Stephen Opat

• MBBS(HONS)
• Unit Head, Clinical Haematology at Monash University (Australia)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO...

Peripheral neuropathy (PN) is a significant cause of morbidity associated with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of zanubrutinib with ibrutinib in patients with WM. This ad hoc analysis examined treatment outcomes with zanubrutinib or ibrutinib on PN symptoms associated with WM in patients...

Introduction: The phase 1/2 AU-003 study (BGB-3111-AU-003; NCT02343120) evaluated zanubrutinib monotherapy in patients with various B-cell malignancies, including chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL). The phase 1b GA-101 study (NCT02569476) evaluated zanubrutinib in combination with obinutuzumab (ZO) for 6 cycles fo...

Introduction: BTK inhibitors (BTKi) have become a standard of care for WM. The ASPEN study (BGB-3111-302; NCT03053440) directly compared outcomes of treatment with zanubrutinib and ibrutinib in patients with MYD88-mutated WM in cohort 1; patients with MYD88-wild type WM received zanubrutinib in cohort 2. At end of study, eligible patients could enr...

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent disease with a median overall survival (OS) of more than 10 years, although a proportion of patients may develop aggressive histology transformation. In a previous report from this large, international dataset, the 10-year cumulative incidence of transformation was 17% (95% 13-21)...

Introduction: The combination of venetoclax, a BCL2 inhibitor, with ibrutinib, a BTK inhibitor, is effective in CLL/SLL, but their clinical use can be limited by toxicity. Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is a more selective and more pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and n...

Introduction: Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody-based systemic therapy are included within the preferred treatment algorithms for Waldenström macroglobulinemia (WM). However, to date, no treatments have been approved for patients with WM that are refractory to both BTK inhibitors and anti-CD20 therapy. Venetoclax, the f...

Introduction: BTKis are a mainstay of therapy for patients with WM, with most receiving continuous oral monotherapy for several years. While dosing is commonly interrupted, data on the impact of BTKi DIs on disease control remain limited. The phase 1/2 BGB-3111-AU-003 study (NCT02343120) evaluated zanubrutinib monotherapy in patients with B-cell ma...

Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale in...

Background: The combination of BCL2 and BTK inhibitors has shown synergistic activity. The combination of venetoclax, a BCL2 inhibitor, and ibrutinib, a BTK inhibitor, is an effective treatment for CLL/SLL. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency >10x that of venetoclax in biochemical assays. Zanubrutinib,...

Background & significance: Hypogammaglobulinemia is common in patients with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), and associated with an increased risk of serious infection. Immunoglobulin (Ig) replacement therapy (IgRT) is widely used to reduce this risk, but national guidelines and clinical prac...

Introduction Bruton's tyrosine kinase inhibitors (BTKi) have improved 1 st line therapy efficacy in elderly (Wang NEJM 2022) and young, fit, MCL-the latter with intermittent dosing during RCHOP in an alternating RCHOP/cytarabine-based regimen (Dreyling Blood 2022). However direct combination of BTKi & intensive chemo is toxic in DLBCL studies. (Kur...

Background: Marginal zone lymphoma (MZL) is an uncommon type of non-Hodgkin lymphoma (NHL) that is generally considered incurable, with most patients experiencing a relapse after remission. Development of novel MZL therapies that are effective and tolerable is needed. Sonrotoclax (BGB-11417) is a next-generation BH3 mimetic which binds and inhibits...

The primary analysis of MAGNOLIA, an open-label, single-arm, multicenter, phase 2 study, demonstrated that the next-generation Bruton tyrosine kinase inhibitor zanubrutinib provided a high overall response rate (ORR) in patients with relapsed/refractory marginal zone lymphoma (R/R MZL), with a favorable safety/tolerability profile. Presented here i...

Utilising tissue whole exome sequencing (WES) and circulating tumor cell-free DNA (ctDNA), this Australasian Leukaemia & Lymphoma Group (ALLG) translational study sought to characterise primary and acquired molecular determinants of response and resistance of MZL to zanubrutinib for patients treated on the MAGNOLIA clinical trial. WES was performed...

Background The association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival. Methods We conducted a population-based family case-cont...

Background Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are i...

Background The influence of early-life growth pattern and body size on follicular lymphoma (FL) risk and survival is unclear. In this study, we aimed to investigate the association between gestational age, growth during childhood, body size, changes in body shape over time, and FL risk and survival. Methods We conducted a population-based family c...

The association between smoking and alcohol consumption and follicular lymphoma (FL) incidence and clinical outcome is uncertain. We conducted a population-based family case-control study (709 cases: 490 controls) in Australia. We assessed lifetime history of smoking and recent alcohol consumption and followed-up cases (median = 83 months). We exam...

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 m...

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have heterogeneous outcomes; durable remissions are infrequently observed with standard approaches. Circulating tumor DNA (ctDNA) assessment is a sensitive, potentially prognostic tool in this setting. We assessed baseline ctDNA to identify patients with R/R DLBCL at high...

Polatuzumab vedotin plus bendamustine and rituximab (pola+BR) received regulatory approvals in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) based on primary results from the randomized arms of the GO29365 study. Following the randomized phase, 106 additional patients received pola+BR in a single-arm extension cohort. We report upda...

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 ibrut...

Purpose: Marginal zone lymphoma (MZL) is an uncommon non-Hodgkin lymphoma with malignant cells that exhibit a consistent dependency on B-cell receptor signaling. We evaluated the efficacy and safety of zanubrutinib, a next-generation selective Bruton tyrosine kinase inhibitor, in patients with relapsed/refractory (R/R) MZL. Experimental design:...

Introduction Bruton’s tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell lymphomas. Zanubrutinib was designed to achieve improved therapeutic concentrations and minimize off-target activities putatively accounting, in part, for the adverse effects seen with other BTK inhibitors. Areas covered : This drug profile covers za...

Zanubrutinib, a highly selective Bruton tyrosine kinase inhibitor, was evaluated in a phase 1/2 study in patients with various B-cell malignancies. In the subgroup of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), zanubrutinib was administered as 160 mg twice daily (n = 14), 320 mg once daily (n = 18), or ≤160 mg total dose (n...

Background: Infections are an important cause of morbidity and mortality in T-cell lymphomas. Factors contributing to increased risk of infection include the nature of the underlying disease, as well as treatment-associated immunosuppression. Currently there are few reports describing the types of infections, including preventable infections, in t...

7501 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line I+V in CLL. We previously reported results from the Minimal Residual Disease (MRD) cohort wherein undetectable MRD (uMRD) was achieved in over two-thirds of patients (pts) with 12 cycles of I+V, and 30-mo PFS rates were ≥95% irrespective of subsequent randomized tre...

Background Ferric carboxymaltose is increasingly utilised to treat iron deficiency and is usually diluted in saline and administered as an intravenous infusion over 15 minutes. Whilst this is highly convenient compared with older formulations, we hypothesised the drug could be administered safely given as a rapid bolus injection. Aims To define th...

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and m...

Background : Ibr is an established standard of care in CLL and is the only once-daily Bruton tyrosine kinase inhibitor with significant overall survival benefit in randomized phase 3 studies in first-line CLL (RESONATE-2; ECOG1912). The synergistic combination of Ibr + Ven (oral inhibitor of BCL2) has been shown to mobilize and clear CLL cells from...

Background: Tazemetostat, a first-in-class, oral, enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. Progression of disea...

Introduction Zanubrutinib is a highly specific, potent BTK inhibitor with minimal off-target inhibition of other kinases such as EGFR, JAK3, TEC and ITK. Zanubrutinib has shown 100% BTK occupancy, sustained over 24-hours, in both the peripheral blood and lymph node biopsies from patients treated at 160 mg twice daily and achieves durable responses...

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenström macroglobulinemi...

Introduction: Patient-derived data can increase breadth of knowledge in rare cancers like Waldenström's Macroglobulinemia (WM), including patient-reported outcomes (PROs). WhiMSICAL (Waldenström's Macroglobulinemia Study Involving CArt-wheeL) is the only global registry capturing patient-derived data for hypothesis generation in WM. Rapidly adaptab...

Background: Marginal zone lymphoma (MZL) is rare and heterogeneous and it has been difficult to define optimal therapeutic strategies. Like other indolent non-Hodgkin lymphomas, advanced stage disease is considered incurable, with most patients experiencing a continuing pattern of relapse and remission. MZL is typically dependent on B-cell receptor...

Introduction Early identification of patients (pts) with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) at high risk for treatment failure may allow for interventions to improve outcomes; however, known prognostic factors are inadequate. Circulating tumor DNA (ctDNA) has demonstrated the ability to identify previously untreated DL...

Introduction: Polatuzumab vedotin (Pola) is a novel antibody-drug conjugate targeting CD79b on B-cell non-Hodgkin lymphoma. In the randomized cohort of GO29365, a Phase [Ph] Ib/II study (NCT02257567; data cut-off: April 30, 2018), Pola plus bendamustine and rituximab (Pola+BR) improved progression-free survival (PFS) and overall survival (OS) compa...

Background Activating mutations of EZH2, an epigenetic regulator, are present in approximately 20% of patients with follicular lymphoma. We investigated the activity and safety of tazemetostat, a first-in-class, oral EZH2 inhibitor, in patients with follicular lymphoma. Methods This study was an open-label, single-arm, phase 2 trial done at 38 cli...

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160...

Primary CNS lymphoma (PCNSL) in immunocompetent patients is a disease of older adults who are often unsuitable for the high dose therapy or experience substantial morbidity from whole brain radiotherapy. As therapeutic studies in older patients are limited, there is a need for real world data to guide patient care. Here we report a series of 38 con...

T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (T-LBL/T ALL) is an aggressive hematological malignancy arising from malignant transformation of T-cell progenitors with poor prognosis in adult patients. Outcomes are particularly dismal in the relapsed/refractory setting, and therapeutic options are limited in this context. Genomic...

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel, highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease we...

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiri...

Background Histologic transformation (HT) is an important event with adverse prognosis in the natural history of indolent lymphomas. There is minimal data on HT in the Australian setting. Aim To characterise patients with biopsy‐proven HT and their outcomes identified at a tertiary Australian Hospital. Methods All patients with biopsy‐proven HT d...

Background In primary central nervous system lymphoma (PCNSL), venous thromboembolism (VTE) can cause significant morbidity and hinder chemotherapy delivery. Objectives To assess VTE incidence, timing and adequacy of inpatient and outpatient VTE prophylaxis in patients with PCNSL receiving chemoimmunotherapy with curative intent. Patients/Methods...

8007 Background: Bruton tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. ASPEN is a randomized phase 3 study comparing zanubrutinib (ZANU), a potent and selective BTK inhibitor, versus ibrutinib (IBR), a first generation BTK inhibitor, in WM patients. Methods: Patients with WM and MYD88 mutation were randomly assigned 1:1 to...

8051 Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naïve (TN) and relapsed/refractory (R/R) patients with WM. Methods: Patients had TN or R/R WM and required treatment as per Internat...

Despite their availability for over a decade, the exact nature of biosimilar medicines is still poorly understood with paucity of clear treatment guidelines for their use in clinical practice in Australia. Although hematologists have had experience with biosimilars in the setting of supportive care, with the approval of the first biosimilar rituxim...

Legionella pneumophila is a well-known cause of pneumonia that is infrequently cultured in clinical practice. We report a case of an immunocompromised patient with persistently positive L. pneumophila cultures from invasive respiratory samples despite prolonged treatment with appropriate antibiotics. In vitro testing showed that the isolate remaine...

Waldenström macroglobulinaemia (WM) is an indolent non-Hodgkin lymphoma which usually presents with symptoms related to infiltration of bone marrow or other tissues like lymph nodes, liver or spleen and has certain unusual clinical manifestations, e.g., renal and central nervous system (CNS) involvement. It also has an array of laboratory features...

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including marginal zone lymphoma (MZL). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor...

Background The time to treatment initiation is determined by tumour burden in patients with follicular lymphoma (FL). The Groupe d'Etude des Lymphomes Folliculaires ('GELF') criteria, defined in the pre-rituximab era, are commonly used to assess tumour burden.2 Patients must meet ≥1 of the following criteria to be considered "high" tumour burden ac...

Background: Zanubrutinib is an investigational, next-generation BTK inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, bioavailable, and irreversible with potentially advantageous pharmacokinetic and pharmacodynamic properties (Tam Blood...

Background: While the majority of diffuse large B-cell lymphoma (DLBCL) patients are cured with R-CHOP immunochemotherapy, a significant proportion of patients still experience disease relapse. Studies using interim PET (iPET) to select patients for therapy intensification have failed to improve survival, at least partially, due to imperfect risk s...

Disclosures: Tam: Novartis: Honoraria; Pharmacyclics LLC, an AbbVie company: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria. Siddiqi:Astra Zeneca: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Kite: Research Funding; TG Therapeuti...

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including CLL/SLL. Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and...

Introduction: Relapsed/refractory (R/R) follicular lymphoma (FL) remains a difficult-to-treat condition, with limited treatment options. New, tolerable treatments with unique mechanisms of action are needed, especially for high-risk patients whose disease progresses within 24 months of diagnosis (POD24). The epigenetic regulator EZH2 catalyzes the...

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigati...

The role of cytarabine-based induction and autologous stem cell transplantation (ASCT) in front-line treatment of younger patients with mantle cell lymphoma (MCL) is well established, however the utility of intensive approaches in older patients remains unclear. This retrospective study compared first line treatment outcomes in patients aged 60 yea...

Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consiste...

Background Zanubrutinib, an investigational BTK inhibitor, achieves high plasma concentrations and sustained complete BTK occupancy in blood and lymph nodes, with greater selectivity for BTK vs other TEC and EGFR family kinases in biochemical assays, and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. Aims To present u...

Background BTK inhibitors have been shown to be highly active in patients with WM harboring the MYD88 L265P mutation, however lower response rates and shorter survival have been reported in patients that lack such mutations (i.e MYD88 WT ; N Engl J Med 2015;372:1430–1440). Zanubrutinib is a potent, specific, and irreversible oral investigational BT...

Background The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known. Methods In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patie...

https://deepblue.lib.umich.edu/bitstream/2027.42/149513/1/hon55_2630.pdf

https://deepblue.lib.umich.edu/bitstream/2027.42/149544/1/hon111_2629.pdf

Background MDS is a heterogeneous group of myeloid neoplasms caused by genetic and epigenetic alterations. While the major driver mutations in MDS have been fully investigated, the role of epigenetic alterations, particularly those of DNA methylation, has less intensively been studied. Aims To clarify the role of epigenetic aberrations in the path...

Background Zanubrutinib, a next generation BTK inhibitor, achieves high plasma concentrations and sustained complete BTK occupancy in blood and lymph nodes, with greater selectivity for BTK vs other TEC and EGFR family kinases in biochemical assays, and favorable pharmacokinetic/pharmacodynamic properties in preclinical studies. Aims We conducted...

Background The multinational, open‐label, phase 3 CLL14 trial (NCT02242942) compared fixed‐duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil‐obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. Aims We present endpoint analyses with particula...

Background The cyclin‐dependent kinase inhibitor dinaciclib induces apoptosis by CDK9 inhibition with antitumor activity in preclinical syngeneic lymphoma models and early phase trials of hematologic malignancies including diffuse large B‐cell lymphoma (DLBCL). Murine syngeneic tumor models (MC‐38) showed combined anti‐tumor activity of anti‐PD‐1 a...

Background Chronic myelomonocytic leukemia (CMML) are associated with a tendency to secondary acute myeloid leukemia (sAML) progression. Aims We sought to examine the patterns of genetic evolution by analyzing a cohort of matched paired samples collected at initial diagnosis and at sAML transformation. Methods Mutational analyses of 33 genes rela...

TPS7568 Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, mediating B-cell proliferation, migration, adhesion and survival. BTK inhibition has emerged as a strategy for targeting B-cell malignancies, including MZL. In preclinical studies, zanubrutinib was shown to be a potent, irreversible, highly specific...

Recently, obinutuzumab was included in the Australian Pharmaceutical Benefits Scheme for use in first line, advanced or bulky stage 2, follicular lymphoma, providing more immunochemotherapy treatment options available than ever before. Rituximab with chemotherapy has been the standard of care since reimbursement in the late 1990s; however, obinutuz...

Mantle cell lymphoma (MCL) is an uncommon and typically aggressive form of lymphoma. Although often initially chemosensitive, relapse is common. Several induction and conditioning regimens are used in transplant‐eligible patients, and the optimal approach remains unknown. We performed an international, retrospective study of transplant‐eligible pat...