Publications by authors named "Peter Mollee"

104 Publications

The Clinical Impact of Proteomics in Amyloid Typing.

Mayo Clin Proc 2021 Apr 8. Epub 2021 Apr 8.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

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http://dx.doi.org/10.1016/j.mayocp.2020.12.002DOI Listing
April 2021

Response of factor X deficiency to darutumumab in the treatment of AL amyloidosis: a novel finding.

BMJ Case Rep 2021 Apr 7;14(4). Epub 2021 Apr 7.

Department of Haematology, Metro South Hospital and Health Service, Woolloongabba, Queensland, Australia.

We report a case of progressive light-chain amyloidosis (otherwise known as AL amyloidosis) with acquired factor X (aFX) deficiency with a complete haematological response and rapid normalisation of FX levels following daratumumab monotherapy. To our knowledge, this is the first case report documenting successful treatment with daratumumab of aFX deficiency secondary to AL amyloidosis. The patient responded well to this therapy, with excellent symptomatic and quality of life improvements as well as a reduction in bleeding manifestations. This case highlights the value in considering daratumumab treatment when AL amyloidosis is complicated by FX deficiency.
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http://dx.doi.org/10.1136/bcr-2020-240631DOI Listing
April 2021

The Myeloma Landscape in Australia and New Zealand: The First 8 Years of the Myeloma and Related Diseases Registry (MRDR).

Clin Lymphoma Myeloma Leuk 2021 Jan 30. Epub 2021 Jan 30.

Department of Haematology, Alfred Health-Monash University, Melbourne, Victoria, Australia. Electronic address:

Background: Real-world multiple myeloma (MM) data are scarce, with most data originating from clinical trials. The Myeloma and Related Diseases Registry (MRDR) is a prospective clinical-quality registry of newly diagnosed cases of plasma cell disorders established in 2012 and operating at 44 sites in Australia and New Zealand as of April 2020.

Methods: We reviewed all patients enrolled onto the MRDR between June 2012 and April 2020. Baseline characteristics, treatment, and outcome data were reviewed for MM patients with comparisons made by chi-square tests (categorical variables) and rank sum tests (continuous variables). Kaplan-Meier analysis was used to estimate progression-free survival and overall survival (OS).

Results: As of April 2020, a total of 2405 MM patients were enrolled (median age, 67 years, with 40% aged > 70 years). High-risk features were present in 13% to 31% of patients: fluorescence in-situ hybridization (FISH) ≥ 1 of t(4;14), t(14;16), or del(17p) 18%, International Staging System (ISS)-3 31%, and Revised ISS (R-ISS)-3 13%. Cytogenetic/FISH analyses were performed in 50% and 68% of patients, respectively, with an abnormal karyotype result in 34%. Bortezomib-containing therapy was the most common first-line therapy (79.3%, n = 1706). Patients not receiving bortezomib were older (median age, 76 vs 65 years, P < .001) with inferior performance status (Eastern Cooperative Oncology Group performance status ≥ 2, 41% vs 18%, P < .001). Median progression-free survival and OS were 30.8 and 65.8 months, respectively. Younger patients had superior OS (76.3 vs 46.7 months, P < .001, < 70 and ≥ 70 years, respectively). R-ISS score was available in 50.7% (n = 1220) of patients, and higher R-ISS was associated with inferior OS (R-ISS-1 vs R-ISS-2 vs R-ISS-3: not reached vs 68.1 months vs 33.2 months, respectively, P < .001).

Conclusion: Clinical registries provide a more complete picture of MM diagnosis and treatment, and highlight the challenges of adhering to best practices in a real-world context.
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http://dx.doi.org/10.1016/j.clml.2021.01.016DOI Listing
January 2021

SIRPα Suppresses Response to Therapeutic Antibodies by Nurse Like Cells From Chronic Lymphocytic Leukemia Patients.

Front Immunol 2020 21;11:610523. Epub 2021 Jan 21.

Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia.

Targeted antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. We have previously shown that resistance to therapeutic antibodies, by monocyte derived macrophages (referred to as nurse like cells, NLCs), from CLL patients is characterized by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. In this regard, an innate immune checkpoint was recently described that uses the CD47:SIRPα axis to suppress phagocytic responses by macrophages. In this study we examine whether the SIRPα axis regulates ADP responses to the anti-CD20 antibody, obinutuzumab, by NLCs. Using siRNA depletion strategies we show that SIRPα is a suppressor of ADP responses. Moreover, we show that this innate immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPα suppression is mediated the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPα innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients.
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http://dx.doi.org/10.3389/fimmu.2020.610523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859087PMC
January 2021

The use of monocyte subset repartitioning by flow cytometry for diagnosis of chronic myelomonocytic leukaemia.

Blood Cancer J 2021 Jan 7;11(1). Epub 2021 Jan 7.

School of Medicine, University of Queensland, Brisbane, QLD, Australia.

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http://dx.doi.org/10.1038/s41408-020-00401-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791046PMC
January 2021

Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial.

J Clin Oncol 2021 Jan 16;39(3):227-237. Epub 2020 Dec 16.

Department of Oncology, Hematology, BMT with Department of Pneumology, University Medical Center Hamburg, Hamburg, Germany.

Purpose: To evaluate the effects of daratumumab, lenalidomide, and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) on patient-reported outcomes (PROs) in the phase III MAIA study.

Patients And Methods: PROs were assessed on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item and the EuroQol 5-dimensional descriptive system at baseline and every 3 months during treatment. By mixed-effects model, changes from baseline are presented as least squares means with 95% CIs.

Results: A total of 737 transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma were randomly assigned to D-Rd (n = 368) or Rd (n = 369). Compliance with PRO assessments was high at baseline (> 90%) through month 12 (> 78%) for both groups. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item global health status scores improved from baseline in both groups and were consistently greater with D-Rd at all time points. A global health status benefit was achieved with D-Rd, regardless of age (< 75 and ≥ 75 years), baseline Eastern Cooperative Oncology Group (ECOG) performance status score, or depth of response. D-Rd treatment resulted in significantly greater reduction in pain scores as early as cycle 3 ( = .0007 Rd); the magnitude of change was sustained through cycle 12. Reductions in pain with D-Rd were clinically meaningful in patients regardless of age, ECOG status, or depth of response. Similarly, PRO improvements were observed with D-Rd and Rd on the EuroQol 5-dimensional descriptive system visual analog scale score.

Conclusion: D-Rd compared with Rd was associated with faster and sustained clinically meaningful improvements in PROs, including pain, in transplant-ineligible patients with newly diagnosed multiple myeloma regardless of age, baseline ECOG status, or depth of treatment response.
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http://dx.doi.org/10.1200/JCO.20.01370DOI Listing
January 2021

Physical Activity in People with Multiple Myeloma: Associated Factors and Exercise Program Preferences.

J Clin Med 2020 Oct 13;9(10). Epub 2020 Oct 13.

School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane 4072, Australia.

People with multiple myeloma (MM) often experience disease symptoms and treatment toxicities that can be alleviated through physical activity (PA). However, the majority of people with MM are insufficiently active. This study explored PA among people with MM, including differences by treatment stage, symptoms and demographics, and programming preferences. Overall, 126 people with MM (77% response rate) completed the survey. Pre-diagnosis, 25.4% were sufficiently active, with 12.0% remaining active after treatment. Respondents who were physically active pre-diagnosis were 46.7 times (95% confidence intervals CI: 2.03, 1072.1) more likely to meet PA guidelines following an MM diagnosis compared to people not meeting guidelines pre-diagnosis. Experiencing MM symptoms and receiving PA advice from healthcare professionals were not associated with meeting PA guidelines. People with MM were interested in exercise programs (55%) that are low-cost (77%), offered at flexible times (74%), and at locations close to home (69%), both during active treatment and remission (57%), and supervised by an exercise oncology specialist (48%). People with MM, particularly those insufficiently active prior to diagnosis, should be offered convenient, low-cost exercise programs supervised by an exercise oncology specialist to increase PA participation.
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http://dx.doi.org/10.3390/jcm9103277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601964PMC
October 2020

Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis.

J Clin Oncol 2020 10 30;38(28):3252-3260. Epub 2020 Jul 30.

Amyloidosis Research and Treatment Center "Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo," Pavia, Italy.

Purpose: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex).

Methods: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016.

Results: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% 52%; = .002). Higher rates of very good partial or complete response rates (64% 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed.

Conclusion: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.
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http://dx.doi.org/10.1200/JCO.20.01285DOI Listing
October 2020

Identifying an obinutuzumab resistant subpopulation of monocyte-derived-macrophages from patients with CLL.

Leuk Lymphoma 2020 11 14;61(11):2738-2742. Epub 2020 Jun 14.

University of Queensland, Woolloongabba, Australia.

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http://dx.doi.org/10.1080/10428194.2020.1775211DOI Listing
November 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

Bortezomib use and outcomes for the treatment of multiple myeloma.

Intern Med J 2020 09;50(9):1059-1066

School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.

Background: The public subsidy in Australia of bortezomib (Velcade) for untreated non-transplant multiple myeloma patients was based on the VISTA trial.

Aims: To ascertain the health outcomes of bortezomib in 'real world' transplant-ineligible elderly patients, compared to trial data.

Methods: Patient and treatment data were extracted from an oncology information system, laboratory information system and medical chart audits for three Queensland public hospitals.

Results: We identified 74 patients; the median age was 75 years. Our cohort comprised 47% patients who were International Staging System stage III, 45% at stage II and 8% at stage I. Patients who had comorbidities, such as cardiac disease (41%), pulmonary disease (14%), diabetes (22%), peripheral neuropathy (14%) and other comorbidities (41%) at baseline were included. The common regimens prescribed were VMP, CVD and VD, and most patients (n = 73) received bortezomib on a once-weekly or twice-a-week basis. The overall response rate was 81%. Half (53%) of the patients did not complete their planned therapy due to toxicity (30%), suboptimal response or disease progression (15%), or death on treatment (8%). Overall survival was 40.7 months and progression free survival was 17.7 months.

Conclusions: Our patients were older, had worse disease characteristics and more comorbidities than patients in the VISTA trial. While response rates were similar, survival outcomes appeared worse. Bortezomib-based treatment in the real world setting still carries a high risk of toxicity in the elderly population.
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http://dx.doi.org/10.1111/imj.14886DOI Listing
September 2020

Catheter-related thrombosis incidence and risk factors in adult cancer patients with central venous access devices.

Intern Med J 2020 Dec;50(12):1475-1482

Division of Cancer Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.

Background: Central venous access devices (CVAD) are commonly employed in the management of cancer patients. While having several benefits they are associated with significant risks.

Aim: To review the incidence and risk factors for catheter-related thrombosis (CRT) in cancer patients with a CVAD.

Methods: We performed a prospective observational cohort study of adult patients with cancer requiring a CVAD between 1 January 2004 and 29 June 2016. The rate of, and risk factors for the development of, symptomatic CRT were evaluated.

Results: A total of 4920 central lines was inserted into 3130 patients. The incidence of CRT was 3.6%. CRT developed a median of 12 days following line insertion. Peripherally inserted central catheters (PICC) were associated with the highest rates of CRT (hazards ratio (HR) 22.2, 95% confidence interval (CI) 2.9-170.6). Older age groups developed CRT at lower rates (HR 0.57; 95% CI 0.39-0.84 for age 50-61 years, and HR 0.63; 95% CI 0.45-0.89 for age >61 years) compared to age <50 years. Increased CRT was seen in patients with prior CRT (HR 1.81; 95% CI 1.19-2.77). There was a trend to more CRT events with a Khorana tumour score of 1 compared to those with a score of 0 (HR 1.37, 95% CI 1.00-1.88). Hodgkin lymphoma, germ cell and oesophagus cancers had the highest CRT rates. Side of insertion was not associated with thrombosis risk (HR 0.77; 95% CI 0.57-1.05; P = 0.10).

Conclusions: Age <50 years, PICC lines and prior CRT were associated with highest CRT rate. Cancer subtype and insertion side were not predictive of thrombosis.
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http://dx.doi.org/10.1111/imj.14780DOI Listing
December 2020

Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: Probing the lipid metabolome.

PLoS One 2020 8;15(1):e0227455. Epub 2020 Jan 8.

The University of Queensland Diamantina Institute, Faculty of Medicine, University of Queensland, Woolloongabba, Brisbane, Australia.

Background: Multiple myeloma (MM) is a hematological malignancy characterized by the clonal expansion of malignant plasma cells. Though durable remissions are possible, MM is considered incurable, with relapse occurring in almost all patients. There has been limited data reported on the lipid metabolism changes in plasma cells during MM progression. Here, we evaluated the feasibility of concurrent lipidomics and proteomics analyses from patient plasma cells, and report these data on a limited number of patient samples, demonstrating the feasibility of the method, and establishing hypotheses to be evaluated in the future.

Methods: Plasma cells were purified from fresh bone marrow aspirates using CD138 microbeads. Proteins and lipids were extracted using a bi-phasic solvent system with methanol, methyl tert-butyl ether, and water. Untargeted proteomics, untargeted and targeted lipidomics were performed on 7 patient samples using liquid chromatography-mass spectrometry. Two comparisons were conducted: high versus low risk; relapse versus newly diagnosed. Proteins and pathways enriched in the relapsed group was compared to a public transcriptomic dataset from Multiple Myeloma Research Consortium reference collection (n = 222) at gene and pathways level.

Results: From one million purified plasma cells, we were able to extract material and complete untargeted (~6000 and ~3600 features in positive and negative mode respectively) and targeted lipidomics (313 lipids), as well as untargeted proteomics analysis (~4100 reviewed proteins). Comparative analyses revealed limited differences between high and low risk groups (according to the standard clinical criteria), hence we focused on drawing comparisons between the relapsed and newly diagnosed patients. Untargeted and targeted lipidomics indicated significant down-regulation of phosphatidylcholines (PCs) in relapsed MM. Although there was limited overlap of the differential proteins/transcripts, 76 significantly enriched pathways in relapsed MM were common between proteomics and transcriptomics data. Further evaluation of transcriptomics data for lipid metabolism network revealed enriched correlation of PC, ceramide, cardiolipin, arachidonic acid and cholesterol metabolism pathways to be exclusively correlated among relapsed but not in newly-diagnosed patients.

Conclusions: This study establishes the feasibility and workflow to conduct integrated lipidomics and proteomics analyses on patient-derived plasma cells. Potential lipid metabolism changes associated with MM relapse warrant further investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227455PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948732PMC
April 2020

A practical guide to laboratory investigations at diagnosis and follow up in Waldenström macroglobulinaemia: recommendations from the Medical and Scientific Advisory Group, Myeloma Australia, the Pathology Sub-committee of the Lymphoma and Related Diseases Registry and the Australasian Association of Clinical Biochemists Monoclonal Gammopathy Working Group.

Pathology 2020 Feb 3;52(2):167-178. Epub 2020 Jan 3.

Department of Haematology, ACT Pathology, Canberra Hospital, ACT, Australia; ANU Medical School, College of Medicine and Health, Australian National University, Canberra, ACT, Australia; Medical and Scientific Advisory Group, Myeloma Australia; Pathology Sub-committee of the Lymphoma and Related Diseases Registry (LaRDR), Australia. Electronic address:

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 including hypersecretion of IgM, cryoglobulinaemia, increased plasma viscosity and identification of mutated MYD88 in more than 90% of cases. In this review, we aim to provide a guide to the laboratory investigations recommended for WM at initial diagnosis and at follow-up. A discussion on the nuances of diagnosis and differential diagnoses is followed by bone marrow (BM) assessment, measurement of paraprotein and other ancillary investigations. Recommendations are provided on laboratory work-up at diagnosis, in the asymptomatic follow-up phase, and during and post-treatment. Finally, we briefly discuss the implications of laboratory diagnosis in regard to recruitment and monitoring on clinical trials.
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http://dx.doi.org/10.1016/j.pathol.2019.11.002DOI Listing
February 2020

Trends in myeloma relative survival in Queensland by treatment era, age, place of residence, and socioeconomic status.

Leuk Lymphoma 2020 03 14;61(3):721-727. Epub 2019 Nov 14.

Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia.

Relative survival (RS) in myeloma has improved in younger but not older patients (≥80 years) with treatment advances. Whether place of residence or socioeconomic status (SES) affect RS is unknown. We used the Queensland cancer registry to calculate the five-year RS of myeloma patients diagnosed between 1982 and 2014. This period was divided into three eras: (1) 1982-1995 chemotherapy alone; (2) 1996-2007 autologous stem cell transplantation; (3) 2008-2014 novel agents (proteasome inhibitors and IMIDs). 6025 patients were diagnosed from 1982 to 2014. RS improved across eras: (1) 30% vs. (2) 43% vs. (3) 53% ( < .001 (2) vs. (1);  < .001 (3) vs. (2)). RS improved across all age groups, including patients ≥80 years. Patients with disadvantaged SES (39% vs. affluent 46%;  < .001) and rural patients (40% vs. urban 45%;  < .001) had an inferior RS. RS has improved across all ages with treatment advances.
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http://dx.doi.org/10.1080/10428194.2019.1688322DOI Listing
March 2020

A Comparison of High-Dose Cytarabine During Induction Versus Consolidation Therapy in Newly Diagnosed AML.

Hemasphere 2018 Dec 28;2(6):e158. Epub 2018 Nov 28.

Princess Alexandra Hospital, Brisbane, Australia.

The proportion of patients with acute myeloid leukemia (AML) cured is increased by administering high-dose cytarabine (HiDAC). It remains uncertain whether to administer HiDAC as induction or consolidation, and whether ≥1 cycle of HiDAC is required. Our retrospective study of 416 adult AML patients, excluding good risk cytogenetics, compared a single cycle of HiDAC-based therapy followed by 2 cycles of standard-dose cytarabine (SDAC) (HiDAC induction cohort) with SDAC-based chemotherapy followed by 2 cycles of HiDAC-based chemotherapy (HiDAC consolidation cohort). Complete remission (CR) rate was greater in the HiDAC induction cohort (90% vs 78%,  < 0.01) which did not lead to an improved overall survival (48% vs 43%,  = 0.18) or disease-free survival (DFS) (39% vs 45%,  = 0.95). We noted that, after censoring for allogeneic hematopoetic stem cell transplant (alloHSCT) in CR1, the cumulative incidence of relapse was lower in the HiDAC consolidation cohort in patients with intermediate risk cytogenetics (68% vs 44%,  = 0.01), which lead to a greater DFS (30% vs 47%,  = 0.095). In the patients with adverse risk cytogenetics, the RR was numerically greater in the HiDAC consolidation cohort (52% vs 80%,  = 0.60) which lead to a lower DFS (27% vs 4%,  = 0.11). Our data show that, although the HiDAC induction cohort (1 cycle of HiDAC) achieved a greater CR rate, there were no overall survival differences between the 2 cohorts, and that the HiDAC consolidation cohort (2 cycles of HiDAC) had a lower RR and greater DFS in those patients with intermediate risk cytogenetics who did not undergo alloHSCT in CR1.
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http://dx.doi.org/10.1097/HS9.0000000000000158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745967PMC
December 2018

Outcomes of stage I/II follicular lymphoma in the PET era: an international study from the Australian Lymphoma Alliance.

Blood Adv 2019 10;3(19):2804-2811

Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia.

Management practices in early-stage (I/II) follicular lymphoma (FL) are variable and include radiation (RT), systemic therapy, or combined modality therapy (CMT). There is a paucity of data regarding maintenance rituximab in this cohort. We conducted an international retrospective study of patients with newly diagnosed early-stage FL staged with positron emission tomography (PET)-computed tomography and bone marrow biopsy. Three hundred sixty-five patients (stage I, n = 221), median age 63 years, treated from 2005-2017 were included, with a median follow-up of 45 months. Management included watchful waiting (WW; n = 85) and active treatment (n = 280). The latter consisted of RT alone (n = 171) or systemic therapy (immunochemotherapy [n = 63] or CMT [n = 46]). Forty-nine systemically treated patients received maintenance rituximab; 72.7% of stage I patients received RT alone, compared to 42.6% with stage II ( < .001). Active therapies yielded comparable overall response rates ( = .87). RT alone and systemic therapy without maintenance rituximab yielded similar progression-free survival (PFS) (hazard ratio [HR], 1.32; 95% confidence interval [CI], 0.77-2.34; = .96). Maintenance rituximab improved PFS (HR, 0.24; 95% CI, 0.095-0.64; = .017). The incidence of transformation was lower with systemic therapy compared to RT or WW (HR, 0.20; 95% CI, 0.070-0.61; = .034). Overall survival was similar among all practices, including WW ( = .40). In the largest comparative assessment of management practices in the modern era, variable practices each resulted in similar excellent outcomes. Randomized studies are required to determine the optimal treatment in early-stage FL.
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http://dx.doi.org/10.1182/bloodadvances.2019000458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784528PMC
October 2019

PI3K-p110δ contributes to antibody responses by macrophages in chronic lymphocytic leukemia.

Leukemia 2020 02 28;34(2):451-461. Epub 2019 Aug 28.

University of Queensland Diamantina Institute, Woolloongabba, QLD, Australia.

Fcγ receptor (FcγR) signalling in monocyte derived macrophages from chronic lymphocytic leukaemia (CLL) patients is poorly understood. This signalling pathway is the key determinant of the ability of the macrophages to respond to therapeutic antibodies in current clinical use for CLL. Muted FcγR signalling activity accompanies disease progression and results in resistance to therapeutic antibodies. The molecular mechanisms controlling FcγR signalling and resistance are unknown. Here, we demonstrate that the class I phosphoinositide 3-kinase (PI3K) catalytic subunit p110δ is essential for CLL-derived macrophages to respond to therapeutic antibodies. Inhibition of p110δ in the macrophages reduces FcγR-mediated antibody immune responses. Surprisingly, our studies indicated that FcγR downstream signalling is independent of SYK and BTK activity. Thus, we show that FcγR antibody responses occur via a previously unidentified p110δ-dependent pathway, which is independent of the previously described SYK/BTK activation pathway. These data provide novel insights into the effectors of antibody responses. Our data also provide mechanistic insights into therapy resistance in CLL.
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http://dx.doi.org/10.1038/s41375-019-0556-zDOI Listing
February 2020

Progression of Disease Within 24 Months in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune Infiltration.

J Clin Oncol 2019 12 28;37(34):3300-3309. Epub 2019 Aug 28.

Mater Research, University of Queensland, Brisbane, QLD, Australia.

Purpose: Understanding the immunobiology of the 15% to 30% of patients with follicular lymphoma (FL) who experience progression of disease within 24 months (POD24) remains a priority. Solid tumors with low levels of intratumoral immune infiltration have inferior outcomes. It is unknown whether a similar relationship exists between POD24 in FL.

Patients And Methods: Digital gene expression using a custom code set-five immune effector, six immune checkpoint, one macrophage molecules-was applied to a discovery cohort of patients with early- and advanced-stage FL (n = 132). T-cell receptor repertoire analysis, flow cytometry, multispectral immunofluorescence, and next-generation sequencing were performed. The immune infiltration profile was validated in two independent cohorts of patients with advanced-stage FL requiring systemic treatment (n = 138, rituximab plus cyclophosphamide, vincristine, prednisone; n = 45, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), with the latter selected to permit comparison of patients experiencing a POD24 event with those having no progression at 5 years or more.

Results: Immune molecules showed distinct clustering, characterized by either high or low expression regardless of categorization as an immune effector, immune checkpoint, or macrophage molecule. Low programmed death-ligand 2 (PD-L2) was the most sensitive/specific marker to segregate patients with adverse outcomes; therefore, PD-L2 expression was chosen to distinguish immune infiltration (ie, high PD-L2) FL biopsies from immune infiltration (ie, low PD-L2) tumors. Immune infiltration tissues were highly infiltrated with macrophages and expanded populations of T-cell clones. Of note, the immune infiltration subset of patients with FL was enriched for POD24 events (odds ratio [OR], 4.32; c-statistic, 0.81; = .001), validated in the independent cohorts (rituximab plus cyclophosphamide, vincristine, prednisone: OR, 2.95; c-statistic, 0.75; = .011; and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone: OR, 7.09; c-statistic, 0.88; = .011). Mutations were equally proportioned across tissues, which indicated that degree of immune infiltration is capturing aspects of FL biology distinct from its mutational profile.

Conclusion: Assessment of immune-infiltration by PD-L2 expression is a promising tool with which to help identify patients who are at risk for POD24.
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http://dx.doi.org/10.1200/JCO.18.02365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881104PMC
December 2019

Renal Impairment at Diagnosis in Myeloma: Patient Characteristics, Treatment, and Impact on Outcomes. Results From the Australia and New Zealand Myeloma and Related Diseases Registry.

Clin Lymphoma Myeloma Leuk 2019 08 16;19(8):e415-e424. Epub 2019 May 16.

Department of Haematology, Alfred Health-Monash University, Melbourne, Victoria, Australia.

Background: Renal impairment (RI) is a common complication of multiple myeloma (MM) and remains a poor prognostic factor despite improved survival with newer therapies.

Patients And Methods: We evaluated baseline characteristics, treatment, and outcomes of newly diagnosed MM patients with RI at diagnosis in the Australia and New Zealand Myeloma and Related Diseases Registry over 5 years to April 2018; we compared patients with RI (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m) with those with eGFR ≥60. In autologous stem cell transplantation (ASCT) analyses, patients aged 70 years and younger and ≥1 year from diagnosis were included.

Results: Overall, 36% of patients with newly diagnosed MM had RI; they were older, had more advanced disease and comorbidities, and worse performance status. Bortezomib-based induction therapy was most commonly used, although administered to fewer RI patients, despite similar response rates. Patients with RI were less likely to receive ASCT; however, recipients had longer progression-free survival (PFS) and overall survival (OS). Patients with RI had shorter OS and PFS after adjusting for age. In ASCT recipients with RI versus no RI, there was no difference in PFS and OS.

Conclusion: Our findings in "real world" MM patients with RI confirm that patient-, disease-, and treatment-related factors (such as suboptimal bortezomib and ASCT use), and delays in commencing therapy, might contribute to poorer outcomes, and support the use of ASCT in patients with RI.
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http://dx.doi.org/10.1016/j.clml.2019.05.010DOI Listing
August 2019

The epidemiology of amyloidosis in Queensland, Australia.

Br J Haematol 2019 09 31;186(6):829-836. Epub 2019 May 31.

Pathology Queensland, Woolloongabba, Queensland, Australia.

Published studies on the epidemiology of amyloidosis have relied on death certificate data for case ascertainment. We estimated the incidence and mortality burden of amyloidosis among residents of the Australian state, Queensland, aged ≥20 years for the years 1999-2013 based on case ascertainment from histopathology reports. Information systems for participating laboratories were scrutinised to identify histopathology reports that documented a diagnosis of amyloidosis. Case mortality status was determined via linkage to the National Death Index. A total of 447 cases of amyloidosis were identified, with a median age at diagnosis of 66 years. A plasma cell dyscrasia was identified in 72% of patients who had paraprotein studies performed. The estimated incidence for Queenslanders aged ≥20 years was 12·1 cases per million person years. The median survival was 2·45 years. Age at diagnosis, presence of a paraprotein, earlier year of diagnosis, and inner regional location of residence (compared with residence in a major city) were independently associated with reduced survival. Our data confirms previously reported incidence data for amyloidosis of approximately 10 cases per million patient years and indicates that survival for Queensland patients with amyloidosis is improving, though it remains poor for the elderly and patients with AL amyloidosis.
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http://dx.doi.org/10.1111/bjh.16000DOI Listing
September 2019

Validation of the Boston University staging system in AL amyloidosis.

Amyloid 2019 Sep 30;26(3):125-127. Epub 2019 May 30.

c Department of Haematology, Princess Alexandra Hospital Amyloidosis Centre, Princess Alexandra Hospital , Brisbane , Australia.

We aimed to externally validate Lilleness' et al. Boston University (BU) prognostic score that replaced NT-proBNP with brain natriuretic peptide (BNP), which will allow centres without access to NT-proBNP to accurately stage and prognosticate AL amyloidosis. Forty-four were identified that had BNP, NTpro-BNP and TnI taken simultaneously, with a mean follow up of 7.3 years. Median age of the 44 patients was 67 years and 27% were female, with 61% having cardiac involvement, and 61% having renal involvement. Using the BU BNP-based staging system, we identified 12/44 (27%) of patients as stage I, 18/44 (41%) of patients as stage II and 14/44 (31%) of patients as stage III. This correlated closely with stratification via the Mayo score, with only one patient miscategorised (97.7% agreement,  = 0.98). Median overall survival for our BU stage I was not reached, stage II was 40 months and stage III was 5 months (long rank  = .0012). Mayo 2004 median overall survival was identical for stages I, II and III. We have provided external validation of the BU staging system, a novel prognostic scoring system incorporating BNP, instead of NT-proBNP, for AL amyloidosis.
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http://dx.doi.org/10.1080/13506129.2019.1608941DOI Listing
September 2019

Paraprotein Sample Exchange in Australia and New Zealand - 2018.

Clin Biochem Rev 2019 Feb;40(1):43-54

Haematology Department, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia.

Quantification of co-migrating paraproteins in the beta-region presents an ongoing challenge for laboratories performing serum protein electrophoresis. The between-laboratory variation may impact patient care if the patient uses different pathology services during plasma cell dyscrasia monitoring. To identify the practical difficulties and determine the extent of agreement in the reporting of beta-migrating paraproteins in Australia and New Zealand (NZ), sample exchanges were conducted in five Australian states and in NZ in early 2018. This study has highlighted the variation in quantification and reporting of beta-migrating paraproteins which could potentially affect patient monitoring and management.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370286PMC
February 2019

Report of the Survey Conducted by RCPAQAP on Current Practice for Paraprotein and Serum Free Light Chain Measurement and Reporting: a Need for Harmonisation.

Clin Biochem Rev 2019 Feb;40(1):31-42

Haematology Department, Princess Alexandra Hospital, Woolloongabba, Qld 4102, Australia.

Clinical laboratory testing is vital in the diagnosis, monitoring and prognostication of monoclonal gammopathies. Although the 2012 recommendations for standardised reporting of protein electrophoresis in Australia and New Zealand aimed to harmonise the laboratory practices related to paraprotein testing, the between-laboratory variation still exists. A survey was conducted to assess the between-laboratory variation in certain aspects of laboratory testing related to monoclonal gammopathy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370284PMC
February 2019

Proposed Addendum to 2012 Recommendations for Standardised Reporting of Protein Electrophoresis in Australia and New Zealand.

Clin Biochem Rev 2019 Feb;40(1):23-30

Haematology Department, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia.

It is apparent that there is a need for greater harmonisation of the reporting and quantification of paraproteins on protein electrophoresis with the introduction of the electronic health record and recent survey findings indicating ongoing areas of heterogeneity on serum protein electrophoresis. The proposed addendum aims to update the 2012 recommendations for standardised reporting of protein electrophoresis in Australia and New Zealand. The sections which need to be updated include those on the quantification of gamma- and non-gamma-migrating paraproteins; interpretive commenting in specimens with a paraprotein and/or small abnormal bands; the utility of serum free light chains compared with Bence Jones protein measurement; and a new table with interpretive commenting for serum free light chains. It is expected that such standardised reporting will reduce both variation between laboratories and the risk of misinterpretation of results.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370285PMC
February 2019

Combination bone marrow imaging using positron emission tomography (PET)-MRI in plasma cell dyscrasias: correlation with prognostic laboratory values and clinicopathological diagnosis.

BJR Open 2019 13;1(1):20180020. Epub 2019 Feb 13.

Princess Alexandra Hospital, University of Queensland, QLD, Australia.

Objective: This prospective observational study of positron emission tomography (PET)-MRI findings in 16 consecutive newly diagnosed patients with a plasma cell dyscrasia describes and compares MRI-detected myeloma lesions with F-fludeoxyglucose PET-avid myeloma lesions, and correlates quantitative imaging findings to a range of biochemical and prognostic parameters.

Methods: Simultaneously acquired whole body PET and MRI images were evaluated qualitatively for the presence of focal or generalised abnormalities of bone marrow (BM) on either modality. Quantitative analysis comprised mean standardised uptake values (SUVmean) and fractional water content of the BM measured from PET and chemical shift MRI images of the second to fourth lumbar vertebrae.

Results: Final diagnoses comprised symptomatic myeloma ( = 10), asymptomatic myeloma ( = 4) and monoclonal gammopathy of uncertain significance ( = 2). 8/10 patients with symptomatic myeloma demonstrated BM abnormalities on qualitative assessment of MRI compared to 4/10 on PET. BM SUVmean inversely correlated with serum albumin ( = 0.57, = 0.017). BM water fraction correlated with trephine cellularity and blood platelet count ( = 0.78, = 0.00039 and = 0.61, = 0.0013 respectively). BM water fraction correlated with SUVmean in patients with low plasma cell burden ( = 0.91, = 0.0015) but not in patients with high plasma cell burden ( = 0.18, = 0.61).

Conclusion: PET-MRI shows promise in both morphological and functional multiparametric quantitative assessment of myeloma.

Advances In Knowledge: For the first time, multiparametric imaging in myeloma has been shown to predict BM abnormalities and correlate with known biochemical prognostic markers, moving PET-MRI beyond simple diagnostic applications into potential prognostic and treatment selection applications.
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http://dx.doi.org/10.1259/bjro.20180020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592407PMC
February 2019