323 results on '"Or, Reuven"'
Search Results
2. Prognostic Value of Blood Biomarkers in Steroid-Refractory/Dependent Acute Graft-vs-Host Disease: A REACH2 Analysis
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Socie, Gérard, primary, Niederwieser, Dietger, additional, von Bubnoff, Nikolas, additional, Mohty, Mohamad, additional, Szer, Jeff, additional, Or, Reuven, additional, Garrett, James, additional, Prahallad, Anirudh Cadapa, additional, Wilke, Celine, additional, and Zeiser, Robert, additional
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- 2023
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3. Prognostic Value of Blood Biomarkers in Steroid-Refractory/Dependent Acute Graft-vs-Host Disease: A REACH2 Analysis
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Gérard Socie, Dietger Niederwieser, Nikolas von Bubnoff, Mohamad Mohty, Jeff Szer, Reuven Or, James Garrett, Anirudh Cadapa Prahallad, Celine Wilke, and Robert Zeiser
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Systemic steroids are the standard first-line treatment for acute graft-vs-host disease (aGVHD), but approximately 50% of patients become steroid refractory or dependent (SR/D). Ruxolitinib is the only FDA and EMA approved therapy for patients with SR/D aGVHD. In the phase 3 REACH2 trial (NCT02913261), ruxolitinib demonstrated superior efficacy to best available therapy (BAT) in treating SR/D aGVHD, with significantly higher overall response rate (ORR) at day 28, durable ORR at day 56, and longer median overall survival. Identifying biomarkers and clinical characteristics associated with increased probability of response could guide treatment decisions. In this exploratory analysis of the REACH2 study, we developed baseline (pretreatment) and Day 14 models to identify patient characteristics and biomarkers (12 aGVHD-associated cytokines/chemokines, 6 immune cell types, and 3 inflammatory proteins) before and during treatment that affected the probability of response at day 28. Treatment with ruxolitinib versus BAT, type of conditioning, skin involvement, and age were strongly associated with increased likelihood of response in ≥1 model. Lower levels of most aGVHD and immune cell markers at baseline were associated with increased probability of response. In the Day 14 model, levels of aGVHD markers at day 14, rather than change from baseline, impacted probability of response. For both models, bias-corrected area under receiver operating characteristic (AUROC) values (baseline, 0.73; Day 14, 0.80) indicated high level of correspondence between fitted and actual outcomes. This first biomarker study in context of a randomized phase 3 aGVHD trial, highlights the potential prognostic value of select biomarkers and patient characteristics.
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- 2023
4. Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation
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Fioredda, Francesca, Iacobelli, Simona, van Biezen, Anja, Gaspar, Bobby, Ancliff, Phil, Donadieu, Jean, Aljurf, Mahmoud, Peters, Christina, Calvillo, Michaela, Matthes-Martin, Susanne, Morreale, Giuseppe, van 't Veer-Tazelaar, Nelleke, de Wreede, Liesbeth, Al Seraihy, Amal, Yesilipek, Akif, Fischer, Alain, Bierings, Marc, Ozturk, Gulyuz, Smith, Owen, Veys, Paul, Ljungman, Per, Peffault de Latour, Régis, Sánchez de Toledo Codina, José, Or, Reuven, Ganser, Arnold, Afanasyev, Boris, Wynn, Robert, Kalwak, Krzysztof, Marsh, Judith, and Dufour, Carlo
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- 2015
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5. High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial
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R. Spencer Tong, Robert B. Gerbing, Todd A. Alonzo, Jeffrey W. Taub, Jim Wang, Lisa Eidenschink Brodersen, Reuven J. Schore, Maureen M. O'Brien, Amy Heerema-McKenney, Jason N. Berman, Shelton A Viola, Michael R. Loken, E. Anders Kolb, Betsy A. Hirsch, Alan S. Gamis, Karen M. Chisholm, Susana C. Raimondi, Nobuko Hijiya, Amy Beckman, Johann Hitzler, and Todd E. Druley
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Male ,Antimetabolites, Antineoplastic ,medicine.medical_specialty ,Down syndrome ,Neoplasm, Residual ,medicine.medical_treatment ,Immunology ,Biochemistry ,Gastroenterology ,Cog ,Internal medicine ,medicine ,Humans ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Cytarabine ,Infant ,Myeloid leukemia ,Cell Biology ,Hematology ,Prognosis ,Interim analysis ,medicine.disease ,Confidence interval ,Young age ,Treatment Outcome ,Leukemia, Myeloid ,Child, Preschool ,Female ,Down Syndrome ,business ,medicine.drug - Abstract
Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children’s Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (
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- 2021
6. High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial
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Hitzler, Johann, primary, Alonzo, Todd, additional, Gerbing, Robert, additional, Beckman, Amy, additional, Hirsch, Betsy, additional, Raimondi, Susana, additional, Chisholm, Karen, additional, Viola, Shelton, additional, Brodersen, Lisa, additional, Loken, Michael, additional, Tong, Spencer, additional, Druley, Todd, additional, O’Brien, Maureen, additional, Hijiya, Nobuko, additional, Heerema-McKenney, Amy, additional, Wang, Yi-Chang, additional, Shore, Reuven, additional, Taub, Jeffrey, additional, Gamis, Alan, additional, Kolb, E. Anders, additional, and Berman, Jason N., additional
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- 2021
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7. Racial, Ethnic, and Socioeconomic Factors Result in Disparities in Outcome Among Children with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease Prognosticators: A Children's Oncology Group (COG) Study
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Gupta, Sumit, primary, Teachey, David T., additional, Devidas, Meenakshi, additional, Dai, Yunfeng, additional, Aplenc, Richard, additional, Winestone, Lena, additional, Bona, Kira O, additional, Rabin, Karen R, additional, Zweidler-McKay, Patrick A, additional, Maloney, Kelly W, additional, Mattano, Leonard A., additional, Larsen, Eric C, additional, Angiolillo, Anne L, additional, Schore, Reuven J, additional, Burke, Michael J., additional, Salzer, Wanda L, additional, Winter, Stuart S., additional, Dunsmore, Kimberly P., additional, Winick, Naomi J, additional, Carroll, William L., additional, Hunger, Stephen P, additional, and Loh, Mignon L., additional
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- 2021
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8. Comparison of Current and Enhanced Risk Stratification of 21,199 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Using Objective Risk Categorization Criteria: A Children's Oncology Group Report
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Delrocco, Natalie, primary, Loh, Mignon L., additional, Borowitz, Michael, additional, Rabin, Karen R, additional, Zweidler-McKay, Patrick A, additional, Maloney, Kelly W, additional, Mattano, Leonard A., additional, Larsen, Eric C, additional, Angiolillo, Anne L, additional, Schore, Reuven J, additional, Burke, Michael J., additional, Salzer, Wanda L, additional, Wood, Brent L., additional, Carroll, Andrew J, additional, Heerema, Nyla A., additional, Reshmi, Shalini C, additional, Gastier-Foster, Julie M, additional, Harvey, Richard C, additional, Chen, I-Ming L, additional, Roberts, Kathryn G, additional, Mullighan, Charles G., additional, Willman, Cheryl L, additional, Winick, Naomi J, additional, Carroll, William L., additional, Hunger, Stephen P., additional, Raetz, Elizabeth A., additional, Devidas, Meenakshi, additional, and Kairalla, John, additional
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- 2021
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9. Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Combination with UK ALL-R3 Induction Chemotherapy for Children, Adolescents and Young Adults with Relapsed Acute Lymphoblastic Leukemia (ALL): A Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium Trial
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Shah, Nirali N., primary, Schafer, Eric S, additional, Heym, Kenneth Matthew, additional, Place, Andrew E., additional, Burns, Melissa A., additional, Gossai, Nathan, additional, Shaw, Peter, additional, Burke, Michael J., additional, Chang, Bill H., additional, Hermiston, Michelle L., additional, Schore, Reuven J, additional, Rushing, Teresa, additional, Jarosinski, Paul F, additional, Sposto, Richard, additional, Florendo, Ellynore, additional, Malvar, Jemily, additional, Chi, Yueh-Yun, additional, Whitlock, James A., additional, Silverman, Lewis B., additional, Bhojwani, Deepa, additional, and Wayne, Alan S., additional
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- 2021
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10. Standardization in the Diagnosis of Mixed Phenotype Acute Leukemia (MPAL): Semiquantitative, Universally Applicable Flow Cytometric Criteria for Immunophenotypic Lineage Assignment and Isolated MPO
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Kovach, Alexandra E., primary, Raikar, Sunil S., additional, Oberley, Matthew J., additional, Wertheim, Gerald, additional, Rabin, Karen R, additional, Punia, Jyotinder N., additional, Seif, Alix E., additional, Schore, Reuven J, additional, Luca, Dragos C., additional, Guinipero, Terri, additional, Woods, William G, additional, Cahen, Viviane, additional, O'Gorman, Maurice R.G., additional, Orgel, Etan, additional, and Wood, Brent L., additional
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- 2021
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11. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation
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Feuchtinger, Tobias, Opherk, Kathrin, Bethge, Wolfgang A., Topp, Max S., Schuster, Friedhelm R., Weissinger, Eva M., Mohty, Mohamad, Or, Reuven, Maschan, Michael, Schumm, Michael, Hamprecht, Klaus, Handgretinger, Rupert, Lang, Peter, and Einsele, Hermann
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- 2010
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12. Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group
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Klingebiel, Thomas, Cornish, Jacqueline, Labopin, Myriam, Locatelli, Franco, Darbyshire, Philippe, Handgretinger, Rupert, Balduzzi, Adriana, Owoc-Lempach, Joanna, Fagioli, Franca, Or, Reuven, Peters, Christina, Aversa, Franco, Polge, Emmanuelle, Dini, Giorgio, and Rocha, Vanderson
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- 2010
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13. Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Combination with UK ALL-R3 Induction Chemotherapy for Children, Adolescents and Young Adults with Relapsed Acute Lymphoblastic Leukemia (ALL): A Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium Trial
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Nirali N. Shah, Eric S Schafer, Kenneth Matthew Heym, Andrew E. Place, Melissa A. Burns, Nathan Gossai, Peter Shaw, Michael J. Burke, Bill H. Chang, Michelle L. Hermiston, Reuven J Schore, Teresa Rushing, Paul F Jarosinski, Richard Sposto, Ellynore Florendo, Jemily Malvar, Yueh-Yun Chi, James A. Whitlock, Lewis B. Silverman, Deepa Bhojwani, and Alan S. Wayne
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Introduction: Vincristine intensification has the potential to improve outcomes in ALL, but severe neurotoxicity has prohibited escalation beyond standard capped doses. Vincristine sulfate liposome injection, VSLI (Marqibo®) is a liposomal formulation of aqueous vincristine that optimizes pharmacokinetics, prolongs circulating half-life, increases tissue penetration, and may be better tolerated than standard vincristine. VSLI received accelerated FDA approval for adults with relapsed/refractory (r/r) ALL, at a dose of 2.25 mg/m 2/dose without a dose cap. A phase I trial of VSLI in children and young adults with r/r ALL demonstrated safety, tolerability, and evidence for single-agent activity (Shah NN, et al. Pediatric Blood Cancer, 2016). Studies of VSLI with combination chemotherapy in children have not been conducted. With emerging data supporting improved outcomes for patients (pts) with r/r ALL who proceed to immunotherapy with low-burden disease, identifying safe and effective reinduction regimens to reduce disease burden remains a priority. Methods: This multicenter pilot study conducted through the TACL consortium was designed to assess safety and feasibility of VSLI as replacement for standard vincristine with combination chemotherapy for individuals between the ages of 2-21 years with r/r ALL. Two dose levels of VSLI were utilized without a dose cap: Dose level 1 (DL1) 1.5 mg/m 2/dose; and Dose level 2 (DL2) 2.0 mg/m 2/dose. Treatment success was determined by both 1) the absence of a dose-limiting toxicity (DLT) (as defined by any > Grade 3 regimen related non-hematologic toxicity which precluded completion of the pre-specified treatment course or from proceeding to subsequent therapy within 7 weeks) and 2) completion of the prescribed treatment regimen. Adverse event grading was based on CTCAE v4.03. Bone marrow aspirate was used for standard morphologic assessment of response with central flow cytometric analysis for minimal residual disease (MRD) determination with a cut-off of Results: A total of 10 pts with r/r B-ALL, median age 13.4 (range 5.0-17.3 years) were treated on Cohort A. Pts were heavily pre-treated, with 3 having relapsed after prior allogeneic stem cell transplantation; 8 of 10 had an M3 marrow (>/= 25% blasts). The first 4 pts were treated at DL1. All 4 were evaluable for toxicity and response and met the criteria for treatment success, facilitating dose escalation to DL2. At DL2, 4 pts were treated, with 2 experiencing DLT, including one grade (Gr) 5 event (Table 1). Two additional pts were subsequently treated at DL1 and achieved treatment success, confirming safety and feasibility of DL1 with a VSLI dose of 1.5 mg/m 2 in combination with UK ALL-R3 4-drug induction. Nine of 10 (90%) pts achieved a morphologic complete remission (CR), 5 of which were MRD negative. The median VSLI dose administered at DL1 was 2.3 mg (range, 1.8-3.2 mg) and at DL2 was 2.2 mg (range, 1.5-3.3 mg) demonstrating the feasibility of dosing beyond the standard vincristine dose-cap of 2 mg. Transient aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations were seen in 8 pts, 6 of whom had a grade 1-2 toxicity. Gr 3 hepatic toxicities were seen in 3 pts: 1 each with ALT elevation and hyperbilirubinemia; ALT and AST elevation; gamma-glutamyl transferase elevation. Toxicities were generally consistent with the UK ALL-R3 regimen. Conclusions: In children with r/r ALL, the combination of UK ALL-R3 with VSLI was highly effective with an acceptable safety profile. DL1 (1.5 mg/m 2/dose) was found to be the maximum tolerated dose in combination with this intensive re-induction regimen. The trial continues to enroll at DL1 in the expansion phase to obtain additional safety and response data with this 4-drug regimen. Additionally, 2 cohorts have been added to gain further experience with VSLI in combination with 3-drug induction (Cohort B: UK ALL-R3 without mitoxantrone) and with ALL maintenance chemotherapy (Cohort C: dexamethasone, methotrexate, mercaptopurine). VSLI has potential as a vincristine dose-intensification strategy in combination with reinduction chemotherapy for r/r ALL in pediatric patients. Figure 1 Figure 1. Disclosures Hermiston: Novartis: Consultancy; Sobi: Consultancy. Whitlock: Amgen; Jazz Pharmaceuticals: Honoraria; Novartis: Research Funding; Sobi Pharmaceuticals: Consultancy. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Wayne: Spectrum/Acrotech: Research Funding; KITE/Gilead: Research Funding.
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- 2021
14. Standardization in the Diagnosis of Mixed Phenotype Acute Leukemia (MPAL): Semiquantitative, Universally Applicable Flow Cytometric Criteria for Immunophenotypic Lineage Assignment and Isolated MPO
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Brent L. Wood, Sunil S. Raikar, William G. Woods, Alexandra E. Kovach, Maurice R.G. O'Gorman, Gerald Wertheim, Karen R. Rabin, Alix E. Seif, Terri Guinipero, Jyotinder N. Punia, Viviane Cahen, Reuven J. Schore, Etan Orgel, Matthew J. Oberley, and Dragos C. Luca
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Mixed phenotype acute leukemia ,Lineage (genetic) ,Immunology ,Cell Biology ,Hematology ,Biology ,Biochemistry - Abstract
Mixed phenotype acute leukemia (MPAL) is a rare group of acute leukemias defined by immunophenotypic expression of more than one hematopoietic cell lineage. The World Health Organization (WHO) diagnostic immunophenotypic criteria for MPAL rely on the intensity of lineage-defining antigen expression, predominantly a qualitative assessment, and are often difficult to apply to a phenotypically heterogeneous leukemia. Cases of MPAL defined by isolated myeloperoxidase (isoMPO) expression on otherwise typical acute lymphoblastic leukemia (ALL) are variably diagnosed as MPAL or ALL based on the incompletely defined criteria for assigning MPO expression. We hypothesized that quantitative criteria for antigen intensity could be developed and applied in a uniform manner across flow cytometry instruments, reagents, and analysis software to enable a consistent approach to diagnosing MPAL and better defining isoMPO. We previously reported on a multicenter cohort identified by respective institutions as MPAL with subsequent central review according to 2008 WHO criteria (Oberley et al 2020). Of these, 100 had suitable dot plots for reevaluation (89: B/Myeloid, 10: T/Myeloid, 1: B/T). Antigen expression was concurrently reviewed by two hematopathologists to reach consensus (BLW, AEK). The cohort was divided a priori into randomly selected training and testing cases (n=30/n=70). Classification criteria were generated in the training cohort for WHO lineage-defining antigen expression (myeloid: cMPO, CD64, CD14; B: CD19, T: cCD3) from 10 cases and then refined through review of an additional 20 cases. Positive antigen expression was classified as maximal intensity approaching that of the mature normal counterpart population (NCP) (cMPO: neutrophils; CD64, CD14 and CD11c: monocytes; CD19: B cells; cCD3: T cells) either by 1) range of expression recapitulating maturation of the NCP, irrespective of the percentage on the leukemic population (Figure 1A); or 2) uniform expression above background on a discrete (sub)population (Figure 1B). To account for technical variation within and among laboratories, maximal antigen intensity on the leukemic population was measured in 0.5 log increments and normalized to the maximal intensity of the NCP. An intensity of ≥50% of the NCP above background was defined as sufficient for MPAL lineage assignment and Using this approach, 41/98 (42%) cases previously classified as MPAL remained classified as MPAL: 31 as B/Myeloid (25 by maturational MPO expression, 6 by maturational CD64 and/or CD14 expression); 9 as T/Myeloid (8 by maturational MPO expression, 1 with maturational CD64, CD14 and CD11c expression); and 1 as B/T. No cases in the cohort showed uniform expression ≥50% of the NCP. The remaining 57 showed isolated low-level MPO expression (maximal intensity Novel semiquantitative immunophenotypic criteria applied to a large cohort of acute leukemias originally diagnosed as MPAL was able to objectively identify a large subset as having dim, uniform MPO expression (isoMPO). Our approach emphasizes antigen expression recapitulating maturational expression similar to their non-leukemic cellular counterparts, normalizes absolute intensities to internal positive and negative control populations to minimize technical variability between observers and assays, and as per the 2017 WHO, does not require a specific percent threshold of positivity. While requiring validation, this is a critical first step toward establishing a reproducible delineation of these complex cases to practically implement the WHO classification to support treatment decisions and ongoing investigation into MPAL genomics and outcomes (available for this cohort by ASH). Figure 1 Figure 1. Disclosures Oberley: Caris LIfe Science: Current Employment. Orgel: Jazz Pharmaceuticals: Consultancy.
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- 2021
15. Racial, Ethnic, and Socioeconomic Factors Result in Disparities in Outcome Among Children with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease Prognosticators: A Children's Oncology Group (COG) Study
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Wanda L. Salzer, Karen R. Rabin, Lena E. Winestone, Richard Aplenc, Mignon L. Loh, Naomi J. Winick, Leonard A. Mattano, Kimberly P. Dunsmore, Eric Larsen, Meenakshi Devidas, Stuart S. Winter, Sumit Gupta, Reuven J. Schore, David T. Teachey, Kira Bona, Kelly W. Maloney, Stephen P. Hunger, Michael J. Burke, William L. Carroll, Yunfeng Dai, Patrick A. Zweidler-McKay, and Anne L. Angiolillo
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Pediatrics ,medicine.medical_specialty ,business.industry ,Lymphoblastic Leukemia ,Immunology ,Cell Biology ,Hematology ,Disease ,Biochemistry ,Outcome (game theory) ,Racial ethnic ,Cog ,medicine ,business ,Socioeconomic status - Abstract
Introduction: Health disparities are major issue for racial, ethnic, and socioeconomically disadvantaged groups. Though outcomes in childhood acute lymphoblastic leukemia (ALL) have steadily improved, identifying persistent disparities is critical. Prior studies evaluating ALL outcomes by race or ethnicity have noted narrowing disparities or that residual disparities are secondary to differences in leukemia biology or socioeconomic status (SES). We aimed to identify persistent inequities by race/ethnicity and SES in childhood ALL in the largest cohort ever assembled for this purpose. Methods: We identified a cohort of newly-diagnosed patients with ALL, age 0-30.99 years who were enrolled on COG trials between 2004-2019. Race/ethnicity was categorized as non-Hispanic white vs. Hispanic vs. non-Hispanic Black vs. non-Hispanic Asian vs. Non-Hispanic other. SES was proxied by insurance status: United States (US) Medicaid (public health insurance for low-income individuals) vs. US other (predominantly private insurance) vs. non-US patients (mainly jurisdictions with universal health insurance). Event-free and overall survival (EFS, OS) were compared across race/ethnicity and SES. The relative contribution of disease prognosticators (age, sex, white blood cell count, lineage, central nervous system status, cytogenetics, end Induction minimal residual disease) was examined with Cox proportional hazard multivariable models of different combinations of the three constructs of interest (race/ethnicity, SES, disease prognosticators) and examining hazard ratio (HR) attenuation between models. Results: The study cohort included 24,979 children, adolescents, and young adults with ALL. Non-Hispanic White patients were 13,872 (65.6%) of the cohort, followed by 4,354 (20.6%) Hispanic patients and 1,517 (7.2%) non-Hispanic Black patients. Those insured with US Medicaid were 6,944 (27.8%). Five-year EFS (Table 1) was 87.4%±0.3% among non-Hispanic White patients vs. 82.8%±0.6% [HR 1.37, 95 th confidence interval (95CI) 1.26-1.49; p Table 2 shows the multivariable models and illustrates different patterns of HR adjustment among specific racial/ethnic and SES groups. Inferior EFS among Hispanic patients was substantially attenuated by the addition of disease prognosticators (HR decreased from 1.37 to 1.17) and further (but not fully) attenuated by the subsequent addition of SES (HR 1.11). In contrast, the increased risk among non-Hispanic Black children was minimally attenuated by both the addition of disease prognosticators and subsequent addition of SES (HR 1.45 to 1.38 to 1.32). Similarly, while the superior EFS of non-US insured patients was substantially attenuated by the addition of race/ethnicity and disease prognosticators (HR 0.79 to 0.94), increased risk among US Medicaid patients was minimally attenuated by the addition of race/ethnicity or disease prognosticators (HR 1.21 to 1.16). OS disparities followed similar patterns but were consistently worse than in EFS, particularly among patients grouped as non-Hispanic other. Conclusions: Substantial disparities in survival outcomes persist by race/ethnicity and SES in the modern era. Our findings suggest that reasons for these disparities vary between specific disadvantaged groups. Additional work is required to identify specific drivers of survival disparities that may be mitigated by targeted interventions. Figure 1 Figure 1. Disclosures Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Teachey: NeoImmune Tech: Research Funding; Sobi: Consultancy; BEAM Therapeutics: Consultancy, Research Funding; Janssen: Consultancy. Zweidler-McKay: ImmunoGen: Current Employment. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees.
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- 2021
16. Comparison of Current and Enhanced Risk Stratification of 21,199 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Using Objective Risk Categorization Criteria: A Children's Oncology Group Report
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Natalie Delrocco, Mignon L. Loh, Michael Borowitz, Karen R Rabin, Patrick A Zweidler-McKay, Kelly W Maloney, Leonard A. Mattano, Eric C Larsen, Anne L Angiolillo, Reuven J Schore, Michael J. Burke, Wanda L Salzer, Brent L. Wood, Andrew J Carroll, Nyla A. Heerema, Shalini C Reshmi, Julie M Gastier-Foster, Richard C Harvey, I-Ming L Chen, Kathryn G Roberts, Charles G. Mullighan, Cheryl L Willman, Naomi J Winick, William L. Carroll, Stephen P. Hunger, Elizabeth A. Raetz, Meenakshi Devidas, and John Kairalla
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Contemporary risk stratification algorithms commonly use threshold-defined categories of clinically relevant risk factors. The Children's Oncology Group (COG) uses National Cancer Institute (NCI) risk group (RG), cytogenetics, and early response to therapy measured by minimal residual disease (MRD) using flow cytometry on day 8 peripheral blood (D8 PB) and day 29 bone marrow (D29 BM). However, it is unclear whether assigning different weights to individual risk factors, as well as using numerical values as continuous, rather than categorical, would more accurately predict relapse risk. Previous work (Loh, ASH 2020) described validation of a continuous prognostic index (PI) for risk of relapse published by UK investigators incorporating favorable and unfavorable genetics, white blood cell count (WBC), and D29 BM as continuous variables (O'Connor, JCO 2018; Enshaei, Blood 2020), and assessed the added value of D8 PB. We now extend this work by comparing patient outcomes with current COG risk classification to PI-derived risk classifications on the previously described population (Loh, ASH 2020). We first retrospectively classified patients (pts) (N=21,199 from prior COG trials AALL0331/0232 or AALL0932/1131 enrolled 2004-2019) in our analysis population using the COG risk stratification algorithm employed in the current generation of COG trials. Pts with Down syndrome or BCR/ABL1 were excluded. We classified our analysis population as SR-Favorable [SR-Fav, 24.5% (5-year relapse free survival (RFS) probability 0.97)], SR-Favorable/Average (not distinguishable because of missing D8 PB) [SR-Fav/Avg, 5.3% (.96)], SR-Avg [20.5% (0.93)], SR-High [12.5% (0.83)], HR-Fav [3.0% (0.96)], HR [29.6% (0.82)], and Very HR [VHR, 1.1% (0.54)] according to NCI RG, CNS status, cytogenetics, D8 PB where relevant, D29 BM, and EOC MRD. Ninety-seven percent of pts had sufficient data to be retrospectively classified and thus 20,176 pts were considered for subsequent analyses. We next developed a multivariable model for RFS using log transformed MRD (τ(MRD)). Temporal external validation was first employed by developing models considering AALL0932/1131 data (n=12,453) and then validating them with AALL0331/0232 data (n=7,723). Of the full cohort of 20,176 pts, 24.4% could not be classified by COG PI, primarily due to missing D8 PB MRD which was not assessed routinely in earlier studies; thus the model was developed on 11,151 pts and validated on 4,103 pts. The COG PI (PI COG) was calculated using the equation [τ(d8 MRD) x -0.036 + τ(d29 MRD) x -0.119 + CYTO-GR x -0.914 + CYTO-HR x 0.752 + WBC log x 0.178]. The UK PI (PI UK) was also calculated using published coefficients [τ(d29 MRD) x -0.218 + CYTO-GR x -0.440 + CYTO-HR x 1.066 + WBC log x 0.138] for comparison to assess the practical significance of adding D8 PB. In contrast to the UK method, we identified risk groups by selecting PI cutoffs that maximized the discrimination of the predictive model as quantified by the concordance probability estimator (CPE) (Barrio, SORT 2017). This objective method of cutpoint determination allows for risk group definition without investigator agreement on exact prespecified risk group characteristics; this method also defined four risk groups (Low, Standard, Intermediate, and High). Cutpoints derived from the two different indices, applied to the pts who could be classified by PI COG (n=15,254), resulted in different proportions of pts in each of the risk groups with generally similar RFS estimates for each group. Using cutpoints estimated for PI COG (-2.073, -1.307, and -0.857) 36.0% (RFS = 0.97) were classified as low, 29.6% (0.93) standard, 17.1% (0.88) intermediate, and 17.4% (0.73) high risk of relapse. For PI UK ( -2.916, -2.534, and -1.15), among those who were classifiable by PI COG, 33.4% (0.97) were classified as low, 26.3% (0.93) standard, 30% (0.87) intermediate, and 10.4% (0.69) high. Finally, we compared the COG risk stratification to PI CPE-defined risk stratification in the cohort. As shown in the table, PI COG improves discrimination among individuals by identifying groups with different relapse risk than expected. The PI COG can thus identify patients for whom therapeutic intensification may not result in significantly better outcomes while improving the discrimination of HR pts to allow randomized interventions with achievable hazard ratios. Figure 1 Figure 1. Disclosures Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz: Amgen, Blueprint Medicines: Honoraria. Zweidler-McKay: ImmunoGen: Current Employment. Mullighan: AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company; Illumina: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Hunger: Amgen: Current equity holder in publicly-traded company. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member.
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- 2021
17. Enhanced Risk Stratification of 21,178 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia (ALL) Incorporating White Blood Count (WBC), Age, and Minimal Residual Disease (MRD) at Day 8 and 29 As Continuous Variables: A Children's Oncology Group (COG) Report
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Loh, Mignon L., primary, DelRocco, Natalie, additional, Borowitz, Michael J, additional, Rabin, Karen R, additional, Zweidler-McKay, Patrick A, additional, Maloney, Kelly W, additional, Mattano, Leonard A., additional, Larsen, Eric C, additional, Angiolillo, Anne L, additional, Schore, Reuven J, additional, Burke, Michael J, additional, Salzer, Wanda L, additional, Wood, Brent L, additional, Carroll, Andrew J, additional, Heerema, Nyla A, additional, Reshmi, Shalini C, additional, Gastier-Foster, Julie M, additional, Harvey, Richard C, additional, Chen, I-Ming L, additional, Willman, Cheryl L, additional, Winick, Naomi J, additional, Carroll, William, additional, Hunger, Stephen P, additional, Raetz, Elizabeth A., additional, Devidas, Meenakshi, additional, Kairalla, John, additional, Roberts, Kathryn G, additional, and Mullighan, Charles G, additional
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- 2020
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18. Outcomes of Patients with Down Syndrome and CRLF2-Overexpressing Acute Lymphoblastic Leukemia (ALL): A Report from the Children's Oncology Group (COG)
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Rabin, Karen R, primary, Devidas, Meenakshi, additional, Chen, Zhiguo, additional, Dai, Yunfeng, additional, Tasian, Sarah K, additional, Hitzler, Johann K, additional, Roberts, Kathryn G, additional, Carroll, Andrew J, additional, Heerema, Nyla A, additional, Borowitz, Michael J, additional, Wood, Brent L, additional, Mullighan, Charles G, additional, Harvey, Richard C, additional, Chen, I-Ming L, additional, Willman, Cheryl L, additional, Reshmi, Shalini C, additional, Gastier-Foster, Julie M, additional, Maloney, Kelly W, additional, Larsen, Eric C, additional, Schore, Reuven J, additional, Burke, Michael J, additional, Salzer, Wanda L, additional, Winick, Naomi J, additional, Carroll, William L., additional, Raetz, Elizabeth A., additional, Angiolillo, Anne, additional, Loh, Mignon L., additional, and Hunger, Stephen P, additional
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- 2020
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19. Biomarker Analysis in Patients (pts) with Steroid-Refractory Acute Graft-Vs-Host Disease (aGVHD) Treated with Ruxolitinib (RUX) or Best Available Therapy (BAT) in the Randomized, Phase 3 REACH2 Study
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Socié, Gérard, primary, Niederwieser, Dietger, additional, Von Bubnoff, Nikolas, additional, Mohty, Mohamad, additional, Szer, Jeffrey, additional, Or, Reuven, additional, Butler, Jason P, additional, Wagner, Eva Maria, additional, Forcade, Edouard, additional, Caballer, Jaime Sanz, additional, Russo, Domenico, additional, Grillo, Giovanni, additional, Zuckerman, Tsila, additional, Civriz Bozdag, Sinem, additional, Ritchie, David, additional, Chaturvedi, Shalini, additional, Prahallad, Anirudh, additional, Sinclair, Karen, additional, Wilke, Celine, additional, and Zeiser, Robert, additional
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- 2020
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20. Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group
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Tasian, Sarah K, primary, Dai, Yunfeng, additional, Devidas, Meenakshi, additional, Roberts, Kathryn G, additional, Harvey, Richard C, additional, Chen, I-Ming L, additional, Carroll, Andrew J, additional, Heerema, Nyla A, additional, Reshmi, Shalini C, additional, Gastier-Foster, Julie M, additional, Borowitz, Michael J, additional, Wood, Brent L, additional, Mullighan, Charles G, additional, Willman, Cheryl L, additional, Maloney, Kelly W, additional, Larsen, Eric C, additional, Angiolillo, Anne L, additional, Schore, Reuven J, additional, Burke, Michael J, additional, Salzer, Wanda L, additional, Winick, Naomi J, additional, Carroll, William L., additional, Hunger, Stephen P, additional, Raetz, Elizabeth A., additional, Rabin, Karen R, additional, and Loh, Mignon L., additional
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- 2020
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21. Enhanced Risk Stratification of 21,178 Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia (ALL) Incorporating White Blood Count (WBC), Age, and Minimal Residual Disease (MRD) at Day 8 and 29 As Continuous Variables: A Children's Oncology Group (COG) Report
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Eric Larsen, Brent L. Wood, Reuven J. Schore, Shalini C. Reshmi, Kathryn G. Roberts, Nyla A. Heerema, Leonard A. Mattano, Michael J. Borowitz, Wanda L. Salzer, Richard C. Harvey, Elizabeth A. Raetz, John A. Kairalla, Stephen P. Hunger, Cheryl L. Willman, Julie M. Gastier-Foster, Andrew J. Carroll, Meenakshi Devidas, Charles G. Mullighan, Michael J. Burke, Patrick A. Zweidler-McKay, Kelly W. Maloney, Natalie DelRocco, Karen R. Rabin, Anne L. Angiolillo, Mignon L. Loh, Naomi J. Winick, William L. Carroll, and I-Ming L. Chen
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Pediatrics ,medicine.medical_specialty ,business.industry ,Lymphoblastic Leukemia ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Minimal residual disease ,Continuous variable ,White blood count ,Cog ,Risk stratification ,Medicine ,Early adolescents ,Young adult ,business - Abstract
Current risk stratification for COG ALL patients (pts) relies on National Cancer Institute (NCI) risk group (RG) at diagnosis, somatic genetics, and early response to therapy as measured by specific thresholds of minimal residual disease (MRD) using flow cytometry on day 8 peripheral blood (D8 PB) and day 29 bone marrow (D29 BM). NCI RG is defined as age 1-10 years (yrs) and white blood cell count (WBC) We first log transformed WBC, D8 and D29 MRD and displayed these by treatment protocol, NCI RG, and FRG/URG (separating out Ph-like independently). Age and WBC followed the normal expected distribution with the median age of SR pts 4.0 yrs (range 1-9) and HR 12 yrs (range 1-30). Transformed MRD was displayed as a variable t(MRD), corresponding to the negative log; max t(D29 MRD) was 13.82, corresponding to MRD We next conducted a univariate analysis for risk factors for relapse, including sex, age, WBClog, CNS status, protocol-defined rapid early response status, FRG, URG, t(D8 MRD), and t(D29 MRD); all variables except CNS status were significant p < 0.0001). Multivariable modeling showed that WBClog, FRG, URG, t(D8 MRD), t(D29 MRD) retained significance (p < 0.0001). Finally, we applied the UK Prognostic Index (PIUKALL) equation [t(d29 MRD) x -0.218 + CYTO-GR x -0.440 + CYTO-HR x 1.066 + WBClog x 0.138] to the COG data using protocol, NCI RG, FRG, URG, IRG, or Ph-like RG in the model and validated the trends for relapse-free survival (RFS), which were similar in our groups with an overall median PIUKALL of -2.63 (mean -2.32, SD -.90, min -3.54, max 1.79). We next added in t(D8 MRD) to define a PICOG and determined that D8 PB MRD added significantly to the model, mostly through discriminating between the hazard ratios of the FRG and the URG RGs. Importantly, the D8 PB MRD led to a qualitatively more distinctive group with a potentially lower predicted RFS in NCI SR pts, a group that has been more difficult to predict in the past, and yet comprises nearly half of all relapse events. Our analyses of 21,178 COG B-ALL pts confirm and extend the utility of integrating WBC and MRD as continuous rather than categorical values to refine risk stratification for patient treatment and trial design. Disclosures Loh: Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. Mattano:Melinta Therapeutics: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Hunger:Amgen: Current equity holder in publicly-traded company, Honoraria; Novartis: Consultancy. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; AbbVie, Inc.: Research Funding.
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- 2020
22. Biomarker Analysis in Patients (pts) with Steroid-Refractory Acute Graft-Vs-Host Disease (aGVHD) Treated with Ruxolitinib (RUX) or Best Available Therapy (BAT) in the Randomized, Phase 3 REACH2 Study
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Jeff Szer, Gérard Socié, Karen Sinclair, Shalini Chaturvedi, Mohamad Mohty, Jason Butler, Anirudh Prahallad, Eva Wagner, Edouard Forcade, C. Wilke, Tsila Zuckerman, David Ritchie, Nikolas von Bubnoff, Giovanni Grillo, Dietger Niederwieser, Sinem Civriz Bozdag, Domenico Russo, Reuven Or, Robert Zeiser, and Jaime Sanz Caballer
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Oncology ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Immunology ,Cell Biology ,Hematology ,Exploratory analysis ,Serum samples ,Biochemistry ,Internal medicine ,medicine ,Current employment ,In patient ,Host disease ,business ,Steroid refractory ,health care economics and organizations ,Treatment Arm ,medicine.drug - Abstract
BACKGROUND aGVHD, a common complication of allogeneic stem cell transplant (alloSCT), is driven by proinflammatory cytokines and chemokines that activate the immune system, resulting in end-organ damage. Steroids are first-line treatment but up to 50% of pts are steroid refractory (SR), resulting in high mortality and morbidity. RUX, a JAK1/JAK2 inhibitor, inhibits cytokine-dependent activation of the JAK-STAT pathway and cell proliferation and differentiation, which prevents worsening of aGVHD and allows recovery. JAK pathway inhibition by RUX may also lead to modulation of proinflammatory cytokines and prognostic GVHD biomarkers. The phase 3 randomized REACH2 trial (NCT02913261) in SR aGVHD demonstrated superiority of RUX vs BAT, with a significantly higher overall response rate (ORR; complete [CR] + partial response [PR]) at D28 (62% vs 39%; P < .001) and higher durable ORR at D56 (40% vs 22%; P < .001) (Zeiser R, et al. N Engl J Med. 2020). In this exploratory analysis of REACH2, we assessed whether baseline (BL) levels of proinflammatory cytokines and GVHD markers were prognostic for response and how this changed over time related to treatment. METHODS Pts (N = 309; ≥ 12 y old with grade II-IV SR aGVHD after alloSCT) were randomized 1:1 to RUX (starting at 10 mg bid) or investigator-selected BAT and stratified by aGVHD grade; 295 pts had valid biomarker levels. Serum samples were collected at BL, D14, and D28 and biomarkers, including inflammatory cytokines, soluble receptors of cytokines, chemokines, and tissue-specific markers for gastrointestinal (GI), liver, and skin GVHD, were assessed (Table). Biomarker levels at BL were stratified by response (CR, PR, none [NR]) at D28 for each treatment arm; those that differed by response were analyzed by logistic regression (LR) to assess the association (CR+PR vs NR), adjusting for treatment. The analysis was repeated, adjusting for key covariates that had significant impact on the biomarker-response relationship. Change in biomarkers over time (BL to D28) was assessed via geometric mean values at each visit, along with fold change from BL for each treatment arm. RESULTS Of 22 GVHD biomarkers assessed, 17 (77%) were evaluable (Table). Higher median BL levels of proinflammatory cytokines (IL-6, IL-8, TNF-α), soluble cytokine receptors (IL2RA, TNFRSF1A, ST2) and tissue-specific GVHD markers (REG3A, HGF) were generally observed in NR vs CR pts (Table) and were further analyzed. Higher BL levels of these markers were significantly associated with a lower probability of OR (P[OR]) in the LR analysis (Figure). An interaction term was investigated to assess whether there was a differing biomarker effect within treatment groups; however, this was insignificant and not retained. The addition of skin involvement to the LR for all biomarkers had an impact on P(OR), with increased P(OR) for pts with skin involvement at BL. Liver involvement at BL was added to the LR for HGF, IL6, REG3A, TNFα, and TNFRSF1A. The LR models showed a significant decrease in P(OR) for pts with liver involvement at BL. GI involvement did not have a significant impact for any biomarker. Geometric mean levels of TNFα, TNFRSF1A, IL2RA, REG3A, and ST2 decreased from BL to D14 in CR pts in the RUX arm but increased with BAT. NR pts had increases in these biomarkers regardless of treatment; however, longer follow-up is needed. Treatment had an underlying impact on P(OR) but no further impact on the effect of biomarkers on P(OR). Maximum change from BL was observed at D14; a slight return to BL levels was observed at D28 in CR pts. Surprisingly, IL6 levels increased with RUX regardless of response. IL6, like TNFα, is directly modulated by the JAK-STAT pathway and was therefore expected to decrease with RUX. CONCLUSIONS This is the first biomarker study in a phase 3 trial in GVHD. BL levels of IL6, IL8, TNFα, IL2RA, TNFRSF1A, ST2, REG3A, and HGF tended to be higher in NR vs CR pts; higher levels were associated with lower P(OR) when adjusted for treatment arm. Skin and liver involvement also had an impact on response. Skin involvement was associated with higher P(OR), regardless of biomarker BL levels, possibly because no skin involvement implied other organ involvement and tended to be associated with a higher overall severity grade at BL. CR pts in the RUX group had lower BL levels of TNFα and showed trends toward decreases from BL to D14 in the soluble cytokine receptors ST2, TNFRSF1A, and IL2RA and tissue-specific marker REG3A. Disclosures Socié: Elsalys: Honoraria; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Niederwieser:Amgen: Speakers Bureau; Daiichi: Research Funding; Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees. Von Bubnoff:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical biomarker research, steering committee, Patents & Royalties: Research support, Research Funding; Astra Zeneca: Honoraria, Other: Lectures, Patents & Royalties: Astra Zeneca. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Szer:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Or:Hadassah Hebrew University Medical Center: Consultancy, Current Employment. Wagner:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Shire: Other: Travel grand. Forcade:JAZZ: Other: Travel grant for congress; NEOVII: Other: Travel grant for congress; Gilead: Speakers Bureau; Sanofi: Other: Travel grant for congress; Novartis: Other: Travel grant for congress. Civriz Bozdag:Novartis: Research Funding. Chaturvedi:Novartis: Current Employment. Wilke:Novartis Pharma AG: Current Employment, Other: Stock owner. Zeiser:Novartis: Honoraria; Incyte: Honoraria; Malinckrodt: Honoraria.
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- 2020
23. Outcomes of Patients with Down Syndrome and CRLF2-Overexpressing Acute Lymphoblastic Leukemia (ALL): A Report from the Children's Oncology Group (COG)
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Reuven J. Schore, Michael J. Burke, Cheryl L. Willman, Zhiguo Chen, Mignon L. Loh, Julie M. Gastier-Foster, William L. Carroll, I-Ming L. Chen, Naomi J. Winick, Eric Larsen, Michael J. Borowitz, Brent L. Wood, Karen R. Rabin, Wanda L. Salzer, Richard C. Harvey, Johann K. Hitzler, Elizabeth A. Raetz, Anne L. Angiolillo, Kathryn G. Roberts, Nyla A. Heerema, Sarah K. Tasian, Yunfeng Dai, Andrew J. Carroll, Meenakshi Devidas, Charles G. Mullighan, Shalini C. Reshmi, Stephen P. Hunger, and Kelly W. Maloney
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Oncology ,medicine.medical_specialty ,Down syndrome ,Younger age ,medicine.diagnostic_test ,business.industry ,Lymphoblastic Leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Clinical trial ,Cog ,Internal medicine ,Medicine ,Young adult ,business ,Fluorescence in situ hybridization - Abstract
Background: Patients with Down syndrome (DS) have an approximately 10-fold increased risk of developing ALL, and the spectrum of genetic alterations differs from that of non-DS ALL. Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of DS ALL, compared to only 5-10% CRLF2+ cases in non-DS children and adolescents. JAK2 or JAK1 mutations co-occur in about half of CRLF2+ cases in both DS and non-DS ALL. The prognostic significance of CRLF2+ ALL also appears to differ in the limited data reported to date, with less adverse impact in patients with DS compared to non-DS ALL. Here, we report the clinical characteristics and prognostic significance of B-ALL with CRLF2 overexpression and JAK alterations in children and adolescents/young adults (AYA) with DS who were treated on Children's Oncology Group (COG) clinical trials from 2003-2016. Methods: We analyzed clinical, laboratory, and outcome data for 317 patients with DS B-ALL treated on standard risk (SR) trials AALL0331 and AALL0932 and high risk (HR) trials AALL0232 and AALL1131, for whom CRLF2 status and rearrangement partners (IGH or P2RY8) were ascertained by flow cytometric assessment of surface expression; fluorescence in situ hybridization; and/or polymerase chain reaction (PCR) testing. JAK mutations were ascertained in a subset by PCR and sequencing. Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at end of consolidation (EOC) for a subset of EOI MRD+ patients. Results: We identified 168/317 (53.0%) CRLF2+ cases, and among those assessed for CRLF2 partner, 17/73 (23.3%) were IGH-CRLF2 and 56/73 (76.7%) were P2RY8-CRLF2. In the subset of 165 cases tested for JAK mutations (85 CRLF2- and 80 CRLF2+), 42/165 (25.4%) had JAK mutations, all of which co-occurred in CRLF2+ cases. CRLF2 positivity was significantly associated with younger age at diagnosis: 140/168 (83.3%) of CRLF2+ cases were under 10 years old, versus 106/149 (71.1%) of CRLF2- cases, p Discussion: Whereas CRLF2 and JAK alterations are associated with higher MRD, poorer survival, and increased CIR in patients with high-risk ALL without DS, these alterations do not demonstrate strong adverse prognostic impact in children and AYAs with DS-ALL treated on recent frontline COG trials, although larger sample sizes are needed to adequately assess for possible poorer prognoses associated with the CRLF2+/JAK+ and IGH-CRLF2 subgroups. Regardless, given the frequency of these targetable lesions and the increased risk of relapse and chemotherapy-associated toxicities in patients with DS-ALL, targeted therapies currently under investigation for these genetic lesions may be beneficial to replace some intensive blocks of therapy in DS-ALL with CRLF2 and/or JAK alterations, both to enhance anti-leukemic efficacy and decrease intensive chemotherapy-associated toxicities. Figure 1 Disclosures Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; AbbVie, Inc.: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau. Raetz:Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria.
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- 2020
24. Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group
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Mignon L. Loh, Naomi J. Winick, Eric Larsen, Julie M. Gastier-Foster, Cheryl L. Willman, Wanda L. Salzer, Meenakshi Devidas, Yunfeng Dai, Richard C. Harvey, Karen R. Rabin, Michael J. Borowitz, Michael J. Burke, Reuven J. Schore, William L. Carroll, I-Ming L. Chen, Brent L. Wood, Nyla A. Heerema, Andrew J. Carroll, Sarah K. Tasian, Charles G. Mullighan, Anne L. Angiolillo, Stephen P. Hunger, Kelly W. Maloney, Elizabeth A. Raetz, Shalini C. Reshmi, and Kathryn G. Roberts
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Oncology ,medicine.medical_specialty ,Down syndrome ,business.industry ,Internal medicine ,Lymphoblastic Leukemia ,Immunology ,medicine ,Cell Biology ,Hematology ,medicine.disease ,business ,Biochemistry - Abstract
Background: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) occurs in 5-30% of children and adolescents/young adults (AYAs) with B-ALL, is driven by genetic alterations that induce constitutive cytokine receptor and kinase signaling, and is associated with poor clinical outcomes across the older pediatric-to-adult age spectrum (Tasian Blood 2017c, Reshmi Blood 2017, Roberts Blood 2018). Rearrangement and/or overexpression of cytokine receptor-like factor 2 (CRLF2+) occurs in 50% of Ph-like ALL cases with frequently co-occurring JAK2 or JAK1 point mutations or IL7R indel mutations. This study reports the clinical outcomes of children and AYAs with newly-diagnosed National Cancer Institute (NCI) standard-risk (SR) or high-risk (HR) CRLF2+ ALL without Down syndrome treated on four successive Children's Oncology Group (COG) phase 3 clinical trials from 2003 to 2018. Methods: We retrospectively assessed demographic characteristics, laboratory data, and clinical outcomes of 3757 patients with B-ALL treated on COG trials AALL0331 and AALL0932 (SR) and AALL0232 and AALL1131 (HR) whose diagnostic leukemia specimens were analysed by low-density microarray (LDA), fluorescence in situ hybridization, polymerase chain reaction (PCR), and/or anchored multiplex PCR testing (Harvey and Tasian Blood Advances 2020). Minimal residual disease (MRD) was assessed by flow cytometry at the end of induction (EOI) and at the end of consolidation for a subset of EOI MRD+ patients. Results: We identified 77/1541 (5.0%) SR and 244/2216 (11.0%) HR patients with CRLF2+ B-ALL in this cohort. Amongst those with diagnostic leukemia specimens analysed by LDA, 57/72 (79.2%) of SR CRLF2+ and 175/213 (82.2%) of HR CRLF2+ patients were positive for the Ph-like gene expression profile with an 8-gene score ≥0.5. P2RY8-CRLF2 fusions and IGH-CRLF2 translocations were detected in 64/77 (83.1%) and 10/77 (13.0%) of SR CRLF2+ patients and in 98/244 (40.2%) and 103/244 (42.2%) of HR CRLF2+ patients, respectively. CRLF2 rearrangements or F232C mutations were not found in the remaining 3 SR and 43 HR CRLF2+ patients, although other Ph-like alterations were discovered in some (n=3 IGH-EPOR fusions, 1 IL7R indel). Importantly, CRLF2+ vs non-CRLF2-overexpressing (CRLF2-) status was associated with older age (10.8 ±6.5 vs 7.8 ±5.8 years [mean ±SD], p Discussion: Patients with newly-diagnosed CRLF2+ B-ALL treated on frontline COG trials have higher rates of EOI MRD positivity, inferior survival, and increased CIR compared to their CRLF2- counterparts. EFS is especially poor in children and AYAs with NCI HR CRLF2+ ALL, particularly those with the Ph-like expression profile. Conversely, outcomes for children with NCI SR CRLF2+ ALL are reasonably favourable, irrespective of Ph-like status. Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321). Figure 1 Disclosures Tasian: Gilead Sciences: Research Funding; Incyte Corporation: Research Funding; Aleta Biotherapeutics: Membership on an entity's Board of Directors or advisory committees. Borowitz:Amgen: Honoraria. Mullighan:AbbVie, Inc.: Research Funding; Illumina: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hunger:Novartis: Consultancy; Amgen: Current equity holder in publicly-traded company, Honoraria. Raetz:Pfizer: Research Funding; Celgene/BMS: Other. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees.
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- 2020
25. Excellent Outcomes with Reduced Frequency of Vincristine and Dexamethasone Pulses in Children with National Cancer Institute (NCI) Standard-Risk B Acute Lymphoblastic Leukemia (SR B-ALL): A Report from Children's Oncology Group (COG) Study AALL0932
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Angiolillo, Anne, primary, Schore, Reuven J., primary, Kairalla, John, primary, Devidas, Meenakshi, primary, Rabin, Karen R., primary, Zweidler-McKay, Patrick A., primary, Borowitz, Michael J., primary, Wood, Brent L, primary, Carroll, Andrew J., primary, Heerema, Nyla A., primary, Relling, Mary V., primary, Lane, Ashley, primary, Maloney, Kelly, primary, Wang, Cindy, primary, Carroll, William L., primary, Winick, Naomi, primary, Raetz, Elizabeth A., primary, Loh, Mignon L., primary, and Hunger, Stephen P., primary
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- 2019
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26. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase
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Or, Reuven, Shapira, Michael Y., Resnick, Igor, Amar, Avraham, Ackerstein, Aliza, Samuel, Simcha, Aker, Memet, Naparstek, Elizabeth, Nagler, Arnon, and Slavin, Shimon
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- 2003
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27. Excellent Outcomes with Reduced Frequency of Vincristine and Dexamethasone Pulses in Children with National Cancer Institute (NCI) Standard-Risk B Acute Lymphoblastic Leukemia (SR B-ALL): A Report from Children's Oncology Group (COG) Study AALL0932
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John A. Kairalla, Mignon L. Loh, Reuven J. Schore, Elizabeth A. Raetz, Naomi J. Winick, Andrew J. Carroll, Ashley R. Lane, Stephen P. Hunger, Mary V. Relling, Cindy Wang, Karen R. Rabin, Meenakshi Devidas, Kelly W. Maloney, Nyla A. Heerema, Brent L. Wood, Patrick A. Zweidler-McKay, Anne L. Angiolillo, William L. Carroll, and Michael J. Borowitz
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Oncology ,medicine.medical_specialty ,Vincristine ,Randomization ,business.industry ,Immunology ,Context (language use) ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Maintenance therapy ,Acute lymphocytic leukemia ,Internal medicine ,medicine ,B Acute Lymphoblastic Leukemia ,business ,Dexamethasone ,medicine.drug - Abstract
Background: A key component of COG maintenance chemotherapy for pediatric B-ALL has been the inclusion of vincristine/steroid pulses administered every 4 weeks. With the intensification of pre-maintenance therapy and modern risk stratification, there is uncertainty regarding the optimal frequency of these pulses in the context of modern ALL therapy. AALL0932 was designed to optimize maintenance therapy by asking two questions: (1) whether giving vincristine/dexamethasone (VCR/DEX) pulses every 12 weeks was non-inferior to every 4 week pulses; and (2) whether a starting weekly oral methotrexate (MTX dose) of 40 mg/m²/dose would be superior to the standard 20 mg/m2/dose. We previously reported that there was no benefit to intensifying oral methotrexate during maintenance therapy (ASH 2017). We now report on the outcomes of the VCR/DEX pulses. Methods: Average risk (AR) patients participating in the randomization had NCI SR B-ALL without CNS3 or testicular leukemia, unfavorable genetic characteristics or Down syndrome, AND either favorable genetics (trisomies of chromosomes 4 &10 or ETV6/RUNX1 fusion) with Day 8 peripheral blood (PB) minimal residual disease (MRD) ≥ 0.01% or CNS2 status, Day 29 bone marrow (BM) MRD < 0.01%, OR if neutral cytogenetics, had Day 8 PB MRD < 1% and Day 29 BM MRD < 0.01%. AR patients were randomized to 1 of 4 Maintenance regimens using a 2 x 2 factorial design: (A): VCR/DEX pulses every 4 weeks and oral MTX 20 mg/m²/week (standard arm); (B): VCR/DEX pulses every 4 weeks and oral MTX 40 mg/m²/week; (C): VCR/DEX pulses every 12 weeks and oral MTX 20 mg/m²/week; and (D): VCR/DEX pulses every 12 weeks and oral MTX 40 mg/m²/week. Results from the MTX randomization have been previously reported (ASH 2017). Between 2010 and 2016, 2364 patients were randomized at the start of maintenance to VCR/DEX pulses every 4 weeks [Arms A and B (n=1186)] or VCR/DEX pulses every 12 weeks [Arms C & D (n=1178)]. Results: The 5-year disease-free survival (DFS) (±SE) measured from the time of randomization for the AR subset of patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 94.1% ±1.0% vs. 95.1% ±0.9%, respectively (one-sided p=0.86 indicating no evidence of DFS inferiority for 12 week frequency). The 5-year overall survival (OS) (±SE) for the AR patients randomized to receive VCR/DEX pulse every 4 weeks vs. every 12 weeks was 98.3% ±0.5%, vs. 98.6% ±0.5%, respectively (one sided p=0.69). There was no evidence of significant interaction between the MTX and VCR/DEX pulses randomizations. Conclusions: AALL0932 demonstrated that the AR subset of patients with SR B-ALL who received VCR/DEX pulses every 12 weeks maintained outstanding outcomes similar to those who received pulses every 4 weeks. The decreased frequency of VCR/DEX pulses will be incorporated into frontline B-lineage COG ALL trials thereby dramatically improving patient and family quality of life. Disclosures Angiolillo: Servier Pharmaceuticals: Consultancy. Schore:Janssen Research & Development, LLC: Research Funding; AMGEN INC: Research Funding. Zweidler-McKay:ImmunoGen: Employment. Borowitz:Beckman Coulter: Honoraria. Relling:Servier Pharmaceuticals: Research Funding. Raetz:Pfizer: Research Funding. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Hunger:Bristol Myers Squibb: Consultancy; Amgen: Consultancy, Equity Ownership; Jazz: Honoraria; Novartis: Consultancy.
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- 2019
28. Clinical Outcomes in Pediatric Mixed Phenotype Acute Leukemia (MPAL) Differ Depending on Disease Classification Criteria; A Multi-Center Cohort Study
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Oberley, Matthew J., primary, Wertheim, Gerald, additional, Raikar, Sunil S., additional, Malvar, Jemily, additional, Sposto, Richard, additional, Punia, Jyotinder N., additional, Rabin, Karen R., additional, Seif, Alix E., additional, Schore, Reuven J., additional, Luca, Dragos C., additional, Guinipero, Terri, additional, Woods, William G., additional, O'Gorman, Maurice R.G., additional, and Orgel, Etan, additional
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- 2018
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29. Minimal Residual Disease Risk-Stratification in Pediatric Mixed Phenotype Acute Leukemia: Results of a Multi-Center Cohort Study
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Oberley, Matthew J., primary, Raikar, Sunil S., additional, Malvar, Jemily, additional, Wertheim, Gerald, additional, Seif, Alix E., additional, Guinipero, Terri, additional, Sposto, Richard, additional, Rabin, Karen R., additional, Punia, Jyotinder N., additional, Schore, Reuven J., additional, Luca, Dragos C., additional, Woods, William G., additional, O'Gorman, Maurice R.G., additional, and Orgel, Etan, additional
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- 2018
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30. A New Cellular Immunotherapy for the Treatment of Multiple Myeloma without Development of Graft-Versus-Host Disease
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Firer, Michael A, primary, Yado, Sofi, additional, Galia, Luboshits, additional, and Or, Reuven, additional
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- 2018
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31. Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells
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Guido Marcucci, Yan Liu, Yin Wang, Yang Liu, Fei Tang, Kelsie M. Bernot, Pan Zheng, Michael A. Caligiuri, and Reuven J. Schore
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Time Factors ,Immunology ,Echinomycin ,Biology ,Biochemistry ,chemistry.chemical_compound ,Cancer stem cell ,hemic and lymphatic diseases ,medicine ,Animals ,Progenitor cell ,neoplasms ,Bone Marrow Transplantation ,Mice, Knockout ,Myeloid Neoplasia ,Antibiotics, Antineoplastic ,fungi ,Remission Induction ,food and beverages ,Myeloid leukemia ,Cell Biology ,Hematology ,Flow Cytometry ,Hematopoietic Stem Cells ,Hypoxia-Inducible Factor 1, alpha Subunit ,medicine.disease ,Leukemia ,Haematopoiesis ,Treatment Outcome ,medicine.anatomical_structure ,chemistry ,Leukemia, Myeloid ,Acute Disease ,Neoplastic Stem Cells ,Cancer research ,RNA Interference ,Bone marrow ,Neoplasm Recurrence, Local ,Stem cell - Abstract
Acute myeloid leukemia (AML) often relapses following chemotherapy-induced remission and is generally chemo-resistant. Given the potential role for cancer stem cells in relapse, targeting of the leukemia-initiating cell (LIC) in AML may provide improved outcome following remission induction. However, due to overlap in their self-renewal program with normal hematopoietic stem cells (HSCs), therapeutic targeting of the LIC may have an adverse effect on long-term hematopoietic recovery. Here we used a mouse model of relapsed AML to explore whether the hypoxia-inducible factor (HIF)1α inhibitor echinomycin can be used to treat relapsed AML without affecting host HSCs. We show that echinomycin cured 40% to 60% of mice transplanted with relapsed AML. Bone marrow cells from the cured mice displayed normal composition of HSCs and their progenitors and were as competent as those isolated from nonleukemic mice in competitive repopulation assays. Importantly, in mice with complete remission, echinomycin appeared to completely eliminate LICs because no leukemia could be propagated in vivo following serial transplantation. Taken together, our data demonstrate that in a mouse model of relapsed AML, low-dose echinomycin selectively targets LICs and spares normal hematopoiesis.
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- 2014
32. Clinical Outcomes in Pediatric Mixed Phenotype Acute Leukemia (MPAL) Differ Depending on Disease Classification Criteria; A Multi-Center Cohort Study
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Terri Guinipero, Jyotinder N. Punia, Maurice R.G. O'Gorman, Etan Orgel, Richard Sposto, Matthew J. Oberley, Reuven J. Schore, William G. Woods, Gerald Wertheim, Sunil S. Raikar, Karen R. Rabin, Dragos C. Luca, Jemily Malvar, and Alix E. Seif
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medicine.medical_specialty ,Acute leukemia ,Myeloid ,Surrogate endpoint ,business.industry ,Immunology ,Becton dickinson ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Leukemia ,medicine.anatomical_structure ,Internal medicine ,Cohort ,medicine ,business ,Cohort study - Abstract
INTRODUCTION: Mixed phenotype acute leukemia (MPAL) is a category of acute leukemia established in the World Health Organization (WHO) 2001 classification, significantly modified in WHO2008, and again refined in the most recent WHO2016 update. The current WHO2016 iteration conceptualizes MPAL as a stem cell disorder whereby most cases will manifest heterogeneity of lineage-specific antigen expression by multi-parameter flow cytometry. The WHO2016 definition also urges caution for cases otherwise consistent with B-cell acute lymphoblastic leukemia (B-ALL) that express myeloperoxidase (MPO) as the sole representation of myeloid lineage. These cases met the WHO2008 definition but may not meet the newer WHO2016 criteria. There is limited data on the clinical impact of these recent changes in the WHO classification for MPAL. METHODS: Six institutions identified cases diagnosed as MPAL between 2008 and 2016 according to WHO criteria. The diagnostic flow cytometry was then reanalyzed by two independent hematopathologists blinded to clinical outcomes. The cases were evaluated as to whether they met criteria for WHO2008 MPAL and/or WHO2016 MPAL. Cases of WHO2008 MPAL were further subdivided into those that otherwise met criteria for B-ALL (including non-lineage specific expression of ±CD13, ±CD15, ±CD33) but qualified as MPAL due to MPO expression (MPO+MPAL) and all remaining cases of MPAL that demonstrated additional myeloid lineage specificity as described by the WHO criteria (MLS+MPAL). Data for a distinct cohort of pediatric B-ALL without significant MPO expression diagnosed during the same study period was submitted from one participating site to serve as a reference cohort (n=258). Endpoints of interest to evaluate clinical outcomes according to the WHO classification were event-free and overall survival (EFS, OS). All statistical tests were two-sided with significance set at p RESULTS: The cohort consisted of 112 cases submitted for central review; 94/112 met the strict criteria for WHO2008 MPAL. Of these, 21/94 cases also had sufficiently comprehensive testing performed at diagnosis to meet criteria for WHO2016 MPAL. Five-year EFS and OS for patients identified as WHO2016 MPAL (63±11% and 69±11%) was significantly worse than the remainder meeting only the WHO2008 criteria (69±7% and 87±5%, p=0.024 and p CONCLUSIONS: Reported survival rates for MPAL continue to vary with changes to the WHO classification. The subset fulfilling WHO2016 criteria demonstrated significantly worse EFS and OS than the WHO2008 cohort; WHO2016-defined MPAL may better represent the concept of MPAL as a stem cell disorder. Applying WHO2016 versus WHO2008 criteria to diagnostic flow cytometry in this retrospective cohort resulted in fewer patients classified as MPAL. As a retrospective study, the antigen combinations necessary to fulfill newer WHO2016 criteria for blast heterogeneity were not tested in many cases; however, it remains likely that the updated WHO2016 criteria will reduce apparent disease prevalence. While cases of WHO2008 MPAL otherwise meeting criteria for B-ALL apart from MPO expression were less likely to have favorable prognostic features at diagnosis, survival on multivariable analysis was similar to B-ALL; it remains unclear how best to categorize this group of MPO+ acute leukemia. Better understanding of the biology of MPAL is therefore essential to appropriately classify these rare leukemias and to develop optimal therapy. Disclosures O'Gorman: Becton Dickinson: Consultancy.
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- 2018
33. Minimal Residual Disease Risk-Stratification in Pediatric Mixed Phenotype Acute Leukemia: Results of a Multi-Center Cohort Study
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Jyotinder N. Punia, Maurice R.G. O'Gorman, Etan Orgel, Matthew J. Oberley, Karen R. Rabin, Terri Guinipero, Jemily Malvar, Sunil S. Raikar, Alix E. Seif, Richard Sposto, Gerald Wertheim, Reuven J. Schore, William G. Woods, and Dragos C. Luca
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Neoadjuvant therapy ,Surrogate endpoint ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Chemotherapy regimen ,Minimal residual disease ,Leukemia ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Cohort study - Abstract
BACKGROUND: Mixed phenotype acute leukemia (MPAL) is a rare form of leukemia in children. Current evidence supports the use of acute lymphoblastic leukemia (ALL)-directed regimens as initial therapy for MPAL; Children's Oncology Group (COG) ALL regimens are commonly used for pediatric ALL in the United States. Data for the predictive value of minimal residual disease (MRD) to risk-stratify therapy for pediatric MPAL is sparse overall and currently unknown in the context of COG ALL regimens. The primary objective for this study was to therefore examine the predictive value of MRD for event-free and overall survival (EFS, OS) in a centrally-reviewed, strictly-defined pediatric MPAL cohort treated according to COG ALL regimens. METHODS: A retrospective cohort of pediatric MPAL treated from 2008-2016 was assembled from six institutions in the United States. All sites submitted primary diagnostic flow cytometry for central review. Two independent hematopathologists blinded to clinical outcomes confirmed the diagnosis of MPAL according to the WHO2008 and/or WHO2016 classification and assigned a MPAL phenotype. MRD was assessed by multi-parameter flow cytometry ("negative" defined as RESULTS: Of the 112 cases diagnosed by institutions as MPAL, 94 (84%) fulfilled strict WHO criteria. The majority of MPAL patients were B/Myeloid (89%), with a single blast population (87%), and without hyperleukocytosis (WBC≥50K/uL) or central nervous system involvement at presentation (Table 1). Within the cohort, 85/94 were treated with a COG ALL regimen with EOI MRD available (1/85 suffered an induction death prior to MRD assessment). ALL induction therapy resulted in a MRD-negative CR in 72% (61/85); three MRD-negative patients nonetheless converted to non-ALL therapy. Of those EOI MRD+ (≥0.01%), 12 of 14 who continued with COG ALL therapy achieved an EOC MRD-negative CR (i.e. 70/85 [82%] were MRD-negative by EOC). Induction failure (IF) occurred in 7% (6/85) and was defined as disease progression prior to EOI (n=2) or by EOI MRD ≥5% (n=4). The two patients with early disease progression were successfully "salvaged" with AML therapy (0.50 for both); five-year EFS and OS for ALL chemotherapy without HSCT (n=73) were 78±6% and 90±4%, respectively. The presence of multiple blast populations of distinct lineages at diagnosis was similarly rare and was potentially associated with worse OS on multivariable analysis (p=0.024). No other candidate predictors were associated with EFS or OS. No difference in the predictive value of MRD was present when analyses were limited to patients with "neutral" cytogenetics. CONCLUSION: In a retrospective analysis of pediatric MPAL, the majority of patients treated with ALL chemotherapy achieved a MRD-negative CR by EOC (~week 12 of therapy); overall survival in this group was excellent. Further prospective validation of MRD is essential to refine risk-stratified therapy for pediatric MPAL. Optimal salvage for those who fail to achieve remission with ALL chemotherapy is unknown and requires further study. Disclosures O'Gorman: Becton Dickinson: Consultancy.
- Published
- 2018
34. A New Cellular Immunotherapy for the Treatment of Multiple Myeloma without Development of Graft-Versus-Host Disease
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Michael A. Firer, Sofi Yado, Luboshits Galia, and Reuven Or
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Chemotherapy ,business.industry ,T cell ,medicine.medical_treatment ,Immunology ,Spleen ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Donor lymphocyte infusion ,Transplantation ,medicine.anatomical_structure ,Graft-versus-host disease ,medicine ,Cancer research ,Bone marrow ,business ,Multiple myeloma - Abstract
Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematological cancers. Despite recent advances, long-term survival is rare after autologous bone marrow transplantation (auto-BMT) and/or treatment with recently introduced anti-myeloma agents and disease recurs in virtually all patients. Allogeneic bone marrow transplantation (allo-BMT) is an effective treatment that can provide partial or complete remission in patients with MM. The therapeutic potential of allo-BMT is attributed to the "graft-versus-myeloma" (GvM) effect that aims to destroy residual tumor cells that survived an induction protocol of chemotherapy/radiotherapy and to maintain immune surveillance to prevent relapse. However, allo-BMT remains a controversial treatment, since the donor T cells that mediate the GvM effect are also the source of the cells that react to other tissue alloantigens and induce graft versus-host disease (GvHD), a major cause of morbidity and mortality in allo-BMT recipients. Nonetheless, allo-BMT remains the only potentially curable treatment for MM. Recently TCR Vβ CDR3-size spectratype analyses in an animal model of MM identified T cells subfamilies involved in the anti-host and anti-tumor reactivity. We have now carried this work further and tested the potential of integrating auto-BMT with a donor lymphocyte infusion (DLI) composed only of anti-MM reactive Vβ 2, 3 and 8.3 T cell subfamilies. The results demonstrate that these T cell subsets are indeed involved in the generation of a potent GvM response in MM bearing mice and is associated with enhanced survival. Importantly, the GvM response was not accompanied by the development of GvHD. Nonetheless, the GvM response was not sufficient to completely inhibit relapse. We then pre-stimulated donor T cells with MM cells in vitro in the presence of co-stimulatory factors and found that our selective DLI protocol induced a vigorous and long-lasting GvM which translated into long-term survival, again in the complete absence of GvHD. Interestingly, quite similar results were obtained by treating MM-bearing mice with repeat doses of naïve donor Vβ 2, 3 and 8.3 T cell subfamilies. The treated mice showed significantly lower serum paraprotein levels and myeloma infiltration in bone marrow and spleen. Taken together, the results suggest that a transplantation protocol involving only tumor cell-reactive donor T cell subfamilies might be devised for MM patients that results in a potent GvM with enhanced survival but without symptoms of GvHD. Disclosures No relevant conflicts of interest to declare.
- Published
- 2018
35. The CXCR4 Antagonist BL-8040 Induces a Robust Mobilization of CD34+CD38−CD45RA−CD90+ CD49f+ HSCs with Long-Term and Secondary Myeloid and Lymphoid Repopulating Activity
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Abraham, Michal, primary, Oberkovitz, Galia, additional, Bulvik, Baruch, additional, Shiri, Klein, additional, Wald, Hanna, additional, Eizenberg, Orly, additional, Beider, Katia, additional, Nagler, Arnon, additional, Vainstein, Abi, additional, Benami, Eyal, additional, Golan, Rotem, additional, Galun, Eithan, additional, Caraco, Yoseph, additional, Or, Reuven, additional, and Peled, Amnon, additional
- Published
- 2017
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36. Myeloablative Conditioning for First Allogeneic Hematopoietic Stem Cell Transplantation in Children with ALL: Total Body Irradiation or Chemotherapy? - a Multicenter EBMT-PDWP Study
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Willasch, Andre Manfred, primary, Peters, Christina, additional, Sedlacek, Petr, additional, Dalle, Jean-Hugues, additional, Graphakos, Stelios, additional, Yesilipek, Akif, additional, Wachowiak, Jacek, additional, Lankester, Arjan, additional, Prete, Arcangelo, additional, Hamidieh, Amir Ali, additional, Ifversen, Marianne, additional, Büchner, Jochen, additional, Krivan, Gergely, additional, Hamladji, Rose-Marie, additional, Diaz de Heredia, Cristina, additional, Skorobogatova, Elena, additional, Michel, Gerard, additional, Locatelli, Franco, additional, Bertaina, Alice, additional, Veys, Paul, additional, Dupont, Sophie, additional, Or, Reuven, additional, Guengoer, Tayfun, additional, Aleinikova, Olga, additional, Sufliarska, Sabina, additional, Sundin, Mikael, additional, Rascon, Jelena, additional, Kaare, Ain, additional, Nemet, Damir, additional, Fagioli, Franca, additional, Klingebiel, Thomas, additional, Styczynski, Jan, additional, Bierings, Marc B, additional, Nagy, Kalman, additional, Abecasis, Manuel, additional, Afanasyev, Boris V, additional, Ansari, Marc, additional, Dalissier, Arnaud, additional, Labopin, Myriam, additional, Beohou, Eric, additional, and Bader, Peter, additional
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- 2017
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37. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation
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Kathrin Opherk, Mohamad Mohty, Max S. Topp, Michael Maschan, Friedhelm R. Schuster, Tobias Feuchtinger, Wolfgang Bethge, Hermann Einsele, Rupert Handgretinger, Peter Lang, Reuven Or, Michael Schumm, Klaus Hamprecht, and Eva M. Weissinger
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Adult ,Adoptive cell transfer ,Time Factors ,Adolescent ,T-Lymphocytes ,medicine.medical_treatment ,Immunology ,Congenital cytomegalovirus infection ,Hematopoietic stem cell transplantation ,Haploidy ,Biochemistry ,Viral Matrix Proteins ,Recurrence ,Betaherpesvirinae ,medicine ,Humans ,Child ,biology ,business.industry ,Histocompatibility Testing ,virus diseases ,Cell Biology ,Hematology ,Middle Aged ,Phosphoproteins ,biology.organism_classification ,medicine.disease ,Adoptive Transfer ,Virology ,Transplantation ,Treatment Outcome ,Child, Preschool ,Cytomegalovirus Infections ,Feasibility Studies ,Viral disease ,Stem cell ,business ,Viral load ,Follow-Up Studies ,Stem Cell Transplantation - Abstract
Cytomegalovirus (CMV) disease and infection refractory to antiviral treatment after allogeneic stem cell transplantation (allo-SCT) is associated with a high mortality. Adoptive transfer of CMV-specific T cells could reconstitute viral im-munity after SCT and could protect from CMV-related complications. However, logistics of producing virus-specific T-cell grafts limited the clinical application. We treated 18 patients after allo-SCT from human leukocyte antigen–mismatched/haploidentical or human leukocyte antigen–matched unrelated donors with polyclonal CMV-specific T cells generated by ex vivo stimulation with pp65, followed by isolation of interferon-γ–producing cells. Patients with CMV disease or viremia refractory to antiviral chemotherapy or both were eligible for adoptive T-cell transfer and received a mean of 21 × 103/kg pp65-specific T cells. In 83% of cases CMV infection was cleared or viral burden was significantly reduced, even in cases of CMV encephalitis (n = 2). Viral control was associated with in vivo expansion of CMV-specific T lymphocytes in 12 of 16 evaluable cases, resulting in reconstitution of antiviral T-cell responses, without graft-versus-host disease induction or acute side effects. Our findings indicate that the infusion of low numbers of CMV-specific T cells is safe, feasible, and effective as a treatment on demand for refractory CMV infection and CMV disease after allo-SCT.
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- 2010
38. Myeloablative Conditioning for First Allogeneic Hematopoietic Stem Cell Transplantation in Children with ALL: Total Body Irradiation or Chemotherapy? - a Multicenter EBMT-PDWP Study
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Marianne Ifversen, Peter Bader, Christina Peters, Jacek Wachowiak, Marc Bierings, Gérard Michel, Boris V. Afanasyev, Myriam Labopin, Paul Veys, Rose-Marie Hamladji, Jochen Büchner, K. Nagy, Sabina Sufliarska, Marc Ansari, Thomas Klingebiel, Sophie Dupont, Arcangelo Prete, Jan Styczyński, Eric Beohou, Andre Willasch, E V Skorobogatova, Tayfun Guengoer, Alice Bertaina, Arjan C. Lankester, Damir Nemet, Ain Kaare, Petr Sedlacek, Mikael Sundin, Jelena Rascon, Stelios Graphakos, Amir Ali Hamidieh, Gergely Kriván, Jean-Hugues Dalle, Manuel Abecasis, Akif Yeşilipek, Reuven Or, Franca Fagioli, Cristina Díaz de Heredia, Franco Locatelli, Olga Aleinikova, and Arnaud Dalissier
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Oncology ,medicine.medical_specialty ,Univariate analysis ,Chemotherapy ,Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,Total body irradiation ,Biochemistry ,Chemotherapy regimen ,Internal medicine ,medicine ,business ,Busulfan ,Etoposide ,medicine.drug - Abstract
Introduction: Most pediatric patients (pts) with ALL receive total body irradiation (TBI) for myeloablative conditioning of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unproven whether TBI can be replaced by chemotherapy (CHT). Methods: To compare the outcomes of TBI- versus (vs.) CHT-based conditioning, we performed a retrospective EBMT-registry based study. Children between 2 and 18 years of age (y.) after myeloablative conditioning for first allo-HSCT of bone marrow (BM) or peripheral blood SC (PBSC) from matched sibling (MSD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to consider the covariate "distribution of TBI recipients" for pts who did not receive TBI. Results: In total 3071 pts (CR1: 1504 (49%), CR2: 1567 (51%)) were included. CR1: 1045 pts (69%) received BM and 459 pts (31%) PBSC from MSD (760 (51%)) or UD (744 (49%)). CR2: 1067 pts (68%) received BM and 500 pts (32%) PBSC from MSD (675 (43%)) or UD (892 (57%)). Overall, conditioning was TBI- in 2647 (86%) and CHT-based in 424 pts (14%). Busulfan/Cyclophosphamide (Bu/Cy) and Bu/Cy/Etoposide (Bu/Cy/Eto) were the two most frequently applied CHT combinations in CR1 (68 (32%), 66 (31%)) and CR2 (68 (32%), 52 (25%)). The remaining conditionings included 5 different combinations of chemotherapeutics (other chemo). 1504 pts in CR1 were conditioned with TBI (1291), Bu/Cy/Eto (66) or other chemo (147) with a median follow-up of 4.4, 3.4 and 2.4 y. In weighted univariate analysis no significant differences were detected for LFS (5-y.-LFS, range: 62.4 to 67.5%) and relapse incidence (5-y.-RI, range: 24.0 to 29.0%). In pairwise testing, OS after Bu/Cy/Eto was significantly better compared with TBI (5-y.-OS, 78.7 vs. 66.8%, P=.006). Non-relapse mortality was significantly higher after other chemo (5-y.-NRM, 12.7%, P Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 65.8 vs. 12-18 y. 58.0%, P=.009), y. of HSCT (2008-2012 65.9 vs. 2000-2007 59.6%, P=.035) and donor type (MSD 64.9 vs. UD 59.5%, P=.007). RI was influenced by y. of HSCT (5-y.-RI, 2008-2012 21.7 vs. 2000-2007 26.8%. P=.026). OS was influenced by age (5-y.-OS, 2-11 y. 72.7 vs. 12-18 y. 61.7%, P In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR1 was associated with lower RI (HR 0.70, P=.047), lower OS (HR 1.54, P=.017) and higher NRM (HR 3.97, P 1567 pts in CR2 were conditioned with TBI (1356), Bu/Cy (68) or other chemo (143) with a median follow-up of 3.9, 3.2 and 3.1 y. In weighted univariate analysis highly significant differences of survival were detected. TBI-based conditioning resulted in highest 5-y.-LFS of 52.2% (Bu/Cy 41.0%, other chemo 18.4%, P Other significant influencing factors on LFS were age (5-y.-LFS, 2-11 y. 53.5 vs. 12-18 y. 43.0%, P In weighted multivariable Cox model clustered on EBMT centers, TBI-based conditioning in CR2 was associated with higher LFS (HR 0.48, P Conclusion: Conditioning by TBI demonstrated clear superiority in comparison to CHT for children with ALL undergoing HSCT in CR2. For pts in CR1, TBI- and CHT-based conditioning showed similar results. This retrospective data is currently re-evaluated in a prospective, randomized, international trial (ALL SCTped 2012 FORUM). Disclosures Büchner: Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Consultancy. Veys: Bellicum: Research Funding; Servier: Research Funding. Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.
- Published
- 2017
39. The CXCR4 Antagonist BL-8040 Induces a Robust Mobilization of CD34+CD38−CD45RA−CD90+ CD49f+ HSCs with Long-Term and Secondary Myeloid and Lymphoid Repopulating Activity
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Reuven Or, Orly Eizenberg, Klein Shiri, Eyal Benami, Rotem Golan, Galia Oberkovitz, Eithan Galun, Arnon Nagler, Katia Beider, Baruch Bulvik, Abi Vainstein, Yoseph Caraco, Hanna Wald, Amnon Peled, and Michal Abraham
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0301 basic medicine ,Myeloid ,Chemistry ,Immunology ,CD34 ,hemic and immune systems ,Cell Biology ,Hematology ,CD38 ,Biochemistry ,Molecular biology ,Transplantation ,03 medical and health sciences ,Haematopoiesis ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,medicine ,CD90 ,Progenitor cell ,Stem cell - Abstract
Introduction: Lifelong blood cell production is dependent on rare hematopoietic stem cells (HSCs) to perpetually replenish mature cells via a series of lineage-restricted intermediates. The bulk of HSCs are CD34+, however, most CD34+ cells are lineage-restricted progenitors and HSCs remain rare. HSCs can be enriched further based on CD45RA, Thy1 (CD90), and CD38 expression. Loss of CD90 expression was proposed to be sufficient to separate CD34+CD38−CD45RA− CD90+ HSCs from CD34+CD38−CD45RA− CD90- multipotent progenitors (MPPs). Recently, it was demonstrated that the expression CD49f is a specific HSC marker. Single CD49f(+) cells were highly efficient in generating long-term multilineage grafts, and the loss of CD49f expression identified transiently engrafting MPPs. Results: CD34+ cells were purified from BL-8040 and G-CSF mobilized grafts and stained for CD38, CD45RA, CD90, and CD49f. The percentage of CD34+CD38- hematopoietic stem and progenitors was similar in both grafts (Figure 1A). However, whereas 23.2 % of BL-8040 mobilized CD34+ CD38- cells did not express CD45RA; only 1.6% of G-CSF mobilized CD34+ CD38- cells did not express CD45RA (Figure 1B). The percentages of CD34+CD38−CD45RA−CD49f+CD90+/-, CD34+CD38−CD45RA−CD49f+ CD90+, and CD34+CD38−CD45RA− CD90+ HPCS were increased significantly by 45, 25 and 12 -fold in the BL-8040 graft compared to G-CSF graft derived CD34+CD38- cells (Figure 1C). To assess the long-term engraftment potential of the BL-8040 mobilized CD34+ cells, engraftment was allowed for 4, 8, and 22 weeks after transplantation. Successful and robust long-term human engraftment of CD45+ and CD45+CD34+ cells was observed at week 22 (Figure 2A, 2B). The % of human CD45 cells remained stable in the BM whereas the percentage of CD45 cells in the blood and spleen increased at week 22 (Figure 2C). At 4 weeks, human CD3+CD4+ T cells were only observed at a low percentage in the spleen but not in the BM, whereas no significant percentage of CD3+CD8+ cells were found neither in the BM nor in the spleen (Figure 2D, 2E). 22 weeks after transplantation, the percentage of human CD3+CD4+ and CD3+CD8+ T cells was significantly increased in the spleen (30% vs. 5%, respectively) and to much lower levels in the BM (Figure 2D, 2E). Furthermore, successful and robust long-term human engraftment of secondary recipient was observed 14 weeks following the second transplantation (Figure 2A and 2B). Conclusion: In association with the high percentage of HPCs in the BL-8040-derived graft, we found a robust myeloid and lymphoid long-term engraftment (week 22) of BL-8040 mobilized human CD34+ cells in NSG mice. The ability of BL-8040 to collect high numbers of HPCs may be beneficial for a variety of HPCs dependent therapeutics. Disclosures Abraham: Biokine: Employment. Oberkovitz: BiolineRx: Employment. Eizenberg: Biokine: Employment. Vainstein: BiolineRx: Employment. Benami: BiolineRx: Employment. Golan: BiolineRx: Employment. Or: Bioline: Consultancy. Peled: Biokine: Consultancy; Biosight: Consultancy.
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- 2017
40. Regional Intra-Arterial Steroid Treatment in 113 Patients with Steroid Resistant or Dependent Graft-Versus-Host Disease
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Shapira, Michael Y, primary, Vipul, Sheth, additional, Klimov, Alexander, additional, Griesaro, Sigal, additional, Tsirigotis, Panagiotis, additional, Avni, Batia Ronit, additional, Or, Reuven, additional, and Bloom, Allan, additional
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- 2016
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41. Anti-Pegaspargase, Anti-Calaspargase Pegol , and Anti-Polyethelene Glycol Antibody Incidence in High Risk Acute Lymphoblastic Leukemia Patients Receiving Pegaspargase or Calaspargase Pegol and Associated Anaphylactic or Hypersensitivity Reaction Rates: Results from Children's Oncology Group (COG) Study AALL07P4
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Schore, Reuven J, primary, Devidas, Meenakshi, additional, Bleyer, Archie, additional, Reaman, Gregory, additional, Lebedinsky, Claudia, additional, Zhang, Hui, additional, Koppensteiner, Herwig, additional, Loh, Mignon L., additional, Raetz, Elizabeth, additional, Winick, Naomi, additional, Carroll, William L., additional, Hunger, Stephen P., additional, and Angiolillo, Anne, additional
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- 2016
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42. Integrated Genomic Analysis of Down Syndrome Acute Lymphoblastic Leukemia Reveals Recurrent Cancer Gene Alterations and Evidence of Frequent Subclonal Driver Events
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Hampton, Oliver A,, primary, Ramos, Enrique I., additional, Kakkar, Nipun, additional, Junco, Jacob J., additional, Reuther, Jacquelyn, additional, Angiolillo, Anne, additional, Schore, Reuven J, additional, Burke, Michael J., additional, Salzer, Wanda, additional, Devidas, Meenakshi, additional, Carroll, Andrew J., additional, Heerema, Nyla A., additional, Maloney, Kelly, additional, Winick, Naomi, additional, Carroll, William L., additional, Raetz, Elizabeth, additional, Loh, Mignon L., additional, Hunger, Stephen P., additional, Jain, Juhi, additional, Doddapaneni, Harsha, additional, Muzny, Donna M., additional, Wheeler, David A., additional, Fisher, Kevin E., additional, Lopez-Terrada, Dolores H., additional, Roy, Angshumoy, additional, Parsons, Donald Williams, additional, and Rabin, Karen R., additional
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- 2016
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43. Results from the Phase 1 Portion of a Trial of Oral Ixazomib Combined with Chemotherapy in Relapsed/Refractory Acute Lymphoblastic Leukemia or Lymphoma in Children, Adolescents and Young Adults: A Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium
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Schafer, Eric S., Chi, Yueh-Yun, Malvar, Jemily, Rushing, Teresa, Doan, Andrew, Pacenta, Holly L., Schore, Reuven J., Sposto, Richard, Leong, Roy, Gaynon, Paul S., Rubnitz, Jeffrey E., Barredo, Julio C., Slone, Tamra, Pauly, Melinda, Wayne, Alan S., Bhojwani, Deepa, and Horton, Terzah M.
- Abstract
Proteasome inhibitors potentiate anti-tumor effects of standard cytotoxic chemotherapy in childhood leukemia. Ixazomib is an oral proteasome inhibitor that has a shorter proteasome dissociation half-life than bortezomib, which leads to a higher tumor-to-blood ratio inhibition. We performed a phase 1 trial to determine the dose limiting toxicities (DLT), Recommended Phase 2 Dose (RP2D) of ixazomib in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoma (LL).
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- 2023
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44. Understanding the Macrophage's Role in Regulating Cancer-Associated Thrombosis
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Parker, Olivia D, Risman, Rebecca, Apte, Vaidehi, Rosen, Reuven, Schloss, Rene, and Tutwiler, Valerie
- Abstract
Background:With the risk of thrombosis elevated in cancer patients, there is a need to find treatments that can regulate clotting abnormalities during this disease. The immune system has become a target for treating cancer-associated thrombosis (CAT). Notably, the macrophage, a key immune cell, has been shown to play a role in mediating cancer progression and thrombosis. A regulator of the coagulation process, urokinase plasminogen activator (uPA) also mediates cancer progression. uPA regulates blood clot breakdown through fibrinolysis. Monocytes have receptors for uPA. In addition, upon stimulation, they can release tumor necrosis factor alpha (TNF-α), a prothrombotic cytokine. Furthermore, macrophages can release higher quantities of tissue factor upon polarization through interleukins (IL-4 and IL-13). However, no known studies show the macrophage phenotypes' (pro-inflammatory or anti-inflammatory) effects on clot formation, structure, and fibrinolysis. Given that uPA has a role in cancer progression, monocytes contain receptors for uPA, and macrophage phenotype influences tissue factor expression, there is a need to determine how macrophage phenotype and components of the urokinase system can mediate clot formation, structure, and resolution.
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- 2023
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45. Real-World Performance of 2022 Revised World Health Organization (WHO) Criteria for Mixed Phenotype Acute Leukemia (MPAL) B/Myeloid Defined Only By Isolated MPO Expression (isoMPO)
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Kovach, Alexandra E., Raikar, Sunil S., Malvar, Jemily, Oberley, Matthew J., Wertheim, Gerald, Rabin, Karen R., Punia, Jyotinder N., Seif, Alix, Schore, Reuven J., Luca, Dragos C., Guinipero, Terri L., Woods, William G., Cahen, Viviane, Chi, Yueh-Yun, O'Gorman, Maurice R.G., Wood, Brent L., and Orgel, Etan
- Abstract
Mixed phenotype acute leukemia (MPAL) is biologically and immunophenotypically heterogeneous, and optimal diagnostic criteria remain unclear. The two current pathologic classifications [2022 World Health Organization (WHO) 5 thEd. and International Consensus Classification (ICC)] group MPAL by cell lineages and, when present, cytogenetic drivers. In both, myeloperoxidase (MPO) is a key determinant of myeloid lineage. However, the diagnosis of MPAL has been inconsistently applied to cases of acute leukemia expressing MPO alone to define myeloid lineage. To address this, the 2022 WHO revised prior cell lineage definitions to emphasize antigen intensity (≥50%) relative to a positive control population, attempting to standardize lineage assignment across flow cytometer settings and pathologist interpreters. Distinction between pediatric B-lymphoblastic leukemia (B-ALL) and MPAL B/Myeloid with isolated MPO is crucial for therapeutic decision-making. For example, on Children's Oncology Group (COG) regimens, patients with MPAL B/Myeloid receive an anthracycline during induction and intensified chemotherapy post-induction, whereas standard-risk B-ALL patients do not. We hypothesized that the 2022 WHO criteria applied to MPO expression in children with acute leukemia would identify leukemic subtypes (B-ALL vs. MPAL B/Myeloid with isolated MPO) with differences in clinical characteristics and/or outcome.
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- 2023
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46. Regional Intra-Arterial Steroid Treatment in 113 Patients with Steroid Resistant or Dependent Graft-Versus-Host Disease
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Allan I. Bloom, Panagiotis Tsirigotis, Michael Y. Shapira, Reuven Or, Sigal Griesaro, Alexander Klimov, Sheth Vipul, and Batia Avni
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medicine.medical_specialty ,Univariate analysis ,medicine.diagnostic_test ,business.industry ,medicine.medical_treatment ,Immunology ,Interventional radiology ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Gastroenterology ,Transplantation ,Gastroduodenal artery ,medicine.anatomical_structure ,Graft-versus-host disease ,Internal medicine ,medicine.artery ,Cohort ,medicine ,business ,Artery - Abstract
Introduction : Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), resulting in death in the majority of steroid-resistant patients. In the past 15 years, we revolutionized the use of interventional radiology procedures in the field of stem cell transplantation. This study was aimed to assess the efficacy of regional intra-arterial steroid (IAS) treatment in the largest published cohort of patients with resistant/dependent hepatic and/or gastrointestinal (GI) GVHD. In total, 113 patients with steroid resistant or dependent grade 3-4 hepatic (n = 21), gastrointestinal (GI) (n = 62) GVHD or both (n = 30) were given intra-arterial treatment. Patients and methods: Patients with liver GVHD received IAS in hepatic artery and patients with gastrointestinal GVHD received IAS in the superior and inferior mesenteric as well as the internal iliac arteries. Patients with pronounced upper GI symptoms also received IAS to the gastroduodenal artery. In total 148 procedures were carried out (range 1-3 per patient). Results : Partial responses were observed in 33 out of 51 (65%) patients with hepatic GVHD, out of which (55%) had complete response. Median time to complete response was 45 days (range - 5 to 300 days). For GI GVHD complete responses were observed in 69 out of 92 (75%) and partial responses were observed in 76 out of 92 (83%). The median time to complete response was 20 days (range - 3 to 200 days ). As this is the largest published cohort of regional IAS therapy for GVHD, multivariate and univariate analysis was done in order to identify the patients with highest chance of response. Conclusions : Regional treatment of severe GVHD with IAS treatment is effective and safe. GI treatment is more effective than intrahepatic treatment. Early administration of isolated intra-arterial therapy in high-risk patients may further improve the outcome and reduce untoward effects of prolonged systemic immunosuppressive treatment. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
47. Integrated Genomic Analysis of Down Syndrome Acute Lymphoblastic Leukemia Reveals Recurrent Cancer Gene Alterations and Evidence of Frequent Subclonal Driver Events
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Mignon L. Loh, Andrew J. Carroll, David A. Wheeler, Naomi J. Winick, Donna M. Muzny, William L. Carroll, Anne L. Angiolillo, Angshumoy Roy, Jacob J. Junco, Harsha Doddapaneni, Karen R. Rabin, Enrique I. Ramos, Kelly W. Maloney, Jacquelyn Reuther, Kevin E. Fisher, Elizabeth A. Raetz, Stephen P. Hunger, Donald W. Parsons, Wanda L. Salzer, Nyla A. Heerema, Meenakshi Devidas, Juhi Jain, Michael J. Burke, Dolores Lopez-Terrada, Nipun Kakkar, Oliver A. Hampton, and Reuven J. Schore
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Oncology ,Down syndrome ,medicine.medical_specialty ,business.industry ,Lymphoblastic Leukemia ,Immunology ,Cancer ,Signs and symptoms ,Cancer Care Facilities ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Internal medicine ,Disease remission ,Recurrent Cancer ,medicine ,business ,Gene - Abstract
Introduction: Children with Down syndrome (DS) have a 10-20 fold increased risk of acute lymphoblastic leukemia (ALL) and suffer significantly poorer outcomes due to increased relapse and treatment-related mortality. DS-ALL exhibits a distinct spectrum of cytogenetic alterations, with a lower incidence of common recurrent ALL alterations, a higher incidence of alterations involving CRLF2 and JAK2, and a higher proportion of cases lacking a known oncogenic driver compared to non-DS ALL. We hypothesized that identifying genetic drivers in DS-ALL will facilitate improved risk-based treatment stratification and lead to novel therapeutic targets that may be harnessed to improve outcomes in this vulnerable population. Methods: We interrogated diagnostic tumor (bone marrow or peripheral blood) and matched remission ("normal") blood samples from a cohort of 63 DS-ALL cases (65% male; median age 5 years, range 1-21 years) obtained from Texas Children's Cancer Center and the Children's Oncology Group. Samples were selected to include ~1/3 CRLF2-rearranged (CRLF2-R) and ~2/3 CRLF2-wild-type (CRLF2-WT) cases. Whole exome sequencing (WES) and copy number analysis using the OmniExpress array were performed on both tumor and normal DNA and transcriptome sequencing (RNAseq) was conducted on tumor RNA, all using the Illumina platform and existing informatic pipelines at the Baylor College of Medicine Human Genome Sequencing Center. A median of >97% of targeted bases with at least 20x coverage (range 93.5-98.1%) was observed for WES, and an average of 55.4 million paired reads were generated per RNAseq. Results: Analysis of RNAseq data (n=60) using deFuse and SOAPfuse algorithms revealed known ALL-associated gene rearrangements in 37/60 (62%) of cases, including CRLF2-R (21/60, 35%) involving P2RY8 (n=17) or IGH (n=4); ETV6-RUNX1 fusions (14/60, 23%) and TCF3 fusions (PBX1 x 2 and a novel in-frame fusion with FLI1 x 1). WES (n=62) identified a median of 19 nonsilent somatic mutations per case (range 6-228). We did not find evidence of somatic or germline mismatch repair gene mutations in the 3 cases with >50 somatic mutations. WES findings included recurrent activating hotspot mutations in JAK2 (predominantly p.R683G/S) in 14 cases (23%) and CRLF2 (p.F232C) in 2 cases, all of which also had CRLF2-R. Somatic RAS pathway mutations (13 KRAS, 7 NRAS, and 2 PTPN11) were found in 20/62 cases (32%), 4 CRLF2-R and 16 CRLF2-WT, including 2 cases also harboring JAK2 activating mutations. Recurrent mutations in epigenetic or chromatin remodeling genes (e.g. KMT2C, SETD2, KDM6A, WHSC1, DOT1L) were observed in ~25% of patients, as were mutations in other known ALL genes (e.g. FLT3, IL7R, IKZF1, PAX5). Interestingly, inactivating mutations in the deubiquitinase USP9X, also recently reported in acute promyelocytic leukemia, were identified in 5/62 (8%) cases. Evaluation for internal tandem duplications (ITDs) demonstrated typical in-frame events in FLT3 (n=2) and an out-of-frame ITD in SETD2. Copy number analysis revealed frequent losses in cell cycle genes (CDKN2A/B, BTG1, RB1) and other known B-cell development genes (IKZF1, PAX5). Other putative candidate alterations detected by RNAseq, WES, and array are currently being validated by orthogonal platforms. We observed multiple subclonal driver events in >10% of patients, including one case with CRLF2-R and mutations in CRLF2, JAK2, KRAS, and NRAS; and a second case with CRLF2 and ETV6-RUNX1 rearrangements and a PTPN11 hotspot mutation. Six cases exhibited 2 different JAK2, KRAS, or NRAS mutations: in all four cases where evaluation was feasible, these mutations were present on different sequencing reads, suggesting the existence of distinct subclones. Clinical features (gender, age, initial white blood count) did not appear to co-cluster with any of the recurrent alterations. Conclusions: These findings detail the landscape of genomic and transcriptomic alterations in the largest cohort of DS-ALL comprehensively characterized to date. Our data confirm the frequency and occasional polyclonal nature of JAK2 and RAS pathway mutations, and demonstrate that mutations in these pathways are not mutually exclusive. We also identified several novel, recurrent mutations and fusions. Future analyses of additional cohorts will be needed to assess recurrence frequency and prognostic impact of these alterations. Disclosures Schore: Baxalta: Honoraria; Millennium Pharmaceuticals, Inc: Research Funding; Onyx/Amgen: Research Funding; Merck: Research Funding.
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- 2016
48. Anti-Pegaspargase, Anti-Calaspargase Pegol , and Anti-Polyethelene Glycol Antibody Incidence in High Risk Acute Lymphoblastic Leukemia Patients Receiving Pegaspargase or Calaspargase Pegol and Associated Anaphylactic or Hypersensitivity Reaction Rates: Results from Children's Oncology Group (COG) Study AALL07P4
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William L. Carroll, Stephen P. Hunger, Hui Zhang, Gregory H. Reaman, Mignon L. Loh, Naomi J. Winick, Anne L. Angiolillo, Archie Bleyer, Claudia Lebedinsky, Meenakshi Devidas, Herwig Koppensteiner, Reuven J. Schore, and Elizabeth A. Raetz
- Subjects
Oncology ,medicine.medical_specialty ,Asparaginase ,Immunology ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Maintenance therapy ,Acute lymphocytic leukemia ,Internal medicine ,medicine ,CASP ,Pegaspargase ,biology ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,humanities ,Hypersensitivity reaction ,chemistry ,030220 oncology & carcinogenesis ,Pharmacodynamics ,biology.protein ,Antibody ,business ,030215 immunology ,medicine.drug - Abstract
Introduction Asparaginase is a critical component in the treatment of acute lymphoblastic leukemia (ALL). COG AALL07P4 evaluated the pharmacokinetic (PK) and pharmacodynamic comparability of pegaspargase (ASP) and calaspargase pegol (CASP) as part of an augmented BFM chemotherapy regimen for the treatment of newly-diagnosed, NCI high-risk, B-precursor ALL (Angiolillo, JCO 2014). Both ASP and CASP consist of E. coli L-asparaginase linked to polyethelene glycol (PEG) utilizing a succinimidyl succinate or succinimidyl carbamate linker, respectively. Antibodies to either asparaginase or PEG have been associated with rapid clearance of asparaginase. Methods Of the 166 patients randomized, 1 was inevaluable; 54 patients were randomized to ASP at 2500 IU/m2,43 to CASP at 2500 IU/m2 and 69 toCASP at 2100 IU/m2; both CASP treatment groups were pooled for this report. Blinded analyses of anti-ASP and anti-CASP antibodies were performed on samples obtained prior to asparaginase administration and at protocol specified time-points through the second cycle of maintenance therapy inpatients withadequatesamples (50 and 111 patients in the ASP and CASP treatment groups, respectively). Immunogenicity assessment included the detection of binding anti-ASP or anti-CASP antibodies by a validated direct enzyme-linked immunosorbent assay (ELISA). All detected antibodies were analyzed in a neutralizing anti-ASP/anti-CASP antibody assay for their neutralizing capacity using a validated enzymatic coupled activity assay. Analysis of anti-PEG antibodies using ELISA was assessed retrospectively, in a subset of patients who had available specimens, as this had not been part of the initial trial design, in 26 and 42 patients in the ASP and CASP treatment groups, respectively, including all patients with anti-ASP/anti-CASP antibody positive samples. All grades of anaphylactic reactions and hypersensitivity were reported according to the CTCAE v3.0 prior to July 2011 and converted into v4.0 codes with subsequent AEs collected in v4.0 beginning with the first asparaginase dose until 60 days after the last dose of asparaginase or being switched to erwinia asparaginase. Results Our analysis of anti-ASP and anti-CASP antibodies showed fewer anti-CASP antibodies: 3.6% (4 /111 patients) than anti-ASP antibodies: 10.0% (5/50 patients). The majority of positive post treatment antibodies were transient and not detectable at subsequent visits. Three patients (one in the CASP and two in the ASP treatment group) showed positive results for binding antibodies at the last tested time point; it is unknown whether these antibodies are of transient or persistent nature. Among 111 patients treated with CASP, 29 (26.1%) developed an anaphylactic and/or hypersensitivity reaction and 2 of these (6.9%) had anti-CASP present at the time of reaction; among 50 patients treated with ASP, 14 (28%) developed an anaphylactic and/or hypersensitivity reaction and 2 of these (14.3%) had anti-ASP present at the time of reaction. Only one patient in the CASP treatment group tested positive for neutralizing antibodies at one time point with negative results at subsequent time points. Focusing on the subset of patients who had available anti-PEG antibody data, we found that 6/46 (13%) in the CASP treatment group had detectable anti-PEG antibodies as compared to the 5/26 (19.2%) in the ASP treatment group. In the patients who had anaphylactic and hypersensitivity reactions, 2/10 (20%) patients treated with CASP had either anti-CASP or anti-PEG antibodies, as compared to 5/8 (62.5%) patients treated with ASP who had either anti-ASP or anti-PEG antibodies. Observed differences in antibody responses were not statistically significant. As we previously reported, many patients with clinical anaphylactic and hypersensitivity reactions did not have antibodies detected. Conclusions In this preliminary analysis of COG AALL07P4, patients receiving CASP have numerically less antibody formation to both asparaginase and PEG than patients receiving ASP. Fewer patients with anaphylactic and hypersensitivity reactions to CASP had detectable antibodies as compared to those who received ASP. Since these antibodies may be associated with rapid clearance of asparaginase, further evaluation of PK and immunogenicity is ongoing. Additional investigation is warranted to better understand the clinical significance of these findings. Table Table. Disclosures Schore: Onyx/Amgen: Research Funding; Millennium Pharmaceuticals, Inc: Research Funding; Baxalta: Honoraria; Merck: Research Funding. Bleyer:Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Lebedinsky:Shire: Employment. Zhang:Shire: Employment. Koppensteiner:Shire: Employment. Loh:Abbvie: Research Funding; Briston Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Hunger:Erytech: Honoraria; Patent: Patents & Royalties: Dr. Hunger is a co-inventor of a patent (#8658,964) for the identification of novel subgroups in high risk B-ALL and outcome correlations and diagnostic methods related to the same; Spectrum Pharmaceuticals: Honoraria; Sigma Tau Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Honoraria; Merck: Equity Ownership; Pfizer: Equity Ownership; Amgen: Equity Ownership.
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- 2016
49. Outcome of BONE Marrow Transplantation in Congenital Diskeratosis: Preliminary DATA from the European Group for BONE Marrow Transplantation (EBMT)
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Fioredda, Francesca, primary, Korthof, Elisabeth T, additional, Iacobelli, Simona, additional, Knol, Cora, additional, Veelken, Joan H, additional, Veys, Paul, additional, Yoshimi, Ayami, additional, Mellegren, Karin, additional, Fagioli, Franca, additional, Zecca, Marco, additional, Maschan, Alexey, additional, O'Brien, Tracey, additional, Diaz, Miguel Angel, additional, Smith, Owen, additional, Socie, Gerard, additional, Josue, de la Fuente, additional, Or, Reuven, additional, and Dufour, Carlo, additional
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- 2015
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50. Thiotepa-Based Conditioning for Allogeneic Stem Cell Transplantation (allo-HSCT) in Acute Lymphoblastic Leukaemia (ALL) - a Survey from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)
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Eder, Sandra, primary, Beohou, Eric, additional, Labopin, Myriam, additional, Sanz, Jaime, additional, Finke, Jürgen, additional, Arcese, William, additional, Or, Reuven, additional, Bonifazi, Francesca, additional, Cortelezzi, Agostino, additional, Majolino, Ignazio, additional, Bacigalupo, Andrea, additional, Spyridonidis, Alexandros, additional, Alessandrino, Emilio Paolo, additional, Giebel, Sebastian, additional, Mohty, Mohamad, additional, and Nagler, Arnon, additional
- Published
- 2015
- Full Text
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