First name
Gerald
Last name
Wertheim

Title

Clinical impact of genomic characterization of 15 patients with acute megakaryoblastic leukemia-related malignancies.

Year of Publication

2021

Date Published

2021 Apr

ISSN Number

2373-2873

Abstract

<p>Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia but is approximately 500 times more likely to develop in children with Down syndrome (DS) through transformation of transient abnormal myelopoiesis (TAM). This study investigates the clinical significance of genomic heterogeneity of AMKL in children with and without DS and in children with TAM. Genomic evaluation of nine patients with DS-related TAM or AMKL, and six patients with non-DS AMKL, included conventional cytogenetics and a comprehensive next-generation sequencing panel for single-nucleotide variants/indels and copy-number variants in 118 genes and fusions involving 110 genes. Recurrent gene fusions were found in all patients with non-DS, including two individuals with complex genomes and either a or a - fusion, and the remaining harbored a fusion, which arose from both typical and atypical cytogenetic mechanisms. These fusions guided treatment protocols and resulted in a change in diagnosis in two patients. The nine patients with DS had constitutional trisomy 21 and somatic mutations, and those with DS-AMKL had two to four additional clinically significant somatic mutations. Comprehensive genomic characterization provides critical information for diagnosis, risk stratification, and treatment decisions for patients with AMKL. Continued genetic and clinical characterization of these rare cancers will aid in improving patient management.</p>

DOI

10.1101/mcs.a005975

Alternate Title

Cold Spring Harb Mol Case Stud

PMID

33832921

Title

Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T-cell Therapy for Acute Lymphoblastic Leukemia.

Year of Publication

2016

Number of Pages

664-79

Date Published

2016 06

ISSN Number

2159-8290

Abstract

<p><strong>UNLABELLED: </strong>Chimeric antigen receptor (CAR)-modified T cells with anti-CD19 specificity are a highly effective novel immune therapy for relapsed/refractory acute lymphoblastic leukemia. Cytokine release syndrome (CRS) is the most significant and life-threatening toxicity. To improve understanding of CRS, we measured cytokines and clinical biomarkers in 51 CTL019-treated patients. Peak levels of 24 cytokines, including IFNγ, IL6, sgp130, and sIL6R, in the first month after infusion were highly associated with severe CRS. Using regression modeling, we could accurately predict which patients would develop severe CRS with a signature composed of three cytokines. Results were validated in an independent cohort. Changes in serum biochemical markers, including C-reactive protein and ferritin, were associated with CRS but failed to predict development of severe CRS. These comprehensive profiling data provide novel insights into CRS biology and, importantly, represent the first data that can accurately predict which patients have a high probability of becoming critically ill.</p>

<p><strong>SIGNIFICANCE: </strong>CRS is the most common severe toxicity seen after CAR T-cell treatment. We developed models that can accurately predict which patients are likely to develop severe CRS before they become critically ill, which improves understanding of CRS biology and may guide future cytokine-directed therapy. Cancer Discov; 6(6); 664-79. ©2016 AACR.See related commentary by Rouce and Heslop, p. 579This article is highlighted in the In This Issue feature, p. 561.</p>

DOI

10.1158/2159-8290.CD-16-0040

Alternate Title

Cancer Discov

PMID

27076371

Title

Pediatric chronic myeloid leukemia with inv(3)(q21q26.2) and T lymphoblastic transformation: a case report.

Year of Publication

2016

Number of Pages

14

Date Published

2016

ISSN Number

2050-7771

Abstract

<p><strong>BACKGROUND: </strong>Chronic myeloid leukemia (CML) comprises ~3&nbsp;% of pediatric leukemia. Although therapy with tyrosine kinase inhibitors (TKIs) is highly effective for CML, multiple factors have been identified as predictive of treatment failure. Chromosomal abnormalities involving the MECOM locus at 3q26 portend therapy resistant disease in adults, yet have never been described in pediatric patients and have not been associated with T lymphoblastic progression.</p>

<p><strong>CASE PRESENTATION: </strong>We present a case of an 11-year-old boy with CML possessing the unique combination of T lymphoblastic transformation and a subclone harboring inv(3)(q21q26.2) at diagnosis. This is the first reported case of pediatric CML with inv(3)(q21q26.2) and the first case of T lymphoblastic progression associated with this karyotype. The patient was treated with single agent TKI therapy with robust initial response. Marrow histology at one month showed restoration of trilineage hematopoiesis and BCR-ABL RT-PCR at three months showed a 1.4 log reduction in transcript levels.</p>

<p><strong>CONCLUSIONS: </strong>The karyotypic abnormality of inv(3)(q21q26.2) in CML is not restricted to adult patients. Moreover, while chromosome 3 abnormalities are markers of TKI resistance in adults, our patient showed a robust early response to single agent TKI therapy. This finding suggests pediatric CML with inv(3)(q21q26.2) may have distinct features and more favorable treatment responses than those described in adults.</p>

DOI

10.1186/s40364-016-0069-0

Alternate Title

Biomark Res

PMID

27453784

Title

Atypical Chronic Myeloid Leukemia in Two Pediatric Patients.

Year of Publication

2016

Number of Pages

156-9

Date Published

2016 Jan

ISSN Number

1545-5017

Abstract

<p>Atypical chronic myeloid leukemia, BCR-ABL1-negative, (aCML) is a rare myeloid neoplasm. Recent adult data suggest the leukemic cells in a subset of patients are dependent on JAK/STAT signaling and harbor CSF3R-activating mutations. We hypothesized that, similar to adult patients, the presence of CSF3R-activating mutations would be clinically relevant in pediatric myeloid neoplasms as patients would be sensitive to the JAK inhibitor, ruxolitinib. We report two cases of morphologically similar pediatric aCML, BCR-ABL1-negative based on WHO 2008 criteria. One patient had CSF3R-activating mutation (T618I) and demonstrated a robust response to ruxolitinib, which was used to bridge to a successful stem cell transplant. The other patient did not have a CSF3R-activating mutation and succumbed to refractory disease &lt;6 months from diagnosis. This report documents CSF3R-T618I in pediatric aCML and demonstrates the efficacy of ruxolitinib in a pediatric malignancy. As the third documented case successfully treating aCML with ruxolitinib, this case highlights the importance of prompt CSF3R sequencing analysis for myeloproliferative and myelodysplastic/myeloproliferative neoplasms. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.</p>

DOI

10.1002/pbc.25694

Alternate Title

Pediatr Blood Cancer

PMID

26274939

Title

CLL/SLL diagnosed in an adolescent.

Year of Publication

2014

Number of Pages

1107-10

Date Published

2014 Jun

ISSN Number

1545-5017

Abstract

<p>Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a disease of older adults. Pediatric CLL/SLL is vanishingly rare in the literature. We present a case of CLL/SLL diagnosed in a 17-year-old male. The pathologic findings of this case were those of classic CLL/SLL with an ATM deletion, a characteristic genetic abnormality in CLL/SLL. Management guidelines for CLL/SLL are tailored to older adults making determination of the optimal therapy for this patient a unique challenge.</p>

DOI

10.1002/pbc.24884

Alternate Title

Pediatr Blood Cancer

PMID

24281971

Title

Acquired isochromosome 12p, somatic TP53 and PTEN mutations, and a germline ATM variant in an adolescent male with concurrent acute megakaryoblastic leukemia and mediastinal germ cell tumor.

Year of Publication

2014

Number of Pages

153-9

Date Published

2014 Apr

ISSN Number

2210-7762

Abstract

<p>Previous reports have described an association between hematologic malignancies (HMs) and extragonadal germ cell tumor (GCT). Most patients have been adolescent males with mediastinal nonseminomatous GCT. Although a variety of HMs have been reported, there is a striking predilection toward acute megakaryoblastic leukemia (AMKL). Shared cytogenetic anomalies--particularly isochromosome 12p [i(12p)]--have suggested common clonal origins to the tumors. We report the case of a 17-year-old boy presenting with AMKL and a synchronous mediastinal GCT, with the characteristic i(12p) in both neoplasms. The common clonal origin of the AMKL and GCT was further confirmed with massively parallel sequencing, which identified somatic TP53 and PTEN mutations, as well as a rare germline ATM variant. Although these represent commonly mutated genes in cancer, this combination of mutations is not typically associated with either GCT or AMKL, suggesting that these tumors may represent unique biologic entities when they co-occur.</p>

DOI

10.1016/j.cancergen.2014.03.009

Alternate Title

Cancer Genet

PMID

24831771

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