71% of requests were based on disease histology. Lack of pediatric clinical trial (65%) was the most common reason for use. 48 approved requests were ultimately administered. The median duration of treatment was 84 days (range: 4–1590), with 3 patients remaining on treatment at time of analysis. Only 7% discontinued treatment due to toxicity. Three‐year overall survival was 50% (95% CI, 35–64). Conclusions Single patient INDs in pediatric oncology were universally approved in our national and single‐center analysis. In our cohort, single patient INDs were primarily utilized based on disease histology, rather than genomics, for agents that lacked a clinical trial. Single patient Investigational New Drug (IND) applications in pediatric oncology are universally approved in a timely fashion in our analysis. Single patient IND therapy is pursued for a range of reasons, with few patients discontinuing therapy due to toxicity.
    Subject(s): single patient IND ; FDA ; pediatric oncology ; investigational new drug ; IND ; Clinical trials ; Pediatrics ; Drug approval ; Analysis ; Toxicity ; Brain cancer ; Medical records ; Oncology ; FDA approval ; Patients ; Cancer therapies ; Children & youth ; Chemotherapy ; Hospitals ; Drug dosages ; Age ; Tumors ; Index Medicus
    ISSN: 2045-7634
    E-ISSN: 2045-7634
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Directory of Open Access Journals
    Source: EBSCOhost EJS
    Source: © ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
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  • 9
    Language: English
    In: Clinical cancer research, 2003-07-01, Vol.9 (7), p.2798-2806
    Description: 1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a novel synthetic triterpenoid more potent than its parent compound, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), both in vitro and in vivo . CDDO-Im is highly active in suppressing cellular proliferation of human leukemia and breast cancer cell lines (IC 50 , ∼10–30 n m ). In U937 leukemia cells, CDDO-Im also induces monocytic differentiation as measured by increased cell surface expression of CD11b and CD36. In each of these assays, CDDO-Im is several-fold more active than CDDO. Although CDDO and CDDO-Im both bind and transactivate peroxisome proliferator-activated receptor (PPAR) γ, the irreversible PPARγ antagonist GW9662 does not block the ability of either CDDO or CDDO-Im to induce differentiation; moreover, PPARγ-null fibroblasts are still sensitive to the growth-suppressive effects of CDDO. Thus, CDDO-Im has significant actions independent of PPARγ transactivation. In addition, the rexinoid LG100268 and the deltanoid ILX23-7553 (ILX7553) synergize with CDDO and CDDO-Im to induce differentiation. In vivo , CDDO-Im is a potent inhibitor of de novo inducible nitric oxide synthase expression in primary mouse macrophages. Moreover, CDDO-Im inhibits growth of B16 murine melanoma and L1210 murine leukemia cells in vivo . The potent effects of CDDO-Im, both in vitro and in vivo , suggest it should be considered for clinical use.
    Subject(s): Biological and medical sciences ; Chemical agents ; Carcinogenesis, carcinogens and anticarcinogens ; Medical sciences ; Tumors ; Cholecalciferol - analogs & derivatives ; Models, Chemical ; Monocytes - cytology ; Humans ; Oleanolic Acid - analogs & derivatives ; Transcriptional Activation ; Oleanolic Acid - pharmacology ; Nitric Oxide Synthase Type II ; Dose-Response Relationship, Drug ; Flow Cytometry ; Time Factors ; U937 Cells ; Cell Division ; Inhibitory Concentration 50 ; Female ; Antineoplastic Agents - pharmacology ; Cell Differentiation ; Fibroblasts - metabolism ; Cell Separation ; Imidazoles - pharmacology ; Inflammation ; Neoplasms - drug therapy ; Transcription Factors - metabolism ; CD36 Antigens - biosynthesis ; Animals ; Cell Line, Tumor ; Mice ; Nitric Oxide Synthase - metabolism ; CD11b Antigen - biosynthesis ; Cholecalciferol - pharmacology ; Receptors, Cytoplasmic and Nuclear - metabolism
    ISSN: 1078-0432
    E-ISSN: 1557-3265
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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  • 10
    Language: English
    In: Blood, 2020-11-05, Vol.136 (Supplement 1), p.31-32
    Description: Background: Adolescent and young adult (AYA) patients (pts) with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. These regimens, which rely heavily on corticosteroids and asparaginase (asp), are known to increase the risk of osteonecrosis (ON). In children older than 10 years (yrs), reported rates of symptomatic ON range from 5-25% (Mattano JCO 2000, Mattano Lancet Onc 2012, Toft Eur J Haematol 2016, Larsen JCO 2016). In adults, the frequency of ON and fractures (fx) are not well described including among those treated on pediatric regimens. In the recently reported C10403 trial (Stock Blood 2019), a 4% rate of ON was reported among patients aged 17-39 yrs. Here, we describe the orthopedic toxicities of AYA pts treated on sequential Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Methods: Pts aged 1-50 yrs were treated on four sequential multi-center DFCI ALL Consortium protocols between 2000 and 2018. Additional pts treated as per these protocols at DFCI, Massachusetts General Hospital (MGH), and Boston Children's Hospital (BCH) were identified by chart review. Earlier pts were enrolled on parallel Pediatric 00-001 (2000-2004) and Adult 01-175 (2002-2008) trials while later pts were enrolled on parallel Pediatric 05-001 (2005-2011) and Adult 06-254 (2007-2011) trials. Protocol 00-001 randomized pts between dexamethasone (dex) and prednisone (pred) during consolidation, while the other three trials used dex (all trials used pred during induction). Both 00-001 and 01-175 used native E.Coli asp, while later protocols (05-001, 06-254) used PEG asp for some (05-001, randomized) or all (06-254) pts. All pts were intended to receive 30 weeks of asp during consolidation. Pts aged 15-50 yrs were included in this study. Orthopedic toxicities were extracted from case report forms for trial pts and by chart review for those not on trial. Additional chart review was performed on all pts treated at DFCI, MGH, and BCH to identify surgical events. All pts were combined in the modeling based on the treatment backbone. The 5-yr cumulative incidences (CIs) of ON and fx were estimated and compared using the Gray test. Univariate and multivariable competing risk regression models were constructed with death as a competing risk. Results: A total of 367 pts with a median age of 23 yrs (68% 〈 30 yrs) were identified. The majority (61%) of pts were male and the median BMI was 24.5 kg/m2 (46% overweight or obese). The median follow-up for pts remaining alive was 5 yrs (range, 0.01-14.1). In total, 60 pts experienced ON (5-yr CI 17%, [95% CI 13-22]) and 40 pts experienced fx (5-yr CI 12%, [8-15]). The median time to develop ON was 1.6 yrs (range, 0.5-7.7). The median time to fx was 1.4 yrs (range, 0.2-5.2). Pts 〈 30 yrs were significantly more likely to be diagnosed with ON (21%, [16-27]) compared to those aged 30-50 yrs (8%, [4-14], univariate HR 2.77 [1.35-5.65]; p=0.005). Pts treated on PEG-asp based protocols were significantly more likely to be diagnosed with ON (5-yr CI 24% [18-30]) compared to those treated on earlier trials with native E.coli asp (5-yr CI 5% [2-10], HR 5.28 [95% CI 2.24-12.48], p〈0.001). These results remained statistically significant in multivariate analysis including treatment backbone, age, BMI, and sex. BMI and sex were not associated with orthopedic toxicity, although there was a trend toward fewer fx in male pts (HR 0.55, [0.29-1.02]). Of the 54 ONs for which adequate information was available, surgery was performed in 25 (46%) and total joint replacement in 18 (33%). Of the 9 fx with adequate information, 3 (33%) required surgery. Conclusions: In a large cohort of AYA ALL pts aged 15-50 yrs treated on a pediatric regimen, orthopedic toxicities were common (17% for ON, 12% for fx at 5 yrs). Younger pts (〈 30 yrs) experienced higher rates of ON, as well as pts treated on later-generation PEG-asp protocols which combined dex and PEG asp. Increased rates of orthopedic toxicity in later generation protocols may be driven by the pharmacokinetic drug interaction between PEG asp and dex, leading to higher dex exposure (Yan JCO 2008, Panetta Clin Pharmacol Ther 2009). Increased awareness may be useful in early identification of orthopedic toxicities. Future efforts should focus on further understanding the pathophysiology and risk factors for orthopedic toxicity in ALL AYA regimens and developing prophylactic interventions. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board. Brunner:Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. DeAngelo:Blueprint Medicines Corporation: Consultancy, Research Funding; Forty-Seven: Consultancy; Jazz: Consultancy; Incyte Corporation: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Takeda: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy; Autolos: Consultancy; Agios: Consultancy; Pfizer: Consultancy.
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    Source: American Society of Hematology
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