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  • American Society of Clinical Oncology (ASCO)  (7)
  • Loh, Mignon L.  (7)
  • 1
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    Online Resource
    Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children’s Oncology Group Trial AALL0331
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 6 ( 2020-02-20), p. 602-612
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 6 ( 2020-02-20), p. 602-612
    Abstract: Children’s Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% ( P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% ( P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to 〈 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION The 6-year OS rate for 〉 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.19.01086
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Favorable Trisomies and ETV6-RUNX1 Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 14 ( 2021-05-10), p. 1540-1552
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 14 ( 2021-05-10), p. 1540-1552
    Abstract: Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC 〈 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, 〈 5% marrow blasts by day 15, end-induction marrow minimal residual disease 〈 0.1%, and favorable cytogenetics ( ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P 〈 .0001). CONCLUSION Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.20.02370
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Prognostic Impact of CNS-2 status in T-ALL: A report from the Children’s Oncology Group.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 10003-10003
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 10003-10003
    Abstract: 10003 Background: In B-acute lymphoblastic leukemia (B-ALL), CNS2 was associated with inferior 5-year (yr) event-free and overall survival (EFS/OS) in recent trials. Here, we report the impact of CNS2 in T-ALL on AALL0434 and AALL1231, recently completed consecutive randomized phase 3 trials for children and young adults with T-ALL and T Lymphoblastic Lymphoma. This report is limited to T-ALL. Both trials used augmented Berlin Frankfurt Münster regimens. AALL0434 compared Capizzi escalating methotrexate+pegaspargase (C-MTX) vs High Dose MTX (HDMTX) +/- six nelarabine (Nel) courses; outcomes improved with CMTX and Nel. CNS1/CNS2 patients, except those defined as low risk (LR) received 12Gy cranial radiation (CRT); CNS3 patients received 18Gy CRT. AALL1231 randomized patients to +/- bortezomib (Bort). AALL1231 changed the AALL0434 backbone, using dexamethasone instead of prednisone throughout. CRT was given only to patients with CNS3 disease (18Gy) and those defined as very high risk (VHR) (12Gy). CNS2 patients could not be classified as LR on AALL0434 or standard risk (SR) on AALL1231. CNS1/CNS2 patients received the same intrathecal therapy frequency on both studies. Methods: CNS status was assigned at diagnosis. CNS2 defined as: presence of 〈 5/ μL WBCs and cytospin positive for blasts or ≥ 5/μLWBCs with negative Steinherz Bleyer algorithm. Outcomes by CNS status were compared between AALL0434 and AALL1231. Results: From 2007-2014, AALL0434 enrolled 1562 evaluable T-ALL patients, including 1128 (72.8%) CNS1, 306 (19.7%) CNS2 and 116 (7.5%) CNS3. 90.8% received CRT, including 90.4% of CNS1 patients. 5yr EFS rates for CNS1, 2, and 3 were 85.2±1.3%, 83.1±2.6%, and 71.4±5.2% (p = 0.0007); OS rates were 90.4±1.1%, 89.2±2.1%, and 83.1±4.3% (p = 0.0438). There were no differences in 5yr disease free survival (DFS) between CNS1 and CNS2 treated with CMTX (89.7% vs. 92.9%, p = 0.17) or CMTX+Nel (91.8% vs. 89.9%; p = 0.62). AALL1231 accrued 614 evaluable T-ALL patients [CNS1 437 (71.1%), CNS2 134 (21.8%), CNS3 43 (7.0%)] from 2014 to early closure in 2017. Of these, only 12% were scheduled to receive CRT. 3yr EFS rates for CNS1, 2 and 3 were 84.1±2.1%, 84.6±3.8% and 78.6±7.9% (p = 0.50). 3yr OS was: CNS1 87.5±1.9%, CNS2 92.2±2.8%, CNS3 78.5±7.9% (p = 0.017) . 3yr EFS was not statistically distinct without Bort in CNS1, 2 or 3 (85.3±2.9%, 81.4±5.6%, 71.9±13.4%) (p = 0.10) or with Bort (82.9±3.0%, 88.3±4.9%, 83.3±9,4%; p = 0.43). Intermediate risk (IR) CNS1 and CNS2 patients received identical therapy and had similar 3yr EFS (88.8±2.8% vs 88.8±3.5%, p = 0.98). Conclusions: Unlike in B-ALL, EFS/OS was similar for CNS1 and CNS2 on AALL0434 (with CRT) and AALL1231 (without CRT). Further, IR CNS1 and CNS2 on AALL1231 had similar outcomes with identical therapy. Thus, CNS2 status is non-prognostic in T-ALL on these contemporary COG regimens. CNS3 patients have poor outcomes in T-ALL despite CRT and intensive chemotherapy, novel approaches are needed. Clinical trial information: NCT00408005, NCT02112916.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.10003
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Successful Outcomes of Newly Diagnosed T Lymphoblastic Lymphoma: Results From Children’s Oncology Group AALL0434
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 26 ( 2020-09-10), p. 3062-3070
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 26 ( 2020-09-10), p. 3062-3070
    Abstract: The Children’s Oncology Group (COG) protocol AALL0434 evaluated the safety and efficacy of multi-agent chemotherapy with Capizzi-based methotrexate/pegaspargase (C-MTX) in patients with newly diagnosed pediatric T-cell lymphoblastic lymphoma (T-LL) and gained preliminary data using nelarabine in high-risk patients. PATIENTS AND METHODS The trial enrolled 299 patients, age 1-31 years. High-risk (HR) patients had ≥ 1% minimal detectable disease (MDD) in the bone marrow at diagnosis or received prior steroid treatment. Induction failure was defined as failure to achieve a partial response (PR) by the end of the 4-week induction. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) C-MTX regimen. HR patients were randomly assigned to receive or not receive 6 5-day courses of nelarabine incorporated into ABFM. Patients with induction failure were nonrandomly assigned to ABFM C-MTX plus nelarabine. No patients received prophylactic cranial radiation; however, patients with CNS3 disease (CSF WBC ≥ 5/μL with blasts or cranial nerve palsies, brain/eye involvement, or hypothalamic syndrome) were ineligible. RESULTS At end-induction, 98.8% of evaluable participants had at least a PR. The 4-year event-free survival (EFS) and overall survival (OS) were 84.7% ± 2.3% and 89.0% ± 2.0%. The 4-year disease-free survival (DFS) from end-induction was 85.9% ± 2.6%. There was no difference in DFS observed between the HR and standard-risk groups ( P = .29) or by treatment regimen ( P = .55). Disease stage, tumor response, and MDD at diagnosis did not demonstrate thresholds that resulted in differences in EFS. Nelarabine did not show an advantage for HR patients. CNS relapse occurred in only 4 patients. CONCLUSION COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provided excellent EFS and OS without cranial radiation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.20.00531
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 19 ( 2022-07-01), p. 2106-2118
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 19 ( 2022-07-01), p. 2106-2118
    Abstract: To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS ( P = .412) and OS ( P = .600). CONCLUSION Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.21.02678
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 6
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    Online Resource
    Targeted gene expression classifier identifies pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients at high risk for end induction minimal residual disease positivity.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 10002-10002
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 10002-10002
    Abstract: 10002 Background: The heterogeneity of T-ALL has hindered biomarker identification and limited biology-based risk stratification. Historically, minimal residual disease (MRD) has been the strongest predictor of poor outcomes. However, stratification by MRD does not allow for risk-adapted therapy early in treatment, which may induce deeper remissions and decrease risk of relapse. We hypothesized that gene expression profiling at diagnosis may have prognostic value in identifying high risk patients. Methods: We analyzed RNA-seq data from 189 diagnostic samples from the Children’s Oncology Group (COG) AALL0434 trial. Using leave-one-out cross-validation, we identified a set of genes that optimally differentiated MRD+ and MRD- samples. We then derived a risk score (RS) that indicates a probability of being MRD+ for a given gene expression pattern. Finally, we validated this model in an independent cohort of COG AALL1231 samples. Results: The AALL0434 early T-cell precursor (ETP) samples (n = 19), which have high rates of MRD+, had the highest RS, with an average of 81.3 (SD 18.7), versus 24.9 (SD 22.7) for non-ETPs (n = 146). Intriguingly, non-ETPs with RS 〉 50 had a gene expression pattern that mirrored ETPs and was distinct from the remaining non-ETPs. In this RS 〉 50 non-ETP cohort, 80% were MRD+, versus 20% of the 〈 50 cohort (p 〈 0.0001). When applied to 31 diagnostic non-ETP samples from COG AALL1231, 57% of the RS 〉 50 cohort were MRD+, versus 17% of the RS 〈 50 cohort (p = 0.05). Importantly, AALL0434 used prednisone during induction, while AALL1231 used dexamethasone, indicating that the predictive value is independent of the induction steroid. Finally, we converted our model to the customizable Nanostring nCounter platform by analyzing 96 AALL0434 samples on the Nanostring assay. The Nanostring data closely recapitulated the RNA-seq data, with a tight correlation between the resulting RS (concordance correlation coefficient = 0.91). Conclusions: We have developed a gene expression classifier that differentiates a subset of non-ETP T-ALLs with an ETP-like gene expression pattern and a high risk of MRD+, and have adapted the classifier to a clinically tractable targeted platform. Identification of this high-risk subset at diagnosis has the potential to facilitate risk-adapted trials to evaluate the utility of novel or more intensive therapies aimed at improving clinical outcomes.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.10002
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Online Resource
    Gene expression signature associated with in vitro dexamethasone resistance and post-induction minimal residual disease in pediatric T-cell acute lymphoblastic leukemia.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 10033-10033
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 10033-10033
    Abstract: 10033 Background: T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease, which has largely precluded the use of genetic mutations for risk stratification. We hypothesized that despite this heterogeneity, diverse T-ALLs may have functional similarities that underlie patterns of chemotherapy sensitivity. Methods: We used flow cytometry to evaluate in vitro dexamethasone (DEX) sensitivity and baseline expression of signal transduction effectors and BCL2-family proteins in 68 fresh diagnostic T-ALL samples from patients enrolled on the Children’s Oncology Group (COG) trial AALL1231. We also performed RNA-sequencing (RNA-seq) on 40 AALL1231 samples and used hierarchical clustering and linear regression to analyze these and published T-ALL RNA-seq data from COG AALL0434. Comparisons between groups were made using t-tests and Fisher’s exact tests. Results: Of the proteins analyzed, only high BCL2 expression was significantly associated with increased in vitro DEX resistance (p = 0.002). Hierarchical clustering of the AALL1231 RNA-seq data identified two distinct clusters. Cluster 1 was associated with significantly higher BCL2 transcript expression (p = 0.0002) and in vitro DEX resistance (p = 0.04) relative to cluster 2. We defined a gene set consisting of the top 210 differentially expressed genes between these clusters and applied this gene set to the COG AALL0434 cohort. In this analysis, the early T-cell precursor (ETP) and near-ETP samples clustered together (p 〈 0.0001) in cluster 1 along with 39 of 146 non-ETP samples. Not only did these cluster 1 non-ETP samples have significantly higher BCL2 transcript expression relative to the non-ETP samples in cluster 2 (p 〈 0.0001), but 54% of these non-ETP samples were minimal residual disease (MRD) positive (≥0.01%) at the end of induction, as opposed to only 16% of the non-ETP samples in cluster 2 (p 〈 0.0001). Conclusions: Gene expression profiling identifies non-ETP T-ALLs that cluster with ETP/near-ETP T-ALLs and have significantly higher BCL2 expression and increased rates of post-induction MRD.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.10033
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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