Publications by authors named "Stephen Mulligan"

72 Publications

Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial.

Blood Adv 2020 Dec;4(23):6009-6018

Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

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 minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.
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http://dx.doi.org/10.1182/bloodadvances.2020003010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724905PMC
December 2020

IBL-202 is synergistic with venetoclax in CLL under in vitro conditions that mimic the tumor microenvironment.

Blood Adv 2020 Oct;4(20):5093-5106

Northern Blood Research Centre, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia.

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α-induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.
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http://dx.doi.org/10.1182/bloodadvances.2019001369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594376PMC
October 2020

Ibrutinib restores immune cell numbers and function in first-line and relapsed/refractory chronic lymphocytic leukemia.

Leuk Res 2020 10 11;97:106432. Epub 2020 Aug 11.

Translational Medicine, Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, United States. Electronic address:

Ibrutinib positively modulates many T-cell subsets in chronic lymphocytic leukemia (CLL). To understand ibrutinib's effects on the broader landscape of immune cell populations, we comprehensively characterized changes in circulating counts of 21 immune blood cell subsets throughout the first year of treatment in patients with relapsed/refractory (R/R) CLL (n = 55, RESONATE) and previously untreated CLL (n = 50, RESONATE-2) compared with untreated age-matched healthy donors (n = 20). Ibrutinib normalized abnormal immune cell counts to levels similar to those of age-matched healthy donors. Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4 and CD8 T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes. T-cell function was assessed in response to T-cell receptor stimulation in patients with R/R CLL (n = 21) compared with age-matched healthy donors (n = 18). Ibrutinib significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets. These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function.
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http://dx.doi.org/10.1016/j.leukres.2020.106432DOI Listing
October 2020

A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study.

Blood 2020 Oct;136(18):2038-2050

Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece.

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 were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.
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http://dx.doi.org/10.1182/blood.2020006844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596850PMC
October 2020

Environmental influences on Aedes aegypti catches in Biogents Sentinel traps during a Californian "rear and release" program: Implications for designing surveillance programs.

PLoS Negl Trop Dis 2020 06 12;14(6):e0008367. Epub 2020 Jun 12.

College of Public Health, Medical and Veterinary Sciences, James Cook University, Smithfield, Australia.

As Aedes aegypti continues to expand its global distribution, the diseases it vectors (dengue, Zika, chikungunya and yellow fever) are of increasing concern. Modern efforts to control this species include "rear and release" strategies where lab-reared mosquitoes are distributed throughout the landscape to replace or suppress invasive populations. These programs require intensive surveillance efforts to monitor their success, and the Biogents Sentinel (BGS) trap is one of the most effective tools for sampling adult Ae. aegypti. BGS trap catches can be highly variable throughout landscapes, so we investigated the potential impacts of environmental factors on adult Ae. aegypti capture rates during a "rear and release" program in California to better understand the relative contributions of true variability in population density across a landscape and trap context. We recorded male and female Ae. aegypti catches from BGS traps, with and without CO2, throughout control sites where no mosquitoes were released and in treatment sites where males infected with Wolbachia were released. BGS trap catches were positively influenced by higher proportions of shade or bushes in the front yard of the premises as well as the presence of potential larval habitats such as subterranean vaults. In contrast, an increase in residential habitat within a 100 m radius of trap locations negatively influenced BGS trap catches. For male Ae. aegypti, increased visual complexity of the trap location positively influenced capture rates, and the presence of yard drains negatively affected catch rates in control sites. Lastly, for BGS traps using CO2, higher catch rates were noted from traps placed greater than one meter from walls or fences for both male and female mosquitoes. These results have important implications for surveillance programs of Ae. aegypti throughout the Californian urban environment including adult monitoring during "rear and release" programs.
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http://dx.doi.org/10.1371/journal.pntd.0008367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314095PMC
June 2020

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

Intern Med J 2020 06 15;50(6):667-679. Epub 2020 May 15.

Department of Haematology, St Vincent's Hospital, Sydney, New South Wales, Australia.

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.
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http://dx.doi.org/10.1111/imj.14859DOI Listing
June 2020

Managing haematology and oncology patients during the COVID-19 pandemic: interim consensus guidance.

Med J Aust 2020 06 13;212(10):481-489. Epub 2020 May 13.

Peter MacCallum Cancer Centre, Melbourne, VIC.

Introduction: A pandemic coronavirus, SARS-CoV-2, causes COVID-19, a potentially life-threatening respiratory disease. Patients with cancer may have compromised immunity due to their malignancy and/or treatment, and may be at elevated risk of severe COVID-19. Community transmission of COVID-19 could overwhelm health care services, compromising delivery of cancer care. This interim consensus guidance provides advice for clinicians managing patients with cancer during the pandemic.

Main Recommendations: During the COVID-19 pandemic: In patients with cancer with fever and/or respiratory symptoms, consider causes in addition to COVID-19, including other infections and therapy-related pneumonitis. For suspected or confirmed COVID-19, discuss temporary cessation of cancer therapy with a relevant specialist. Provide information on COVID-19 for patients and carers. Adopt measures within cancer centres to reduce risk of nosocomial SARS-CoV-2 acquisition; support population-wide social distancing; reduce demand on acute services; ensure adequate staffing; and provide culturally safe care. Measures should be equitable, transparent and proportionate to the COVID-19 threat. Consider the risks and benefits of modifying cancer therapies due to COVID-19. Communicate treatment modifications, and review once health service capacity allows. Consider potential impacts of COVID-19 on the blood supply and availability of stem cell donors. Discuss and document goals of care, and involve palliative care services in contingency planning.

Changes In Management As A Result Of This Statement: This interim consensus guidance provides a framework for clinicians managing patients with cancer during the COVID-19 pandemic. In view of the rapidly changing situation, clinicians must also monitor national, state, local and institutional policies, which will take precedence.

Endorsed By: Australasian Leukaemia and Lymphoma Group; Australasian Lung Cancer Trials Group; Australian and New Zealand Children's Haematology/Oncology Group; Australia and New Zealand Society of Palliative Medicine; Australasian Society for Infectious Diseases; Bone Marrow Transplantation Society of Australia and New Zealand; Cancer Council Australia; Cancer Nurses Society of Australia; Cancer Society of New Zealand; Clinical Oncology Society of Australia; Haematology Society of Australia and New Zealand; National Centre for Infections in Cancer; New Zealand Cancer Control Agency; New Zealand Society for Oncology; and Palliative Care Australia.
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http://dx.doi.org/10.5694/mja2.50607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273031PMC
June 2020

Chronic lymphocytic leukemia, skin and other second cancers.

Leuk Lymphoma 2019 12 24;60(13):3104-3106. Epub 2019 Sep 24.

Royal North Shore Hospital, Joint CLL Dermatology and Oncology Clinic, St Leonards, Sydney, Australia.

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http://dx.doi.org/10.1080/10428194.2019.1665669DOI Listing
December 2019

Ibrutinib-associated invasive fungal diseases in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: An observational study.

Mycoses 2019 Dec 22;62(12):1140-1147. Epub 2019 Oct 22.

Infectious Diseases Unit, Shaare-Zedek Medical Center, affiliated with Hebrew University Medical School, Jerusalem, Israel.

Background: Invasive fungal diseases (IFD) are life-threatening infections most commonly diagnosed in acute leukaemia patients with prolonged neutropenia and are uncommonly diagnosed in patients with lymphoproliferative diseases.

Objectives: Following the initial report of aspergillosis diagnosed shortly after beginning ibrutinib for chronic lymphocytic leukaemia, a survey was developed to seek additional cases of IFD during ibrutinib treatment.

Methods: Local and international physicians and groups were approached for relevant cases. Patients were included if they met the following criteria: diagnosis of chronic lymphocytic leukaemia/non-Hodgkin lymphoma; proven or probable IFD; and ibrutinib treatment on the date IFD were diagnosed. Clinical and laboratory data were captured using REDCap software.

Result: Thirty-five patients with IFD were reported from 22 centres in eight countries: 26 (74%) had chronic lymphocytic leukaemia. The median duration of ibrutinib treatment before the onset of IFD was 45 days (range 1-540). Aspergillus species were identified in 22 (63%) of the patients and Cryptococcus species in 9 (26%). Pulmonary involvement occurred in 69% of patients, cranial in 60% and disseminated disease in 60%. A definite diagnosis was made in 21 patients (69%), and the mortality rate was 69%. Data from Israel regarding ibrutinib treated patients were used to evaluate a prevalence of 2.4% IFD.

Conclusions: The prevalence of IFD among chronic lymphocytic leukaemia/non-Hodgkin lymphoma patients treated with ibrutinib appears to be higher than expected. These patients often present with unusual clinical features. Mortality from IFD in this study was high, indicating that additional studies are urgently needed to identify patients at risk for ibrutinib-associated IFD.
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http://dx.doi.org/10.1111/myc.13001DOI Listing
December 2019

Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma.

Am J Hematol 2019 12 13;94(12):1353-1363. Epub 2019 Oct 13.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).
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http://dx.doi.org/10.1002/ajh.25638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899718PMC
December 2019

Molecular pathogenesis of chronic lymphocytic leukaemia.

Br J Haematol 2019 09 31;186(5):668-684. Epub 2019 Jul 31.

Northern Blood Research Centre, Kolling Institute of Medical Research, Sydney, NSW, Australia.

Chronic lymphocytic leukaemia (CLL) is characterised by the clonal expansion of mature, CD5 positive, B lymphocytes in the blood, marrow, lymph nodes and spleen. For the majority of patients, CLL follows an indolent clinical course, while a proportion of patients experience rapid disease progression. Despite the strong correlation between certain genetic defects and prognosis, there remains no single unifying pathogenic lesion in CLL. With recent advances in therapy it is increasingly important to stratify CLL patients according to risk. This has been highlighted by two recent studies, the first showing that immunoglobulin heavy chain mutational status predicts a durable response to frontline chemoimmunotherapy and the second showing that complex karyotype is a stronger predictor of poor response to ibrutinib and venetoclax therapy than TP53 deletion. In this review we discuss the molecular features of CLL and how technological advances can identify patient subsets and stratify them according to risk.
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http://dx.doi.org/10.1111/bjh.16102DOI Listing
September 2019

Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab.

Blood 2019 05 6;133(19):2031-2042. Epub 2019 Mar 6.

CLL Center, Dana-Farber Cancer Institute, Boston, MA.

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of or mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.
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http://dx.doi.org/10.1182/blood-2018-08-870238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509542PMC
May 2019

Dual inhibition of MEK1/2 and AKT by binimetinib and MK2206 induces apoptosis of chronic lymphocytic leukemia cells under conditions that mimic the tumor microenvironment.

Leuk Lymphoma 2019 07 16;60(7):1632-1643. Epub 2019 Jan 16.

a Northern Blood Research Centre, Kolling Institute , Royal North Shore Hospital , St Leonards , NSW , Australia.

Several key pathways mediate signaling via the B-cell receptor, including the mitogen-activated protein kinase-ERK1/2 pathway. However, inhibition of MEK1/2, a key component of the MAPK-ERK1/2 signaling cascade, results in paradoxical activation of AKT in chronic lymphocytic leukemia (CLL) cells. In the current study we demonstrate synergy between the MEK1/2 inhibitor binimetinib and the AKT inhibitor MK2206, which combined induce apoptosis of primary CLL cells and restrict the cell cycle progression and proliferation of the OSU-CLL cell line. The mechanisms of action of the drug combination involve dual inhibition of MAPK-ERK1/2 and AKT signaling and down-regulation of Mcl-1 expression. Collectively, these data suggest that dual inhibition of MEK1/2 and AKT may represent a therapeutic option for CLL, capable of overcoming the pro-survival effects of the lymph node and bone marrow microenvironments.
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http://dx.doi.org/10.1080/10428194.2018.1542148DOI Listing
July 2019

Improvement in Parameters of Hematologic and Immunologic Function and Patient Well-being in the Phase III RESONATE Study of Ibrutinib Versus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Clin Lymphoma Myeloma Leuk 2018 12 18;18(12):803-813.e7. Epub 2018 Aug 18.

The Leeds Teaching Hospitals, St. James University Hospital, Leeds, United Kingdom.

Background: Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

Patients And Methods: Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization.

Results: With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at ≤6 months vs. 5% at 12-18 months). With ibrutinib, grade ≥ 3 hypertension occurred in 6%, grade ≥ 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients.

Conclusion: Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.
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http://dx.doi.org/10.1016/j.clml.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527106PMC
December 2018

The dual inhibitor of the phosphoinositol-3 and PIM kinases, IBL-202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment.

Br J Haematol 2018 09 5;182(5):654-669. Epub 2018 Jul 5.

Northern Blood Research Centre, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Sydney, Australia.

Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan-PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL-202 in CLL. Importantly, IBL-202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL-202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL-202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug-resistance.
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http://dx.doi.org/10.1111/bjh.15447DOI Listing
September 2018

Immune failure, infection and survival in chronic lymphocytic leukemia.

Haematologica 2018 07;103(7):e329

Department of Haematology, Royal North Shore Hospital, Kolling Institute, University of Sydney, St Leonards, Australia.

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http://dx.doi.org/10.3324/haematol.2018.196543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029549PMC
July 2018

Inhibition of the Raf-1 kinase inhibitory protein (RKIP) by locostatin induces cell death and reduces the CXCR4-mediated migration of chronic lymphocytic leukemia cells.

Leuk Lymphoma 2018 12 18;59(12):2917-2928. Epub 2018 Jun 18.

a Northern Blood Research Centre , Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards , Sydney , Australia.

The Raf-1 kinase inhibitory protein (RKIP) is an important regulatory element in multiple signaling pathways, including MAPK-ERK1/2. We investigated whether targeted disruption of RKIP is a therapeutic option for chronic lymphocytic leukemia (CLL). The RKIP inhibitor locostatin-induced apoptosis of CLL cells, irrespective of poor prognostic indications or treatment history. Locostatin down-regulated MAPK-ERK1/2 and AKT phosphorylation, decreased expression of the chemokine receptor CXCR4 (p = .04) and reduced the migratory capacity of CLL cells toward stroma-derived factor 1α (SDF-1α, p = .02). Immuno-blotting and immuno-precipitation showed that RKIP is constitutively phosphorylated and highly expressed in CLL cells and that the actions of locostatin may be mediated by binding of G-protein receptor kinase-2 (GRK2) to MEK1 and AKT. Collectively, our data suggest that inhibition of RKIP may be effective against CLL, reducing the survival and migratory capacity of the leukemic cells through down-regulation of MAPK-ERK1/2 and AKT-mediated signaling.
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http://dx.doi.org/10.1080/10428194.2018.1455974DOI Listing
December 2018

MEK1/2 inhibition by binimetinib is effective as a single agent and potentiates the actions of Venetoclax and ABT-737 under conditions that mimic the chronic lymphocytic leukaemia (CLL) tumour microenvironment.

Br J Haematol 2018 08 16;182(3):360-372. Epub 2018 May 16.

Northern Blood Research Centre, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, Sydney, Australia.

The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA). Binimetinib was also significantly more toxic towards CLL cells cultured in the presence of either anti-IgM antibody or stroma-derived factor-1α (SDF-1α) and reduced CLL cell cycle progression and proliferation. Furthermore, binimetinib significantly increased the sensitivity of CLL cells co-cultured with CD40 ligand (CD40L)-expressing fibroblasts to the BH3-mimetics ABT-737 and Venetoclax (ABT-199) via a mechanism involving down-regulation of Mcl-1 (MCL1) activity and Bim (BCL2L11) and Bcl-xL (BCL2L1) expression. Collectively, these data suggest that binimetinib may have both cytotoxic and cytostatic effects on CLL cells by blocking microenvironment-derived signals known to drive survival and proliferation. The combination of binimetinib with a BH3 mimetic may be an effective treatment strategy for CLL, particularly against the proliferative fraction of the disease within the tumour microenvironment.
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http://dx.doi.org/10.1111/bjh.15282DOI Listing
August 2018

Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial.

J Clin Oncol 2018 07 1;36(19):1973-1980. Epub 2018 May 1.

Stephan Stilgenbauer and Johannes Bloehdorn, Ulm University, Ulm; Stephan Stilgenbauer, Klinik für Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg; Barbara Eichhorst and Michael Hallek, Universitätsklinikum Köln, Köln; Johannes Schetelig, University Hospital, Technische Universität Dresden, Dresden; Clemens-Martin Wendtner, Klinikum Schwabing, Munich; Sebastian Böttcher, University Hospital of Schleswig-Holstein, Kiel, Germany; Peter Hillmen and Talha Munir, St James's University Hospital, Leeds; Anna Schuh, University of Oxford; Anna Schuh, Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, United Kingdom; John F. Seymour, Peter MacCallum Cancer Centre; John F. Seymour, University of Melbourne; Andrew W. Roberts, Royal Melbourne Hospital, Parkville, Victoria; Stephen P. Mulligan, Royal North Shore Hospital, St Leonards, New South Wales, Australia; Steven Coutre, Stanford University Medical Center, Stanford, CA; Wojciech Jurczak, Jagiellonian University, Kraków, Poland; Sarit Assouline, McGill University, Montreal, Quebec, Canada; Matthew S. Davids, Dana-Farber Cancer Institute, Boston, MA; Lang Zhou, Ahmed Hamed Salem, Monali Desai, Brenda Chyla, Jennifer Arzt, Su Young Kim, Maria Verdugo, and Gary Gordon, AbbVie, North Chicago, IL; Ahmed Hamed Salem, Ain Shams University, Cairo, Egypt; and William G. Wierda, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were ≥ 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10 was achieved in this high-risk population.
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http://dx.doi.org/10.1200/JCO.2017.76.6840DOI Listing
July 2018

Humoral immune failure defined by immunoglobulin class and immunoglobulin G subclass deficiency is associated with shorter treatment-free and overall survival in Chronic Lymphocytic Leukaemia.

Br J Haematol 2018 04 21;181(1):97-101. Epub 2018 Feb 21.

Department of Haematology, Royal North Shore Hospital, Kolling Institute, University of Sydney, St Leonards, Sydney, Australia.

Immune dysfunction attributed to hypogammaglobulinaemia is common in chronic lymphocytic leukaemia (CLL) and infection is a major contributor to morbidity and mortality. A higher incidence of multiple immunoglobulin and immunoglobulin G (IgG) subclass deficiency was associated with more advanced disease (P < 0·001 and P < 0·001, respectively) in a cohort of 147 CLL patients. Multiple immunoglobulin and IgG subclass deficiency were significantly associated with shorter treatment-free survival (TFS) (P < 0·001 and P = 0·006, respectively). The association between disease stage and immune dysfunction demonstrated by these data suggest aspects of immune deficiency correlate with disease severity and may be associated with shorter TFS in CLL.
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http://dx.doi.org/10.1111/bjh.15146DOI Listing
April 2018

Ibrutinib and idelalisib block immunophenotypic changes associated with the adhesion and activation of CLL cells in the tumor microenvironment.

Leuk Lymphoma 2018 08 22;59(8):1927-1937. Epub 2017 Nov 22.

a School of Life and Environmental Sciences , University of Sydney , Sydney , Australia.

The lymph node and bone marrow microenvironments promote the survival and proliferation of CLL cells. Defining the immunophenotype of CLL cells from the tumor microenvironment may help to better understand the mechanisms of action of current therapies and identify novel drug targets. Significant changes in the levels of 25 CD antigens were identified using the DotScan™ antibody microarray following CLL-cell culture with CD40L-expressing fibroblasts. Ibrutinib or idelalisib countered the change in expression of 11 of these antigens (CD23, CD27, CD53, CD58, CD71, CD80, CD84, CD97, CD126, CD150, and FMC7), which have known roles in cell activation and adhesion. The immunophenotypic changes identified may provide further insight into the mechanisms by which CLL cells interact with the tumor microenvironment and better define how ibrutinib and idelalisib release CLL cells from the lymph nodes and bone marrow.
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http://dx.doi.org/10.1080/10428194.2017.1403598DOI Listing
August 2018

Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project.

Cytometry B Clin Cytom 2018 01 17;94(1):121-128. Epub 2018 Jan 17.

Department of Hematology, Hospital Clinic, University of Barcelona, Barcelona, Spain.

The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim of this project was to identify reproducible criteria and consensus on markers recommended for the diagnosis of CLL. ERIC/ESCCA members classified 14 of 35 potential markers as "required" or "recommended" for CLL diagnosis, consensus being defined as >75% and >50% agreement, respectively. An approach to validate "required" markers using normal peripheral blood was developed. Responses were received from 150 participants with a diagnostic workload >20 CLL cases per week in 23/150 (15%), 5-20 in 82/150 (55%), and <5 cases per week in 45/150 (30%). The consensus for "required" diagnostic markers included: CD19, CD5, CD20, CD23, Kappa, and Lambda. "Recommended" markers potentially useful for differential diagnosis were: CD43, CD79b, CD81, CD200, CD10, and ROR1. Reproducible criteria for component reagents were assessed retrospectively in 14,643 cases from 13 different centers and showed >97% concordance with current approaches. A pilot study to validate staining quality was completed in 11 centers. Markers considered as "required" for the diagnosis of CLL by the participants in this study (CD19, CD5, CD20, CD23, Kappa, and Lambda) are consistent with current diagnostic criteria and practice. Importantly, a reproducible approach to validate and apply these markers in individual laboratories has been identified. Finally, a consensus "recommended" panel of markers to refine diagnosis in borderline cases (CD43, CD79b, CD81, CD200, CD10, and ROR1) has been defined and will be prospectively evaluated. © 2017 International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817234PMC
January 2018

Recommendations for skin cancer monitoring for patients with chronic lymphocytic leukemia.

Leuk Lymphoma 2018 03 3;59(3):578-582. Epub 2017 Aug 3.

c Department of Dermatology , Royal North Shore Hospital , St Leonards , Australia.

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http://dx.doi.org/10.1080/10428194.2017.1349903DOI Listing
March 2018

Surface Profiling of Extracellular Vesicles from Plasma or Ascites Fluid Using DotScan Antibody Microarrays.

Methods Mol Biol 2017 ;1619:263-301

School of Life and Environmental Sciences, University of Sydney, Sydney, NSW, 2006, Australia.

DotScan antibody microarrays were initially developed for the extensive surface profiling of live leukemia and lymphoma cells. DotScan's diagnostic capability was validated with an extensive clinical trial using mononuclear cells from the blood or bone marrow of leukemia or lymphoma patients. DotScan has also been used for the profiling of surface proteins on peripheral blood mononuclear cells (PBMC) from patients with HIV, liver disease, and stable and progressive B-cell chronic lymphocytic leukemia (CLL). Fluorescence multiplexing allowed the simultaneous profiling of cancer cells and leukocytes from disaggregated colorectal and melanoma tumor biopsies after capture on DotScan. In this chapter, we have used DotScan for the surface profiling of extracellular vesicles (EV) recovered from conditioned growth medium of cancer cell lines and the blood of patients with CLL. The detection of captured EV was performed by enhanced chemiluminescence (ECL) using biotinylated antibodies that recognized antigens expressed on the surface of the EV subset of interest. DotScan was also used to profile EV from the blood of healthy individuals and the ascites fluid of ovarian cancer patients. DotScan binding patterns of EV from human plasma and other body fluids may yield diagnostic or prognostic signatures for monitoring the incidence, treatment, and progression of cancers.
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http://dx.doi.org/10.1007/978-1-4939-7057-5_20DOI Listing
March 2018

Hematology oncology practice in the Asia-Pacific APHCON survey results from the 6th international hematologic malignancies conference: bridging the gap 2015, Beijing, China.

Oncotarget 2017 Jun;8(25):41620-41630

Faculty of Medicine Siriraj Hospital, Bangkok, Thailand.

This report serves as a snapshot of the state-of-knowledge in the Asia Pacific (APAC) Hematology Oncology community, and establishes a baseline for longitudinal investigations to follow changes in best practices over time. The objective of this study was to understand the approach to hematologic diseases, common standards of care and best practices, issues that remain controversial or debated, and educational or resource gaps that warrant attention. We used mobile application to disseminate and distribute questionnaires to delegates during the 6th international hematologic malignancies conference hosted by the APAC Hematology Consortium at Beijing, China. User responses were collected in an anonymous fashion. We report survey results in two ways: the overall responses, and responses as stratified between Chinese physicians and "Other" represented nationalities. Overall geographical concordance in survey responses was positive and strong. Perhaps more interesting than instances of absolute agreement, these data provide a unique opportunity to identify topics in which physician knowledge or opinions diverge. We assigned questions from all modules to broad categories of: patient information; diagnosis; treatment preference; transplantation; and general knowledge/opinion. On average, we observed a geographic difference of 15% for any particular answer choice, and this was fairly constant across survey modules. These results reveal utility and need for widespread and ongoing initiatives to assess knowledge and provide evidence-based education in real time. The data will be made more valuable by longitudinal participation, such that we can monitor changes in the state of the art over time.
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http://dx.doi.org/10.18632/oncotarget.15655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522281PMC
June 2017

Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL.

Blood 2017 05 3;129(19):2612-2615. Epub 2017 Apr 3.

The Ohio State University Medical Center, The Ohio State University, Columbus, OH.

Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ∼9 months. Pharmacokinetic assessment of ibrutinib exposure at 420-mg dose suggested similar exposure regardless of patient weight or age. As assessed by independent review committee, patients with higher DI experienced longer median progression-free survival (PFS) compared with those with lower DI regardless of del17p and/or status. Of 79 patients requiring a drug hold, treatment was restarted at the original dose in 73 (92%) patients. Mean duration of a missed-dose event was 18.7 days (range, 8-56). Patients missing ≥8 consecutive days of ibrutinib had a shorter median PFS vs those missing <8 days (10.9 months vs not reached). These results support sustained adherence to once-daily ibrutinib dosing at 420 mg as clinically feasible to achieve optimal outcomes in patients with previously treated CLL. The trial was registered at www.clinicaltrials.gov as #NCT01578707.
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http://dx.doi.org/10.1182/blood-2016-12-737346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437732PMC
May 2017

Successful use of Bruton's kinase inhibitor, ibrutinib, to control paraneoplastic pemphigus in a patient with paraneoplastic autoimmune multiorgan syndrome and chronic lymphocytic leukaemia.

Australas J Dermatol 2017 Nov 13;58(4):e240-e242. Epub 2017 Mar 13.

Department of Dermatology, Royal North Shore Hospital, Sydney, New South Wales, Australia.

We present the case of a 51-year-old man who developed paraneoplastic pemphigus (PNP) in the context of chronic lymphocytic leukemia (CLL). His CLL was successfully controlled with ibrutinib. Concurrently, there was significant improvement of his PNP, suggesting that ibrutinib may be a very useful addition to the treatment options in this potentially life-threatening autoimmune disorder.
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http://dx.doi.org/10.1111/ajd.12615DOI Listing
November 2017

Modeling the chronic lymphocytic leukemia microenvironment in vitro.

Leuk Lymphoma 2017 02 18;58(2):266-279. Epub 2016 Oct 18.

a Northern Blood Research Centre , Kolling Institute of Medical Research, Royal North Shore Hospital , Sydney , Australia.

Microenvironments within the lymph node and bone marrow promote proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Successful treatment of CLL must therefore target the leukemic cells within these compartments. A better understanding of the interaction between CLL cells and the tumor microenvironment has led to the development of in vitro models that mimic the mechanisms that support leukemic cell survival and proliferation in vivo. Employing these models as part of the pre-clinical evaluation of novel therapeutic agents enables a better approximation of their potential clinical efficacy. In this review we summarize the current literature describing how different aspects of the tumor microenvironment have been modeled in vitro and detail how these models have been employed to study the biology of the disease and potential efficacy of novel therapeutic agents.
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http://dx.doi.org/10.1080/10428194.2016.1204654DOI Listing
February 2017