%0 Journal Article
%~ PubMed
%A Brown, Ross
%A Kabani, Karieshma
%A Favaloro, James
%A Yang, Shihong
%A Ho, P Joy
%A Gibson, John
%A Fromm, Phillip
%A Suen, Hayley
%A Woodland, Narelle
%A Nassif, Najah
%A Hart, Derek
%A Joshua, Douglas
%T CD86+ or HLA-G+ myeloma cells are associated with poor prognosis and once acquired by trogocytosis create novel Tregacq cells.
%B Blood
%D 2012
%C United States
%I American Society of Hematology
%V 120
%N 10
%P 2055-2063
%@ 0006-4971
%X The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukaemia (CLL) and Waldenstrom''s macroglobulinaemia (WM); that T cells are more likely to be recipients than B or NK cells; that trogocytosis occurs independently of either the TCR receptor or HLA compatibility and that following trogocytosis, T cells with acquired antigens can become novel regulators of T cell proliferation. We screened 168 patients with MM and found that CD86 and HLA-G were antigens commonly acquired by T cells from malignant plasma cells. CD3(+)CD86(acq+) and CD3(+) HLA-G(acq+) cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38(++)side population (SP) cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G(+) T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.
%Z FOR Codes: 110709 111206


%0 Journal Article
%~ PubMed
%A Ling, Silvia C W
%A Lau, Edwin K K
%A Al-Shabeeb, Ammira
%A Nikolic, Angela
%A Catalano, Albert
%A Iland, Harry
%A Horvath, Noemi
%A Ho, P Joy
%A Harrison, Simon
%A Fleming, Shaun
%A Joshua, Douglas E
%A Allen, John D
%T Response of myeloma to the proteasome inhibitor bortezomib is correlated with the unfolded protein response regulator XBP-1.
%B Haematologica
%D 2012
%C Italy
%I Fondazione Ferrata Storti
%V 97
%N 1
%P 64-72
%@ 1592-8721
%X Multiple myeloma, a malignancy of the antibody-secreting plasma cells, remains incurable by current therapy. However, the proteasome inhibitor bortezomib and other new drugs are revolutionizing its treatment. It remains unclear why myelomas are peculiarly sensitive to bortezomib, or what causes primary or acquired resistance. The ''unfolded protein response'' is necessary for folding and assembly of immunoglobulin chains in both normal and malignant plasma cells, as well as for the disposal of incorrectly folded or unpaired chains via the ubiquitin-proteasome pathway. We tested the hypothesis that levels of transcription factor XBP-1, a major regulator of the unfolded protein response, predict response to bortezomib.
%Z FOR Codes: 1112


%0 Journal Article
%~ PubMed
%A Ho, P Joy
%A Brown, Ross D
%A Spencer, Andrew
%A Jeffels, Melinda
%A Daniher, Daniel
%A Gibson, John
%A Joshua, Douglas E
%T Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial.
%B Leukemia & Lymphoma
%D 2012
%C Switzerland
%I Informa Healthcare
%V 53
%N 9
%P 1728-1734
%@ 1029-2403
%X The translocation t(4;14) is associated with a poor prognosis in myeloma, but its effect in the setting of new drugs such as thalidomide, bortezomib and lenalidomide continues to be investigated, and the role of candidate genes such as FGFR3 (fibroblast growth factor receptor 3) is not yet clarified. In the Australasian Leukaemia and Lymphoma Group (ALLG) MM6 randomized study comparing consolidation thalidomide and prednisolone with prednisolone alone following autologous stem cell transplant, patients on consolidation thalidomide and prednisolone had superior progression-free (PFS) and overall survival (OS). We now show that thalidomide consolidation benefited both t(4;14)-positive (PFS 29 vs. 17 months, p =0.03) and -negative (52 vs. 24 months, p =0.04) disease. PFS for patients with normal FGFR3 expression was significantly better than for those with up-regulated FGFR3 (31 vs. 21 months, p =0.02). Consolidation thalidomide conferred an improved PFS in patients with normal FGFR3 expression (41 vs. 19 months, p =0.02), but there was no improvement in patients with up-regulated FGFR3 (31 vs. 29 months, p =0.76). We conclude that consolidation thalidomide may mitigate the poor prognostic effect of t(4;14), and improves PFS in normal but not up-regulated FGFR3 expression. Thus the level of FGFR3 expression provides additional prognostic information to t(4;14) in myeloma induction and consolidation therapy.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Ho, Pj
%A Tay, L
%A Lindeman, R
%A Catley, L
%A Bowden, Dk
%T Australian Guidelines for the assessment of iron overload and iron chelation in transfusion-dependent thalassaemia major, sickle cell disease and other congenital anaemias.
%B Internal medicine journal
%D 2011
%C Australia, United Kingdom, Netherlands, United States
%I Wiley-Blackwell Publishing Asia
%V 41
%N 7
%P 516-24
%@ 1445-5994
%X Iron overload is the most important cause of mortality in patients with thalassaemia major. Iron chelation is therefore a critical issue in the management of these patients and others with transfusion-dependent haemoglobinopathies and congenital anaemias. In recent years, significant developments have been made in the assessment of iron overload, including the use of magnetic resonance imaging for measuring liver and cardiac iron. Advances in the modalities available for iron chelation, with the advent of oral iron chelators including deferiprone and deferasirox in addition to parenteral desferrioxamine, have expanded treatment options. A group of Australian haematologists has convened to formulate guidelines for managing iron overload on the basis of available evidence, and to describe best consensus practice as undertaken in major Australian Haemoglobinopathy units. The results of their discussions are described in this article, with the aim of providing guidance in the management of iron overload in these patients.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Viprakasit, Vip
%A Ibrahim, Hishamshah
%A Ha, Shau-Yin
%A Ho, Phoebe Joy
%A Li, Chi-Kong
%A Chan, Lee-Lee
%A Chiu, Chang-Fang
%A Sutcharitchan, Pranee
%A Habr, Dany
%A Domokos, Gabor
%A Roubert, Bernard
%A Xue, Hong-Ling
%A Bowden, Donald K
%A Lin, Kai-Hsin
%T Clinical efficacy and safety evaluation of tailoring iron chelation practice in thalassaemia patients from Asia-Pacific: a subanalysis of the EPIC study of deferasirox.
%B International Journal of Hematology
%D 2011
%C Japan
%I Springer Japan KK
%V 93
%N 3
%P 319-328
%@ 1865-3774
%X Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients'' Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.
%Z FOR Codes: 110202


%0 Journal Article
%~ PubMed
%A Reid, S
%A Yang, S
%A Brown, R
%A Kabani, K
%A Aklilu, E
%A Ho, P J
%A Woodland, N
%A Joshua, D
%T Characterisation and relevance of CD138-negative plasma cells in plasma cell myeloma.
%B International journal of laboratory hematology
%D 2010
%C United Kingdom, Unit
%I Wiley-Blackwell Publishing Ltd.
%V 32
%N 6 Pt 1
%P e190-6
%@ 1751-5521
%X The use of CD138 to isolate CD138(+) plasma cells (PCs) from plasma cell myeloma (PCM) patients'' bone marrow samples has been used extensively in myeloma research. We sought to highlight the problem with this selection process, by demonstrating that a subpopulation of CD138??? plasma cells exists which is not included in these analyses.
%Z FOR Codes: 110399 110701 110701


%0 Journal Article
%~ PubMed
%A Li, Jia
%A Sze, Daniel M-Y
%A Brown, Ross D
%A Cowley, Mark J
%A Kaplan, Warren
%A Mo, Sui-Lin
%A Yang, Shihong
%A Aklilu, Esther
%A Kabani, Karieshma
%A Loh, Yen S
%A Yamagishi, Tetsuo
%A Chen, Yuling
%A Ho, P Joy
%A Joshua, Douglas E
%T Clonal expansions of cytotoxic T cells exist in the blood of patients with Waldenstrom's Macroglobulinaemia but exhibit anergic properties and are eliminated by nucleoside analogue therapy.
%B Blood
%D 2010
%C United States
%I American Society of Hematology
%V 115
%N 17
%P 3580-8
%@ 0006-4971
%X T cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8(+)CD57(+) T-cell receptor Vbeta-positive (TCRVbeta(+))-restricted cytotoxic T-cell (CTL) clones are found in 48% of patients with multiple myeloma and confer a favorable prognosis. We now report that CTL clones with varying TCRVbeta repertoire are present in 70% of patients with Waldenstr??m macroglobulinemia (WM; n = 20). Previous nucleoside analog (NA) therapy, associated with increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVbeta expansions (chi(2) = 11.6; P < .001), as 83% of patients without (n = 6) and only 7% with (n = 14) TCRVbeta expansions had received NA. Clonality of CD3(+)CD8(+)CD57(+)TCRVbeta(+)-restricted CTLs was confirmed by TCRVbeta CDR3 size analysis and direct sequencing. The differential expression of CD3(+)CD8(+)CD57(+)TCRVbeta(+) cells was profiled using DNA microarrays and validated at mRNA and protein level. By gene set enrichment analysis, CTL clones expressed not only genes from cytotoxic pathways (GZMB, PRF1, FGFBP2) but also genes that suppress apoptosis, inhibit proliferation, arrest cell-cycle G1/S transition, and activate T cells (RAS, CSK, and TOB pathways). Proliferation tracking after stimulation confirmed their anergic state. Our studies demonstrate the incidence, NA sensitivity, and nature of clonal CTLs in WM and highlight mechanisms that cause anergy in these cells.
%Z FOR Codes: 110704 110709


%0 Journal Article
%~ PubMed
%A Perera, N J
%A Lau, N S
%A Mathews, S
%A Waite, C
%A Ho, P J
%A Caterson, I D
%T Overview of endocrinopathies associated with &#946;-thalassaemia major.
%B Internal Medicine Journal
%D 2010
%C Australia, United Kingdom, Netherlands, United States
%I Wiley-Blackwell Publishing Asia
%V 40
%N 10
%P 689-696
%@ 1445-5994
%X Background:??? Thalassaemia major is a common and serious medical problem worldwide that is associated with a range of complications, including effects on multiple endocrine pathways. Minimizing or preventing comorbidities is important for these individuals who need life-long multidisciplinary care and treatment. However, there are limited overviews of the endocrine complications associated with this illness, nor any consensus regarding management guidelines. Method:??? A retrospective cohort analysis of ??-thalassaemia patients attending an ambulatory transfusion clinic at Royal Prince Alfred Hospital was conducted from June 2008. Results:??? All of our subjects (n???=???29) had at least one endocrinopathy present with 16 patients (55%) having three or more (???3) endocrinopathies. Hypogonadism was the most prevalent followed by osteoporosis and growth failure (less than 3rd centile) with a frequency of 16/29 (55%), 14/29 (48%) and 10/29 (35%) patients respectively. Those with more endocrinopathies (???3) had a longer duration of transfusion therapy when compared with those with fewer endocrinopathies. Conclusion:??? A summary of our clinical guidelines, which have been used to monitor and manage these complications, is presented along with a discussion on the results and pathophysiology of the associated endocrinopathies.
%Z FOR Codes: 110202 110306


%0 Journal Article
%~ PubMed
%A Brown, Ross D
%A Spencer, Andrew
%A Ho, Phoebe Joy
%A Kennedy, Nola
%A Kabani, Karieshma
%A Yang, Shihong
%A Sze, Daniel M
%A Aklilu, Esther
%A Gibson, John
%A Joshua, Douglas E
%T Prognostically significant cytotoxic T cell clones are stimulated after thalidomide therapy in patients with multiple myeloma.
%B Leukemia and Lymphoma
%D 2009
%C United Kingdom
%I Informa Healthcare
%V 50
%N 11
%P 1860-1864
%@ 1029-2403
%X The expanded T cell clones are associated with a prolonged survival in patients with multiple myeloma. We sought to confirm this prognostic significance in a multicenter patient cohort and investigate the effect of thalidomide on clones and T regulatory cells (T(regs)). Blood was collected from 120 patients enrolled in a Phase III trial of maintenance therapy +/- thalidomide after autologous stem cell transplantation. TCR Vbeta repertoire analysis identified T cell expansions in 48% of patients pre-transplant and 68% after 8-month maintenance. T cell expansions, previously shown to be clonal, were predominantly CD8+ (93%) and all 24 TCR Vbeta families tested were represented. Thalidomide therapy was associated with a significant increase in the incidence of patients with multiple expansions (49% vs. 23%; chi2 = 6.8; p = 0.01). The presence of expansions regardless of therapy was associated with a significantly longer median progression free survival (PFS) (32.1 vs. 17.6 months; chi2 = 5.6; p = 0.02) and overall survival (OS) (chi2 = 3.9; p < 0.05). Median PFS in the thalidomide arm was 50.9 months for patients with expansions and 28.3 months for patients without expansions (chi2 = 19.4; p = 0.0002). Thalidomide did not appear to modulate T(reg) numbers. Expanded T cell clones are prognostically significant and have an impact on progression after thalidomide therapy in a proportion of patients.
%Z FOR Codes: 60199


%0 Journal Article
%~ PubMed
%A Joshua, Douglas E
%A Brown, Ross D
%A Ho, P Joy
%A Gibson, John
%T Regulatory T cells and Multiple Myeloma.
%B Clinical Lymphoma & Myeloma
%D 2008
%C United States
%I Cancer Information Group
%V 8
%N 5
%P 283-286
%@ 1557-9190
%X Many clinical observations point to active immunologic phenomena in patients with myeloma. These consist of active suppression of the host''s immune system and partially successful attempts by the host''s immune system to suppress the malignant B-cell population. Clinical conditions such as asymptomatic myeloma, which represents clinical presentation in the plateau phase of the disease, plateau establishment after conventional induction therapy without the ongoing need for therapy, and the positive prognostic importance of the presence of clones of cytotoxic T cells in the peripheral blood of some patients, suggest that host-tumor interaction is an active dynamic state. Regulatory T (Treg) cells comprise 5%-10% of peripheral CD4 T cells and are responsible for the control of autoimmune phenomena. Deficiency of the FoxP3 transcription factor, which normally characterizes Treg cells, leads to multiorgan autoimmune disorders in humans and mice. The role of Treg cells in the protection from malignancy is unclear, but their depletion can lead to the induction of tumor rejection in murine models, and their demonstration as tumorinfiltrating lymphocytes in malignancy point to a significant immunomodulator role. In myeloma, host-tumor immune interactions are complex. However, patients can clearly exhibit control of their B-cell malignancy for many years with stability of paraprotein levels, demonstrating a homeostasis between tumor and host. Whether Treg cells are playing a role in this homeostasis is unclear. At present, there is considerable debate in the literature regarding observations such as whether Treg cells are increased or decreased, functional or dysfunctional. In this review, we will discuss the potential importance of Treg cells and their role in myeloma, a disease characterized by a unique set of host-tumor interactions.
%Z FOR Codes: 1107


%0 Journal Article
%~ PubMed
%A Sanders, J
%A Crawford, B
%A Gibson, J
%A Joy Ho, P
%A Iland, H
%A Joshua, D
%T Is there a case for the early use of bisphosphonates in smouldering myeloma and MGUS? (Bisphosphonates in SMM & MGUS).
%B International journal of laboratory hematology
%D 2007
%C United Kingdom
%I Blackwell Publishing Ltd.
%V 29
%N 5
%P 395-397
%@ 1751-5521
%X 
%Z FOR Codes:


%0 Book Section
%A Ling, Silvia
%A Campbell, Lynda J
%A Ho, Joy
%A Gibson, John
%A Joshua, Douglas
%T Molecular Biology, Pathology, and Cytogenetics
%B Clinical Malignant Haematology
%D 2007
%C United States
%I McGraw Hill
%V 
%N 
%P 847-857
%@ 9780071436502
%E Sekeres, Mikkael A.
%E Kalaycio, Matt E.
%E Bolwell, Brian J.
%X 
%Z FOR Codes: 110202 111201


%0 Journal Article
%~ PubMed
%A Osborne, Richard H
%A De Abreu Lourenço, Richard
%A Dalton, Andrew
%A Houltram, Jennifer
%A Dowton, David
%A Joshua, Douglas Edgar
%A Lindeman, Robert
%A Ho, Phoebe Joy
%T Quality of life related to oral versus subcutaneous iron chelation: a time trade-off study.
%B Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research
%D 2007
%C United States
%I Wiley-Blackwell Publishing Inc.
%V 10
%N 6
%P 451-456
%@ 1524-4733
%X OBJECTIVE: To investigate the utility associated with subcutaneous infusion (deferoxamine) compared with once-daily oral administration (deferasirox) of iron chelation therapy. METHODS: Interviews using the time trade-off technique were used to estimate preferences (utility) for health states by finding the point at which respondents were indifferent between a longer but lower quality of life (QoL) and a shorter time in full health. Participants (n = 110) were community-based, 51% women, median age 35 years, from four regions in Sydney, Australia. Respondents rated three health states involving equal outcomes for people with thalassemia but with different treatment modalities for iron chelation; an "anchor state" describing a patient receiving iron chelation without administration mode specified, anchor state plus iron chelation via subcutaneous infusion, and anchor state plus iron chelation through once-daily oral medication. RESULTS: On an interval scale between 0 (death) and 1 (full health), median (interquartile range) utility of 0.80 (0.65-0.95) for the anchor state, 0.66 (0.45-0.87) for subcutaneous infusion, and 0.93 (0.80-0.97) for once-daily oral administration was obtained. The mean (median) difference of 0.23 (0.27) between the two treatments was statistically significant (Wilcoxon-signed rank test, P < 0.001). Subcutaneous infusion was associated with a mean (median) utility 0.13 (0.14) lower than the anchor state (P < 0.001), and once-daily oral treatment had a utility 0.10 (0.13) higher (P < 0.001). CONCLUSION: Community respondents associate oral administration of an iron chelator such as deferasirox with enhanced QoL compared with subcutaneous treatment. Assuming equal safety and efficacy, QoL gains from once-daily oral treatment compared with subcutaneous infusion are significant.
%Z FOR Codes: 110202 110502


%0 Journal Article
%A Trent, Ronald
%A Webster, Boyd
%A Bowden, Donald
%A Gilbert, Anne
%A Ho, P Joy
%A Lindeman, Robert
%A Lammi, Ahti
%A Rowell, John
%A Hinchcliffe, Marcus
%A Colley, Alison
%A Wilson, Meredith
%A Saleh, Mona
%A Blackwell, Jennifer
%A Vicki, Petrou
%T Complex phenotypes in the haemoglobinopathies: recommendations on screening and DNA testing
%B Pathology
%D 2006
%C United Kingdom
%I Informa Healthcare
%V 38
%N 6
%P 507-519
%@ 0031-3025
%X 
%Z FOR Codes: 110311


%0 Journal Article
%~ PubMed
%A Sze, Daniel M-Y
%A Brown, Ross
%A Yang, Shihong
%A Ho, P Joy
%A Gibson, John
%A Joshua, Douglas
%T The use of thalidomide in myeloma therapy as an effective anticancer drug.
%B Current cancer drug targets
%D 2006
%C Netherlands
%I Bentham Science Publishers Ltd.
%V 6
%N 4
%P 325-31
%@ 1568-0096
%X Thalidomide and its immunomodulatory derivatives have provided the most significant advance in the therapy of myeloma since the introduction of high dose chemotherapy followed by stem cell transplantation nearly 20 years ago. The mechanism of action of thalidomide is complex and involves many aspects of malignant plasma cell growth and bone marrow stromal cell microenvironment interaction. Thalidomide was first used because of its anti-angiogenic properties, however it is the immunomodulatory actions that involve increasing host tumour-specific immunosurveillance by both T cell and natural killer cells which may be the most important mode of action.
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Ling, Silvia
%A Joshua, Douglas E
%A Gibson, John
%A Young, Graham
%A Iland, Harry
%A Watson, Geoff
%A Ho, P Joy
%T Transformation and progression of Waldenström's macroglobulinemia following cladribine therapy in two cases: natural evolution or iatrogenic causation?
%B American journal of hematology
%D 2006
%C United States
%I John Wiley & Sons, Inc.
%V 81
%N 2
%P 110-4
%@ 0361-8609
%X We report two cases of Waldenström''s macroglobulinemia with an unusual aggressive transformation following treatment with cladribine (2-chlorodeoxyadenosine, 2-CdA), a purine analogue. The first patient developed transformation to a diffuse large-cell non-Hodgkin lymphoma, while the second developed extensive extramedullary involvement. Both patients displayed rapid progression following transformation and were refractory to chemotherapy. Both patients were pretreated with multiple courses of prednisone and chlorambucil, and transformation occurred shortly after therapy with cladribine. We propose that immune suppression from alkylating agents and purine analogues may have contributed to the unusual progression, resulting in a dismal outcome.
%Z FOR Codes: