Publications by authors named "Nobuko Hijiya"

60 Publications

Chronic Myelogenous Leukemia in Childhood.

Curr Oncol Rep 2021 Mar 14;23(4):40. Epub 2021 Mar 14.

Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, CCSR-1215C, 269 Campus Drive, Stanford, CA, USA.

Purpose Of Review: Chronic myelogenous leukemia (CML) is rare in children, requiring extrapolation from treatment of adults. In this review, we explore similarities and differences between adult and pediatric CML with a focus on therapeutic advances and emerging clinical questions.

Recent Findings: Pediatric CML is effectively treated with long-term targeted therapy using tyrosine kinase inhibitors (TKIs). Newly diagnosed pediatric patients in chronic phase can now be treated with imatinib, dasatinib, or nilotinib without allogeneic hematopoietic stem cell transplantation. While treatment-free remission is possible in adults in chronic phase with optimal response to therapy, data are currently insufficient to support stopping TKI in pediatrics outside of a clinical trial. Knowledge gaps remain regarding long-term and late effects of TKIs in pediatric CML. Targeted therapy has markedly improved outcomes for pediatric CML, while raising a number of clinical questions, including the possibility of treatment-free remission and long-term health implications of prolonged TKI exposure at a young age.
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http://dx.doi.org/10.1007/s11912-021-01025-xDOI Listing
March 2021

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

Nat Commun 2021 02 26;12(1):1334. Epub 2021 Feb 26.

Department of Medical Oncology, Division of Hematological Malignancies Dana-Farber Cancer Institute, Boston, MA, USA.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
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http://dx.doi.org/10.1038/s41467-021-21588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910481PMC
February 2021

Access to Technology and Preferences for an mHealth Intervention to Promote Medication Adherence in Pediatric Acute Lymphoblastic Leukemia: Approach Leveraging Behavior Change Techniques.

J Med Internet Res 2021 Feb 18;23(2):e24893. Epub 2021 Feb 18.

Division of Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States.

Background: Suboptimal adherence to 6-mercaptopurine (6-MP) is prevalent in pediatric acute lymphoblastic leukemia (ALL) and associated with increased risk of relapse. Rapid uptake of personal technology makes mobile health (mHealth) an attractive platform to promote adherence.

Objective: Study objectives were to examine access to mobile technology and preferences for an mHealth intervention to improve medication adherence in pediatric ALL.

Methods: A cross-sectional survey was administered in oncology clinic to parents of children with ALL as well as adolescents and young adults (AYAs) with ALL receiving maintenance chemotherapy.

Results: A total of 49 parents (median age [IQR] 39 [33-42] years; female 76% [37/49]) and 15 patients (median age [IQR] 17 [16-19]; male 80% [12/15]) participated. All parents and AYAs owned electronic tablets, smartphones, or both. Parents' most endorsed mHealth app features included a list of medications (71%, 35/49), information about 6-MP (71%, 35/49), refill reminders (71%, 35/49), and reminders to take 6-MP (71%, 35/49). AYAs' most endorsed features included refill reminders (73%, 11/15), reminders to take 6-MP (73%, 11/15), and tracking 6-MP (73%, 11/15).

Conclusions: Parents and AYAs reported ubiquitous access to mobile technology and strong interest in multiple adherence-specific mHealth app features. Parents and AYAs provided valuable insight into preferred features for a multifunctional behavioral intervention (mHealth app) to promote medication adherence in pediatric ALL.
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http://dx.doi.org/10.2196/24893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932843PMC
February 2021

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3.

J Clin Invest 2021 Jan;131(1)

Department of Medicine, Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA.

DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.
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http://dx.doi.org/10.1172/JCI135937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773384PMC
January 2021

Is cancer latency an outdated concept? Lessons from chronic myeloid leukemia.

Leukemia 2020 09 6;34(9):2279-2284. Epub 2020 Jul 6.

Department of Immunology and Inflammation, Haematology Research Centre, Imperial College London, London, UK.

Our concept of cancer latency, the interval from when a cancer starts until it is diagnosed, has changed dramatically. A prior widely-used definition was the interval between an exposure to a cancer-causing substance and cancer diagnosis. However, this definition does not accurately reflect current knowledge of how most cancers develop assuming, mostly incorrectly, one exposure is the sole cause of a cancer, ignoring the possibility the cancer being considered would have developed anyway but that the exposure accelerated cancer development and eliding the randomness in when a cancer is diagnosed. We show, using chronic myeloid leukaemia as a model, that defining cancer latency is not as simple as it once seemed. It is difficult or impossible to know at which event or mutation to start to clock to measure cancer latency. It is equally difficult to know when to stop the clock given the stochastic nature of when cancers are diagnosed. Importantly, even in genetically-identical twins with the same driver mutation intervals to develop cancer vary substantially. And we discuss other confonders. Clearly we need a new definition of cancer latency or we need to abandon the concept of cancer latency in the modern era of cancer biology.
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http://dx.doi.org/10.1038/s41375-020-0957-zDOI Listing
September 2020

A phase I study of panobinostat in children with relapsed and refractory hematologic malignancies.

Pediatr Hematol Oncol 2020 Sep 27;37(6):465-474. Epub 2020 Apr 27.

Division of Pediatric Hematology-Oncology, University of Miami Miller School of Medicine.

Panobinostat demonstrates activity against pediatric cancers in vitro. A phase I trial in children with refractory hematologic malignancies was conducted. The trial evaluated two schedules of oral panobinostat using 3 + 3 dose escalations in 28-day cycles. For children with leukemia, panobinostat was given once daily three days a week each week at 24, 30 and 34 mg/m2/day. For children with lymphoma, panobinostat was given once daily three days a week every other week at 16, 20 and 24 mg/m2/day. Cerebrospinal fluid (CSF) from Day 29 of the first cycle, when available, was evaluated for PK. The study was registered on clinicaltrials.gov (NCT01321346) Twenty-two subjects enrolled with leukemia. Five enrolled at dose level 1, 6 at dose level 2, and 11 at dose level 3. There was one dose limiting toxicity (DLT) in the leukemia arm at dose level 3 (Grade 4 hypertriglyceridemia), but no maximum tolerated dose (MTD) was identified. No subjects required removal from protocol therapy for QTc prolongation. PK studies were available in 11 subjects with similar exposure in children as in adults. Four Day 29 CSF specimens were found to have panobinostat levels below the lower limit of quantification. Five subjects with lymphoma were enrolled and received study drug, and 4 were evaluable for DLT. A DLT was reported (Grade 3 enteritis) on the lymphoma arm. Panobinostat was tolerated in heavily pretreated pediatric subjects. Gastrointestinal effects were observed on this study. There were no cardiac findings. There were no responses.
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http://dx.doi.org/10.1080/08880018.2020.1752869DOI Listing
September 2020

Applying the COM-B model to patient-reported barriers to medication adherence in pediatric acute lymphoblastic leukemia.

Pediatr Blood Cancer 2020 05 18;67(5):e28216. Epub 2020 Feb 18.

Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Adherence to oral chemotherapy, including 6-mercaptopurine (6-MP), is suboptimal in pediatric acute lymphoblastic leukemia (ALL), which is associated with increased risk of relapse. Study objectives were to examine self-reported adherence to 6-MP and related barriers to adherence, mapped to the capability, opportunity, motivation, and behavior (COM-B) model for behavior change.

Procedure: Forty-nine parents (median, 39 years old; 76% females) and 15 patients (median, 17 years old, 20% females) completed the study survey.

Results: Suboptimal adherence was reported in 43% of parents and 73% of patients. Most parents and patients (80% and 90%, respectively) reported ≥1 adherence barrier. Parents reported difficulty helping their child meet others with ALL (43%), contacting community organizations (39%), and meeting other parents (37%). Patients reported difficulty finding out what their medications are (40%), finding out what 6-MP does (47%), and meeting other patients (40%). Using the COM-B, we found that parents and patients endorsed barriers in multiple components, especially physical (55%, 67%) and social opportunity (56%, 47%), highlighting that barriers to adherence may be multifaceted.

Conclusions: Our results suggest that parents and patients with ALL face various prevalent barriers to medication adherence and provide insight into the development of behavioral interventions focused on promoting adherence, which is essential to prevent relapse and optimize health outcomes in ALL.
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http://dx.doi.org/10.1002/pbc.28216DOI Listing
May 2020

Experience with ponatinib in paediatric patients with leukaemia.

Br J Haematol 2020 04 24;189(2):363-368. Epub 2020 Jan 24.

Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.

Ponatinib has proven to be effective in adults with Philadelphia chromosome-positive leukaemias, but data in paediatrics are scarce. Among paediatric patients with chronic myeloid leukaemia (n = 9) or acute lymphoblastic leukaemia (n = 12) treated with varying doses of ponatinib in 13 centres, 71% showed a decrease in disease burden after a median of three months. Ponatinib was well tolerated, with grade 3 toxicities occurring in 29% of patients. Toxicities were similar to those reported in adults, with the exception of arterial thrombotic events, which were not observed. Ponatinib has a favourable safety profile in this paediatric cohort, but dose-finding studies are needed.
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http://dx.doi.org/10.1111/bjh.16338DOI Listing
April 2020

Results from an international phase 2 study of the anti-CD22 immunotoxin moxetumomab pasudotox in relapsed or refractory childhood B-lineage acute lymphoblastic leukemia.

Pediatr Blood Cancer 2020 05 15;67(5):e28112. Epub 2020 Jan 15.

Children's Hospital Los Angeles, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

Background: In a multicenter phase 1 study of children with relapsed/refractory acute lymphoblastic leukemia (ALL), moxetumomab pasudotox, an anti-CD22 immunotoxin, demonstrated a manageable safety profile and preliminary evidence of clinical activity. A phase 2 study further evaluated efficacy.

Procedure: This international, multicenter, phase 2 study enrolled children with relapsed/refractory B-cell precursor ALL who received moxetumomab pasudotox 40 µg/kg intravenously every other day, for six doses per 21-day cycle. The primary objective was to evaluate the complete response (CR) rate. Secondary objectives included safety, pharmacokinetics, and immunogenicity evaluations.

Results: Thirty-two patients (median age, 10 years) were enrolled at 16 sites; 30 received study drug and were evaluable for safety; 28 were evaluable for response. The objective response rate was 28.6%, with three patients (10.7%) achieving morphologic CR, and five patients (17.9%) achieving partial response. Disease progression occurred in 11 patients (39.3%). Ten patients (33.3%) experienced at least one treatment-related serious adverse event, including capillary leak syndrome (CLS; n = 6), hemolytic uremic syndrome (HUS; n = 4), and treatment-related death (n = 1) from pulmonary edema. No differences were observed in inflammatory markers in patients who did or did not develop CLS or HUS.

Conclusions: Despite a signal for clinical activity, this phase 2 study was terminated at interim analysis for a CR rate that did not reach the stage 1 target. Preclinical data suggest enhanced efficacy of moxetumomab pasudotox via continuous infusion or in combination regimens; thus, further studies designed to optimize the efficacy and safety of moxetumomab pasudotox in pediatric ALL may be warranted.
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http://dx.doi.org/10.1002/pbc.28112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485266PMC
May 2020

Pharmacokinetics of Nilotinib in Pediatric Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia or Acute Lymphoblastic Leukemia.

Clin Cancer Res 2020 02 1;26(4):812-820. Epub 2019 Nov 1.

Institute of Cancer and Genomic Sciences, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, United Kingdom.

Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment.

Patients And Methods: Fifteen patients (aged 1-<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib ( = 11) or Ph ALL relapsed on or refractory to standard therapy ( = 4) enrolled in this phase I study. Nilotinib (230 mg/m twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients.

Results: The area under the concentration-time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70-1.06]. Body surface area-adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04-1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph ALL achieved complete remission.

Conclusions: Nilotinib 230 mg/m twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0090DOI Listing
February 2020

The TLR9 agonist (GNKG168) induces a unique immune activation pattern in vivo in children with minimal residual disease positive acute leukemia: Results of the TACL T2009-008 phase I study.

Pediatr Hematol Oncol 2019 Nov 18;36(8):468-481. Epub 2019 Sep 18.

Department of Pediatric Hematology, Oncology & BMT, University of British Columbia, Vancouver, USA.

: Preclinical studies show that TLR9 agonists can eradicate leukemia by induction of immune responses against AML and ALL. These studies demonstrated that TLR9 agonists induce an immediate NK response followed by adaptive T and B cells responses resulting in long term anti-leukemia immunity. : The Therapeutic Advances in Childhood Leukemia and Lymphoma Phase I consortium performed a pilot study on 3 patients with MRD positive acute leukemia after an initial remission on conventional chemotherapy (TACL T2009-008) with the TLR 9 agonist (GNKG168). To guide future trial development, we evaluated the impact of GNKG168 by Nanostring on the expression 608 genes before and 8 days after initiation of GNKG168 therapy. : Twenty-three out of 578 markers on the nanostring panel showed significant difference ( ≤ 0.05). We focused on 8 markers that had the greatest differences with  < 0.01. Two genes were increased, and , and 6 were decreased, and (). Tumor inhibitory pathways were downregulated including the (), important in signaling and NK cell inhibition. TLR9 can induce IL-33, which is known to downregulate ST2 (IL1RL1) a receptor for IL-33. : GNKG168 therapy is associated with immunologic changes in pediatric leukemia patients. Further work with a larger sample size is required to assess the impact of these changes on disease treatment and persistence of leukemia remission.
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http://dx.doi.org/10.1080/08880018.2019.1667461DOI Listing
November 2019

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia.

Blood 2019 12;134(23):2036-2045

Department of Pediatrics, Hematology and Oncology Division, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.
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http://dx.doi.org/10.1182/blood.2019000069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923664PMC
December 2019

Management of chronic myeloid leukemia in children and adolescents: Recommendations from the Children's Oncology Group CML Working Group.

Pediatr Blood Cancer 2019 09 10;66(9):e27827. Epub 2019 Jun 10.

Division of Hematology/Oncology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Chronic myeloid leukemia (CML) accounts for 2-3% of leukemias in children under 15 and 9% in adolescents aged 15-19. The diagnosis and management of CML in children, adolescents, and young adults have several differences compared to that in adults. This review outlines the diagnosis and management of the underlying disease as well as challenges that can occur when dealing with CML in this patient population.
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http://dx.doi.org/10.1002/pbc.27827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944522PMC
September 2019

How I treat chronic myeloid leukemia in children and adolescents.

Blood 2019 05 27;133(22):2374-2384. Epub 2019 Mar 27.

Medical Faculty, Pediatric Hematology and Oncology, Technical University Dresden, Dresden, Germany.

Evidence-based recommendations have been established for treatment of chronic myeloid leukemia (CML) in adults treated with tyrosine kinase inhibitors (TKIs), but the rarity of this leukemia in children and adolescents makes it challenging to develop similar recommendations in pediatrics. In addition to imatinib, which was approved for pediatric CML in 2003, the second-generation TKIs dasatinib and nilotinib were recently approved for use in children, expanding the therapeutic options and pushing allogeneic stem cell transplantation to a third-line treatment of most pediatric cases. Yet, without sufficient data on efficacy and safety specific to pediatric patients, the selection of a TKI continues to rely on clinical experience in adults. Here, we present 4 case scenarios highlighting common yet challenging issues encountered in the treatment of pediatric CML (suboptimal response, poor treatment adherence, growth retardation, and presentation in advanced phases). Limited experience with very young children, the transition of teenagers to adult medicine, and the goal of achieving treatment-free remission for this rare leukemia are additional significant obstacles that require further clinical investigation through international collaboration.
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http://dx.doi.org/10.1182/blood.2018882233DOI Listing
May 2019

Need for new thinking: Treatment of relapsed leukemia in children with Down syndrome.

Pediatr Blood Cancer 2019 06 5;66(6):e27644. Epub 2019 Feb 5.

Division of Hematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/pbc.27644DOI Listing
June 2019

Cost analysis of bronchoalveolar lavage and respiratory tract biopsies in the diagnosis and management of suspected invasive fungal infection in children with cancer or who have undergone stem cell transplant.

Pediatr Blood Cancer 2019 05 4;66(5):e27598. Epub 2019 Jan 4.

Division of Hematology, Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

Background: Identification of an organism is the gold standard for the diagnosis of fungal infection; however, we have previously shown that invasive procedures infrequently lead to a change in management in children with cancer or who have undergone stem cell transplant with suspected respiratory tract invasive fungal infection (RT-IFI). There is also a paucity of data on the cost of RT-IFI in this population. We therefore compared the costs of RT-IFI diagnosed based on CT scan alone versus those who underwent a bronchoalveolar lavage (BAL) or respiratory tract biopsy (RTB).

Procedure: We collected cost data on patients at a single center undergoing chemotherapy or who were post-hematopoietic stem cell transplant (HSCT) and were suspected of having RT-IFI between 2007 and 2012. Cost data were included for 14 days from the day of their diagnostic CT scan or procedure.

Results: Cost data were available for 76 patients. Thirty-six patients were diagnosed with suspected RT-IFI based on CT only, and 40 patients underwent BAL or RTB. Costs related to chest X-rays (CXRs), inpatient/intensive care unit (ICU) beds, anesthesia, operating room (OR) time, and procedures were significantly higher in the BAL/RTB group versus CT scan group (all P < 0.01). Costs related to CT scans were significantly higher in the CT scan group (P = 0.0002). Overall costs were significantly higher for patients who underwent BAL or RTB versus CT scan only (P < 0.0001).

Conclusion: Our previous data showed that BAL and RTB infrequently led to a change in management in this population. We now demonstrate that this strategy is costly as well.
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http://dx.doi.org/10.1002/pbc.27598DOI Listing
May 2019

Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue.

J Clin Oncol 2019 02 4;37(6):461-470. Epub 2019 Jan 4.

1 University of Toronto, Toronto, Ontario, Canada.

Purpose: Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD.

Patients And Methods: In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome.

Results: All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days.

Conclusion: On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
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http://dx.doi.org/10.1200/JCO.18.00474DOI Listing
February 2019

Practice Patterns of Physician Treatment for Pediatric Chronic Myelogenous Leukemia.

Biol Blood Marrow Transplant 2019 02 26;25(2):321-327. Epub 2018 Sep 26.

Department of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Chronic myelogenous leukemia (CML) is a rare disease in children for which pediatric evidence-based guidelines are lacking. We designed an anonymous survey for practicing pediatric oncologists and bone marrow transplantation (BMT) physicians to assess their willingness to recommend BMT for a patient with CML based on various clinical scenarios. A total of 274 physicians responded to the survey (13.4% response rate). Nearly all pediatric oncologists and BMT physicians recommended against BMT at time of diagnosis of CML in the chronic phase, with only 8.0% and 1.9% recommending BMT if a matched sibling donor (MSD) and a matched unrelated donor (MUD), respectively, was available. Similarly, after a first poor response to tyrosine kinase inhibitor (TKI) therapy or hematologic relapse, physicians continued to recommend against BMT (39.5% and 23.3% recommended BMT in patients with a matched sibling donor and matched unrelated donor, respectively). However, 81.7% and 69.8% of respondents would recommend BMT after 2 hematologic relapses on TKI therapy, if an MSD and an MUD, respectively, were available. In addition, there was great interest in developing a clinical trial evaluating the safety and efficacy of stopping TKIs in children with CML who achieve and maintain a deep molecular response, with 86.7% of respondents stating they would offer such a trial to their pediatric patients. This survey highlights the need for evidence-based, pediatric-specific guidelines for the management of children and adolescents with CML.
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http://dx.doi.org/10.1016/j.bbmt.2018.09.029DOI Listing
February 2019

USP7 Cooperates with NOTCH1 to Drive the Oncogenic Transcriptional Program in T-Cell Leukemia.

Clin Cancer Res 2019 01 17;25(1):222-239. Epub 2018 Sep 17.

Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois.

Purpose: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes.

Experimental Design: To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples, and xenograft models.

Results: We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth and .

Conclusions: These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320313PMC
January 2019

Generic formulations of imatinib for treatment of Philadelphia chromosome-positive leukemia in pediatric patients.

Pediatr Blood Cancer 2018 12 30;65(12):e27431. Epub 2018 Aug 30.

Department of General Pediatrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Universitäts-Kinderklinik, Kiel, Germany.

Since the patent for imatinib has expired, the role of generic imatinib (GI) in the management of Philadelphia chromosome-positive (Ph+) leukemia in pediatric patients has had ongoing discussion. Some studies in adults demonstrated that equivalent doses of GI and branded imatinib (BI) result in comparable plasma concentrations and clinical efficacy. However, other studies found that GI users are more likely to stop imatinib, with intolerance and decreased persistence as the main causes. Economic factors also heavily influence GI selection. This article aims to review the present knowledge to support further discussion on the role of GI in the management of pediatric Ph+ leukemia.
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http://dx.doi.org/10.1002/pbc.27431DOI Listing
December 2018

Clinical and Radiographic Response of Extramedullary Leukemia in Patients Treated With Gemtuzumab Ozogamicin.

J Pediatr Hematol Oncol 2019 Apr;41(3):e174-e176

Departments of Pediatrics.

Extramedullary leukemia (EML) is common in pediatric acute leukemia and can present at diagnosis or relapse. CD33 is detected on the surface of myeloid blasts in many patients with acute myelogenous leukemia and is the target of the antibody drug conjugate gemtuzumab ozogamicin (GO). Here we present 2 patients with CD33 EML treated with GO. They achieved significant response, with reduction of EML on both clinical and radiographic exams, specifically fluorine fluorodeoxyglucose positron emission tomography/computed tomography, demonstrating potential for targeted therapy with GO as a means of treating EML in patients with CD33 leukemia and the utility of fluorine fluorodeoxyglucose positron emission tomography/computed tomography monitoring in EML.
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http://dx.doi.org/10.1097/MPH.0000000000001201DOI Listing
April 2019

Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study.

Leukemia 2018 11 15;32(11):2316-2325. Epub 2018 Mar 15.

The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1038/s41375-018-0094-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224404PMC
November 2018

Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia.

Pediatr Blood Cancer 2018 07 30;65(7):e27062. Epub 2018 Mar 30.

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, Massachusetts.

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/m /day). Additional patients were enrolled at the 3- and 5 mg/m /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/m /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 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/m /day. This promising combination should be further evaluated in a larger patient cohort.
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http://dx.doi.org/10.1002/pbc.27062DOI Listing
July 2018

Dasatinib in Pediatric Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Phase II Trial.

J Clin Oncol 2018 05 2;36(13):1330-1338. Epub 2018 Mar 2.

Lia Gore, University of Colorado School of Medicine/Children's Hospital Colorado, Aurora, CO; Pamela R. Kearns, University of Birmingham, Birmingham, West Midlands; Donna Lancaster, Royal Marsden Hospital, Sutton, Surrey, United Kingdom; Maria Lucia de Martino Lee, Support Group for Children and Adolescents with Cancer; Carmino Antonio De Souza, University of Campinas, São Paulo, Brazil; Yves Bertrand, L'Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France; Nobuko Hijiya, Ann and Robert H. Lurie Children's Hospital of Chicago, and Northwestern University Feinberg School of Medicine, Chicago, IL; Linda C. Stork, Oregon Health & Science University, Portland, OR; Nack-Gyun Chung, The Catholic University of Korea, Seoul St. Mary's Hospital; Jong Jin Seo, University of Ulsan College of Medicine, and Asan Medical Center, Seoul, Republic of Korea; Rocio Cardenas Cardos, Instituto Nacional De Pediatria, Mexico City, Mexico; Tapan Saikia, Prince Aly Khan Hospital, Mumbai, India; Franca Fagioli, Regina Margherita Hospital, Turin, Italy; Judith Landman-Parker, Hôpital Enfants Armand-Trousseau, Paris, France; Andrew E. Place, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA; Karen R. Rabin, Texas Children's Cancer Center, and Baylor College of Medicine, Houston, TX; Mariana Sacchi and Rene Swanink, Bristol-Myers Squibb, Princeton, NJ; C. Michel Zwaan, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands; Pamela R. Kearns and C. Michel Zwaan, Innovative Therapies for Children with Cancer Consortium, European Union.

Purpose Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP. A phase I study determined suitable dosing for children with Philadelphia chromosome-positive (Ph+) leukemias. Methods CA180-226/NCT00777036 is a phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving dasatinib. There are three cohorts: (1) imatinib-resistant/intolerant CML-CP, (2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ acute lymphoblastic leukemia (n = 17), and (3) newly diagnosed CML-CP treated with tablets or powder for oral suspension. Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest. Results Of 113 patients with CML-CP, 14 (48%) who were imatinib-resistant/intolerant and 61 (73%) who were newly diagnosed remained on treatment at time of analysis. Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group. CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group. Progression-free survival by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP groups, respectively. No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial hypertension were reported. Bone growth and development events were reported in 4% of patients. Conclusion In the largest prospective trial to date in children with CML-CP, we demonstrate that dasatinib is a safe, effective treatment of pediatric CML-CP. Target responses to first- or second-line dasatinib were met early, and deep molecular responses were observed. Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.
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http://dx.doi.org/10.1200/JCO.2017.75.9597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929218PMC
May 2018

Identifying patient- and family-centered outcomes relevant to inpatient versus at-home management of neutropenia in children with acute myeloid leukemia.

Pediatr Blood Cancer 2018 04 29;65(4). Epub 2017 Dec 29.

Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.

Efficacy of therapeutic strategies relative to patient- and family-centered outcomes in pediatric oncology must be assessed. We sought to identify outcomes important to children with acute myeloid leukemia and their families related to inpatient versus at-home management of neutropenia. We conducted qualitative interviews with 32 children ≥8 years old and 54 parents. Analysis revealed the impact of neutropenia management strategy on siblings, parent anxiety, and child sleep quality as being outcomes of concern across respondents. These themes were used to inform the design of a questionnaire that is currently being used in a prospective, multiinstitutional comparative effectiveness trial.
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http://dx.doi.org/10.1002/pbc.26927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857179PMC
April 2018

Combination of clofarabine, cyclophosphamide, and etoposide for relapsed or refractory childhood and adolescent acute myeloid leukemia.

Pediatr Hematol Oncol 2017 May 17;34(4):187-198. Epub 2017 Oct 17.

g Division of Hematology/Oncology/Stem Cell Transplant, Ann and Robert H. Lurie Children's Hospital of Chicago and Department of Pediatrics , Northwestern University Feinberg School of Medicine , IL , USA.

Relapsed/refractory acute myeloid leukemia (AML) has an extremely poor prognosis. We describe 17 children and adolescents with relapsed/refractory AML who received clofarabine, cyclophosphamide, and etoposide. Seven patients (41%) responded: 4 with a complete response (CR); 1 with CR with incomplete platelet recovery; and 2 with a partial response. Additionally, 4 developed hypocellular marrow without evidence of leukemia; 5 patients had resistant disease; and 1 suffered early toxic death. After further therapy including transplantation, 4 patients (24%) are alive without evidence of disease at a median of 60 months. This anthracycline-free regimen may be studied for relapsed or refractory AML, but due to the high risk of marrow aplasia reduced doses of clofarabine and cyclophosphamide should be used.
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http://dx.doi.org/10.1080/08880018.2017.1360970DOI Listing
May 2017

Classical Hodgkin lymphoma and Castleman disease: a rare morphologic combination.

Blood 2017 07;130(3):381

Ann & Robert H. Lurie Children's Hospital of Chicago.

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http://dx.doi.org/10.1182/blood-2017-05-782128DOI Listing
July 2017

The complexity of growth failure in children receiving tyrosine kinase inhibitor therapy for chronic myelogenous leukemia.

Pediatr Blood Cancer 2017 12 11;64(12). Epub 2017 Jul 11.

Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

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http://dx.doi.org/10.1002/pbc.26703DOI Listing
December 2017

Patterns and predictors of clustered risky health behaviors among adult survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

Cancer 2016 09 3;122(17):2747-56. Epub 2016 Jun 3.

Epidemiology/Cancer Control Department, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Health complications related to childhood cancer may be influenced by risky health behaviors (RHBs), particularly when RHBs co-occur. To the authors' knowledge, only limited information is available describing how RHBs cluster among survivors of childhood cancer and their siblings and the risk factors for co-occurring RHBs.

Methods: Latent class analysis was used to identify RHB clusters using longitudinal survey data regarding smoking, alcohol use, and physical activity from adult survivors (4184 survivors) and siblings (1598 siblings) in the Childhood Cancer Survivor Study. Generalized logistic regression was used to evaluate associations between demographic characteristics, treatment exposures, psychological distress, health conditions, and cluster membership.

Results: Three RHB clusters were identified: a low-risk cluster, an insufficiently active cluster, and a high-risk cluster (tobacco and risky alcohol use and insufficient activity). Compared with siblings, survivors were more likely to be in the insufficiently active cluster (adjusted odds ratio [ORadj ], 1.17; 95% confidence interval [95% CI], 1.06-1.27) and were less likely to be in the high-risk cluster (ORadj , 0.79; 95% CI, 0.69-0.88). Risk factors for membership in the high-risk cluster included psychological distress (ORadj , 2.76; 95% CI, 1.98-3.86), low educational attainment (ORadj , 7.49; 95% CI, 5.15-10.88), income <$20,000 (ORadj , 2.62; 95% CI, 1.93-3.57), being divorced/separated or widowed (ORadj , 1.36; 95% CI, 1.03-1.79), and limb amputation (ORadj , 1.52; 95% CI, 1.03-2.24). Risk factors for the insufficiently active cluster included chronic health conditions, psychological distress, low education or income, being obese or overweight, female sex, nonwhite race/ethnicity, single marital status, cranial radiation, and cisplatin exposure.

Conclusions: RHBs co-occur in survivors of childhood cancer and their siblings. Economic and educational disadvantages and psychological distress should be considered in screening and interventions to reduce RHBs. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2747-2756. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992459PMC
September 2016