scholarly journals FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children’s Oncology Group trial AALL0631

Leukemia ◽  
2021 ◽  
Author(s):  
Patrick A. Brown ◽  
John A. Kairalla ◽  
Joanne M. Hilden ◽  
ZoAnn E. Dreyer ◽  
Andrew J. Carroll ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Flt3 Inhibitor ◽  
Group Trial ◽  
Infant Acute Lymphoblastic Leukemia

Outcomes of Patients with CRLF2-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Sarah K Tasian ◽  
Yunfeng Dai ◽  
Meenakshi Devidas ◽  
Kathryn G Roberts ◽  
Richard C Harvey ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Advisory Committees

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<0.0001), leukocytosis (diagnostic white blood cell count 77.5 ±98.5 vs 49.8 ±119.4 x 10e9/L [mean ±SD], p<0.0001), and higher rates of EOI MRD positivity at a ≥0.01% threshold (47.9% vs 30.1%, p<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<0.003). Overall, CRLF2+ patients had inferior 5-year event-free survival (EFS; 63.3% ±3.1 vs 82.1% ±0.7, p<0.0001) and overall survival (OS; 79.6% ±2.6 vs 90.5% ±0.6, p<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<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<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.

ARID5B Regulates Leukemia Sensitivity to Antimetabolites in Children with Acute Lymphoblastic Leukemia Via Effects on Cell Cycle Progression

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 791-791 ◽  
Author(s):  
Jun J. Yang ◽  
Heng Xu ◽  
Deepa Bhojwani ◽  
Takaya Moriyama ◽  
Maoxiang Qian ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Drug Sensitivity ◽  
Lymphoblastic Leukemia ◽  
Hdac Inhibitors ◽  
G1 Phase ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Childhood All

Abstract Acute lymphoblastic leukemia (ALL) in children is a prototype of cancer that can be cured by chemotherapy alone. However, the molecular mechanisms for anti-leukemic drug sensitivity and genetic basis of inter-patient variability in treatment response are not fully understood. Taking a genome-wide approach, we recently identified genetic variants in the ARID5B gene that strongly predispose children to developing ALL and also a high risk of relapse following therapy (J Clin Oncol 2012 30:751, Nat Genet 2009 41:1001). To understand the mechanisms by which ARID5B is linked to treatment outcome in childhood ALL, we sought to 1) characterize ARID5B expression in different genetic subtypes of ALL, 2) determine the effects of ARID5B expression on cytotoxicity of chemotherapeutic agents commonly used in ALL therapy, and 3) describe molecular pathways linking ARID5B to anti-leukemic drug sensitivity. In 567 children with newly diagnosed ALL treated at St. Jude Children’s Research Hospital (GSE33315), ARID5B expression was highest in cases with hyperdiploid karyotype (>50 chromosomes) and lowest in T-cell ALL and cases with MLL rearrangements. This pattern was validated in an independent cohort of 106 children from the Dutch Childhood Oncology Group (GSE13351). In 59 patients treated on the Children’s Oncology Group (COG) CCG1961 trial, lower ARID5B expression was associated with higher rates of relapse (P=0.01, GSE7440). Importantly, when we compared matched newly-diagnosed vs. relapsed ALL blasts from a cohort of 60 patients enrolled in COG trials (GSE28460), ARID5B expression was further downregulated at disease recurrence (P=0.0009). shRNA-mediated ARID5B knockdown in 3 ALL cell lines (Nalm6, SEM, and UOCB-1) substantially increased resistance to antimetabolites (an average of 5.16 and 35.3-fold increase in IC50 for methotrexate [MTX] and 6-mercaptopurine [6MP], respectively), with minimal effects on glucocorticoids, vincristine, asparaginase, and daunorubicin. Because cytotoxic effects of MTX and 6MP are highly dependent on the rate of cell proliferation, we postulate that ARID5B directly influences cell cycle entry. In all 3 cell lines, ARID5B knockdown led to significant blockade at the G1/S checkpoint, increasing the percent of cells in G0/G1 phase. At the molecular level, downregulation of ARID5B resulted in higher levels of p21 and reduction in phosphorylated Rb, consistent with the retention at G0/G1 phase. ARID5B expression was restricted to nucleus but affected both nuclear and cytoplasmic p21 expression in a time-dependent fashion. Interestingly, there was a highly significant negative correlation between p21 expression and MTX- and 6MP-induced apoptosis in all 3 ALL cell lines. Taken together, we hypothesize that lower expression of ARID5B impairs ALL cell cycling by upregulating p21, contributing to resistance to MTX and 6MP and eventually leukemia relapse. Finally, we compared global gene expression in ARID5B knockdown vs. control ALL cells, and via the Connectivity Map analysis we identified histone deacetylase (HDAC) inhibitors as promising agents for overcoming ARID5B-related drug resistance. Indeed, ARID5B knockdown cells were significantly more sensitive to panobinostat than controls, suggesting HDAC inhibitors as potential therapeutic options for patients with ARID5B-deficient and drug resistant ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children's Oncology Group

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3010-3015 ◽  
Author(s):  
David R. Freyer ◽  
Meenakshi Devidas ◽  
Mei La ◽  
William L. Carroll ◽  
Paul S. Gaynon ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Initial Treatment ◽  
Lymphoblastic Leukemia ◽  
Initial Therapy ◽  
Late Relapse ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Retrieval Rate ◽  
Standard Intensity ◽  
B Lineage

Abstract While intensification of therapy has improved event-free survival (EFS) and survival in newly diagnosed children with acute lymphoblastic leukemia (ALL), postrelapse outcomes remain poor. It might be expected that patients relapsing after inferior initial therapy would have a higher retrieval rate than after superior therapy. In the Children's Oncology Group Study CCG-1961, significantly superior EFS and survival were achieved with an augmented (stronger) versus standard intensity regimen of postinduction intensification (PII) for children with newly diagnosed high-risk ALL and rapid day 7 marrow response (EFS/survival 81.2%/88.7% vs 71.7%/83.4%, respectively). This provided an opportunity to evaluate postrelapse survival (PRS) in 272 relapsed patients who had received randomly allocated initial treatment with augmented or standard intensity PII. As expected, PRS was worse for early versus late relapse, marrow versus extramedullary site, adolescent versus younger age and T versus B lineage. However, no difference in 3-year PRS was detected for having received augmented versus standard intensity PII (36.4% ± 5.7% vs 39.2% ± 4.1%; log rank P = .72). Similar findings were noted within subanalyses by timing and site of relapse, age, and immunophenotype. These findings provide insight into mechanisms of relapse in ALL, and are consistent with emergence of a resistant subclone that has acquired spontaneous mutations largely independent of initial therapy. This study is registered at www.clinicaltrials.gov as NCT00002812.

scholarly journals Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia

2020 ◽  
Vol 38 (28) ◽  
pp. 3282-3293 ◽  
Author(s):  
Kimberly P. Dunsmore ◽  
Stuart S. Winter ◽  
Meenakshi Devidas ◽  
Brent L. Wood ◽  
Natia Esiashvili ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Oncology Group ◽  
Leucovorin Rescue ◽  
Cell Acute Lymphoblastic Leukemia ◽  
To Receive

PURPOSE Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS From 2007 to 2014, Children’s Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005 ) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( P = .029). Differences between DFS in a four-arm comparison were significant ( P = .01), with no interactions between the MTX and nelarabine randomizations ( P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

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