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  • 1
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    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
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2382-2382
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2382-2382
    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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-148593
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 2
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    Abstract 4729: Frequency of actionable gene fusions in patients with Philadelphia chromosome-like (Ph-like) B-acute lymphoblastic leukemia (ALL): A retrospective study from the Children's Oncology Group (COG)
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4729-4729
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4729-4729
    Abstract: Introduction: While cure rates exceed 80%, many children with B-ALL still relapse. Many of these patients (pts) display a Ph-like gene expression profile (GEP), but lack canonical BCR-ABL1 fusion. We have identified alternate kinase fusions in Ph-like ALL that induce cell proliferation sensitive to tyrosine kinase inhibitors (TKI) (Roberts, NEJM 2014). We report retrospective analyses of 1390 B-ALL pts, 885 NCI high risk and 505 standard risk B-ALL pts with elevated minimal residual disease. Methods: Cases were screened using an 8-gene Taqman low-density array (LDA) PCR assay to identify the Ph-like GEP (Harvey, ASH 2013). Ph-like cases with elevated CRLF2 expression were tested for CRLF2 rearrangement (CRLF2-R; P2RY8-CRLF2 by Taqman PCR on the LDA card and IGH-CRLF2 by FISH). JAK mutations in CRLF2-R cases were tested by Sanger sequencing. Ph-like cases without CRLF2-R were tested for previously identified kinase fusions involving ABL1, ABL2, CSF1R, JAK2, NTRK3, and PDGFRB by RT-PCR. Ph-like cases without detected fusions underwent RNA-sequencing, either using standard Illumina library preparation or a customized kinome capture kit (Agilent). Results: 339 (24%) pts were Ph-like. BCR-ABL1 (N = 45) and ETV6-RUNX1 (N = 11) were excluded from further analyses, as the former already receives TKI therapy and ETV6-RUNX1 ALL lacks targetable kinase fusions (unpublished). Of the remaining 283 Ph-like cases, 153 were CRLF2high (defined by CRLF2 expression levels on the LDA card). 61 (40%) had P2RY8-CRLF2 fusion, and of the remaining 91 CRLF2high cases, 56 of 69 tested had CRLF2-R (55 to IGH, 1 to an unknown partner). Thus, 117/130 (90%) CRLF2high Ph-like cases had a documented CRLF2 genomic lesion and 52 (44%) of these had a JAK mutation. Of the 130 Ph-like CRLF2low cases, 61 (47%) had a previously reported targetable TK fusion identified by RT-PCR, kinome capture or RNA sequencing. These included: 38 ABL class fusions (17 ABL1, 5 ABL2, 3 CSF1R, 13 PDGFRB) sensitive to imatinib/dasatinib; 14 JAK2 and 8 EPOR fusions sensitive to ruxolitinib; and 1 NTRK3 fusion sensitive to crizotinib. Nine cases had known fusions with new alternate breakpoints, and an additional 9 cases had fusions of novel N-terminal partners with known actionable C-terminal kinase genes. RNA sequencing identified 8 cases with IGH-EPOR fusions not previously captured by the kinome assay, indicating the cryptic and complex nature of this rearrangement. Conclusion: Almost half of Ph-like pediatric B-ALL pts lacking CRLF2-R harbor altered TKs with compelling pre-clinical data that they are likely amenable to targeted therapy using FDA-approved TKIs. The COG will start real-time screening with this algorithm in 2015 and allocate pts with ABL class fusions to treatment with chemotherapy plus dasatinib. Citation Format: Shalini C. Reshmi, Richard C. Harvey, Amy Smith, I-Ming Chen, Marc Valentine, Yu Liu, Yongjin Li, Jinghui Zhang, Kathryn G. Roberts, Ying Shao, John Easton, Debbie Payne-Turner, Meenakshi Devidas, Nyla Heerema, Andrew J. Carroll, Elizabeth A. Raetz, Michael J. Borowitz, Brent L. Wood, Anne L. Angiolillo, Michael M. Burke, Wanda L. Salzer, Patrick A. Zweidler-McKay, Karen R. Rabin, William L. Carroll, Mignon L. Loh, Stephen P. Hunger, Charles G. Mullighan, Cheryl L. Willman, Julie M. Gastier-Foster. Frequency of actionable gene fusions in patients with Philadelphia chromosome-like (Ph-like) B-acute lymphoblastic leukemia (ALL): A retrospective study from the Children's Oncology Group (COG). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4729. doi:10.1158/1538-7445.AM2015-4729
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4729
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    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
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 39-40
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 39-40
    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) & lt;50,000/uL (Standard Risk, SR); all other non-infant patients are high risk (HR). Using COG risk stratification, current therapies for SR and HR patients are based on 5-year projected event-free survival (EFS) of 92-97%, and 65-86%. Currently, two subsets, Ph-like and very high risk (VHR) ALL are identified with additional assays-genomic sequencing for Ph-like, and persistent BM MRD on D29 and at end of consolidation for VHR, and are eligible for different treatments. However, as UK investigators recently published (O'Connor, JCO 2018; Enshaei, Blood 2020), using multiple continuous variables as threshold-defined categorical data may diminish the power of accurately predicting relapse, and thus prescribe inappropriate post induction therapy. We tested the UK approach of transforming categorical variables into continuous data on 13,870 NCI SR and 7308 NCI HR B-ALL pts treated on two generations of COG trials: AALL0331 (SR; n=5094), AALL0932 (SR; n=8776), AALL0232 (HR; n=2883), and AALL1131 (HR; n=4425). Down syndrome and Ph+ pts were excluded from analysis. Clinical characteristics are listed in Table 1. ETV6-RUNX1 (25.24%) and double trisomies of chromosome 4, 10 (DT) (23.77%) comprised the favorable risk genetic RG (FRG) group (48.15% of risk classified) while KTM2A rearranged (1.71%), hypodiploidy (1.67%), and iAMP21 (2.56%) comprised the unfavorable risk genetic RG (URG) (6.26%). All others with genetic information were classified as intermediate risk genetic RG (IRG) (45.59% of risk classified). Among 4873 pts tested, 20.46% had Ph-like ALL. D8 PB and D29 BM MRD data were available for 76.42% and 96.69% pts, respectively. 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 & lt;1.0 x 10-5.The great majority of pts were MRD-positive at D8 (mean t(D8 MRD) 7.42); but there was broad distribution of values, with NCI SR and FRG pts having lower t(D8 MRD) (mean 7.52 and 8.08) than NCI HR and URG pts (mean 7.20 and 6.56) (p & lt; 0.001) . The great majority of pts were D29 MRD-negative (mean t(D29 MRD) 12.08), with NCI SR and FRG pts achieving lower D29 MRD (mean t(D29 MRD) 12.43 and 12.73) than NCI HR and URG pts (mean 11.40 and 10.95) (p & lt; 0.0001). Ph-like ALL pts had a mean t(D8 MRD) and t(D29 MRD) of 6.22 and 9.37. 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 & lt; 0.0001). Multivariable modeling showed that WBClog, FRG, URG, t(D8 MRD), t(D29 MRD) retained significance (p & lt; 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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-139081
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 4
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    Targetable kinase gene fusions in high-risk B-ALL: a study from the Children’s Oncology Group
    American Society of Hematology ; 2017
    In:  Blood Vol. 129, No. 25 ( 2017-06-22), p. 3352-3361
    Details
    In: Blood, American Society of Hematology, Vol. 129, No. 25 ( 2017-06-22), p. 3352-3361
    Abstract: Ph-like ALL is characterized by a diverse array of genetic alterations activating cytokine receptor and tyrosine kinase signaling. Pediatric patients with Ph-like ALL can be identified in real time for effective treatment stratification.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2016-12-758979
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
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  • 5
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    Abstract 222: Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 222-222
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 222-222
    Abstract: Purpose: Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) compared to children without DS. While genome-wide association studies (GWAS) have identified several susceptibility loci in childhood ALL, studies of ALL in children with DS are lacking. Therefore, we conducted the first GWAS of DS-ALL. Methods: We analyzed independent cohorts of: 1) 226 newly diagnosed DS-ALL cases from Children's Oncology Group (COG) ALL trials (2000-2013) and 436 DS controls from the National Down Syndrome Project (NDSP), 2) 124 additional COG ALL cases (2011-2015) and 336 additional NDSP DS controls, 3) 20 DS-ALL cases and 275 DS controls from Michigan neonatal bloodspots, and 4) 157 DS-ALL cases and 145 DS controls largely from neonatal bloodspots from California and Washington. Genotyping was performed with Affymetrix or Illumina single nucleotide polymorphism (SNP) arrays. STRUCTURE software was used to define European (372 cases, 1,056 controls), Hispanic (140 cases, 136 controls), and African (15 cases, 62 controls) genetic ancestry. After genome-wide imputation and quality control, ancestry- and cohort-specific associations were evaluated at & gt;6,000,000 autosomal SNPs with minor allele frequency ≥1%. Associations were meta-analyzed across cohort and ancestry groups, assuming additive allelic effects. Results: Genome-wide significant (p & lt;5x10-8) association signals were identified for known ALL susceptibility loci, including rs58923657 near IKZF1 (Odds Ratio [OR]=2.02, p=5.32x10-15), CDKN2A missense mutation rs3731249 (OR=3.63, p=3.91x10-10), rs3781093 near GATA3 (OR=1.73, p=2.89x10-8), and rs7090445 near ARID5B (OR=1.57, p=2.93x10-8). A novel potential risk locus was identified at chromosome 20q11.21 (rs78019519, OR=3.17, p=5.11x10-7) with consistent effects observed across each cohort and ancestry group. This SNP is in the promoter region of the oncogene TPX2 and is also associated with expression of HM13 in whole blood in the Genotype-Tissue Expression (GTEx) Portal. Conclusion: We confirmed that known ALL susceptibility loci in children without DS, including IKZF1, CDKN2A, GATA3, PIP4K2A and ARID5B, also confer risk of ALL in children with DS, with CDKN2A showing the largest effect size. We also identified a potentially novel locus associated with ALL susceptibility in DS at chromosome 20q11.21. Additional investigation of these loci is ongoing and may advance our understanding of DS-ALL etiology and biology. Citation Format: Austin L. Brown, Adam J. de Smith, Michael E. Scheurer, Noah A. Kallsen, Shanna A. Peyton, Gareth E. Davies, Erik A. Ehli, Michael E. Zwick, Naomi Winick, Kelly Maloney, Anne L. Angiolillo, Reuven Schore, MIchael M. Burke, Wanda L. Salzer, Nyla A. Heerema, Andrew J. Carroll, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Elizabeth A. Raetz, Elanor Feingold, Stephanie L. Sherman, Wenjian Yang, Meenakshi Devidas, Kyle Walsh, Andrew T. DeWan, Maria S. Pombo-de-Oliveira, Jeffrey W. Taub, Daniel Sinnett, Jasmine Healy, Jillian M. Birch, Lisa F. Barcellos, Helen Hansen, Ivan Smirnov, Charles G. Mullighan, Stephen P. Hunger, Ching-Hon Pui, Mignon Loh, Joe L. Wiemels, Xiaomei Ma, Catherine Metayer, Beth A. Mueller, Mary V. Relling, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. Genome-wide association study of acute lymphoblastic leukemia in children with Down syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Ab stract nr 222.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-222
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 6
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    Outcomes of Patients with CRLF2 -Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 45-46
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 45-46
    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 & lt;0.0001), leukocytosis (diagnostic white blood cell count 77.5 ±98.5 vs 49.8 ±119.4 x 10e9/L [mean ±SD], p & lt;0.0001), and higher rates of EOI MRD positivity at a ≥0.01% threshold (47.9% vs 30.1%, p & lt;0.0001), which appeared largely driven by the Ph-like HR cohort as expected (57.9% MRD+ vs 42.1% MRD- in HR CRLF2+ and 44.6% MRD+ vs 55.4% MRD- in SR CRLF2+ patients, p & lt;0.003). Overall, CRLF2+ patients had inferior 5-year event-free survival (EFS; 63.3% ±3.1 vs 82.1% ±0.7, p & lt;0.0001) and overall survival (OS; 79.6% ±2.6 vs 90.5% ±0.6, p & lt;0.0001) compared to CRLF2- patients (Figure 1A-B) and a greater 5-year cumulative incidence of relapse (CIR; 30.4% ±2.7 vs 13.2% ±0.6, p & lt;0.001). While 5-year EFS and OS were particularly poor in Ph-like CRLF2+ HR patients (56.3% ±4.6 and 75.4% ± 3.9, respectively) and non-Ph-like CRLF2+ HR patients (EFS 63.7% ±10.2 and OS 74.4% ±8.9), outcomes for Ph-like CRLF2+ SR (EFS 87.2% ±4.5 and OS 94.5% ±3.1) and non-Ph-like CRLF2+ SR patients (EFS 86.2% ±9.3 and OS 100%) were quite good (p & lt;0.0001 for both EFS and OS; Figure 1C-D). 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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-134327
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 7
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    Outcomes in children with Down syndrome (DS) and B-lymphoblastic leukemia (B-ALL): A Children’s Oncology Group (COG) report.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 10510-10510
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 10510-10510
    Abstract: 10510 Background: Patients with DS and B-ALL experience increased rates of relapse and toxicities. Here, we report results from 4 COG trials (2003-2018). Methods: We analyzed clinical, and outcome data for DS (n = 743) and non-DS (n = 21,703) patients age 1-30 enrolled on standard-risk (SR) trials AALL0331 and AALL0932 and high-risk (HR) trials AALL0232 and AALL1131. Initially, DS-ALL patients on AALL0232/AALL0331 experienced excess mortality, prompting enhanced supportive care and omission of induction anthracycline except for slow responders on AALL1131. Other modifications included: non-random assignment to treatment strata without investigational agents; leucovorin rescue after intrathecal methotrexate (MTX); equal maintenance length for boys and girls; every 12-week maintenance vincristine/steroid pulses; and reduced anthracycline and intravenous MTX for HR patients. Results: Across all 4 trials, DS and non-DS patients did not differ significantly in age, sex, initial WBC, or CNS status. DS-ALL patients had significantly higher end of induction (EOI) minimal residual disease (MRD) vs non-DS patients on both AALL0932 and AALL1131, but the difference persisted at end of consolidation (EOC) only on AALL1131, with fewer EOI MRD+ DS patients achieving EOC MRD 〈 0.01% (76.1 vs 88.0%, p = 0.001). 5-year EFS and OS were significantly poorer for DS vs non-DS across all trials (EFS 79.6+2.1% vs 86.3+0.3%, p 〈 0.0001; OS 86.5+1.8% vs 93.1+0.2%, p 〈 0.0001), as well as on each individual trial. In Cox regression analysis for all DS patients, inferior EFS was associated with several known risk factors (age 〉 10, EOI MRD 〉 0.01%) but not with cytogenetics or CRLF2 status Induction death was more frequent in DS patients (3.4% vs 0.8%, p 〈 0.0001) as was death in remission (4.8+0.8% vs 1.8+0.1%, p 〈 0.0001). For death in remission, the increased frequency occurred pre-maintenance and in patients taken off protocol therapy, but not during maintenance, in contrast to prior reports. Grade 〉 3 mucositis, infections, and hyperglycemia were significantly more frequent in DS patients on all trials. Grade 〉 3 seizures were significantly more frequent in DS patients on HR but not SR trials (4.1% vs 1.7%. p = 0.001) and occurred in all phases pre-maintenance. Conclusions: Patients with DS and B-ALL continue to have inferior outcomes compared to non-DS, with increased relapse and toxicities. Less toxic approaches such as immunotherapies and targeted therapies hold promise to improve outcomes in both these areas.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.10510
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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    Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia: secondary analyses of eight Children's Oncology Group cohort trials
    Elsevier BV ; 2023
    In:  The Lancet Haematology Vol. 10, No. 2 ( 2023-02), p. e129-e141
    Details
    In: The Lancet Haematology, Elsevier BV, Vol. 10, No. 2 ( 2023-02), p. e129-e141
    Type of Medium: Online Resource
    ISSN: 2352-3026
    URL: Article
    DOI: 10.1016/S2352-3026(22)00371-4
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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    The genomic landscape of pediatric acute lymphoblastic leukemia
    Springer Science and Business Media LLC ; 2022
    In:  Nature Genetics Vol. 54, No. 9 ( 2022-09), p. 1376-1389
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 54, No. 9 ( 2022-09), p. 1376-1389
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/s41588-022-01159-z
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 10
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    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
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 211-211
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 211-211
    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 & lt;0.0001] among Hispanic patients and 81.9%±1.2% (HR 1.45, 95CI 1.28-1.56; p & lt;0.0001) among non-Hispanic Black patients. Outcomes for non-Hispanic Asian patients were similar to those of non-Hispanic White patients. US patients on Medicaid had inferior 5-year EFS as compared to other US patients (83.2%±0.5% vs. 86.3%±0.3%, HR 1.21, 95CI 1.12-1.30; p & lt;0.0001) while non-US patients had the best outcomes (5-year EFS 89.0%±0.7%, HR 0.78, 95CI 0.71-0.88; p & lt;0.0001). There was substantial imbalance in traditional disease prognosticators (e.g. T-cell lineage) across both race/ethnicity and SES, and of race/ethnicity by SES. For example, T-lineage ALL accounted for 17.6%, 9.4%, and 6.6% of Non-Hispanic Black, Non-Hispanic White, and Hispanic patients respectively (p & lt;0.0001). 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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-147386
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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