Laura Pardo

Hospital Pedro de Elizalde

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Soheil Meshinchi

Fred Hutch Cancer Center

Michael R. Loken

Applied Biomathematics (United States)

Todd A. Alonzo

University of Southern California

Robert B. Gerbing

Children's Oncology Group

Rhonda E. Ries

Fred Hutch Cancer Center

Alan S. Gamis

Children's Mercy Hospital

Richard Aplenc

Children's Hospital of Philadelphia

Tiffany Hylkema

Fred Hutch Cancer Center

Lisa Eidenschink Brodersen

Children's Hospital of Philadelphia

Katherine Tarlock

Seattle Children's Hospital

Cooperative Institutions

Fred Hutch Cancer Center

University of Washington

Children's Oncology Group

Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa

Cancer Research Center

Seattle Children's Hospital

Hospital Universitari de Girona Doctor Josep Trueta

St. Jude Children's Research Hospital

Seattle University

University of British Columbia

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Transcriptome Profiling of Glycosylation Genes Defines Correlation with E-Selectin Ligand Expression and Clinical Outcome in AML

Blood (2019)

Amanda R. Leonti Laura Pardo Todd A. Alonzo Robert B. Gerbing Lisa Eidenschink Brodersen

Sialyl-Lewis X

10.1182/blood-2019-124525

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Citations (11)

CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group

Journal of Clinical Oncology (2021)

Adam J. Lamble Lisa Eidenschink Brodersen Todd A. Alonzo Jim J. Wang Laura Pardo

Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial (NCT01371981).AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels.The study population was divided into CD123 expression-based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk KMT2A rearrangements and FLT3-ITD mutations (P < .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and CEBPA mutations (P < .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% v 39%, P < .001), lower event-free survival (49% v 69%, P < .001), and lower overall survival (32% v 50%, P < .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis.CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.

Interleukin-3 receptor

Immunophenotyping

Quartile

Minimal Residual Disease

CEBPA

10.1200/jco.21.01595

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Citations (35)

Newly Diagnosed Childhood AML Patients Treated with Bortezomib Show Superior Survival If CD74 Is Expressed: A Report of 991 Patients from the Children's Oncology Group AAML1031 Protocol

Blood (2020)

Lisa Eidenschink Brodersen Chad A. Hudson Todd A. Alonzo Robert B. Gerbing Laura Pardo

10.1182/blood-2020-142659

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Citations (1)

Figure S2 from Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia

Katherine Tarlock Todd A. Alonzo Yi‐Cheng Wang Robert B. Gerbing Rhonda E. Ries

Supplemental Figure 2. Functional Evaluation and TKI response of E11 mutations. (A) Evaluation of the phosphorylation status of KIT following transfection of the mutations in exon 11, V559D and L576P, into HEK293 cell line. (B) IL-3 independent growth following transduction into Ba/F3 cells. (C) pKIT response following dasatinib exposure in HEK293 cell line transfected with E11 V559D mutation. (D) pKIT response following crenolanib exposure in HEK293 cell line transfected with E11 V559D mutation. (E) pKIT response following dasatinib exposure in HEK293 cell line transfected with E11 L576P mutation. (F) pKIT response following crenolanib exposure in HEK293 cell line transfected with E11 V559D mutation.

HEK 293 cells

10.1158/1078-0432.22473642.v1

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CD74 is expressed in a subset of pediatric acute myeloid leukemia patients and is a promising target for therapy: a report from the Children’s Oncology Group

Haematologica (2024)

Andrew J. Menssen Chad A. Hudson Todd A. Alonzo Robert B. Gerbing Laura Pardo

As curative therapies for pediatric acute myleoid leukemia (AML) remain elusive, identifying potential new treatment targets is vital. We assessed the cell surface expression of CD74, also known as the major histocompatibility complex-II invariant chain, by multidimensional flow cytometry in 973 patients enrolled in the Children’s Oncology Group AAML1031 clinical trial (clinicaltrials gov. Identifier: NCT01371981). Thirty-eight percent of pediatric AML patients expressed CD74 at any level and a comparison to normal hematopoietic cells revealed a subset with increased expression relative to normal myeloid progenitor cells. Pediatric AML patients expressing high intensity CD74 typically had an immature immunophenotype and an increased frequency of lymphoid antigen expression. Increased CD74 expression was associated with older patients with lower white blood cells and peripheral blood blast counts, and was enriched for t(8;21), trisomy 8, and CEBPA mutations. Overall, high CD74 expression was associated with low-risk status, however 26% of patients were allocated to high-risk protocol status and 5-year event-free survival was 53%, indicating that a significant number of high expressing patients had poor outcomes. In vitro preclinical studies indicate that anti-CD74 therapy demonstrates efficacy against AML cells but has little impact on normal CD34+ cells. Together, we demonstrate that CD74 is expressed on a subset of pediatric AML at increased levels compared to normal hematopoietic cells and is a promising target for therapy in expressing patients. Given that nearly half of patients expressing CD74 at high levels experience an adverse event within 5 years, and the availability of CD74 targeting drugs, this represents a promising line of therapy worthy of additional investigation.

CD74

Immunophenotyping

10.3324/haematol.2023.283757

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Citations (2)

Table S2 from Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia

Katherine Tarlock Todd A. Alonzo Yi‐Cheng Wang Robert B. Gerbing Rhonda E. Ries

Supplementary Table 2. Clinical outcomes for patients with CBF AML according to E17+ vs KIT- mutational status

10.1158/1078-0432.22473633.v1

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Citations (0)

Table S5 from Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia