Medicine (St Vincent's) - Research Publications

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    Zanubrutinib monotherapy in relapsed/refractory indolent non-Hodgkin lymphoma
    Phillips, T ; Chan, H ; Tam, CS ; Tedeschi, A ; Johnston, P ; Oh, SY ; Opat, S ; Eom, H-S ; Allewelt, H ; Stern, JC ; Tan, Z ; Novotny, W ; Huang, J ; Trotman, J (ELSEVIER, 2022-06-14)
    Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.
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    Indirect comparison of tisagenlecleucel and historical treatments for relapsed/refractory diffuse large B-cell lymphoma
    Maziarz, RT ; Zhang, J ; Yang, H ; Chai, X ; Yuan, C ; Schwarz, E ; Jakovac, M ; Martinez-Prieto, M ; Agarwal, A ; Degtyarev, E ; Tam, C ; Salles, G (ELSEVIER, 2022-04-26)
    No head-to-head trials have compared the efficacy of tisagenlecleucel vs historical treatments for adults with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study indirectly compared the overall survival (OS) and overall response rate (ORR) associated with tisagenlecleucel, using data from the JULIET study (Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients; #NCT02445248), vs historical treatments assessed in the CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study follow-up population. To assess treatment effects in the treated (full analysis set [FAS]) and enrolled (intention-to-treat [ITT]) study populations, the JULIET FAS vs the CORAL follow-up FAS and JULIET ITT vs CORAL follow-up ITT populations were separately compared. Propensity score weighting using standardized mortality ratio weight (SMRW) and fine stratification weight (FSW) was used to compare OS and ORR, adjusting for baseline confounders. The results indicated that tisagenlecleucel was associated with a lower hazard of death among the FAS (adjusted hazard ratio [95% confidence interval], both FSW and SMRW, 0.44 [0.32, 0.59]) and ITT populations (FSW, 0.60 [0.44, 0.77]; SMRW, 0.57 [0.44, 0.73]; all, P < .001). Median OS was 12.48 months (JULIET) vs 4.34 to 4.40 months (CORAL) for the FAS, and 8.25 (JULIET) months vs 4.04 to 4.86 (CORAL) months for the ITT populations. Tisagenlecleucel was associated with a significantly higher ORR compared with historical treatments among the FAS (adjusted response rate difference [95% confidence interval], both FSW and SMRW, 36% [22%, 0.48%]; P < .001) and among the ITT populations after SMRW adjustment (11% [0%, 22%]; P = .043). This analysis supports that improved response and OS are achieved in patients with r/r DLBCL treated with tisagenlecleucel compared with those treated with alternative historical treatments.
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    Impact of chronic lymphocytic leukaemia on melanoma outcomes: A retrospective case-control study
    Jobson, D ; McCormack, CJ ; Mar, V ; Tam, C ; Henderson, MA (WILEY, 2022-03-14)
    With new, effective treatments for chronic lymphocytic leukaemia (CLL) the impact of second malignancies is increasingly important. We performed a retrospective case-controlled study examining the effect of CLL and its treatment on melanoma-specific survival and recurrence. A total of 56 patients with melanoma with CLL were matched 1:1 to patients without CLL for age, date of diagnosis, gender and melanoma tumour, node, metastasis (TNM) stage. Multivariate analysis found CLL was associated with significantly worse melanoma-specific mortality (hazard ratio [HR] 2.46, 95% confidence interval [CI] 1.27-4.74, p = 0.007) and recurrence (HR 3.44, 95% CI 1.79-6.63, p < 0.001). Patients with CLL had poor immunotherapy tolerance and prior CLL treatment was not associated with melanoma outcomes.
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    Zanubrutinib for treatment-naive and relapsed/refractory chronic lymphocytic leukaemia: long-term follow-up of the phase I/II AU-003 study
    Cull, G ; Burger, JA ; Opat, S ; Gottlieb, D ; Verner, E ; Trotman, J ; Marlton, P ; Munoz, J ; Johnston, P ; Simpson, D ; Stern, JC ; Prathikanti, R ; Wu, K ; Novotny, W ; Huang, J ; Tam, CS (WILEY, 2021-12-16)
    The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.
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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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    Targeted Agents in the Treatment of Indolent B-Cell Non-Hodgkin Lymphomas.
    Minson, A ; Tam, C ; Dickinson, M ; Seymour, JF (MDPI AG, 2022-03-01)
    Targeted therapies continue to change the landscape of lymphoma treatment, resulting in improved therapy options and patient outcomes. Numerous agents are now approved for use in the indolent lymphomas and many others under development demonstrate significant promise. In this article, we review the landscape of targeted agents that apply to the indolent lymphomas, predominantly follicular lymphoma, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinaemia and marginal zone lymphoma. The review covers small molecule inhibitors, immunomodulators and targeted immunotherapies, as well as presenting emerging and promising combination therapies.
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    Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort
    Tam, CS ; Allan, JN ; Siddiqi, T ; Kipps, TJ ; Jacobs, R ; Opat, S ; Barr, PM ; Tedeschi, A ; Trentin, L ; Bannerji, R ; Jackson, S ; Kuss, BJ ; Moreno, C ; Szafer-Glusman, E ; Russell, K ; Zhou, C ; Ninomoto, J ; Dean, JP ; Wierda, WG ; Ghia, P (AMER SOC HEMATOLOGY, 2022-06-02)
    CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.
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    Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies
    Tam, CS ; Dimopoulos, M ; Garcia-Sanz, R ; Trotman, J ; Opat, S ; Roberts, AW ; Owen, R ; Song, Y ; Xu, W ; Zhu, J ; Li, J ; Qiu, L ; D'Sa, S ; Jurczak, W ; Cull, G ; Marlton, P ; Gottlieb, D ; Munoz, J ; Phillips, T ; Du, C ; Ji, M ; Zhou, L ; Guo, H ; Zhu, H ; Chan, WY ; Cohen, A ; Novotny, W ; Huang, J ; Tedeschi, A (ELSEVIER, 2022-02-22)
    Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.
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    Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenstrom's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study
    Buske, C ; Tedeschi, A ; Trotman, J ; Garcia-Sanz, R ; MacDonald, D ; Leblond, V ; Mahe, B ; Herbaux, C ; Matous, JV ; Tam, CS ; Heffner, LT ; Varettoni, M ; Palomba, ML ; Shustik, C ; Kastritis, E ; Treon, SP ; Ping, J ; Hauns, B ; Arango-Hisijara, I ; Dimopoulos, MA (LIPPINCOTT WILLIAMS & WILKINS, 2022-01-01)
    PURPOSE: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS: Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS: With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time. CONCLUSION: In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.
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    Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study
    Wierda, WG ; Allan, JN ; Siddiqi, T ; Kipps, TJ ; Opat, S ; Tedeschi, A ; Badoux, XC ; Kuss, BJ ; Jackson, S ; Moreno, C ; Jacobs, R ; Pagel, JM ; Flinn, I ; Pak, Y ; Zhou, C ; Szafer-Glusman, E ; Ninomoto, J ; Dean, JP ; James, DF ; Ghia, P ; Tam, CS (LIPPINCOTT WILLIAMS & WILKINS, 2021-12-01)
    PURPOSE: CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS: Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS: One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9]; P = .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION: The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.