About

Thomas B. Alexander, MD, MPH, is an associate professor in the Department of Pediatrics at UNC-Chapel Hill and a member of the UNC Lineberger Comprehensive Cancer Center. His research combines cancer genomic sequencing with early phase clinical trials to enhance understanding of disease response dynamics and improve outcomes in childhood leukemia and other hematological malignancies. Dr. Alexander's primary focus is on developing resource-appropriate diagnostic techniques for pediatric cancer in low- and middle-income countries (LMIC), where over 80% of children with cancer are diagnosed, yet access to diagnostic technologies remains limited, resulting in low survival rates. He is advancing innovative, cost-effective sequencing approaches, including Nanopore sequencing, to expand global access to comprehensive pediatric cancer diagnostics, initially focusing on leukemia and expanding to pediatric solid tumors. His work involves technical and computational development, implementation science through international collaborations, and partnerships with researchers at UNC, St. Jude Children's Research Hospital, and teams in Malawi, Pakistan, Uganda, Brazil, and India. Additionally, Dr. Alexander participates in clinical trial development and leadership within pediatric oncology networks, including serving as the site principal investigator for the Children's Oncology Group at UNC, where he oversees multiple active trials aimed at improving therapy for children with acute leukemia.

Research topics

• Medicine
• Internal medicine
• Oncology
• Immunology
• Biology
• Cancer research
• Physics

Selected publications

• From blueprint to biobank: Leveraging expert recommendations for implementing change (ERIC) to pediatric cancer biobanking in Pakistan

  PLoS ONE · 2025-05-16 · 2 citations

  articleOpen access

  BACKGROUND: In low- and middle-income countries, limited infrastructure and resources hinder biobank establishment, affecting specimen diversity. Addressing this gap is crucial for equitable health outcomes, as current databases are skewed towards Northern-European populations. In Pakistan, pediatric cancer biobanks are non-existent. Indus Hospital & Health Network (IHHN) in Karachi, with its large pediatric cancer unit, aims to establish a biobank to address region-specific pediatric cancer research needs. This manuscript describes the biobank implementation process using implementation science frameworks. METHODS: The pediatric cancer biobank at IHHN collects FFPE specimens for solid tumors, and isolated mononuclear cells from peripheral blood and bone marrow of suspected acute leukemia. Implementation planning workgroups included clinicians, EMR, IT, management, senior leadership, IRB, and external support from UNC and St. Jude Children's Cancer Hospital. The selection of applicable ERIC (Expert Recommendations for Implementing Change) strategies through stakeholder workgroups considered scope, budget, and feasibility, and context. Standard protocols from ISBER and BCNet guided alignment with best practices. IHHN's past experiences and tacit knowledge gained through rapid, successful implementation also facilitated strategy selection. The EPIS framework (exploration, preparation, implementation, sustainment) was used to map and organize the selected intervention strategies. RESULTS: Biobank implementation at IHHN, organized by EPIS stages, has been described through a set of 41 implementation strategies. Of these, 34 were selected out of 73 originally published ERIC strategies, while 7 were added based on contextually based workgroup consensus. 599 acute leukemia and 1137 solid tumor specimens have been banked since inception of the biobank operations 2 years earlier. The implementation activities and challenges described include infrastructure, swift specimen collection, prior to treatment, and informed consent. The ancillary processes including training and quality control have also been described and related data presented. CONCLUSION: The implementation of Pakistan's first acute leukemia biobank using ERIC and EPIS frameworks offers a structured approach beneficial for settings with limited biobanking experience. This intervention aligns with recognized implementation science frameworks, while addressing aspects pertinent in low- and middle-income countries.

  PublisherDOI

• SAFETY AND EFFICACY OF PERCUTANEOUS TRANSCATHETER EDGE-TO-EDGE MITRAL VALVE REPAIR FOR FUNCTIONAL MITRAL REGURGITATION IN HEART FAILURE: A META-ANALYSIS

  Journal of the American College of Cardiology · 2025-03-29

  articleOpen accessSenior author
  PublisherDOI

• Editorial: Global approaches to molecular diagnostics for pediatric cancer

  Frontiers in Oncology · 2025-03-06

  editorialOpen accessSenior authorCorresponding

  During conversations with nearly every parent of a child with cancer, oncologists must acknowledge the uncertainty about whether a child’s cancer will respond to the treatment prescribed. Our prognostic abilities have improved in settings where molecular testing is available, but crippling uncertainty about treatment response remains, emphasizing the depth of biology that we have yet to uncover. In this research topic, we present articles that cover a range of research types, each relying on molecular diagnostic approaches, to work toward better tools and knowledge for clinicians and their patients.For extremely rare tumors and presentations, case reports with literature reviews offer initial suggestions of natural history, prognosis, and molecular alterations. Pellegrino et al demonstrate this through a case report of malignant ectomesenchymoma, calling attention to the frequency of HRAS mutations (in this instance found through whole exome sequencing) in this biphenotypic tumor type with features of mesenchymal and neuroectodermal elements. In a similar type of report, Ogawa et al describe an unusual case of an atypical lipomatous tumor, with the diagnosis supported by the identification of MDM2 amplification on fluorescence in situ hybridization. In both cases, molecular findings support the final diagnosis. However, the molecular results are not required to complete the diagnosis, and are not fully specific for each diagnosis, highlighting the challenge for pathologists to determine appropriate molecular evaluations for various pediatric tumors. The next set of articles focuses on molecular-based translational research, assessing potential prognostic markers and cancer vulnerabilities. Braghini et al present research that relies on knowledge of potential therapeutic targets in hepatocellular carcinoma to explore similar pathways in hepatoblastoma. Their early in vitro data suggest that overexpression and activation of focal adhesin kinase (FAK) occurs in hepatoblastoma, and inhibition of this pathway can slow proliferation and induce apoptosis of cell lines. This early work must be followed by expanded research with larger cohorts of hepatoblastoma and in vivo models. Other efforts to explore new biomarkers of prognosis and targets focus exosomes and telomere biology. Bhavsar et al presents a review describing recent progress in understanding and exploiting exosomes in tumor biology. With a focus on neuroblastoma, the authors emphasize the growing literature utilizing exosomes as potential circulating biomarkers and therapeutic vehicles for precision tumor treatment and vaccination. Similarly, Burrow et al summarize data about telomere biology as potential prognostic markers with potential therapeutic implications. Using a highly sensitive rtPCR-based C-circle assay (CCA) to detect alternative lengthening of telomeres (ALT), they characterize the prevalence and clinicopathological association of ALT in pediatric sarcomas.For most cancer types, molecular testing is required for complete clinical classification to inform prognosis and therapeutic decision-making. Even so, questions about the “what” and “how” of molecular testing for clinical care are complex. What technical assay should be used with which computational algorithm? How can the global community commit to equitable access of molecular diagnostic tools? The last two articles in this collection speak to some of these implementation challenges.Skitchenko et al highlight the analytical challenges of nontargeted genomic sequencing. They assessed germline predisposition to cancer for a child with medulloblastoma. They used whole exome sequencing results taken through two different analytical pipelines. The pipelines provided discrepant clinically relevant results, based upon computational differences as opposed to any technical concerns about the sequencing. While their case description does not provide a solution to the challenge of implementation of computational tools, they shine an important light on the need for ongoing expert discussion to determine necessary validation steps for computationally heavy diagnostic assays.Finally, Gastier-Foster et al demonstrated the potential of the NanoString nCounter system as a targeted fusion detection approach for acute leukemia in Malawi. They demonstrate that this technology can be utilized in a low-income country and that it would provide clinically important diagnostic information beyond the current standard of care testing. Their work is an important contribution to efforts to overcome diagnostic limitations in resource-limited settings. These findings also raise two critical challenges in the implementation of advanced molecular testing specific to low-resource settings: How should molecular tests be validated locally when the “truth” of the sample is not available? How do we consider the scalability and sustainability of a new test at the outset of clinical validation?The collection of papers in this research collection shows exciting progress ranging from improved molecular description of exceedingly rare tumors to identification of additional biomarkers with potential for future clinical use to advancing the conversations about clinical use of new molecular assays and analytic tools. Ongoing needs from the community of pediatric cancer researchers, pathologists, and hospital administrators include (1) continued identification of molecular biomarkers for risk stratification and identification of therapeutic vulnerabilities, (2) development of rational recommendations for clinical molecular testing for different tumor types, potentially with resource-adapted guidance, and (3) a global commitment to implementation of molecular testing across different resource settings.

  PublisherOA PDFDOI

• Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukemia: A multi-center phase II expansion study

  Blood · 2025-11-03

  article

  Abstract Background: The prognosis for pediatric patients with relapsed or refractory acute myeloid leukemia (AML) remains poor, with 5-year survival rates of approximately 35%. Venetoclax, a selective BCL-2 inhibitor has been approved for use in adults unfit for intensive therapy and has shown promise in phase I pediatric data. However, limited published pediatric data are available. Methods: This multicenter Phase I/II trial (NCT03194932) combined venetoclax with cytarabine, with or without idarubicin or azacitidine, in pediatric patients with relapsed/refractory AML. Venetoclax was administered at the recommended phase II dose (RP2D; 360 mg/m2 daily) alongside conventional chemotherapy starting on day 8, including 1,000 mg/m2of cytarabine with or without 12 mg/m2of idarubicin for patients with limited prior anthracycline exposure, and/or azacitidine 75 mg/m2for 7 days. BH3 profiling was conducted to assess anti-apoptotic dependencies. Primary endpoints included safety and clinical response at the end of cycle 1. Secondary endpoints assessed response to venetoclax monotherapy and the correlation of BH3 profiling to treatment response. Results: Results of the phase I portion of this study have been previously published and showed that all dose levels were well tolerated. Venetoclax 360 mg/m2 (max 600 mg) with high-dose cytarabine (HDAC), with or without idarubicin or azacitidine, was identified as the RP2D. Forty of 45 participants treated at the RP2D were evaluable for response. After cycle 1, 25 (62.5%) participants achieved a complete response (CR), with 20/25 becoming minimal residual disease (MRD)-negative. Participants with favorable genetic profiles had the highest CR rate (7/8; 87.5%), while those with adverse genetic alterations including FLT3, TP53, and WT1 mutations, demonstrated variable responses. Among participants refractory to prior therapy, 6/11 (54.5%) achieved CR, with one additional partial response. Of four primary refractory participants, one achieved CR and another a partial response. The most common grade 3-4 adverse events included febrile neutropenia (32.8%), infections (20.9%), and gastrointestinal disorders (16.4%). A 50% reduction in peripheral blast count during venetoclax monotherapy was associated with a higher likelihood of CR with or without count recovery at the end of cycle 1 (18/23 [78.3%] vs 2/8 [25.0%], p=0.022). One treatment-related death occurred due to colitis and sepsis. BH3 profiling identified BCL-2 dependence in 23 patients but did not strongly predict response differences (p=0.266). Conclusion: Venetoclax combined with high-dose cytarabine-containing conventional chemotherapy was well-tolerated and active against pediatric relapse/refractory AML. A good response to venetoclax monotherapy therapy predicted complete response to combination therapy. These findings support further investigation of venetoclax-based regimens in this patient population, including the ongoing randomized pediatric phase 3 APAL2020D trial, which uses a backbone containing high-dose cytarabine and fludarabine.

  PublisherDOI

• Acute Leukemia Classification Using Transcriptional Profiles From Low-Cost Nanopore mRNA Sequencing

  UNC Libraries · 2025-10-11

  articleOpen access

  PURPOSE: Most cases of pediatric acute leukemia occur in low- and middle-income countries, where health centers lack the tools required for accurate diagnosis and disease classification. Recent research shows the robustness of using unbiased short-read RNA sequencing to classify genomic subtypes of acute leukemia. Compared with short-read sequencing, nanopore sequencing has low capital and consumable costs, making it suitable for use in locations with limited health infrastructure. MATERIALS AND METHODS: We show the feasibility of nanopore mRNA sequencing on 134 cryopreserved acute leukemia specimens (26 acute myeloid leukemia [AML], 73 B-lineage acute lymphoblastic leukemia [B-ALL], 34 T-lineage acute lymphoblastic leukemia, and one acute undifferentiated leukemia). Using multiple library preparation approaches, we generated long-read transcripts for each sample. We developed a novel composite classification approach to predict acute leukemia lineage and major B-ALL and AML molecular subtypes directly from gene expression profiles. RESULTS: We demonstrate accurate classification of acute leukemia samples into AML, B-ALL, or T-lineage acute lymphoblastic leukemia (96.2% of cases are classifiable with a probability of > 0.8, with 100% accuracy) and further classification into clinically actionable genomic subtypes using shallow RNA nanopore sequencing, with 96.2% accuracy for major AML subtypes and 94.1% accuracy for major B-lineage acute lymphoblastic leukemia subtypes. CONCLUSION: Transcriptional profiling of acute leukemia samples using nanopore technology for diagnostic classification is feasible and accurate, which has the potential to improve the accuracy of cancer diagnosis in low-resource settings.

  PublisherDOI

• Pediatric ALL Treatment Modifications in Low- and Middle-Income Countries: A Systematic Review

  JCO Global Oncology · 2025-12-01 · 1 citations

  articleOpen access

  PURPOSE For children with ALL in low- and middle-income countries (LMICs), treatment regimen adaptation based on local contexts is often necessary. However, the clinical impact of such modifications is poorly understood. The purpose of this study is to examine pediatric ALL treatment regimens used in LMICs, assess for patterns in adaptation to identify common barriers affecting global delivery of ALL care, and describe the breadth of outcomes. METHODS Using the PRISMA guidelines, a systematic review was conducted, across seven databases, of ALL regimens use in LMICs in 2000-2021, documenting the geographic distribution of treatment backbone adoption, regimen modifications, and outcomes. Article characteristics were summarized using descriptive statistics. RESULTS Of 13,900 articles, 125 met abstraction criteria. Data spanned 36 countries (6.4% low-income, 43.2% lower-middle–income, 50.4% upper-middle–income) and 163 regimens, of which 138 (84.6%) referenced a high-income ALL collaborative group regimen as a backbone. Sixty-four percent of regimens (n = 104) were adapted. Individual modifications (n = 390) were consolidated into 73 distinct regimen changes; reduction/omission of high-dose methotrexate, observed in 30 modified regimens (28.8%), was the most common. Implementation challenges, such as drug access and cost, were cited more frequently than toxicity as the rationale for modification; however, implementation outcomes (eg, feasibility, cost) were only measured in 6.4% of articles. Across all outcomes, 5-year overall survival was higher with modified versus unmodified regimens ( P = .030). CONCLUSION Although implementation barriers are primary drivers of ALL regimen adaptations globally, the paucity of reported implementation outcomes represents a methodological gap in the literature. Incorporating implementation science methods and frameworks is critical for the timely and effective delivery of innovative treatment regimens across resource settings.

  PublisherDOI

• Facilitators and Barriers for Implementing Diagnostic Sequencing Technology for Pediatric Oncology in Low- and Middle-Income Countries

  2025-09-01

  articleOpen access

  Background : Inaccurate or imprecise diagnosis is a major contributor to treatment failure for children with cancer in low- and middle-income countries (LMICs). Sequencing-based diagnostic testing presents an opportunity to overcome diagnostic deficiencies. It is important to identify facilitators and barriers which are common to the implementation of sequencing-based diagnostics in LMICs. Procedure : Pediatric oncology research collaborators at six hospitals in LMICs were invited to participate in the study. Snowball sampling identified additional participants. Thirty-nine virtual, semi-structured interviews were conducted using interview guides informed by the Consolidated Framework for Implementation Research (CFIR) with suggested adaptations for LMICs. Rapid qualitative analysis was conducted to identify facilitators and barriers to the implementation of diagnostic sequencing for pediatric cancers. Barriers were then matched with Expert Recommendation for Implementation Change (ERIC) strategies. Results : Implementation facilitators and barriers were organized by CFIR construct. Predominant facilitators were relative advantage, culture, collective efficacy, self-efficacy, patient needs and resources, leadership engagement, knowledge and beliefs, tension for change, monitoring services for action, and implementation climate. Key barriers to implementation were cost, available resources, resource continuity, engaging participants, and resource source. Conclusions : Participants communicated that the lack of diagnostic classification for pediatric cancer in LMICs is a common key limitation to current cancer care. They described considerable motivating strengths to leverage towards this goal of developing sequencing-based diagnostic testing capacity. Resource availability, continuity, and sustainment are current barriers that must be addressed. Our data highlights the urgent need for creative global implementation partnerships as many centers in LMICs are poised to advance novel diagnostic solutions.

  PublisherOA PDFDOI

• From blueprint to biobank: Leveraging expert recommendations for implementing change (ERIC) to pediatric cancer biobanking in Pakistan

  UNC Libraries · 2025-06-03

  articleOpen access1st authorCorresponding

  BACKGROUND: In low- and middle-income countries, limited infrastructure and resources hinder biobank establishment, affecting specimen diversity. Addressing this gap is crucial for equitable health outcomes, as current databases are skewed towards Northern-European populations. In Pakistan, pediatric cancer biobanks are non-existent. Indus Hospital & Health Network (IHHN) in Karachi, with its large pediatric cancer unit, aims to establish a biobank to address region-specific pediatric cancer research needs. This manuscript describes the biobank implementation process using implementation science frameworks. METHODS: The pediatric cancer biobank at IHHN collects FFPE specimens for solid tumors, and isolated mononuclear cells from peripheral blood and bone marrow of suspected acute leukemia. Implementation planning workgroups included clinicians, EMR, IT, management, senior leadership, IRB, and external support from UNC and St. Jude Children's Cancer Hospital. The selection of applicable ERIC (Expert Recommendations for Implementing Change) strategies through stakeholder workgroups considered scope, budget, and feasibility, and context. Standard protocols from ISBER and BCNet guided alignment with best practices. IHHN's past experiences and tacit knowledge gained through rapid, successful implementation also facilitated strategy selection. The EPIS framework (exploration, preparation, implementation, sustainment) was used to map and organize the selected intervention strategies. RESULTS: Biobank implementation at IHHN, organized by EPIS stages, has been described through a set of 41 implementation strategies. Of these, 34 were selected out of 73 originally published ERIC strategies, while 7 were added based on contextually based workgroup consensus. 599 acute leukemia and 1137 solid tumor specimens have been banked since inception of the biobank operations 2 years earlier. The implementation activities and challenges described include infrastructure, swift specimen collection, prior to treatment, and informed consent. The ancillary processes including training and quality control have also been described and related data presented. CONCLUSION: The implementation of Pakistan's first acute leukemia biobank using ERIC and EPIS frameworks offers a structured approach beneficial for settings with limited biobanking experience. This intervention aligns with recognized implementation science frameworks, while addressing aspects pertinent in low- and middle-income countries.

  PublisherDOI

• Real-time genomic characterization of pediatric acute leukemia using adaptive sampling

  Leukemia · 2025-03-24 · 17 citations

  articleOpen accessCorresponding

  Effective treatment of pediatric acute leukemia is dependent on accurate genomic classification, typically derived from a combination of multiple time-consuming and costly techniques such as flow cytometry, fluorescence in situ hybridization (FISH), karyotype analysis, targeted PCR, and microarrays [1-3]. We investigated the feasibility of a comprehensive single-assay classification approach using long-read sequencing, with real-time genome target enrichment, to classify chromosomal abnormalities and structural variants characteristic of acute leukemia. We performed whole genome sequencing on DNA from diagnostic peripheral blood or bone marrow for 57 pediatric acute leukemia cases with diverse genomic subtypes. We demonstrated the characterization of known, clinically relevant karyotype abnormalities and structural variants concordant with standard-of-care clinical testing. Subtype-defining genomic alterations were identified in all cases following a maximum of 48 h of sequencing. In 18 cases, we performed real-time analysis- concurrent with sequencing-and identified the driving alteration in as little as 15 min (for karyotype) or up to 6 h (for complex structural variants). Whole genome nanopore sequencing with adaptive sampling has the potential to provide genomic classification of acute leukemia specimens with reduced cost and turnaround time compared to the current standard of care.

  PublisherOA PDFDOI

• Nanopore Whole Transcriptome Sequencing Offers the Potential for Accessible Classification of Pediatric Cancers

  2025-07-14

  book-chapter1st authorCorresponding

  For patients diagnosed with cancer, classification of phenotype and genotype is critical for diagnostic accuracy, therapeutic decisions, and prognostic discussions. Single platform sequencing-based assays have the potential to provide comprehensive clinical diagnostic results. Currently developed approaches require high capital investment, which makes it inaccessible to most of the world. Oxford Nanopore Technologies’ (ONT) sequencing approaches offer financially accessible, scalable alternatives with lower capital cost, minimal infrastructure requirements, and straightforward library preparation protocols. While some of the most well studied and publicized benefits of ONT are related to long read capabilities, direct methylation calling, and use in agriculture or infectious disease, we have been developing ONT whole transcriptome sequencing (WTS) approaches for classification for acute leukemia, pediatric solid tumors, and pediatric lymphoma. This chapter describes technical and computational approaches using ONT across two areas of research in our lab: (1) WTS of fresh or frozen acute leukemia specimens and (2) WTS of FFPE stored lymphoma and solid tumor specimens.

  PublisherDOI

Frequent coauthors

• Jeffrey E. Rubnitz

  29 shared

• Charles G. Mullighan

  St. Jude Children's Research Hospital

  25 shared

• Norman J. Lacayo

  Stanford University

  22 shared

• John Choi

  14 shared

• Jessica Conradi

  Fraunhofer Institute for Communication, Information Processing and Ergonomics

  14 shared

• Ching‐Hon Pui

  St. Jude Children's Research Hospital

  14 shared

• Nickhill Bhakta

  St. Jude Children's Research Hospital

  13 shared

• Hiroto Inaba

  St. Jude Children's Research Hospital

  12 shared

Awards & honors

• R01 NIH Grant (2024-2029)
• R21 NIH Grant (2022-2024)
• Clinical Trialist Training Program Scholar (2022-2023)
• UNC K12 Oncology Grant (2021-2023)
• Carolina For The Kids Faculty Investigator Award (2020-2021)