Publications by authors named "Naomi J Winick"

76 Publications

Late isolated central nervous system relapse in childhood B-cell acute lymphoblastic leukemia treated with intensified systemic therapy and delayed reduced dose cranial radiation: A report from the Children's Oncology Group study AALL02P2.

Pediatr Blood Cancer 2021 Jul 24:e29256. Epub 2021 Jul 24.

Department of Pediatrics, Division of Pediatric Hematology Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA.

Background: Patients with late, ≥18 months postdiagnosis, isolated central nervous relapse (iCNS-R) of B-acute lymphoblastic leukemia (ALL) have excellent outcomes with chemotherapy plus cranial radiotherapy, with 5-year overall survival (OS) approaching 80% in POG 9412. Subsequent relapse and radiation-related morbidity remain the causes of treatment failure and long-term sequelae. COG AALL02P2 aimed to maintain outcomes in patients with late iCNS-R using intensified chemotherapy and a decrease in cranial irradiation from 1800 to 1200 cGy.

Procedures: COG AALL02P2 enrolled 118 eligible patients with B-cell ALL (B-ALL) and late iCNS-R who received intensified systemic therapy, triple intrathecal chemotherapy, and 1200 cGy cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until 104 weeks postdiagnosis.

Results: The 3-year event-free survival (EFS) and OS were 64.3% ± 4.5% and 79.6% ± 3.8%, with 46.1% (18/39) of second relapses including the CNS. Of the 112 patients who completed therapy, 78 received protocol-specified radiation. Study enrollment was closed after interim monitoring analysis showed inferior EFS compared to POG 9412. Patients with initial NCI standard-risk classification fared better than high-risk patients.

Conclusions: COG AALL02P2 showed inferior EFS but similar OS compared to POG 9412. Limitations included a small sample size, more intensive prior therapies, and a significant number of patients (34/118, 29%) who did not receive protocol-directed radiation due to early relapse prior to 1 year or did not otherwise follow the treatment plan. New approaches are needed to improve outcome for these patients and determine the optimal timing and dose of cranial radiation in the treatment of iCNS-R.
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http://dx.doi.org/10.1002/pbc.29256DOI Listing
July 2021

Genomic and clinical characterization of early T-cell precursor lymphoblastic lymphoma.

Blood Adv 2021 07;5(14):2890-2900

ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT.

Early T-cell precursor phenotype acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-ALL with a unique immunophenotype and genetic abnormalities distinct from conventional T-ALL. A subset of T lymphoblastic lymphoma (T-LLy) also demonstrates the early T-cell precursor immunophenotype and may be a counterpart of ETP-ALL. Unlike ETP-ALL, the incidence, clinical features, and genomic features of ETP-LLy are unknown. We reviewed the immunophenotyping data of 218 T-LLy patients who enrolled in the Children's Oncology Group AALL0434 clinical trial and identified 9 cases (4%) exhibiting a definitive ETP immunophenotype. We performed single-nucleotide polymorphism array profiling on 9 ETP-LLy and 15 non-ETP T-LLy cases. Compared with non-ETP T-LLy, ETP-LLy showed less frequent deletion of 9p (CKDN2A/B), more frequent deletion of 12p (ETV6) and 1p (RPL22), and more frequent absence of biallelic T-cell receptor γ deletions. Recurrent abnormalities previously described in ETP-ALL such as deletions of 5q and 13q and gain of 6q were not observed in ETP-LLy cases. There were no failures of therapy among the ETP-LLy subtype with a 4-year event-free survival of 100%. Overall, ETP-LLy does not exhibit unifying genetic alterations but shows some distinct genomic features from non-ETP T-LLy suggesting that ETP-LLy may be a distinct entity from non-ETP T-LLy.
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http://dx.doi.org/10.1182/bloodadvances.2021004334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341356PMC
July 2021

Favorable Trisomies and Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331.

J Clin Oncol 2021 05 19;39(14):1540-1552. Epub 2021 Mar 19.

Department of Pediatrics, UT Southwestern, Simmons Cancer Center, Dallas, TX.

Purpose: 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 ( 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% standard 94.0% ± 0.8%; = .13) with no difference in OS (98.1% ± 0.5% 99.2% ± 0.3%; = .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; = .0004; OS hazard ratio 5.42; < .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.
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http://dx.doi.org/10.1200/JCO.20.02370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274747PMC
May 2021

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

Leukemia 2021 05 23;35(5):1279-1290. Epub 2021 Feb 23.

Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-r ALL) have a poor prognosis. KMT2A-r ALL overexpresses FLT3, and the FLT3 inhibitor (FLT3i) lestaurtinib potentiates chemotherapy-induced cytotoxicity in preclinical models. Children's Oncology Group (COG) AALL0631 tested whether adding lestaurtinib to post-induction chemotherapy improved event-free survival (EFS). After chemotherapy induction, KMT2A-r infants received either chemotherapy only or chemotherapy plus lestaurtinib. Correlative assays included FLT3i plasma pharmacodynamics (PD), which categorized patients as inhibited or uninhibited, and FLT3i ex vivo sensitivity (EVS), which categorized leukemic blasts as sensitive or resistant. There was no difference in 3-year EFS between patients treated with chemotherapy plus lestaurtinib (n = 67, 36 ± 6%) vs. chemotherapy only (n = 54, 39 ± 7%, p = 0.67). However, for the lestaurtinib-treated patients, FLT3i PD and FLT3i EVS significantly correlated with EFS. For FLT3i PD, EFS for inhibited/uninhibited was 59 ± 10%/28 ± 7% (p = 0.009) and for FLTi EVS, EFS for sensitive/resistant was 52 ± 8%/5 ± 5% (p < 0.001). Seventeen patients were both inhibited and sensitive, with an EFS of 88 ± 8%. Adding lestaurtinib did not improve EFS overall, but patients achieving potent FLT3 inhibition and those whose leukemia blasts were sensitive FLT3-inhibition ex vivo did benefit from the addition of lestaurtinib. Patient selection and PD-guided dose escalation may enhance the efficacy of FLT3 inhibition for KMT2A-r infant ALL.
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http://dx.doi.org/10.1038/s41375-021-01177-6DOI Listing
May 2021

Prognostic impact of minimal residual disease at the end of consolidation in NCI standard-risk B-lymphoblastic leukemia: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2021 04 9;68(4):e28929. Epub 2021 Feb 9.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

The 5-year disease-free survival (DFS) of National Cancer Institute (NCI) high-risk (HR) B-lymphoblastic leukemia (B-ALL) patients with end of induction (EOI) minimal residual disease (MRD) ≥0.1% and end of consolidation (EOC) MRD ≥0.01% is 39 ± 7%, warranting consideration of hematopoietic stem cell transplant (HSCT). However, the impact of EOC MRD in NCI standard-risk (SR) B-ALL patients using COG regimens is unknown. We found that SR patients with MRD ≥0.01% at both EOI and EOC have a 4-year DFS/overall survival (OS) of 72.9 ± 19.0%/91.7 ± 10.8% versus 90.7 ± 2.9%/95.5 ± 2.0% (p = .0019/.25) for those with EOI MRD ≥0.01% and EOC MRD <0.01%. These data suggest that routine use of HSCT may not be warranted in EOC MRD ≥0.01% SR patients.
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http://dx.doi.org/10.1002/pbc.28929DOI Listing
April 2021

Disparities in Cancer Survival Among Adolescents and Young Adults: A Population-Based Study of 88 000 Patients.

J Natl Cancer Inst 2021 Aug;113(8):1074-1083

Harold C. Simmons Comprehensive Cancer Center, Dallas, TX, USA.

Background: Adolescents and young adults (AYA, aged 15-39 years) diagnosed with cancer comprise a growing, yet understudied, population. Few studies have examined disparities in cancer survival in underserved and diverse populations of AYA.

Methods: Using population-based data from the Texas Cancer Registry, we estimated 5-year relative survival of common AYA cancers and examined disparities in survival by race and ethnicity, neighborhood poverty, urban or rural residence, and insurance type. We also used multivariable Cox proportional hazards regression models to examine associations of race or ethnicity, neighborhood poverty, urban or rural residence, and insurance type with all-cause mortality.

Results: We identified 55 316 women and 32 740 men diagnosed with invasive cancer at age 15-39 years between January 1, 1995, and December 31, 2016. There were disparities in relative survival by race and ethnicity, poverty, and insurance for many cancer types. Racial and ethnic disparities in survival for men with non-Hodgkin lymphoma (74.5% [95% confidence interval (CI) = 72.1% to 76.7%] White vs 57.0% [95% CI = 51.9% to 61.8%] Black) and acute lymphocytic leukemia (66.5% [95% CI = 61.4% to 71.0%] White vs 44.4% [95% CI = 39.9% to 48.8%] Hispanic) were striking, and disparities remained even for cancers with excellent prognosis, such as testicular cancer (96.6% [95% CI = 95.9% to 97.2%] White vs 88.7% [95% CI = 82.4% to 92.8%] Black). In adjusted analysis, being Black or Hispanic, living in high-poverty neighborhoods, and having Medicaid, other government insurance, or no insurance at diagnosis were associated with all-cause mortality in both women and men (all 2-sided P < .01).

Conclusions: Our study adds urgency to well-documented disparities in cancer survival in older adults by demonstrating persistent differences in relative survival and all-cause mortality in AYAs. Findings point to several areas of future research to address disparities in this unique population of cancer patients.
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http://dx.doi.org/10.1093/jnci/djab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328976PMC
August 2021

Reply to A. K. Agrawal et al.

J Clin Oncol 2021 02 14;39(6):695-696. Epub 2021 Jan 14.

Kimberly P. Dunsmore, MD, Virginia Tech Carilion School of Medicine and Carilion Clinic, Roanoke, VA; Stuart S. Winter, MD, Children's Minnesota Cancer and Blood Disorders Program, Minneapolis, MN; Meenakshi Devidas, PhD, Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN; Naomi J. Winick, MD, University of Texas Southwestern/Simmons Cancer Center, Pediatric Hematology/Oncology, Dallas, TX; William L. Carroll, MD, Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, NY; and Stephen P. Hunger, MD, Department of Pediatrics, The Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1200/JCO.20.03370DOI Listing
February 2021

Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932.

J Clin Oncol 2021 05 7;39(13):1437-1447. Epub 2021 Jan 7.

Department of Pediatrics and the Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Purpose: AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL).

Methods: AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 × 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of weekly oral methotrexate of 20 mg/m (MTX20) or 40 mg/m (MTX40).

Results: Five-year event-free survival and overall survival (OS) from enrollment (with 95% CIs), for all eligible and evaluable SR B-ALL patients (n = 9,226), were 92.0% (91.1% and 92.8%) and 96.8% (96.2% and 97.3%), respectively. The 5-year DFS and OS from the start of maintenance for randomly assigned AR patients were 94.6% (93.3% and 95.9%) and 98.5% (97.7% and 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178) were 94.1% (92.2% and 96.0%) and 98.3% (97.2% and 99.4%) 95.1% (93.3% and 96.9%) and 98.6% (97.7% and 99.6%), respectively ( = .86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (93.3% and 96.8%) and 98.8% (97.9% and 99.7%) 94.2% (92.2% and 96.1%) and 98.1% (97.0% and 99.2%), respectively ( = .92 and .89).

Conclusions: The 0NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m/week did not improve outcomes when compared with 20 mg/m/week. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families.
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http://dx.doi.org/10.1200/JCO.20.00494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746PMC
May 2021

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

J Clin Oncol 2020 10 19;38(28):3282-3293. Epub 2020 Aug 19.

Department of Pediatrics and The Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

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 ( = .029). Differences between DFS in a four-arm comparison were significant ( = .01), with no interactions between the MTX and nelarabine randomizations ( = .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% 6.9% ± 1.4%, respectively; = .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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http://dx.doi.org/10.1200/JCO.20.00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719PMC
October 2020

Successful Outcomes of Newly Diagnosed T Lymphoblastic Lymphoma: Results From Children's Oncology Group AALL0434.

J Clin Oncol 2020 09 17;38(26):3062-3070. Epub 2020 Jun 17.

Division of Blood and Marrow Transplantation, Children's National Health System, Washington, DC.

Purpose: 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 ( = .29) or by treatment regimen ( = .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.
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http://dx.doi.org/10.1200/JCO.20.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479761PMC
September 2020

Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group.

J Clin Oncol 2020 06 10;38(17):1897-1905. Epub 2020 Apr 10.

Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN.

Purpose: Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. ASNase () substitution was approved in 2011 for allergic reactions. has, however, been intermittently unavailable because of drug supply issues. The impact of substitution or complete ASNase discontinuation is unknown.

Methods: Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to but receiving all doses versus not receiving all ASNase doses.

Results: We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; = .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; = .03).

Conclusion: Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of shortages.
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http://dx.doi.org/10.1200/JCO.19.03024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7280050PMC
June 2020

Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433.

Haematologica 2021 01 1;106(1):46-55. Epub 2021 Jan 1.

Children's Hospital of Philadelphia.

Outcomes after relapse of childhood B-acute lymphoblastic leukemia (B-ALL) are poor, and optimal therapy is unclear. Children's Oncology Group study AALL0433 evaluated a new platform for relapsed ALL. Between March 2007 and October 2013 AALL0433 enrolled 275 participants with late bone marrow or very early isolated central nervous system (iCNS) relapse of childhood B-ALL. Patients were randomized to receive standard versus intensive vincristine dosing; this randomization closed due to excess peripheral neuropathy in 2010. Patients with matched sibling donors received allogeneic hematopoietic cell transplantation (HCT) after the first three blocks of therapy. The prognostic value of minimal residual disease (MRD) was also evaluated in this study. The 3-year event free and overall survival (EFS/OS) for the 271 eligible patients were 63.6% +/- 3.0% and 72.3% +/- 2.8% respectively. MRD at the end of Induction-1 was highly predictive of outcome, with 3-year EFS/OS of 84.9 +/- 4.0% and 93.8 +/- 2.7% for patients with MRD <0.1%, vs. 53.7 +/- 7.8% and 60.6 +/- 7.8% for patients with MRD ≥0.1% (p<0.0001). Patients who received HCT vs. chemotherapy alone had an improved 3-year disease-free survival (77.5 +/- 6.2% vs. 66.9 +/- 4.5%, p=0.03) but not OS (81.5 +/- 5.8% for HCT vs. 85.8 +/- 3.4% for chemotherapy, p=0.46). Patients with early iCNS relapse fared poorly, with a 3-year EFS/OS of 41.4% +/- 9.2% and 51.7% +/- 9.3%, respectively. Infectious toxicities of the chemotherapy platform were significant. The AALL0433 chemotherapy platform is efficacious for late bone marrow relapse of B-ALL, but with significant toxicities. The MRD threshold of 0.1% at the end of Induction-1 was highly predictive of outcome. The optimal role for HCT for this patient population remains uncertain. This trial is registered at clinicaltrials.gov (NCT# 00381680).
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http://dx.doi.org/10.3324/haematol.2019.237230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776266PMC
January 2021

Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331.

J Clin Oncol 2020 02 11;38(6):602-612. Epub 2019 Dec 11.

Department of Pediatrics, University of Texas (UT) Southwestern, Dallas, TX.

Purpose: 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% ( = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% ( = 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%; = .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.
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http://dx.doi.org/10.1200/JCO.19.01086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7030893PMC
February 2020

Masked hypodiploidy: Hypodiploid acute lymphoblastic leukemia (ALL) mimicking hyperdiploid ALL in children: A report from the Children's Oncology Group.

Cancer Genet 2019 10 30;238:62-68. Epub 2019 Jul 30.

Department of Pathology, The Ohio State University, Columbus, OH, USA.

Hyperdiploidy with greater than 50 chromosomes is usually associated with favorable prognosis in pediatric acute lymphoblastic leukemia (ALL), whereas hypodiploidy with ≤43 chromosomes is associated with extremely poor prognosis. Sometimes, hypodiploidy is "masked" and patients do not have a karyotypically visible clone with ≤43 chromosomes. Instead, their abnormal karyotypes contain 50-78 or more chromosomes from doubling of previously hypodiploid cells. When the hypodiploid and doubled hyperdiploid clones are both present, patients can be identified by traditional test methods [karyotype, DNA Index (DI), fluorescence in situ hybridization (FISH)], but the incidence of masked hypodiploid cases in which only the doubled clone is visible is unknown. We analyzed 7013 patients with B-ALL enrolled in COG AALL03B1 (2003-2011) for whom chromosome studies were available. Of 115 patients with hypodiploidy (25-39 chromosomes), karyotypes of 40 showed only the hypodiploid clone, 47 showed mosaicism with both hypodiploid and hyperdiploid (doubled) karyotypes, and 28 with masked hypodiploidy showed only a hyperdiploid (doubled) clone. Unique karyotypic signatures were identified, and widespread loss of heterozygosity (LOH) was seen in the microsatellite panel for all patients with masked hypodiploidy. An increased awareness of the unusual karyotypic profile associated with a doubled hypodiploid clone and coordinated use of DI, FISH, and LOH studies when indicated can identify patients with masked hypodiploidy and allow appropriate treatment selection.
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http://dx.doi.org/10.1016/j.cancergen.2019.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768693PMC
October 2019

Genome-Wide Association Study of Susceptibility Loci for T-Cell Acute Lymphoblastic Leukemia in Children.

J Natl Cancer Inst 2019 12;111(12):1350-1357

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts.

Methods: We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided.

Results: A novel risk locus in the USP7 gene (rs74010351, odds ratio [OR] = 1.44, 95% confidence interval [CI] = 1.27 to 1.65, P = 4.51 × 10-8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias.

Conclusions: These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).
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http://dx.doi.org/10.1093/jnci/djz043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910193PMC
December 2019

Hematopoietic Stem-Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group.

J Clin Oncol 2019 04 11;37(10):780-789. Epub 2019 Feb 11.

14 New York University Langone Medical Center, New York, NY.

Purpose: Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem-cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children's Oncology Group (COG) trials to evaluate the impact of HSCT on outcome.

Patients And Methods: Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort.

Results: Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes.

Conclusion: Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.
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http://dx.doi.org/10.1200/JCO.18.00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440386PMC
April 2019

Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization.

J Clin Oncol 2018 10 23;36(29):2926-2934. Epub 2018 Aug 23.

Stuart S. Winter, Children's Minnesota Cancer and Blood Disorders Program, Minneapolis, MN; Kimberly P. Dunsmore, Carilion Clinic, Roanoke, VA; Meenakshi Devidas and Zhiguo Chen, University of Florida, Gainesville, FL; Brent L. Wood, Seattle Children's Hospital, Seattle, WA; Natia Esiashvili, Emory University, Atlanta, GA; Nancy Eisenberg, University of New Mexico Health Sciences Center, Albuquerque, NM; Nikki Briegel, Princess Margaret Hospital for Children, Perth, Western Australia, Australia; Robert J. Hayashi, St Louis Children's Hospital, St Louis, MO; Julie M. Gastier-Foster, Nationwide Children's Hospital; Julie M. Gastier-Foster and Nyla A. Heerema, Ohio State University, Columbus, OH; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Barbara L. Asselin, University of Rochester Medical Center and Wilmot Cancer Institute, Rochester; Elizabeth A. Raetz and William L. Carroll, Perlmutter Cancer Center at NYU Langone Health, New York, NY; Paul S. Gaynon, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California, San Francisco, San Francisco, CA; Michael J. Borowitz, Johns Hopkins University, Baltimore, MD; Karen R. Rabin, Baylor College of Medicine, Houston; Naomi J. Winick, University of Texas Southwestern, Dallas, TX; Patrick A. Zweidler-Mckay, ImmunoGen, Waltham, MA; and Stephen P. Hunger, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA.

Purpose: Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen.

Patients And Methods: COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase.

Results: AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement.

Conclusion: AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.
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http://dx.doi.org/10.1200/JCO.2018.77.7250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366301PMC
October 2018

Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622.

J Clin Oncol 2018 08 29;36(22):2306-2314. Epub 2018 May 29.

William B. Slayton, John A. Kairalla, Meenakshi Devidas, Xinlei Mi, and Sherri L. Mizrahy, University of Florida, Gainesville, FL; Kirk R. Schultz, BC Children's Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Michael A. Pulsipher, Children's Hospital of Los Angeles, Los Angeles; Lance Sieger, University of California Los Angles-Harbor, Torrance; Mignon L. Loh, University of California San Francisco, San Francisco, CA; Bill H. Chang, Oregon Health and Science University, Portland, OR; Charles Mullighan, Ilaria Iacobucci, and Thomas Merchant, St Jude's Research Hospital, Memphis, TN; Lewis B. Silverman, Dana-Farber Cancer Institute, Boston, MA; Michael J. Borowitz, Johns Hopkins University, Baltimore, MD; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Nyla A. Heerema, Ohio State University; Julie M. Gastier-Foster, Nationwide Children's Hospital, Columbus, OH; Brent L. Wood, University of Washington Seattle, Seattle, WA; Valerie I. Brown, Penn State Health Children's Hospital, Hershey; Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA; Marilyn J. Siegel, Washington University School of Medicine, St Louis, MO; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; and William L. Carroll, New York University Langone Health Center, New York, NY.

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.
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http://dx.doi.org/10.1200/JCO.2017.76.7228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067800PMC
August 2018

Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group (COG).

Leukemia 2018 06 23;32(6):1370-1379. Epub 2018 Feb 23.

Seattle Children's Hospital, Seattle, WA, USA.

Minimal residual disease (MRD) after initial therapy is integral to risk stratification in B-precursor and T-precursor acute lymphoblastic leukemia (B-ALL, T-ALL). Although MRD determines depth of remission, remission remains defined by morphology. We determined the outcomes of children with discordant assessments of remission by morphology vs. flow cytometry using patients age 1-30.99 years enrolled on Children's Oncology Group ALL trials who underwent bone marrow assessment at the end of induction (N = 9350). Morphologic response was assessed locally as M1 (<5% lymphoblasts; remission), M2 (5-25%), or M3 (>25%). MRD was centrally measured by flow cytometry. Overall, 19.8% of patients with M2/M3 morphology had MRD < 5%. M1 with MRD ≥ 5% was less common in B-ALL (0.9%) than T-ALL (6.9%; p < 0.0001). In B-ALL, M1/MRD ≥ 5% was associated with superior 5-year event-free survival (EFS) than M2/MRD ≥ 5% (59.1% ± 6.5% vs. 39.1% ± 7.9%; p = 0.009), but was inferior to M1/MRD < 5% (87.1% ± 0.4%; p < 0.0001). MRD levels were higher in M2/MRD ≥ 5% than M1/MRD ≥ 5% patients. In T-ALL, EFS was not significantly different between M1/MRD ≥ 5% and M2/MRD ≥ 5%. Patients with morphologic remission but MRD ≥ 5% have outcomes similar to those who fail to achieve morphological remission, and significantly inferior to those with M1 marrows and concordant MRD, suggesting that flow cytometry should augment the definition of remission in ALL.
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http://dx.doi.org/10.1038/s41375-018-0039-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992047PMC
June 2018

Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232.

Cancer Med 2018 01 23;7(1):3-12. Epub 2017 Dec 23.

Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.
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http://dx.doi.org/10.1002/cam4.1206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773964PMC
January 2018

Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia: A report from the Children's Oncology Group study AALL1131.

Cancer 2018 03 19;124(6):1150-1159. Epub 2017 Dec 19.

Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Children, adolescents, and young adults with very high-risk (VHR) B acute lymphoblastic leukemia (B-ALL) have poor outcomes, and novel therapies are needed for this subgroup. The AALL1131 study evaluated postinduction therapy using cyclophosphamide (CPM), etoposide (ETOP), and clofarabine (CLOF) for patients with VHR B-ALL.

Methods: Patients who were 1 to 30 years old and had VHR B-ALL received modified Berlin-Frankfurt-Münster therapy after induction and were randomized to 1) CPM, cytarabine, mercaptopurine, vincristine (VCR), and pegaspargase (control arm), 2) CPM, ETOP, VCR, and pegaspargase (experimental arm 1), or 3) CPM, ETOP, CLOF (30 mg/m /d × 5), VCR, and pegaspargase (experimental arm 2) during the second half of consolidation and delayed intensification.

Results: The rates of grade 4/5 infections and grade 3/4 pancreatitis were significantly increased in experimental arm 2. The dose of CLOF was, therefore, reduced to 20 mg/m /d × 5, and myeloid growth factor was required after CLOF administration. Despite these changes, 4 of 39 patients (10.3%) developed grade 4 infections, with 1 of these patients developing a grade 5 acute kidney injury attributed to CLOF, whereas only 1 of 46 patients (2.2%) in experimental arm 1 developed grade 4 infections, and there were no grade 4/5 infections in the control arm (n = 20). Four patients in experimental arm 2 had prolonged cytopenias for >60 days, whereas none did in the control arm or experimental arm 1. Counts failed to recover for 2 of these patients, one having a grade 5 acute kidney injury and the other removed from protocol therapy; both events occurred 92 days after the start of consolidation part 2.

Conclusions: In AALL1131, CLOF, administered with CPM and ETOP, was associated with unacceptable toxicity. Cancer 2018;124:1150-9. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839964PMC
March 2018

Severe pegaspargase hypersensitivity reaction rates (grade ≥3) with intravenous infusion vs. intramuscular injection: analysis of 54,280 doses administered to 16,534 patients on children's oncology group (COG) clinical trials.

Leuk Lymphoma 2018 07 8;59(7):1624-1633. Epub 2017 Nov 8.

o Department of Pediatrics , Oregon Health and Science University , Portland , OR , USA.

PEGylated asparaginase (pegaspargase) can be administered via intramuscular (IM) injection or intravenous (IV) infusion with a hypersensitivity reaction (HSR) incidence ranging 3-41%. We evaluated grade ≥3 HSRs when given IM vs. IV on six Children's Oncology Group (COG) leukemia trials (2003-2015) to determine differences in HSR rates. 54,280 doses were administered to 16,534 patients. Considering all doses of pegaspargase during induction, consolidation, and delayed intensification, grade ≥3 HSR rate with IM injection was 5.4% (n = 482/8981) compared to 3.2% for IV (n = 245/7553) (p < .0001). If only the second and third doses of pegaspargase were analyzed, where the majority of grade ≥3 HSRs occur, the rate following IM injection was 10.1% (n = 459/4534) compared to 5.0% (n = 222/4443) for IV (p < .0001). On standardized treatment protocols conducted by the COG during 2003-2015, grade ≥3 HSR rates to pegaspargase occurred less frequently with IV infusion than IM injection.
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http://dx.doi.org/10.1080/10428194.2017.1397658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940583PMC
July 2018

Longitudinal analysis of quality-of-life outcomes in children during treatment for acute lymphoblastic leukemia: A report from the Children's Oncology Group AALL0932 trial.

Cancer 2018 02 7;124(3):571-579. Epub 2017 Nov 7.

Section of Pediatric Hematology-Oncology, Yale University School of Medicine, New Haven, Connecticut.

Background: Children with average-risk acute lymphoblastic leukemia (AR-ALL) face many challenges that can adversely affect their quality of life (QOL). However, to the authors' knowledge, patterns and predictors of QOL impairment during therapy have not been well characterized to date.

Methods: Patients with AR-ALL who were enrolled on the Children's Oncology Group AALL0932 trial were offered participation in this prospective cohort study if they were aged ≥4 years at the time of diagnosis and had an English-speaking parent. At approximately 2 months, 8 months, 17 months, 26 months, and 38 months (boys only) after diagnosis, parents completed the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0 (PedsQL4.0) and McMaster Family Assessment Device instruments for QOL (physical, emotional, and social functioning) and family functioning, respectively. The proportions of individuals scoring in the impaired range (2 standard deviations below the population mean) were calculated at each time point. Longitudinal impairment patterns and predictors were examined.

Results: A total of 594 participants with AR-ALL were diagnosed at a mean age of 6.0 years (standard deviation, 1.6 years). At 2 months, a substantial proportion of participants had impaired scores for physical (36.5%; 95% confidence interval [95% CI], 32.3%-40.8%) and emotional (26.2%; 95% CI, 22.5%-30.2%) functioning compared with population norms of 2.3%. These elevations persisted at 26 months. Emotional impairment at 2 months (odds ratio, 3.4; 95% CI, 1.5-7.7) was found to significantly predict emotional impairment at 26 months. In repeated measures analysis with multivariate modeling, unhealthy family functioning (odds ratio, 1.5; 95% CI, 1.1-2.1) significantly predicted emotional impairment controlling for age and sex. QOL outcomes were similar between sexes at the end of therapy (26 months for girls and 38 months for boys).

Conclusions: Many children with AR-ALL experience physical and emotional functioning impairment that begins early in treatment and persists. Early screening may identify high-risk patients who might benefit from family-based interventions. Cancer 2018;124:571-9. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808870PMC
February 2018

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia.

Nat Genet 2017 Aug 3;49(8):1211-1218. Epub 2017 Jul 3.

Department of Pediatrics, Perlmutter Cancer Center, New York University Medical Center, New York, New York, USA.

Genetic alterations that activate NOTCH1 signaling and T cell transcription factors, coupled with inactivation of the INK4/ARF tumor suppressors, are hallmarks of T-lineage acute lymphoblastic leukemia (T-ALL), but detailed genome-wide sequencing of large T-ALL cohorts has not been carried out. Using integrated genomic analysis of 264 T-ALL cases, we identified 106 putative driver genes, half of which had not previously been described in childhood T-ALL (for example, CCND3, CTCF, MYB, SMARCA4, ZFP36L2 and MYCN). We describe new mechanisms of coding and noncoding alteration and identify ten recurrently altered pathways, with associations between mutated genes and pathways, and stage or subtype of T-ALL. For example, NRAS/FLT3 mutations were associated with immature T-ALL, JAK3/STAT5B mutations in HOXA1 deregulated ALL, PTPN2 mutations in TLX1 deregulated T-ALL, and PIK3R1/PTEN mutations in TAL1 deregulated ALL, which suggests that different signaling pathways have distinct roles according to maturational stage. This genomic landscape provides a logical framework for the development of faithful genetic models and new therapeutic approaches.
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http://dx.doi.org/10.1038/ng.3909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535770PMC
August 2017

Circulating microRNAs: Potential Markers of Cardiotoxicity in Children and Young Adults Treated With Anthracycline Chemotherapy.

J Am Heart Assoc 2017 Apr 4;6(4). Epub 2017 Apr 4.

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.

Background: Biomarkers for early detection of anthracycline (AC)-induced cardiotoxicity may allow cardioprotective intervention before irreversible damage. Circulating microRNAs (miRNAs) are promising biomarkers of cardiovascular disease, however, have not been studied in the setting of AC-induced cardiotoxicity. This study aimed to identify AC-induced alterations in plasma miRNA expression in children and correlate expression with markers of cardiac injury.

Methods And Results: Candidate plasma profiling of 24 miRNAs was performed in 33 children before and after a cycle of AC (n=24) or noncardiotoxic chemotherapy (n=9). Relative miRNA changes between the pre- and postcycle time points (6, 12, and 24 hours) were determined within each treatment group and compared across groups. Plasma miRNA expression patterns were further explored with respect to AC dose and high-sensitivity troponin T. Greater chemotherapy-induced dysregulation was observed in this panel of candidate, cardiac-related plasma miRNAs in patients receiving anthracyclines compared with those receiving noncardiotoxic chemotherapy (24-hour MANOVA; =0.024). Specifically, plasma miRs-29b and -499 were upregulated 6 to 24 hours post-AC, and their postchemotherapy expression significantly correlated with AC dose. Patients with acute cardiomyocyte injury (high-sensitivity troponin T increase ≥5 ng/L from baseline) demonstrated higher expression of miR-29b and miR-499 post-AC compared with those without.

Conclusions: In this pilot study, cardiac-related plasma miRNAs are dysregulated following ACs. Plasma miR-29b and -499 are acutely elevated post-AC, with dose response relationships observed with anthracycline dose and markers of cardiac injury. Further evaluation of miRNAs may provide mechanistic insight into AC-induced cardiotoxicity and yield biomarkers to facilitate earlier intervention to mitigate cardiotoxicity.
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http://dx.doi.org/10.1161/JAHA.116.004653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532993PMC
April 2017

Application of a standardized screening protocol for diagnosis of invasive mold infections in children with hematologic malignancies.

Support Care Cancer 2016 12 12;24(12):5025-5033. Epub 2016 Aug 12.

University of Texas Southwestern Medical Center, Dallas, TX, USA.

Purpose: This study describes a standardized screening protocol for diagnosis of invasive mold infections in pediatric oncology patients with neutropenia and prolonged or recurrent fever.

Methods: A retrospective chart review was performed of children receiving intensive chemotherapy for hematologic malignancies who developed invasive mold infections from 2004 to 2011. Characteristics and outcomes were compared before and after implementation of the screening protocol in November 2006. The screen includes direct nasal endoscopy performed at the bedside by an otorhinolaryngologist, noncontrast computed tomography (CT) of the chest, and abdominal ultrasound in patients with neutropenia and prolonged or recurrent fever.

Results: Fifty patients had proven, probable, or possible invasive mold infections. Before routine use of direct nasal endoscopy, invasive nasosinal disease was detected in 5 of 19 patients (26 %) and all had a compatible clinical presentation. Thirteen of 31 patients (42 %) in the post-screen group had nasosinal disease, and fever was the only sign for 8 patients (62 %). Twenty-four patients with nasosinal disease had a sinus CT, and radiologic findings of bony erosion or peri-sinus invasion were never detected. Eight of 19 patients in the pre-screen group died from mold infection (42.1 %) versus 4 of 31 (12.9 %) in the post-screen group (p = 0.04).

Conclusions: A screening protocol including direct nasal endoscopy, noncontrast chest CT, and abdominal ultrasound was effective in detecting invasive mold infections in at-risk patients. Nasosinal involvement often occurs before specific symptoms develop, and sinus CTs are insensitive and nonspecific. Bedside nasal endoscopy precludes radiation exposure associated with sinus CT and was associated with decrease in mold-related mortality, likely due to earlier diagnosis and initiation of appropriate antifungal therapy.
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http://dx.doi.org/10.1007/s00520-016-3367-zDOI Listing
December 2016

Klinefelter syndrome and 47,XYY syndrome in children with B cell acute lymphoblastic leukaemia.

Br J Haematol 2017 12 19;179(5):843-846. Epub 2016 Jul 19.

Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1111/bjh.14258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247399PMC
December 2017

A Pilot Study of Intensified PEG-Asparaginase in High-risk Acute Lymphoblastic Leukemia: Children's Oncology Group Study AALL08P1.

J Pediatr Hematol Oncol 2016 08;38(6):409-17

*Mayo Clinic Children's Center, Division of Pediatric Hematology Oncology, Rochester, MN †Children's Oncology Group Data Center Biostatistics, University of Florida, Gainesville, FL ‡Walter Reed National Military Medical Center, Congressionally Directed Medical Research Program, US Army Medical Research and Materiel Command, Fort Detrick, MD ††Department of Pathology, Johns Hopkins University Sidney Kimmel Cancer Center, John Hopkins University, Baltimore, MD §Division Pediatric Hematology-Oncology, Primary Children's Hospital, University of Utah, Salt Lake City, UT ∥Division of Pediatric Hematology Oncology, UCSF Medical Center-Mssion Bay, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA ¶Department of Genetics, Children's Hospital of Alabama, University of Alabama at Birmingham, Birmingham, AL #Nationwide Children's Hospital, Cytogenetics, The Ohio State University, Columbus, OH **Seattle Children's Hospital, Laboratory Medicine, Seattle, WA ‡‡Midwest Children's Cancer Center, MACC Fund Research Center, Milwaukee, WI §§Division of Pediatric Hematology Oncology, University of Rochester Medical Center, Rochester ¶¶Laura and Isaac Perlmutter Cancer Center at NYU Langone, Hassendfeld Children's Center, New York, NY ∥∥Division Pediatric Hematology-Oncology, UT Southwestern/Simmons Cancer Center, Dallas, TX †††Baylor College of Medicine, Comprehensive Cancer Center, Pediatric Oncology, Houston, TX ##Division of Oncology, Children's Hospital of Philadelphia ***Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

AALL08P1 was designed to determine whether biweekly intensified pegaspargase (I-PEG) was feasible and safe in pediatric patients with newly diagnosed high-risk B-precursor lymphoblastic leukemia when given with Children's Oncology Group hemiaugmented BFM therapy. High-risk average (HR-Avg) patients received standard pegaspargase dosing (6 doses), whereas high-risk high (HR-High) patients received I-PEG biweekly from the start of Consolidation until day 1 of Maintenance. Feasibility and safety were defined in advance as ≥65% of patients tolerating at least 8 doses of I-PEG and 90% requiring ≤49 weeks from day 1 of Consolidation to the initiation of Maintenance. Targeted toxicities included allergic reactions, anaphylaxis, pancreatitis, thrombosis, bleeding, central nervous system events, and sepsis. AALL08P1 enrolled 104 patients; 54 were classified as HR-Avg and 30 as HR-High after completion of induction therapy. Only 53% (16/30) of the HR-High patients received ≥8 total doses of I-PEG and 50% (15/30) took ≤49 weeks from start of Consolidation to the initiation of Maintenance. I-PEG did not significantly increase grade 2 to 5 targeted toxicities. I-PEG was not feasible or safe as defined in AALL08P1. Complete assessment of this regimen was limited due to removal of patients from I-PEG regimen and early closure of the study.
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http://dx.doi.org/10.1097/MPH.0000000000000589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955695PMC
August 2016

Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia.

J Clin Oncol 2016 06 25;34(18):2133-40. Epub 2016 Apr 25.

Chengcheng Liu, Wenjian Yang, Cheng Cheng, Deqing Pei, Colton Smith, Sima Jeha, Ching-Hon Pui, William E. Evans, and Mary V. Relling, St Jude Children's Research Hospital; Scott C. Howard, University of Memphis, Memphis, TN; Meenakshi Devidas, University of Florida, Gainesville, FL; William L. Carroll, New York University Langone Medical Center, New York, NY; Elizabeth A. Raetz, University of Utah, Salt Lake City, UT; W. Paul Bowman, Cook Children's Hospital, Ft Worth; Naomi J. Winick, University of Texas Southwestern Medical Center, Dallas, TX; Eric C. Larsen, Maine Children's Cancer Program, Scarborough, ME; Kelly W. Maloney, University of Colorado Denver, Aurora, CO; Paul L. Martin, Duke University, Durham, NC; Leonard A. Mattano Jr, HARP Pharma Consulting, Mystic, CT; Elaine R. Mardis and Robert S. Fulton, The McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO; Deepa Bhojwani, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California San Francisco Medical Center-Parnassus, San Francisco, CA; and Stephen P. Hunger, Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: 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.
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http://dx.doi.org/10.1200/JCO.2015.64.5812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962704PMC
June 2016
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