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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:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 2
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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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  • 3
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    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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    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
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    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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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
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    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 6
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    Outcomes of Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia Based on Blast Genotype at Diagnosis: A Report from the Children's Oncology Group
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 451-451
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 451-451
    Abstract: Survival for childhood acute lymphoblastic leukemia (ALL) now approaches 90% with risk adapted therapy based on National Cancer Institute risk group (NCI RG) at diagnosis, somatic lymphoblast genetics, and early response to therapy as measured by minimal residual disease (MRD). The Children's Oncology Group AALL03B1 ALL Classification trial enrolled 11,145 children, adolescents, and young adults less than 31 years of age with newly diagnosed B- or T-lineage ALL between December 2003 and September 2011. Companion therapeutic trials for B-lineage ALL included AALL0331 (n= 5226) for NCI standard risk (SR-ALL)(age 1-10 years and white blood cell count (WBC) 〈 50,000/uL) and AALL0232 (n=2907] for NCI high risk (HR) ALL (age 〉 10 years or presenting WBC 〉 50,000/uL). Assessing outcome by lymphoblast genetics revealed statistically significant distributions of genotype and NCI RG, as well as differences in event-free and overall-survival (EFS, OS) (Table 1). Not surprisingly, favorable genetic groups of Trisomy 4/10/17 (TT) and ETV6/RUNX1 were significantly more common in NCI SR patients (p 〈 0.0001 for each) while those with unfavorable characteristics (MLL rearranged [MLLr], intrachromosomal amplification of chromosome 21 [iAMP21] , BCR/ABL1 and hypodiploidy [n 〈 44]) occurred more frequently in NCI HR patients (p 〈 0.0001 for each). Event-free and OS were correspondingly poorer in NCI HR patients with the exception of iAMP21, where EFS in those treated on AALL0232 was better than that in NCI SR (Table 1). Surprisingly, NCI SR BCR/ABL1 positive patients (N= 64, 1.2%) had a 5-year EFS of 85±5.0%, although these patients came off study at end induction and likely received imatinib with chemotherapy on a companion ALL trial for Ph+ ALL. Notably, hypodiploidy was associated with the worst EFS and OS regardless of NCI RG, with 5-year EFS and OS of 51.3±5.0% and 58.2±5.0%, respectively, suggesting that these patients continue to fare poorly with salvage therapies. Multivariable analysis demonstrated age, WBC, and day 29 MRD as significant independent risk factors for sustained CR, and the individual genetic groups of TT, ETV6/RUNX1, iAMP21, BCR/ABL1 and hypodiploidy, but notably, not MLLr, all retained independent prognostic significance when added to the model individually. A subset of consecutively enrolled (N=605) AALL0232 NCI HR patients underwent additional genomic interrogation, including assessment of Ph-like status, ABL1 class fusions, CRLF2r, JAK mutations (JAKm), and IKZF1 alterations. Based on sample availability, patients studied were younger (p 〈 0.0001) and had a higher WBC (p 〈 0.0001) compared to the remainder of AALL0232. There were 85/605 (14.0%) Ph-like patients defined using PAM clustering algorithms and Ph-like status was significantly associated with an IKZF1 alteration (75%) (p 〈 0.0001) and day 29 MRD 〉 .01% (p 〈 0.0001). Five-year EFS for Ph-like versus non Ph-like was 62.3±5.8% vs. 83.9±1.7% (p 〈 0.0001). Outcomes of Ph-like ALL with or without CRLF2r were similar (60.6±8.3% versus 65.4±8.0%, p =0.86). Similarly, 5-year EFS of Ph-like ALL was no different with or without IKZF1 alterations (61.5±7.0% vs. 64.6 ±11.1%). There were 155 (27.1%) IKZF1 alterations, 60 of which occurred in Ph-like ALL with a trend towards concomitant CRLF2r/JAKm (p=0.055). Five-year EFS for patients with IKZF1 alterations was 66.8±4.0% (p 〈 0.0001) versus 86.4±1.8% for those without IKZF1 lesions. Multivariable analysis demonstrated age, WBC and day 29 MRD as independent risk factors for sustained CR while only Ph-like status, IKZF1 alteration, BCR/ABL1 and ETV6/RUNX1retained independent prognostic significance when added to the model individually. In summary, somatic sentinel cytogenetic alterations are independently prognostic in childhood ALL and are strongly associated with NCI RG and outcome, supporting continued incorporation into risk stratification algorithms. Notably, 〉 44% of all patients have favorable blast cytogenetics with 5-year overall survival rates approaching 100%. In contrast, NCI HR patients with Ph-like ALL have poor outcomes with currently available therapy and this subtype is associated with CRLF2 r and IKZF1 alterations, which do not confer an inferior EFS within the Ph-like subgroup. Novel therapies for genomicallydefined Ph-like ALL may improve outcomes. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Borowitz:HTG Molecular: Consultancy; Bristol-Myers Squibb: Research Funding; MedImmune: Research Funding; BD Biosciences: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.451.451
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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    Inherited and de novo variants extend the etiology of TAOK1-associated neurodevelopmental disorder
    Cold Spring Harbor Laboratory ; 2022
    In:  Molecular Case Studies
    Details
    In: Molecular Case Studies, Cold Spring Harbor Laboratory
    Abstract: Alterations in the TAOK1 gene have recently emerged as the cause of developmental delay with or without intellectual impairment or behavioral abnormalities (MIM #619575). The thirty-two cases currently described in the literature have predominantly de novo alterations in TAOK1 and a wide spectrum of neurodevelopmental abnormalities. Here, we report four patients with novel pathogenic TAOK1 variants identified by research genome sequencing, clinical exome sequencing, and international matchmaking. The overlapping clinical features of our patients are consistent with the emerging core phenotype of TAOK1-associated syndrome: facial dysmorphism, feeding difficulties, global developmental delay, joint laxity, and hypotonia. However, behavioral abnormalities and gastrointestinal issues are more common in our cohort than previously reported. Two patients have de novo TAOK1 variants (one missense, one splice site) consistent with most known alterations in this gene. However, we also report the first sibling pair who both inherited a TAOK1 frameshift variant from a mildly affected mother. Our findings suggest that incomplete penetrance and variable expressivity are relatively common in TAOK1-associated syndrome, which holds important implications for clinical genetic testing.
    Type of Medium: Online Resource
    ISSN: 2373-2865 , 2373-2873
    URL: Article
    DOI: 10.1101/mcs.a006180
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2022
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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:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    Functional Analysis of Kinase-Activating Fusions in Ph-like Acute Lymphoblastic Leukemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 786-786
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 786-786
    Abstract: Introduction: Ph-like or BCR-ABL1-like B-progenitor acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by a gene expression profile similar to BCR-ABL1 ALL. The prevalence of Ph-like ALL rises from 10% in standard risk childhood ALL to over 25% in young adults. Next-generation sequencing of Ph-like ALL identified a variety of alterations involving kinase or cytokine receptor genes, including rearrangement, sequence mutation and copy number alterations. Chromosomal rearrangements in about one-third of Ph-like ALL cases create fusion genes of a variety of 5’ partners that involve ABL1-class genes (ABL1, ABL2, CSF1R and PDGFRB) or activate JAK family members (JAK2, TYK2, IL2RB) that are potentially amenable to treatment with ABL1-class or JAK-class tyrosine kinase inhibitors (TKIs). Notably, ABL2 (Abelson-related gene, ARG), a homolog of ABL1, has rarely been identified as a rearrangement partner in ALL. CSF1R (encoding the macrophage colony stimulating receptor) regulates the differentiation of macrophages, and is not normally expressed in lymphocytes. Likewise, rearrangements involving the JAK family member TYK2, the beta chain of the interleukin 2 cytokine receptor (IL2RB), and the neurotrophic tyrosine kinase receptor type 3 (NTRK3), have not been previously described in leukemia. The goals of this study were to assess the role of these kinase alterations in leukemogenesis, to determine the activation of signaling pathways, and to investigate the efficacy of TKIs. Methods: Kinase fusions were expressed in interleukin-3 dependent Ba/F3 cells, and co-expressed with the dominant negative isoform of IKAROS (IK6) in interleukin-7 dependent Arf-/- mouse pre-B cells. Xenograft models of 10 Ph-like ALL tumors - ETV6-ABL1, RANBP2-ABL1, PAG1-ABL2, RCSD1-ABL2, SSBP2-CSF1R, IGH-EPOR, ETV6-NTRK3, ATF7IP-JAK2, PAX5-JAK2 and ZEB2-PDGFRB - were generated by engrafting primary human leukemia cells into NOD-SCID IL2R gamma null (NSG) mice. Activation of kinase signaling was performed using phosphoflow cytometry analysis, and sensitivity to TKIs was assessed ex vivo and in vivo. Results: All kinase fusions (PAG1-ABL2, MYH9-IL2RB, ATF7IP-JAK2, ETV6-NTRK3 or MYB-TYK2) induced cytokine-independent proliferation of Ba/F3 cells. Mice transplanted with Arf-/- pre-B cells co-expressing IK6 and either RCSD1-ABL2 or SSBP2-CSF1R developed pre-B ALL (CD43+, B220+, CD19+, BP-1+ and IgM-) with a median latency of 36 and 40 days respectively, providing evidence that ABL2 and CSF1R fusions contribute to leukemogenesis. In human leukemic cells harvested from xenograft mice we observed distinct patterns of kinase signaling activation and TKI sensitivity for the different fusions. Xenograft cells expressing ABL1-class kinase fusions showed activation of STAT5 that was inhibited with imatinib or dasatinib. Phosphorylation of CRKL, a known target of ABL1 and ABL2, was only observed in cells expressing ABL1/2 fusions. Cells harboring ATF7IP-JAK2, PAX5-JAK2 or IGH-EPOR showed phosphorylation of STAT5 that was attenuated with the JAK2 inhibitor, ruxolitinib. In contrast, cells expressing ETV6-NTRK3 signaled through the MAPK pathway with constitutive pERK1/2 that was inhibited with the ALK-inhibitor, crizotinib. This TKI response profile was confirmed by cytotoxicity assays in xenograft cells, with ABL1-class fusions being sensitive to dasatinib (IC50 range 1-2nM), whilst cases harboring ATF7IP-JAK2 or EPOR rearrangement uniquely responded to ruxolitinib with IC50 values of 500nM and 850nM respectively. Interestingly, in human leukemic cells harboring the ETV6-NTRK3 fusion we observed selective inhibition with both crizotinib and the FLT3 inhibitor, lestaurtinib. Pre-clinical studies on three xenograft models of Ph-like ALL - ETV6-ABL1, RCSD1-ABL2 and SSBP2-CSF1R – showed significantly reduced leukemic burden in dasatinib treated mice (20mg/kg/day p.o) compared to vehicle treated mice. Conclusions: These data provide important insight on new targets of rearrangement in ALL and describe the first engineered mouse models of Ph-like B-ALL. Functional modeling of these alterations is essential to improve the clinical management of Ph-like ALL by identifying patients with specific genomic lesions at diagnosis and directing them to treatment with appropriate TKIs combined with chemotherapy, analogous to current treatment for BCR-ABL1 B-ALL. Disclosures Hunger: Bristol Myers Squibb: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.786.786
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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    Expanding the Clinical Utility of Targeted RNA Sequencing Panels beyond Gene Fusions to Complex, Intragenic Structural Rearrangements
    MDPI AG ; 2023
    In:  Cancers Vol. 15, No. 17 ( 2023-09-02), p. 4394-
    Details
    In: Cancers, MDPI AG, Vol. 15, No. 17 ( 2023-09-02), p. 4394-
    Abstract: Gene fusions are a form of structural rearrangement well established as driver events in pediatric and adult cancers. The identification of such events holds clinical significance in the refinement, prognostication, and provision of treatment in cancer. Structural rearrangements also extend beyond fusions to include intragenic rearrangements, such as internal tandem duplications (ITDs) or exon-level deletions. These intragenic events have been increasingly implicated as cancer-promoting events. However, the detection of intragenic rearrangements may be challenging to resolve bioinformatically with short-read sequencing technologies and therefore may not be routinely assessed in panel-based testing. Within an academic clinical laboratory, over three years, a total of 608 disease-involved samples (522 hematologic malignancy, 86 solid tumors) underwent clinical testing using Anchored Multiplex PCR (AMP)-based RNA sequencing. Hematologic malignancies were evaluated using a custom Pan-Heme 154 gene panel, while solid tumors were assessed using a custom Pan-Solid 115 gene panel. Gene fusions, ITDs, and intragenic deletions were assessed for diagnostic, prognostic, or therapeutic significance. When considering gene fusions alone, we report an overall diagnostic yield of 36% (37% hematologic malignancy, 41% solid tumors). When including intragenic structural rearrangements, the overall diagnostic yield increased to 48% (48% hematologic malignancy, 45% solid tumor). We demonstrate the clinical utility of reporting structural rearrangements, including gene fusions and intragenic structural rearrangements, using an AMP-based RNA sequencing panel.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers15174394
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
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