Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Roberts, Andrew × End date: 2020 × Start date: 2020 ×

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    Immune recovery in patients with mantle cell lymphoma receiving long-term ibrutinib and venetoclax combination therapy
    Davis, JE ; Handunnetti, SM ; Ludford-Menting, M ; Sharpe, C ; Blombery, P ; Anderson, MA ; Roberts, AW ; Seymour, JF ; Tam, CS ; Ritchie, DS ; Koldej, RM (AMER SOC HEMATOLOGY, 2020-10-13)
    Combination venetoclax plus ibrutinib for the treatment of mantle cell lymphoma (MCL) has demonstrated efficacy in the relapsed or refractory setting; however, the long-term impact on patient immunology is unknown. In this study, changes in immune subsets of MCL patients treated with combination venetoclax and ibrutinib were assessed over a 4-year period. Multiparameter flow cytometry of peripheral blood mononuclear cells showed that ≥12 months of treatment resulted in alterations in the proportions of multiple immune subsets, most notably CD4+ and CD8+ effector and central memory T cells and natural killer cells, and normalization of T-cell cytokine production in response to T-cell receptor stimulation. Gene expression analysis identified upregulation of multiple myeloid genes (including S100 and cathepsin family members) and inflammatory pathways over 12 months. Four patients with deep responses stopped study drugs, resulting in restoration of normal immune subsets for all study parameters except myeloid gene/pathway expression, suggesting long-term combination venetoclax and ibrutinib irreversibly affects this population. Our findings demonstrate that long-term combination therapy is associated with immune recovery in MCL, which may allow responses to subsequent immunotherapies and suggests that this targeted therapy results in beneficial impacts on immunological recovery. This trial was registered at www.clinicaltrials.gov as #NCT02471391.
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    Undetectable peripheral blood MRD should be the goal of venetoclax in CLL, but attainment plateaus after 24 months
    Lew, TE ; Anderson, MA ; Lin, VS ; Handunnetti, SM ; Came, NA ; Blombery, P ; Westerman, DA ; Wall, M ; Tam, CS ; Roberts, AW ; Seymour, JF (ELSEVIER, 2020-01-14)
    The highly selective BCL2 inhibitor venetoclax achieves deep responses in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including undetectable minimal residual disease (uMRD). We retrospectively reviewed 62 patients with CLL treated with venetoclax to investigate the performance of peripheral blood (PB) compared with bone marrow (BM) assessment of MRD; the kinetics, clinicopathological associations, and longer-term outcomes of uMRD attainment and recrudescence; and the ability of venetoclax dose escalation to deepen responses. Among 16 patients who achieved PB uMRD and had contemporaneous BM assessments, 13 (81%) had confirmed BM uMRD, and patients with PB uMRD had outcomes at least as favorable as those with BM uMRD for time to progression, overall survival, and MRD recrudescence. Excluding 2 patients lacking earlier assessment, the median time to PB uMRD was 18 (range, 5-26) months, with 90% of instances achieved by 24 months. There was no new PB uMRD attainment after 24 months without treatment intensification. The dominant association with earlier attainment of uMRD was concurrent rituximab (P = .012). Complex karyotype was associated with inferior uMRD attainment after 12 months of therapy (P = .015), and patients attaining uMRD whose disease harbored TP53 abnormalities demonstrated a trend toward earlier recrudescence (P = .089). Of patients who received venetoclax dose escalations, 4 (27%) of 15 achieved improvements in response. For patients with R/R CLL receiving venetoclax, PB uMRD commonly correlates with BM uMRD and is associated with a comparable longer-term prognosis. Concurrent rituximab augments uMRD attainment, but dose escalation and further treatment beyond 24 months infrequently deepen responses.
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    Differential effects of BTK inhibitors ibrutinib and zanubrutinib on NK-cell effector function in patients with mantle cell lymphoma
    Flinsenberg, TWH ; Tromedjo, CC ; Hu, N ; Liu, Y ; Guo, Y ; Thia, KYT ; Noori, T ; Song, X ; Aw Yeang, HX ; Tantalo, DG ; Handunnetti, S ; Seymour, JF ; Roberts, AW ; Ritchie, D ; Koldej, R ; Neeson, PJ ; Wang, L ; Trapani, JA ; Tam, CS ; Voskoboinik, I (FERRATA STORTI FOUNDATION, 2020-01-31)