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  • 1
    Online Resource
    Online Resource
    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:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Glutamate Receptor Polymorphisms Contribute to Glucocorticoid-Associated Osteonecrosis
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 367-367
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 367-367
    Abstract: Background Glucocorticoids are an essential component of current treatment regimens for childhood acute lymphoblastic leukemia (ALL), and are a component of treatment for many autoimmune and inflammatory conditions. A common therapy-related and dose-limiting toxicity in ALL is glucocorticoid-induced osteonecrosis (ON). The mechanism and underlying genetic basis of ON risk are likely multifactorial. Methods We performed the largest genome-wide association study (GWAS) of ON to date in 2285 children with ALL who were treated on the Children's Oncology Group (COG) AALL0232 frontline protocol for high risk B-lineage ALL. We also studied two validation cohorts: 361 children with ALL treated on the frontline St. Jude Total XV protocol for ALL, and 309 children and adults treated with corticosteroids for oncologic and non-oncologic indications in the Vanderbilt University Medical Center BioVU DNA repository. Single nucleotide polymorphism (SNP) genotyping was performed using Illumina and Affymetrix Human Gene Chip Arrays. Additional SNPs were imputed using 1000 Genomes as the reference genome with MaCH-Admix and IMPUTE2. Testing for association was performed by Cox proportional hazard and logistic regression, with meta-analysis across cohorts using Stouffer's Z-score method. Gene based and pathway analyses were performed using SNP-set Kernel Association Test (SKAT) and Ingenuity Pathway Analysis (IPA), respectively. Results In the discovery GWAS for AALL0232, adjusting for gender, age, ancestry and treatment, the SNP with the strongest association was at 9q31.1 (rs28584318, odds ratio [OR] = 2.00, P = 4.86 x 10-7), near the GRIN3A locus (glutamate [NMDA] receptor subunit 3A). The same SNP was validated in both the St. Jude and Vanderbilt cohorts after adjusting for covariates (OR = 1.81 and 2.26, P = 0.0734 and 0.0073 respectively). Overall, patients with the variant genotype at rs28584318 in 9q31.1 had a higher incidence of ON compared with those patients who did not: AALL0232, St. Jude Total XV and Vanderbilt BioVU (15.8% vs 9.7%, 21.8% vs. 20.4%, 35.6% vs 24.0%). In the meta-analysis with both discovery and validation cohorts combined, the SNP at 9q31.1 (P = 5.34 x 10-8), and an additional variant in GRIK1 (glutamate receptor, ionotropic, kainate, rs2154490 P = 7.24 x 10-7) were most associated with risk of ON. Pathway analysis of the genes implicated in the discovery and validation cohorts also identified the glutamate pathway as the top overlapping canonical pathway present in all three cohorts (COG AALL0232 P = 0.045; St. Jude Total XV P = 0.011; Vanderbilt P = 0.037). Conclusions These findings demonstrate an association between loci in the glutamate pathway and glucocorticoid-induced ON. The glutamate pathway could be linked to ON via several mechanisms, including that glutamate receptors are involved in the mechanical signaling of bone and regulation of osteoblasts and osteoclastogenesis, and are affected by glucocorticoids. That this pathway was also implicated in a non-ALL cohort suggests glutamate pathway variation may modulate risk for ON across a wide array of patients treated with glucocorticoids. Figure 1 Figure 1. Disclosures Hunger: Sigma Tau Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Honoraria. Evans:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.367.367
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 3
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    Online Resource
    Development and Validation Of a Highly Sensitive and Specific Gene Expression Classifier To Prospectively Screen and Identify B-Precursor Acute Lymphoblastic Leukemia (ALL) Patients With a Philadelphia Chromosome-Like (“Ph-like” or “BCR-ABL1-Like”) Signature For Therapeutic Targeting and Clinical Intervention
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 826-826
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 826-826
    Abstract: Using gene expression profiling, we and others identified a novel subgroup of B-precursor acute lymphoblastic leukemia (B-ALL) with a gene expression signature similar to Philadelphia (Ph) chromosome (BCR-ABL1)-positive ALL. Termed “Ph-like” or “BCR-ABL1-like” ALL, this subgroup constitutes 10-15% of pediatric and 25% of adolescent/young adult ALL cases and is associated with a very poor clinical outcome. Using next generation sequencing, we have shown that Ph-like ALL is characterized by a highly heterogeneous spectrum of activating mutations or gene fusions targeting genes regulating cytokine receptor and tyrosine kinase signaling (JAK1/2, ABL1/2, PDGFRB, EPOR, CSF1R, AKT2, STAT5B, CRLF2, IL7R, SH2B3). As Ph-like ALLs may be sensitive to tyrosine kinase inhibitors (TKIs) in vivo, incorporating TKIs into therapy may significantly improve clinical outcomes. Here we report the development and validation of a robust gene expression classifier that can prospectively identify Ph-like ALL patients for therapeutic intervention. Methods Supervised learning methods were applied to gene expression profiles (Affymetrix U133_Plus_2.0; RMA normalized) generated from pre-treatment leukemic samples from 811 B-ALL patients accrued to COG High-Risk ALL Trials P9906 and AALL0232. Patients were partitioned into a training (P9906: n=207; AALL0232: n=278) and an independent test set (AALL0232: n=325). Next generation sequencing was used to identify Ph-like ALL-associated genomic lesions in these cohorts. The 54,675 Affymetrix probe sets were evaluated using Prediction Analysis of Microarrays (PAM), applying the method of nearest shrunken centroids to identify those probe sets best distinguishing Ph-like ALL. These probe sets were then distilled by 100 iterations of 10-fold cross-validation using three optimization criteria (overall error, average error, and ROC accuracy), leading to the identification of the 64 most predictive probe sets (derived from 38 unique genes). Quantitative RT-PCR assays were developed for each of the 38 genes by selecting optimized primer/probe sets and assays were run on 384-well Low Density Microarray (LDA) cards; 780/811 cases had residual material for LDA testing. LDA data were remodeled in the training set using double loop cross validation, resulting in a best and final predictive model and statistical algorithm containing 15 of the 38 genes (IGJ, SPATS2L, MUC4, CRLF2, CA6, NRXN3, BMPR1B, GPR110, CHN2, SEMA6A, PON2, SLC2A5, S100Z, TP53INP1, IFITM1). The sensitivity and specificity of the predictor was then evaluated in the independent test set. Results The 15 gene LDA classifier was able to predict Ph or Ph-like ALL in the test set with a high degree of sensitivity (93.0%) and specificity (89.7%) and identified the heterogeneous genomic lesions associated with Ph-like ALL with very high frequency (Table 1). When compared to non-Ph-like ALL, Ph-like cases had a significantly poorer event-free survival (HR 3.58; p 〈 .0001) (Fig. 1, left). A second predictive classifier modeled on the same training/test sets but with true BCR-ABL1 cases excluded yielded a virtually identical performance (97.2% sensitivity, 87.1% sensitivity; HR: 2.9; p 〈 .0001). Strikingly, Ph-like ALL cases with IKZF1 deletions had a significantly worse outcome when compared to ALL cases with IKZF1 deletions alone, emphasizing the clinical importance of the Ph-like signature (Fig. 1, right). Concordance between the LDA predictor and our previously reported PAM method (NEJM 360:470, 2009) was 87.2%, with the largest difference being additional CRLF2 lesions identified by LDA. Conclusions We have developed and validated a highly robust gene expression classifier for the prospective identification of Ph-like ALL. Rapidly screened patients will then undergo targeted sequencing to confirm the presence of specific genomic lesions. This approach will facilitate the therapeutic targeting of Ph-like ALL patients to novel clinical trials, hopefully leading to improved outcomes. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.826.826
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 4
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    Online Resource
    Outcomes of Patients with Down Syndrome and CRLF2 -Overexpressing Acute Lymphoblastic Leukemia (ALL): A Report from the Children's Oncology Group (COG)
    American Society of Hematology ; 2020
    In:  Blood Vol. 136, No. Supplement 1 ( 2020-11-5), p. 44-45
    Details
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 44-45
    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 & lt;0.01. P2RY8-CRLF2 cases were significantly more likely than IGH-CRLF2 cases to be associated with age under 10 years at diagnosis (92.9% vs 29.4%, p & lt;0.0001), initial white blood count (WBC) & lt;50x103 (80.4% vs 52.9%, p & lt;0.024), National Cancer Institute (NCI) standard risk status (73.2% vs 23.5%, p & lt;0.0002), and day 29 MRD & lt;0.01% (67.9% vs 37.5%, p & lt;0.028). There were no significant associations between JAK mutation status and any clinical features assessed (sex, initial WBC, central nervous system or testicular involvement, NCI risk group, or EOI/EOC MRD). Among patients with neutral cytogenetics (defined as neither favorable [ETV6-RUNX1, double trisomies of chromosomes 4 and 10] nor unfavorable [BCR-ABL1, KMT2A-rearranged, hypodiploid, iAMP21] ), survival did not significantly differ between CRLF2+ and CRLF2- patients (Figure 1A,B), either for 5-year event-free survival (EFS) (79.1 +3.6% vs 77.6 +4.7%, p=0.856) or 5-year overall survival (OS) (89.5 ±2.8% vs 84.9 ±4.1%, p=0.674). There were also no significant differences in EFS or OS based on JAK mutation status or CRLF2 partner, although there were trends toward poorer outcomes in the CRLF2+/JAK+ and IGH-CRLF2 subgroups (Figure 1C). Finally, there was no significant difference in 5-year cumulative incidence of relapse (CIR) according to CRLF2 status (CRLF2+ 16.0 +3.0%, CRLF2- 10.6 +2.6%, p=0.179), although there were non-significant trends toward more relapses in CRLF2+ cases overall and in the NCI HR subgroup analysis. 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.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2020-143165
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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    detail.hit.zdb_id: 80069-7
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  • 5
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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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  • 6
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    Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group
    Elsevier BV ; 2019
    In:  Cancer Genetics Vol. 238 ( 2019-10), p. 62-68
    Details
    In: Cancer Genetics, Elsevier BV, Vol. 238 ( 2019-10), p. 62-68
    Type of Medium: Online Resource
    ISSN: 2210-7762
    URL: Article
    DOI: 10.1016/j.cancergen.2019.07.009
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2594323-6
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  • 7
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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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    Case 20-2003 : A Nine-Year-Old Girl with Hepatosplenomegaly and Pain in the Thigh
    Massachusetts Medical Society ; 2003
    In:  New England Journal of Medicine Vol. 348, No. 26 ( 2003-06-26), p. 2669-2677
    Details
    In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 348, No. 26 ( 2003-06-26), p. 2669-2677
    Type of Medium: Online Resource
    ISSN: 0028-4793 , 1533-4406
    URL: Article
    DOI: 10.1056/NEJMcpc030014
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    XA 10000
    Language: English
    Publisher: Massachusetts Medical Society
    Publication Date: 2003
    detail.hit.zdb_id: 1468837-2
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    Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia
    American Society of Clinical Oncology (ASCO) ; 2016
    In:  Journal of Clinical Oncology Vol. 34, No. 18 ( 2016-06-20), p. 2133-2140
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 18 ( 2016-06-20), p. 2133-2140
    Abstract: Acute pancreatitis is one of the common causes of asparaginase intolerance. The mechanism is unknown, and genetic predisposition to asparaginase-induced pancreatitis has not been previously identified. Methods To determine clinical risk factors for asparaginase-induced pancreatitis, we studied a cohort of 5,185 children and young adults with acute lymphoblastic leukemia, including 117 (2.3%) who were diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify genetic risk factors. Results Risk factors associated with pancreatitis included genetically defined Native American ancestry (P 〈 .001), older age (P 〈 .001), and higher cumulative dose of asparaginase (P 〈 .001). No common variants reached genome-wide significance in the genome-wide association study, but a rare nonsense variant rs199695765 in CPA2, encoding carboxypeptidase A2, was highly associated with pancreatitis (hazard ratio, 587; 95% CI, 66.8 to 5166; P = 9.0 × 10 −9 ). A gene-level analysis showed an excess of additional CPA2 variants in patients who did versus those who did not develop pancreatitis (P = .001). Sixteen CPA2 single-nucleotide polymorphisms were associated (P 〈 .05) with pancreatitis, and 13 of 24 patients who carried at least one of these variants developed pancreatitis. Biologic functions that were overrepresented by common variants modestly associated with pancreatitis included purine metabolism and cytoskeleton regulation. Conclusion Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2015.64.5812
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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    Identification of Novel Cluster Groups in High-Risk Pediatric B-Precursor Acute Lymphoblastic Leukemia (HR-ALL) by Gene Expression Profiling: Correlation with Clinical and Outcome Variables. a Children’s Oncology Group (COG) Study.
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 2256-2256
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2256-2256
    Abstract: Children with HR-ALL are traditionally defined by NCI Risk Criteria (age and white blood cell count) and comprise a highly heterogeneous group of ALL cases that have not been well characterized. In an effort to shed light on the genetic diversity of HR-ALL and identify new therapeutic targets in this resistant form of disease, we previously analyzed 207 patients enrolled on COG HR-ALL Trial P9906. These analyses revealed discrete gene expression profiles (Affymetrix U133 Plus2) that distinguished 8 distinct cluster groups. Two of these groups clustered patients with known underlying genetic abnormalities (E2A-PBX1/t(1;19) or MLL rearrangements) while the remaining 6 clusters were novel and the underlying genetic lesions remain to be identified. Two of the novel clusters were associated with extremely good (94.7% 4 year RFS) or very poor outcomes (20.9% 4 year RFS). In order to validate these findings and increase the size of the study cohort to enhance statistical power, we performed gene expression profiling in an additional 283 children with HR-ALL enrolled on COG Trial AALL0232. Patients enrolled on AALL0232 met NCI high risk criteria similar to those enrolled on P9906 but additionally included some HR-ALL patients with BCR-ABL or TEL-AML1 translocations, hypodiploidy, and favorable trisomies of chromosomes 4 and 10. As shown in the table below, the cluster designation and relative composition were very similar between the two cohorts. Two notable exceptions were the decreased number of Group 1 (MLL rearranged) members and the significantly elevated number of TEL-AML1 positive patients on AALL0232. In addition to identifying again the 6 novel clusters initially identified in the P9906 cohort and the TEL-AML1+ patients, AALL0232 contained another novel cluster group with a distinct gene signature. Expression profiles from P9906 and AALL0232 were merged to yield a cohort of 490 HR-ALL patients. When the same clustering methods were applied to the merged cohort, a similar set of clusters were identified with virtually identical group membership despite being independent experimental cohorts and clinical trials. The merged cohort permitted a more rigorous definition of gene signatures distinguishing each cluster, identifying the top 50 rank order genes associated with each cluster, and a more rigorous statistical analysis of the association of cluster group with outcome and clinical variables. Although the outcome data for the AALL0232 samples is not yet mature, the high degree of correlation of this cohort with certain P9906 clusters permits us to make predictions about outcome that will allow for validation with longer follow up. Furthermore, this larger cohort allows us to continue to identify potential new therapeutic targets and underlying genetic abnormalities in HR-ALL. Group P9906(207) AALL0232(283) 1 21 (10.1%) 10 (3.5%) 2 23 (11.1%) 23 (8.1%) 2A 11 (5.3%) 13 (4.6%) 4 13 (6.3%) 14 (4.9%) 5 11 (5.3%) 16 (5.7%) 6 21 (10.1%) 18 (6.4%) 8 24 (11.6%) 26 (9.2%) TEL-AML1 3 (1.4%) 55 (19.4%)
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.2256.2256
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
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