Sir Peter MacCallum Department of Oncology - Research Publications

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    Real-world utility of early measurable residual disease assessments by multi-parametric flow cytometry in adult patients with B-lymphoblastic leukemia receiving Hyper-CVAD induction chemotherapy
    Nedumannil, R ; Ritchie, D ; Bajel, A ; Ng, AP ; Harrison, SJ ; Westerman, D (WILEY, 2023-02)
    Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p = .426) or overall survival (OS) (p = .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p = ·005) and OS (p = .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.
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    Evaluation of T-cell clonality by anti-TRBC1 antibody-based flow cytometry and correlation with T-cell receptor sequencing
    Nguyen, PC ; Nguyen, T ; Wilson, C ; Tiong, IS ; Baldwin, K ; Nguyen, V ; Came, N ; Blombery, P ; Westerman, DA (WILEY, 2024-03)
    Flow cytometry (FC) incorporating the T-cell receptor β constant chain-1 (TRBC1) has been recently proposed as a new standard in T-cell clonality assessment. While early studies demonstrated high sensitivity in samples with conspicuous tumour burden, performance in real-world samples, including those with low tumour burden and correlation with molecular methods has been limited. We evaluated TRBC1-FC performance and correlated the results with high-throughput TRB sequencing and a targeted next-generation sequencing gene panel. Our cohort consisted of 90 evaluable samples from 57 patients. TRBC1-FC confirmed T-cell clonality in 37 out of 38 samples (97%) that were involved in a mature T-cell neoplasm (MTCN). T-cell clonality was also identified in nine samples from patients lacking a current or prior diagnosis of MTCN, consistent with the emerging entity T-cell clonality of uncertain significance. TRBC-FC was polyclonal in all samples and negative for disease involvement by standard pathology assessment. However, correlation with TRB sequencing in 17 of these samples identified two cases that harboured the known clonal sequence from index testing, indicating the presence of measurable residual disease not otherwise detected. Our study provides real-world correlative validation of TRBC1-FC, highlighting the strengths and limitations pertinent to its increasing implementation by general diagnostic laboratories.
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    Identification errors in medical research: Privacy at all costs?
    Rickard, JA ; Rogers, T-M ; Westerman, DA ; Carolan, C ; Fox, SB (ELSEVIER SCIENCE INC, 2023-07)
    In laboratory medicine, a misidentified patient sample can lead to an incorrect tissue diagnosis, a potentially fatal blood transfusion error or other serious adverse events. Although well characterised in routine patient care, the overall impacts of misidentification errors in the clinical research setting are less conspicuous but potentially greater, with downstream effects that may extend beyond care at an individual level. When data discrepancies or queries arise in clinical trial data then a data clarification form (DCF) is issued to the researcher by the overseeing trial coordinator or sponsor. Higher rates of DCF's are sometimes used as a crude surrogate marker of poorer trial quality. However, data is scarce on misidentification rates in clinical trials. In five clinical trials involving 822 histology or blood specimens analysed by our pathology department, DCF's were issued for 21% (174) of specimens. Amongst these 67% (117 / 174) were related to sample identification. Although these errors were recognised before data was compromised or an adverse event occurred, they highlight an alarming lack of stringency of use of patient identifiers in the research setting. We therefore propose the use of an appropriate number of de-identified data points and a formalised specimen accession process as employed in routine care to mitigate misidentification errors and their impact in clinical research. Increased recognition in the research community of the likely effect of truncating or reducing the number of patient identifiers is needed to minimise misidentification errors in the research setting.
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    Health economic evidence for the use of molecular biomarker tests in hematological malignancies: A systematic review
    Vu, M ; Degeling, K ; Thompson, ER ; Blombery, P ; Westerman, D ; IJzerman, MJ (WILEY, 2022-06)
    OBJECTIVES: Molecular biomarker tests can inform the clinical management of genomic heterogeneous hematological malignancies, yet their availability in routine care largely depends on the supporting health economic evidence. This study aims to systematically review the economic evidence for recent molecular biomarker tests in hematological malignancies. METHODS: We conducted a systematic search in five electronic databases for studies published between January 2010 and October 2020. Publications were independently screened by two reviewers. Clinical study characteristics, economic methodology, and results were extracted, and reporting quality was assessed. RESULTS: Fourteen studies were identified, of which half (n = 7; 50%) were full economic evaluations examining both health and economic outcomes. Studies were predominantly conducted in a first-line treatment setting (n = 7; 50%) and adopted a non-lifetime time horizon to measure health outcomes and costs (n = 7; 50%). Five studies reported that companion diagnostics for associated therapies were likely cost-effective for acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, and multiple myeloma. Four studies suggested molecular biomarker tests for treatment monitoring in chronic myeloid leukemia were likely cost-saving. CONCLUSIONS: Although there is initial confirmation of the promising health economic results, the present research for molecular biomarker tests in hematological malignancies is sparse with many applications of technological advances yet to be evaluated.
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    Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors
    Thompson, ER ; Nguyen, T ; Kankanige, Y ; Markham, JF ; Anderson, MA ; Handunnetti, SM ; Thijssen, R ; Yeh, PS-H ; Tam, CS ; Seymour, JF ; Roberts, AW ; Westerman, DA ; Blombery, P (ELSEVIER, 2022-01-25)
    The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each individual disease context.
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    Detection of clinically relevant early genomic lesions in B-cell malignancies from circulating tumour DNA using a single hybridisation-based next generation sequencing assay
    Blombery, PA ; Ryland, GL ; Markham, J ; Guinto, J ; Wall, M ; McBean, M ; Jones, K ; Thompson, ER ; Cameron, DL ; Papenfuss, AT ; Prince, MH ; Dickinson, M ; Westerman, DA (WILEY, 2018-10)
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    Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL
    Blombery, P ; Lew, TE ; Dengler, MA ; Thompson, ER ; Lin, VS ; Chen, X ; Nguyen, T ; Panigrahi, A ; Handunnetti, SM ; Carney, DA ; Westerman, DA ; Tam, CS ; Adams, JM ; Wei, AH ; Huang, DCS ; Seymour, JF ; Roberts, AW ; Anderson, MA (AMER SOC HEMATOLOGY, 2022-02-24)
    The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
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    Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition
    Lew, TE ; Lin, VS ; Cliff, ER ; Blombery, P ; Thompson, ER ; Handunnetti, SM ; Westerman, DA ; Kuss, BJ ; Tam, CS ; Huang, DCS ; Seymour, JF ; Roberts, AW ; Anderson, MA (ELSEVIER, 2021-10-26)
    Covalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.
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    Characterization of a novel venetoclax resistance mutation (BCL2 Phe104Ile) observed in follicular lymphoma
    Blombery, P ; Birkinshaw, RW ; Nguyen, T ; Gong, J-N ; Thompson, ER ; Xu, Z ; Westerman, DA ; Czabotar, PE ; Dickinson, M ; Huang, DCS ; Seymour, JF ; Roberts, AW (WILEY, 2019-09)
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    Quantitation of CMV Specific T-Cell Expansion Using T Cell Receptor Beta Locus Deep Sequencing to Identify Patients at Risk of Viral Complications
    Kuzich, JA ; Kankanige, Y ; Guinto, J ; Ryland, G ; McBean, M ; Thompson, E ; Wong, E ; Koldej, R ; Collins, J ; Westerman, D ; Ritchie, DS ; Blombery, P (ELSEVIER SCIENCE INC, 2020-03)