Medical Specialties Commons^™

Prognostic Impact Of Cooccurring Mutations In Flt3-Itd Pediatric Acute Myeloid Leukemia., Katherine Tarlock, Robert B. Gerbing, Rhonda E. Ries, Jenny L. Smith, Amanda Leonti, Benjamin J. Huang, Danielle Kirkey, Leila Robinson, Jack H. Peplinksi, Beverly Lange, Todd M. Cooper, Alan S. Gamis, E Anders Kolb, Richard Aplenc, Jessica A. Pollard, Todd A. Alonzo, Soheil Meshinchi

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We sought to define the cooccurring mutational profile of FLT3-ITD-positive (ITDpos) acute myeloid leukemia (AML) in pediatric and young adult patients and to define the prognostic impact of cooperating mutations. We identified 464 patients with FLT3-ITD mutations treated on Children's Oncology Group trials with available sequencing and outcome data. Overall survival, event-free survival (EFS), and relapse risk were determined according to the presence of cooccurring risk stratifying mutations. Among the cohort, 79% of patients had cooccurring alterations across 239 different genes that were altered through mutations or fusions. Evaluation of the prognostic impact of the cooccurring mutations demonstrated that patients …

Structural Variants Involving Mllt10 Fusion Are Associated With Adverse Outcomes In Pediatric Acute Myeloid Leukemia., Oussama Abla, Rhonda E. Ries, Tim Triche, Robert B. Gerbing, Betsy Hirsch, Susana Raimondi, Todd Cooper, Jason E. Farrar, Nathaniel Buteyn, Lauren M. Harmon, Hong Wen, Aniruddha J. Deshpande, E Anders Kolb, Alan S. Gamis, Richard Aplenc, Todd Alonzo, Soheil Meshinchi

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MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study with 2080 children and young adults with AML registered on the Children's Oncology Group AAML0531 (NCT00372593) and AAML1031 trials (NCT01371981). Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions: 104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: (2 each of DDX3X and TEC), with 6 partners (DDX3Y, CEP164, SCN2B, …

Characteristics And Prognostic Impact Of Idh Mutations In Aml: A Cog, Swog, And Ecog Analysis., Sara Zarnegar-Lumley, Todd A. Alonzo, Robert B. Gerbing, Megan Othus, Zhuoxin Sun, Rhonda E. Ries, Jim Wang, Amanda Leonti, Matthew A. Kutny, Fabiana Ostronoff, Jerald P. Radich, Frederick R. Appelbaum, Era L. Pogosova-Agadjanyan, Kristen O'Dwyer, Martin S. Tallman, Mark Litzow, Ehab Atallah, Todd M. Cooper, Richard A. Aplenc, Omar Abdel-Wahab, Alan S. Gamis, Selina Luger, Harry Erba, Ross Levine, E Anders Kolb, Derek L. Stirewalt, Soheil Meshinchi, Katherine Tarlock

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Somatic mutations in isocitrate dehydrogenase (IDH) genes occur frequently in adult acute myeloid leukemia (AML) and less commonly in pediatric AML. The objective of this study was to describe the prevalence, mutational profile, and prognostic significance of IDH mutations in AML across age. Our cohort included 3141 patients aged betweenChildren's Cancer Group/Children's Oncology Group (n = 1872), Southwest Oncology Group (n = 359), Eastern Cooperative Oncology Group (n = 397) trials, and in Beat AML (n = 333) and The Cancer Genome Atlas (n = 180) genomic characterization cohorts. We retrospectively analyzed patients in 4 age groups (age range, n): …

Comprehensive Molecular And Clinical Characterization Of Nup98 Fusions In Pediatric Acute Myeloid Leukemia, Eline J M Bertrums, Jenny L. Smith, Lauren Harmon, Rhonda E. Ries, Yi-Cheng J. Wang, Todd A. Alonzo, Andrew J. Menssen, Karen M. Chisholm, Amanda R. Leonti, Katherine Tarlock, Fabiana Ostronoff, Era L. Pogosova-Agadjanyan, Gertjan J L Kaspers, Henrik Hasle, Michael Dworzak, Christiane Walter, Nora Muhlegger, Cristina Morerio, Laura Pardo, Betsy Hirsch, Susana Raimondi, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Jason E. Farrar, Derek Stirewalt, Xiaotu Ma, Tim I. Shaw, Scott N. Furlan, Lisa Eidenschink Brodersen, Michael R. Loken, Marry M. Van Den Heuvel-Eibrink, C Michel Zwaan, Timothy J. Triche, Bianca F. Goemans, Soheil Meshinchi

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NUP98 fusions comprise a family of rare recurrent alterations in AML, associated with adverse outcomes. In order to define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not …

Hlh-Like Toxicities Predict Poor Survival After The Use Of Tisagenlecleucel In Children And Young Adults With B-All., Kevin O. Mcnerney, Stephanie J. Si Lim, Kyle Ishikawa, Alexandra Dreyzin, Anant Vatsayan, John J. Chen, Christina Baggott, Snehit Prabhu, Holly L. Pacenta, Christine Philips, Jenna Rossoff, Heather E. Stefanski, Julie-An Talano, Amy Moskop, Michael Verneris, Douglas Myers, Nicole A. Karras, Patrick Brown, Challice L. Bonifant, Muna Qayed, Michelle Hermiston, Prakash Satwani, Christa Krupski, Amy K. Keating, Susanne H C Baumeister, Vanessa A. Fabrizio, Vasant Chinnabhandar, Emily Egeler, Sharon Mavroukakis, Kevin J. Curran, Crystal L. Mackall, Theodore W. Laetsch, Liora M. Schultz

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Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade …

Three-Year Update Of Tisagenlecleucel In Pediatric And Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia In The Eliana Trial., Theodore W. Laetsch, Shannon L. Maude, Susana Rives, Hidefumi Hiramatsu, Henrique Bittencourt, Peter Bader, André Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A. Pulsipher, Douglas Myers, Heather E. Stefanski, Paul L. Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L. Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A. Grupp

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In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free …

Randomized Clinical Trial Of A Self-Care And Communication Intervention For Parents Of Adolescent/Young Adults Undergoing High-Risk Cancer Treatment: A Report From The Children's Oncology Group., Joan E. Haase, Kristin Stegenga, Sheri L. Robb, Mary C. Hooke, Debra S. Burns, Patrick O. Monahan, Timothy E. Stump, Amanda K. Henley, Paul R. Haut, Brooke Cherven, Lona Roll, Anne-Marie Langevin, Rita H. Pickler, Karen Albritton, Deanna Hawkins, Erin Osterkamp, Pauline Mitby, Jackie Smith, Virginia R. Diaz, Erica Garcia-Frausto, Margo Moore

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BACKGROUND: Parents of adolescents and young adults (AYAs) with cancer offer primary support to their children and often experience their own high levels of distress, affecting parent-AYA communication and quality of life.

OBJECTIVE: To reduce parent distress and improve communication during high-risk cancer treatment, we examined efficacy of a self-care and communication intervention for parents and indirect benefit for AYAs receiving a therapeutic music video (TMV) intervention.

METHODS: In this study, we conducted a multisite, randomized controlled trial with AYAs and parents enrolled as dyads (n = 110). Parents were randomized to intervention or low-dose control; all AYAs received TMV. …

Abcb1 Snp Predicts Outcome In Patients With Acute Myeloid Leukemia Treated With Gemtuzumab Ozogamicin: A Report From Children's Oncology Group Aaml0531 Trial., Roya Rafiee, Lata Chauhan, Todd A. Alonzo, Yi-Cheng Wang, Ahlam Elmasry, Michael R. Loken, Jessica Pollard, Richard Aplenc, Susana Raimondi, Betsy A. Hirsch, Irwin D. Bernstein, A S. Gamis, Soheil Meshinchi, Jatinder K. Lamba

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Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC …

Tisagenlecleucel Model-Based Cellular Kinetic Analysis Of Chimeric Antigen Receptor-T Cells., Andrew M. Stein, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Bruce L. Levine, Lori Tomassian, Sweta Shah, Mimi Leung, Pai-Hsi Huang, Rakesh Awasthi, Karen Thudium Mueller, Patricia A. Wood, Carl H. June

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Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19+ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or …

Inotuzumab Ozogamicin In Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia., Deepa Bhojwani, Richard Sposto, Nirali N. Shah, Vilmarie Rodriguez, Constance Yuan, Maryalice Stetler-Stevenson, Maureen M. O'Brien, Jennifer L. Mcneer, Amrana Quereshi, Aurelie Cabannes, Paul Schlegel, Claudia Rossig, Luciano Dalla-Pozza, Keith August, Sarah Alexander, Jean-Pierre Bourquin, Michel Zwaan, Elizabeth A. Raetz, Mignon L. Loh, Susan R. Rheingold

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Although inotuzumab ozogamicin (InO) is recognized as an effective agent in relapsed acute lymphoblastic leukemia (ALL) in adults, data on safety and efficacy in pediatric patients are scarce. We report the use of InO in 51 children with relapsed/refractory ALL treated in the compassionate use program. In this heavily pretreated cohort, complete remission was achieved in 67% of patients with overt marrow disease. The majority (71%) of responders were negative for minimal residual disease. Responses were observed irrespective of cytogenetic subtype or number or type of prior treatment regimens. InO was well-tolerated; grade 3 hepatic transaminitis or hyperbilirubinemia were noted …

Genomic Prediction Of Relapse In Recipients Of Allogeneic Haematopoietic Stem Cell Transplantation., J Ritari, K Hyvärinen, S Koskela, M Itälä-Remes, R Niittyvuopio, A Nihtinen, U Salmenniemi, M Putkonen, L Volin, T Kwan, T Pastinen, J Partanen

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Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the …

Clinical Pharmacology Of Tisagenlecleucel In B-Cell Acute Lymphoblastic Leukemia., Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. Wood, Shannon L. Maude

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PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( …

Family Strategies To Support Siblings Of Pediatric Hematopoietic Stem Cell Transplant Patients., Taylor E. White, Kristopher A. Hendershot, Margie D. Dixon, Wendy Pelletier, Ann Haight, Kristin Stegenga, Melissa A. Alderfer, Lydia Cox, Jeffrey M. Switchenko, Pamela Hinds, Rebecca D. Pentz

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OBJECTIVE: To describe the strategies families report using to address the needs and concerns of siblings of children, adolescents, and young adults undergoing hematopoietic stem cell transplant (HSCT).

METHODS: A secondary semantic analysis was conducted of 86 qualitative interviews with family members of children, adolescents, and young adults undergoing HSCT at 4 HSCT centers and supplemented with a primary analysis of 38 additional targeted qualitative interviews (23 family members, 15 health care professionals) conducted at the primary center. Analyses focused on sibling issues and the strategies families use to address these issues.

RESULTS: The sibling issues identified included: (1) feeling …

Health-Related Quality Of Life (Hr-Qol) And Chronic Health Conditions In Survivors Of Childhood Acute Myeloid Leukemia (Aml) With Down Syndrome (Ds): A Report From The Children's Oncology Group., Kris Ann P. Schultz, Lu Chen, Alicia Kunin-Batson, Zhengjia Chen, William G. Woods, A S. Gamis, Toana Kawashima, Kevin C. Oeffinger, H Stacy Stacy Nicholson, Joseph P. Neglia

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Survival rates for children with Down syndrome (DS) and acute myeloid leukemia (AML) are high; however, little is known regarding the health-related quality of life (HR-QOL) of these survivors. Individuals who survived ≥5 years following diagnosis of childhood AML were invited to complete parent or patient-report surveys measuring HR-QOL and chronic health conditions. In total, 26 individuals with DS had a median age at diagnosis of 1.8 years (range, 0.77 to 10.9 y) and median age at interview of 15 years (range, 8.3 to 27.6 y). Participants with DS and AML were compared with AML survivors without DS whose caregiver …