First name
Stephen
Middle name
P
Last name
Hunger

Title

Impact of high-risk cytogenetics on outcomes for children and young adults receiving CD19-directed CAR T-cell therapy.

Year of Publication

2022

Number of Pages

2173-2185

Date Published

2022 Apr 07

ISSN Number

1528-0020

Abstract

Chimeric antigen receptor (CAR) T-cell therapy can induce durable remissions of relapsed/refractory B-acute lymphoblastic leukemia (ALL). However, case reports suggested differential outcomes mediated by leukemia cytogenetics. We identified children and young adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19-directed CAR T-cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel from April 2012 to April 2019. Patients were hierarchically categorized according to leukemia cytogenetics: High-risk lesions were defined as KMT2A (MLL) rearrangements, Philadelphia chromosome (Ph+), Ph-like, hypodiploidy, or TCF3/HLF; favorable as hyperdiploidy or ETV6/RUNX1; and intermediate as iAMP21, IKZF1 deletion, or TCF3/PBX1. Of 231 patients aged 1 to 29, 74 (32%) were categorized as high risk, 28 (12%) as intermediate, 43 (19%) as favorable, and 86 (37%) as uninformative. Overall complete remission rate was 94%, with no difference between strata. There was no difference in relapse-free survival (RFS; P = .8112), with 2-year RFS for the high-risk group of 63% (95% confidence interval [CI], 52-77). There was similarly no difference seen in overall survival (OS) (P = .5488), with 2-year OS for the high-risk group of 70% (95% CI, 60-82). For patients with KMT2A-rearranged infant ALL (n = 13), 2-year RFS was 67% (95% CI, 45-99), and OS was 62% (95% CI, 40-95), with multivariable analysis demonstrating no increased risk of relapse (hazard ratio, 0.70; 95% CI, 0.21-2.90; P = .7040) but a higher proportion of relapses associated with myeloid lineage switch and a 3.6-fold increased risk of all-cause death (95% CI, 1.04-12.75; P = .0434). CTL019/huCART19/tisagenlecleucel are effective at achieving durable remissions across cytogenetic categories. Relapsed/refractory patients with high-risk cytogenetics, including KMT2A-rearranged infant ALL, demonstrated high RFS and OS probabilities at 2 years.

DOI

10.1182/blood.2021012727

Alternate Title

Blood

PMID

34871373

Title

Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma.

Year of Publication

2022

Number of Pages

JCO2102678

Date Published

2022 Mar 10

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>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.</p>

<p><strong>PATIENTS AND METHODS: </strong>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.</p>

<p><strong>RESULTS: </strong>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, = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% 86.4% ± 4.0%; = .041); and 4-year OS (78.3% ± 4.9% 89.5% ± 3.6%; = .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 ( = .412) and OS ( = .600).</p>

<p><strong>CONCLUSION: </strong>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.</p>

DOI

10.1200/JCO.21.02678

Alternate Title

J Clin Oncol

PMID

35271306

Title

Understanding Adolescent and Young Adult 6-Mercaptopurine Adherence and mHealth Engagement During Cancer Treatment: Protocol for Ecological Momentary Assessment.

Year of Publication

2021

Number of Pages

e32789

Date Published

2021 Oct 22

ISSN Number

1929-0748

Abstract

<p><strong>BACKGROUND: </strong>Adolescents and young adults (AYAs) with cancer demonstrate suboptimal oral chemotherapy adherence, increasing their risk of cancer relapse. It is unclear how everyday time-varying contextual factors (eg, mood) affect their adherence, stalling the development of personalized mobile health (mHealth) interventions. Poor engagement is also a challenge across mHealth trials; an effective adherence intervention must be engaging to promote uptake.</p>

<p><strong>OBJECTIVE: </strong>This protocol aims to determine the temporal associations between daily contextual factors and 6-mercaptopurine (6-MP) adherence and explore the proximal impact of various engagement strategies on ecological momentary assessment survey completion.</p>

<p><strong>METHODS: </strong>At the Children's Hospital of Philadelphia, AYAs with acute lymphoblastic leukemia or lymphoma who are prescribed prolonged maintenance chemotherapy that includes daily oral 6-MP are eligible, along with their matched caregivers. Participants will use an ecological momentary assessment app called ADAPTS (Adherence Assessments and Personalized Timely Support)-a version of an open-source app that was modified for AYAs with cancer through a user-centered process-and complete surveys in bursts over 6 months. Theory-informed engagement strategies will be microrandomized to estimate the causal effects on proximal survey completion.</p>

<p><strong>RESULTS: </strong>With funding from the National Cancer Institute and institutional review board approval, of the proposed 30 AYA-caregiver dyads, 60% (18/30) have been enrolled; of the 18 enrolled, 15 (83%) have completed the study so far.</p>

<p><strong>CONCLUSIONS: </strong>This protocol represents an important first step toward prescreening tailoring variables and engagement components for a just-in-time adaptive intervention designed to promote both 6-MP adherence and mHealth engagement.</p>

<p><strong>INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): </strong>DERR1-10.2196/32789.</p>

DOI

10.2196/32789

Alternate Title

JMIR Res Protoc

PMID

34677129

Title

Association of Combined Focal 22q11.22 Deletion and IKZF1 Alterations With Outcomes in Childhood Acute Lymphoblastic Leukemia.

Year of Publication

2021

Date Published

2021 Aug 19

ISSN Number

2374-2445

Abstract

<p><strong>Importance: </strong>Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations.</p>

<p><strong>Objective: </strong>To determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death.</p>

<p><strong>Design, Setting, and Participants: </strong>This cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children's Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children's Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021.</p>

<p><strong>Exposures: </strong>Focal 22q11.22 deletions.</p>

<p><strong>Main Outcomes and Measures: </strong>Event-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VRPEB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040).</p>

<p><strong>Results: </strong>This study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P &lt; .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for event-free survival (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and overall survival (HR, 1.83; 95% CI, 1.01-3.34; P = .05).</p>

<p><strong>Conclusions and Relevance: </strong>This cohort study suggests that 22q11.22 deletions identify patients with B-ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine B-ALL risk stratification and treatment strategies.</p>

DOI

10.1001/jamaoncol.2021.2723

Alternate Title

JAMA Oncol

PMID

34410295

Title

Assessment of the impact of inpatient infectious events in pediatric patients with newly diagnosed acute leukemia at Dr. Robert Reid Cabral Children's Hospital, Dominican Republic.

Year of Publication

2020

Number of Pages

e0243795

Date Published

2020

ISSN Number

1932-6203

Abstract

<p>Survival rates for pediatric acute leukemia vary dramatically worldwide. Infections are a leading cause of morbidity and mortality, and the impact is amplified in low and middle-income countries. Defining the epidemiology of infection in a specific health care setting is paramount to developing effective interventions. This study aimed to define the epidemiology of and outcomes from infection in children with acute leukemia treated in a large public pediatric hospital in the Dominican Republic. A retrospective cohort was assembled of children newly diagnosed with acute leukemia between July 1, 2015 to June 30, 2017 at Hospital Infantil Dr. Robert Reid Cabral in Santo Domingo. Patients were identified from the Pediatric Oncology Network Database (PONDTM) and hospital admissions from the Oncology admissions logbook. Medical records and microbiology results were reviewed to identify all inpatient invasive infections. Distance from a child's home to the hospital was determined using ArcGIS by Esri. Infection rates were described in discrete time periods after diagnosis and risk factors for invasive infection were explored using negative binomial regression. Overall, invasive infections were common and a prominent source of death in this cohort. Rates were highest in the first 60 days after diagnosis. Gastroenteritis/colitis, cellulitis, and pneumonia were most frequent, with bacteremia common early on. Multidrug resistant bacteria were prevalent among a small number of positive cultures. In a multivariate negative binomial regression model, age ≥ 10 years and distance from the hospital &gt; 100 km were each protective against invasive infection in the first 180 days after diagnosis, findings that were unexpected and warrant further investigation. Over one-third of patient deaths were related to infection. Interventions aimed at reducing infection should target the first 60 days after diagnosis, improved supportive care inside and outside the hospital, and increased antimicrobial stewardship and infection prevention and control measures.</p>

DOI

10.1371/journal.pone.0243795

Alternate Title

PLoS One

PMID

33320881

Title

Delayed cancer diagnoses and high mortality in children during the COVID-19 pandemic.

Year of Publication

2020

Number of Pages

e28427

Date Published

2020 Jun 26

ISSN Number

1545-5017

DOI

10.1002/pbc.28427

Alternate Title

Pediatr Blood Cancer

PMID

32588960

Title

Development and Clinical Validation of a Large Fusion Gene Panel for Pediatric Cancers.

Year of Publication

2019

Date Published

2019 Jun 27

ISSN Number

1943-7811

Abstract

<p>Gene fusions are one of the most common genomic alterations in pediatric cancer. Many fusions encode oncogenic drivers and play important roles in cancer diagnosis, risk stratification, and treatment selection. We report the development and clinical validation of a large custom-designed RNA sequencing panel, CHOP Fusion panel, using anchored multiplex PCR technology. The panel interrogates 106 cancer genes known to be involved in nearly 600 different fusions reported in hematological malignancies and solid tumors. The panel works well with different types of samples including formalin-fixed, paraffin-embedded samples. The panel demonstrated excellent analytic accuracy with 100% sensitivity and specificity on 60 pediatric tumor validation samples. In addition to identifying all known fusions in the validation samples, three unrecognized yet clinically significant fusions were also detected. Two-hundred and sevety-six clinical cases were analyzed after the validation and 51 different fusions were identified in 104 cases. Of these, 16 fusions were not previously reported at the time of discovery. These fusions provided genomic information useful for clinical management. Our experience demonstrates that CHOP Fusion panel can detect the vast majority of known and certain novel clinically relevant fusion genes in pediatric cancers accurately, efficiently, and cost effectively, and provides an excellent tool for new fusion gene discovery.</p>

DOI

10.1016/j.jmoldx.2019.05.006

Alternate Title

J Mol Diagn

PMID

31255796

Title

Clinical utility of custom-designed NGS panel testing in pediatric tumors.

Year of Publication

2019

Number of Pages

32

Date Published

2019 May 28

ISSN Number

1756-994X

Abstract

<p><strong>BACKGROUND: </strong>Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers.</p>

<p><strong>METHODS: </strong>Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed.</p>

<p><strong>RESULTS: </strong>NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration.</p>

<p><strong>CONCLUSIONS: </strong>Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.</p>

DOI

10.1186/s13073-019-0644-8

Alternate Title

Genome Med

PMID

31133068

Title

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia (T-ALL).

Year of Publication

2018

Number of Pages

995-9

Date Published

2018 Mar

ISSN Number

1528-0020

Abstract

<p>As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-ALL, however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multi-agent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of non-hematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human IgG1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma (MM). We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.</p>

DOI

10.1182/blood-2017-07-794214

Alternate Title

Blood

PMID

29305553

Title

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.

Year of Publication

2018

Number of Pages

3-12

Date Published

2018 Jan

ISSN Number

2045-7634

Abstract

<p>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&nbsp;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.</p>

DOI

10.1002/cam4.1206

Alternate Title

Cancer Med

PMID

29274118

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