Publications by authors named "Kenneth Bradstock"

71 Publications

RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML.

Blood Adv 2020 03;4(6):1131-1144

Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA, Australia.

First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
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http://dx.doi.org/10.1182/bloodadvances.2019000901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094007PMC
March 2020

CD300f epitopes are specific targets for acute myeloid leukemia with monocytic differentiation.

Mol Oncol 2019 10 20;13(10):2107-2120. Epub 2019 Aug 20.

Dendritic Cell Research, ANZAC Research Institute, Sydney, Australia.

Antibody-based therapy in acute myeloid leukemia (AML) has been marred by significant hematologic toxicity due to targeting of both hematopoietic stem and progenitor cells (HSPCs). Achieving greater success with therapeutic antibodies requires careful characterization of the potential target molecules on AML. One potential target is CD300f, which is an immunoregulatory molecule expressed predominantly on myeloid lineage cells. To confirm the value of CD300f as a leukemic target, we showed that CD300f antibodies bind to AML from 85% of patient samples. While one CD300f monoclonal antibody (mAb) reportedly did not bind healthy hematopoietic stem cells, transcriptomic analysis found that CD300f transcripts are expressed by healthy HSPC. Several CD300f protein isoforms exist as a result of alternative splicing. Importantly for antibody targeting, the extracellular region of CD300f can be present with or without the exon 4-encoded sequence. This results in CD300f isoforms that are differentially bound by CD300f-specific antibodies. Furthermore, binding of one mAb, DCR-2, to CD300f exposes a structural epitope recognized by a second CD300f mAb, UP-D2. Detailed analysis of publicly available transcriptomic data indicated that CD34 HSPC expressed fewer CD300f transcripts that lacked exon 4 compared to AML with monocytic differentiation. Analysis of a small cohort of AML cells revealed that the UP-D2 conformational binding site could be induced in cells from AML patients with monocytic differentiation but not those from other AML or HSPC. This provides the opportunity to develop an antibody-based strategy to target AMLs with monocytic differentiation but not healthy CD34 HSPCs. This would be a major step forward in developing effective anti-AML therapeutic antibodies with reduced hematologic toxicity.
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http://dx.doi.org/10.1002/1878-0261.12549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763785PMC
October 2019

A phase II study of a modified hyper-CVAD frontline therapy for patients with adverse risk diffuse large B-cell and peripheral T-cell non-Hodgkin lymphoma.

Leuk Lymphoma 2019 04 14;60(4):904-911. Epub 2018 Dec 14.

j Department of Haematology , Peter MacCallum Cancer Centre , Melbourne , Australia.

To improve complete remission (CR) rates by reducing toxicity and enhancing delivery, we created a modified hyper-CVAD/MA regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate, cytarabine) by reducing the cytarabine dose (3 g/m to 2 g/m) and number of cycles (eight to six). We conducted a phase II trial in the pre-rituximab era in the intermediate-high international prognostic index (IPI) (≥2) de novo diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) (ACTRN12605000105640). CR rates were compared with reported IPI-stratified rates. Sixty-three patients (n = 26 PTCL; n = 37 DLBCL) were evaluated; median follow-up of 30 months. CR rates for PTCL and DLBCL patients were 46% and 49%, respectively, similar with reported CR rates with CHOP-like chemotherapy (p = .6). Of the patients, 51 (81%) experienced ≥1 unplanned hospital admission; only 41 (65%) completed six cycles. The cytarabine modifications did not prevent significant toxicity. Modified hyper-CVAD/MA resulted in similar outcomes to CHOP-like chemotherapy in aggressive lymphomas and was associated with significant toxicity.
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http://dx.doi.org/10.1080/10428194.2018.1516873DOI Listing
April 2019

Unmet supportive care needs of haematological cancer survivors: rural versus urban residents.

Ann Hematol 2018 Jul 10;97(7):1283-1292. Epub 2018 Mar 10.

Leukaemia Foundation of Australia, Windsor, Brisbane, QLD, Australia.

Due to fewer cancer services in rural locations, rural survivors may have unique unmet needs compared to urban survivors. This study compared among rural and urban haematological cancer survivors the most common "high/very high" unmet supportive care needs and the unmet need scores for five domains (information, financial concerns, access and continuity of care, relationships and emotional health). Survivors' socio-demographics, rurality, cancer history and psychological factors associated with each unmet need domain were also explored. A total of 1511 haematological cancer survivors were recruited from five Australian state cancer registries and 1417 (1145 urban, 272 rural) allowed extraction of their residential postcode from registry records. A questionnaire that contained the Survivor Unmet Needs Survey was mailed to survivors. Dealing with feeling tired was the most common "high/very high" unmet need for rural (15.2%) and urban (15.5%) survivors. The emotional health domain had the highest mean unmet need score for rural and urban survivors. Rurality was associated with a decreased unmet emotional health domain score whereas travelling for more than 1 h to treatment was associated with increased unmet financial concerns and unmet access and continuity of care. Depression, anxiety and stress were associated with increased unmet need scores for all five domains. Unmet need domain scores generally did not differ by rurality. Travelling for more than 1 h to treatment was associated with increased unmet need scores on two domains. Telemedicine and increased financial assistance with travel and accommodation may help those travelling long distances for treatment.
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http://dx.doi.org/10.1007/s00277-018-3285-xDOI Listing
July 2018

Identification of sphingosine kinase 1 as a therapeutic target in B-lineage acute lymphoblastic leukaemia.

Br J Haematol 2019 02 23;184(3):443-447. Epub 2018 Jan 23.

Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, Australia.

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http://dx.doi.org/10.1111/bjh.15097DOI Listing
February 2019

Idarubicin Dose Escalation During Consolidation Therapy for Adult Acute Myeloid Leukemia.

J Clin Oncol 2017 May 3;35(15):1678-1685. Epub 2017 Apr 3.

Kenneth F. Bradstock and Warwick Benson, Westmead Hospital, University of Sydney; Arno Enno, Sandra Deveridge, and Philip Rowlings, Calvary Mater Newcastle Hospital, Newcastle; Luke Coyle, Royal North Shore Hospital, St Leonards; Campbell Tiley, Central Coast Health, Gosford; John Moore, St Vincent's Hospital; Mark Hertzberg, Prince of Wales Hospital, Sydney; Kimberly Cartwright, Wollongong Hospital, Wollongong; Ilona Cunningham, Concord Repatriation General Hospital, Concord; John Taper, Nepean Hospital, Penrith, New South Wales; Emma Link, Juliana Di Iulio, and John F. Seymour, Peter MacCallum Cancer Centre; Jeff Szer, Andrew Grigg, Andrew W. Roberts, and John F. Seymour, University of Melbourne; Andrew H. Wei, Monash University; Anthony Schwarer, Box Hill Hospital; Lynda Campbell, Victorian Cancer Cytogenetics Service, Melbourne; Jeff Szer, Andrew Grigg, and Andrew W. Roberts, Royal Melbourne Hospital, Parkville; Phillip Campbell, Deakin University School of Medicine, Geelong, Victoria; Paula Marlton, Anthony K. Mills, and Devinder Gill, University of Queensland, Brisbane, Queensland; Ray M. Lowenthal, University of Tasmania, Hobart, Tasmania; Ian D. Lewis and Peter Bardy, Royal Adelaide Hospital; Uwe Hahn, Queen Elizabeth Hospital, Adelaide, South Australia; James D'Rozario, The Canberra Hospital, Garran, Canberra, Australia Capital Territory; Gavin Cull, Sir Charles Gairdner Hospital; Michael F. Leahy, University of Western Australia; and Paul Cannell, Royal Perth Hospital, Perth, Western Australia, Australia.

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m daily for 5 days, etoposide 75 mg/m daily for 5 days, and idarubicin 9 mg/m daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.
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http://dx.doi.org/10.1200/JCO.2016.70.6374DOI Listing
May 2017

Bone Marrow Graft-Versus-Host Disease in Major Histocompatibility Complex-Matched Murine Reduced-Intensity Allogeneic Hemopoietic Cell Transplantation.

Transplantation 2017 11;101(11):2695-2704

1 Westmead Institute for Medical Research, New South Wales, Australia. 2 University of Sydney, Sydney, Australia. 3 Dendritic Cell Research, ANZAC Research Institute, Sydney, Australia. 4 Sydney Medical School, University of Sydney, Sydney, Australia.

Background: Most clinical allogeneic hemopoietic cell transplants (alloHCT) are now performed using reduced-intensity conditioning (RIC) instead of myeloablative conditioning (MAC); however, the biology underlying this treatment remains incompletely understood.

Methods: We investigated a murine model of major histocompatibility complex-matched multiple minor histocompatibility antigen-mismatched alloHCT using bone marrow (BM) cells and splenocytes from B6 (H-2) donor mice transplanted into BALB.B (H-2) recipients after RIC with fludarabine of 100 mg/kg per day for 5 days, cyclophosphamide of 60 mg/kg per day for 2 days, and total body irradiation (TBI).

Results: The lowest TBI dose capable of achieving complete donor chimerism in this mouse strain combination was 325 cGy given as a single fraction. Mice that underwent RIC had a reduced incidence and delayed onset of graft-versus-host disease (GVHD) and significantly prolonged survival compared with MAC-transplanted recipients (TBI of 850 cGy plus cyclophosphamide of 60 mg/kg per day for 2 days). Compared with syngeneic controls, RIC mice with GVHD showed evidence of BM suppression, have anemia, reduced BM cellularity, and showed profound reduction in BM B cell lymphopoiesis associated with damage to the endosteal BM niche. This was associated with an increase in BM CD8 effector T cells in RIC mice and elevated blood and BM plasma levels of T helper1 cytokines. Increasing doses of splenocytes resulted in increased incidence of GVHD in RIC mice.

Conclusions: We demonstrate that the BM is a major target organ of GVHD in an informative clinically relevant RIC mouse major histocompatibility complex-matched alloHCT model by a process that seems to be driven by CD8 effector T cells.
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http://dx.doi.org/10.1097/TP.0000000000001733DOI Listing
November 2017

Psychological morbidity among Australian rural and urban support persons of haematological cancer survivors: Results of a national study.

Psychooncology 2017 Nov 30;26(11):1952-1958. Epub 2017 Mar 30.

University of Waterloo, Waterloo, Ontario, Canada.

Objective: To compare the prevalence of anxiety, depression, and stress among rural and urban support persons of haematological cancer survivors and explore factors associated with having one or more of these outcomes.

Methods: Haematological cancer survivors were identified via 1 of 5 state-based cancer registries and invited to take part in a survey. Those who agreed were asked to pass on a questionnaire package to their support person. Measures included the Depression, Anxiety, and Stress Scale, Support Persons' Unmet Need Survey, and sociodemographic questions.

Results: Nine-hundred and eighty-nine (66%) participating survivors had a participating support person. There were no significant differences in the proportion of urban versus rural support persons who reported elevated levels of depression (21% vs 23%), anxiety (16% vs 17%), or stress (16% vs 20%), P > .05. Odds of reporting at least 1 indicator of psychological morbidity increased by 10% to 17% for each additional high or very high unmet need and by 2% for those who had relocated from their usual place of residence for the survivor to receive treatment and was decreased by 5% to 54% for those support persons who reported that they had no chronic health conditions.

Conclusions: Psychological outcomes for rural and urban support persons are similar. Those who have poor health, have had to relocate, and who have multiple unmet needs are particularly vulnerable to poor psychological outcomes. These factors should be assessed to enable early intervention for those at risk of poor outcomes.
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http://dx.doi.org/10.1002/pon.4411DOI Listing
November 2017

The Analysis of CD83 Expression on Human Immune Cells Identifies a Unique CD83+-Activated T Cell Population.

J Immunol 2016 12 11;197(12):4613-4625. Epub 2016 Nov 11.

ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, New South Wales 2139, Australia;

CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4, CD8 T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.
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http://dx.doi.org/10.4049/jimmunol.1600339DOI Listing
December 2016

CMRF-56(+) blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses.

Oncoimmunology 2016 Jun 5;5(6):e1168555. Epub 2016 May 5.

ANZAC Research Institute, Concord, NSW, Australia; Sydney Medical School, University of Sydney, Camperdown, NSW, Australia; Department of Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; Department of Haematology, Concord Repatriation General Hospital, Concord, NSW, Australia.

There are numerous transcriptional, proteomic and functional differences between monocyte-derived dendritic cells (Mo-DC) and primary blood dendritic cells (BDC). The CMRF-56 monoclonal antibody (mAb) recognizes a cell surface marker, which is upregulated on BDC following overnight culture. Given its unique ability to select a heterogeneous population of BDC, we engineered a human chimeric (h)CMRF-56 IgG4 mAb to isolate primary BDC for potential therapeutic vaccination. The ability to select multiple primary BDC subsets from patients and load them with in vitro transcribed (IVT) mRNA encoding tumor antigen might circumvent the issues limiting the efficacy of Mo-DC. After optimizing and validating the purification of hCMRF-56(+) BDC, we showed that transfection of hCMRF-56(+) BDC with mRNA resulted in efficient mRNA translation and antigen presentation by myeloid BDC subsets, while preserving superior DC functions compared to Mo-DC. Immune selected and transfected hCMRF-56(+) BDC migrated very efficiently in vitro and as effectively as cytokine matured Mo-DC in vivo. Compared to Mo-DC, hCMRF-56(+) BDC transfected with influenza matrix protein M1 displayed superior MHC peptide presentation and generated potent antigen specific CD8(+) T-cell recall responses, while Wilms tumor 1 (WT1) transfected CMRF-56(+) BDC generated effective primary autologous cytotoxic T-cell responses. The ability of the combined DC subsets within hCMRF-56(+) BDC to present mRNA delivered tumor antigens merits phase I evaluation as a reproducible generic platform for the next generation of active DC immune therapies.
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http://dx.doi.org/10.1080/2162402X.2016.1168555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938320PMC
June 2016

Effects of intensive induction and consolidation chemotherapy with idarubicin and high dose cytarabine on minimal residual disease levels in newly diagnosed adult precursor-B acute lymphoblastic leukemia.

Contemp Clin Trials Commun 2016 Dec 22;4:9-13. Epub 2016 Jun 22.

Department of Haematology, Peter MacCallum Cancer Centre, University of Melbourne, Victoria, Australia.

An intensive induction regimen, consisting of idarubicin and high dose cytarabine, was assessed in 19 adult patients, median age 44 years, with newly diagnosed precursor-B acute lymphoblastic leukemia (ALL). Patients achieving a complete response (CR) were given an attenuated consolidation course. The primary endpoints were induction death rate and incidence of serious non-hematological toxicity. Grades 3-4 diarrhoea occurred in 47% of patients during induction. Two patients (11%) died during induction therapy, and 2 were withdrawn due to resistant disease or prolonged marrow hypoplasia. Fifteen patients achieved CR (79%), but levels of minimal residual disease (MRD) after induction were comparable with those previously observed using a modified pediatric protocol. Overall survival at 5 years was 36.8% while leukemia-free survival was 44.1%. An intensive AML protocol used in adults with ALL resulted in substantial toxicity and provided similar levels of cytoreduction to conventional ALL protocols, without improving long-term outcomes.
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http://dx.doi.org/10.1016/j.conctc.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935861PMC
December 2016

A CD2 high-expressing stress-resistant human plasmacytoid dendritic-cell subset.

Immunol Cell Biol 2016 05 21;94(5):447-57. Epub 2016 Jan 21.

Dendritic Cell Research, ANZAC Research Institute, Concord Repatriation General Hospital, Sydney, NSW, Australia.

Human plasmacytoid dendritic cells (pDCs) were considered to be a phenotypically and functionally homogeneous cell population; however, recent analyses indicate potential heterogeneity. This is of major interest, given their importance in the induction of anti-viral responses and their role in creating immunologically permissive environments for human malignancies. For this reason, we investigated the possible presence of human pDC subsets in blood and bone marrow, using unbiased cell phenotype clustering and functional studies. This defined two major functionally distinct human pDC subsets, distinguished by differential expression of CD2. The CD2(hi) and CD2(lo) pDCs represent discontinuous subsets, each with hallmark pDC functionality, including interferon-alpha production. The rarer CD2(hi) pDC subset demonstrated a significant survival advantage over CD2(lo) pDC during stress and upon exposure to glucocorticoids (GCs), which was associated with higher expression of the anti-apoptotic molecule BCL2. The differential sensitivity of these two human pDC subsets to GCs is demonstrated in vivo by a relative increase in CD2(hi) pDC in multiple myeloma patients treated with GCs. Hence, the selective apoptosis of CD2(lo) pDC during stress represents a novel mechanism for the control of innate responses.
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http://dx.doi.org/10.1038/icb.2015.116DOI Listing
May 2016

Influence of Stem Cell Source on Outcomes of Allogeneic Reduced-Intensity Conditioning Therapy Transplants Using Haploidentical Related Donors.

Biol Blood Marrow Transplant 2015 Sep 14;21(9):1641-5. Epub 2015 Jun 14.

Blood and Marrow Transplant Service, Haematology Department, Westmead Hospital, Westmead, New South Wales, Australia.

We compared outcomes for 2 retrospective cohorts of patients undergoing reduced-intensity conditioning (RIC) therapy transplants using haploidentical related donors and post-transplant prophylaxis against graft-versus-host disease (GVHD) with high-dose cyclophosphamide, tacrolimus, and mycophenolate. The first cohort of 13 was transplanted with bone marrow (BM) as the stem cell source, whereas the second cohort of 23 used peripheral blood stem cells (PBSCs) mobilized with granulocyte colony-stimulating factor. The BM cohort received a single 60-mg/kg dose of cyclophosphamide on day +3, whereas the PBSC cohort received 2 doses on days +3 and +4. Patients in the first cohort were slightly older and had a higher proportion of acute myeloid leukemia, but there were no differences in the distribution of Disease Risk Index scores between the 2 groups. Patients in the PBSC group received double the number of CD34(+) cells in the stem cell graft. Times to neutrophil and platelet recovery were not different between the 2 groups. Three patients, all in the PBSC group, failed to engraft but recovered with autologous hemopoiesis and survived. The 6-month cumulative incidences of acute GVHD were 55.1% for BM and 48.5% for PBSCs (P = .651), whereas 24-month cumulative rates for chronic GHVD were 28.6% for BM and 32.3% for PBSCs (P = .685). Only 2 patients, both in the BM group, died of nonrelapse causes, both of second cancers. The 2-year cumulative incidences of relapse were 43.9% for BM and 23.5% for PBSCs (P = .286). Overall survival at 2 years was significantly better for PBSC patients (P = .028), at 83.4% versus 52.7% for BM. Relapse-free and event-free survival did not differ significantly between BM and PBSC groups. In this retrospective analysis, we conclude that the use of PBSCs for haploidentical RIC transplants is a feasible strategy, with equivalent rates of acute and chronic GVHD and risk of relapse and low nonrelapse mortality compared with BM.
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http://dx.doi.org/10.1016/j.bbmt.2015.06.006DOI Listing
September 2015

Single-Agent High-Dose Cyclophosphamide for Graft-versus-Host Disease Prophylaxis in Human Leukocyte Antigen-Matched Reduced-Intensity Peripheral Blood Stem Cell Transplantation Results in an Unacceptably High Rate of Severe Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2015 May 27;21(5):941-4. Epub 2015 Jan 27.

BMT Service, Westmead Hospital, Sydney, New South Wales, Australia.

High-dose cyclophosphamide given early after allogeneic hemopoietic cell transplantation has been shown to be effective prophylaxis against graft-versus-host disease (GVHD) in the setting of HLA-matched myeloablative bone marrow grafts, allowing avoidance of long-term immunosuppression with calcineurin inhibitors in some patients. Whether this approach is feasible using granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell grafts is unknown. We conducted an exploratory phase 2 trial of cyclophosphamide given at 50 mg/kg i.v. on days 3 and 4 after transplantation as sole GVHD prophylaxis in recipients of G-CSF-mobilized peripheral blood stem cell grafts from HLA-matched related or unrelated donors after reduced-intensity conditioning therapy with fludarabine, carmustine, and melphalan. Five patients, ages 52 to 67 years, with high-risk hematologic malignancies were enrolled. Four of the 5 developed severe acute GVHD of grades 3 to 4, requiring treatment with methylprednisolone and cyclosporine; 3 were steroid refractory and were given salvage therapy. One of these 4 patients died of hepatic GVHD, one died of sepsis, and 2 survived. We conclude that post-transplantation cyclophosphamide is inadequate as sole GVHD prophylaxis in the context of peripheral blood reduced-intensity conditioning transplantations from HLA-matched donors. This trial is registered at ACTRN12613001154796.
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http://dx.doi.org/10.1016/j.bbmt.2015.01.020DOI Listing
May 2015

Thalidomide and prednisolone versus prednisolone alone as consolidation therapy after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the ALLG MM6 multicentre, open-label, randomised phase 3 study.

Lancet Haematol 2014 Dec 1;1(3):e112-9. Epub 2014 Dec 1.

Alfred Health-Monash University, Melbourne, VIC, Australia. Electronic address:

Background: We previously showed that consolidation therapy with thalidomide and prednisolone improved progression-free and overall survival in patients with multiple myeloma who had undergone autologous stem-cell transplantation. We aimed to assess whether these survival advantages were durable at 5 years.

Methods: The ALLG MM6 trial was a multicentre, open-label, randomised phase 3 trial done between Jan 13, 2002, and March 15, 2005, at 29 sites in Australia and New Zealand. Patients with newly diagnosed multiple myeloma were randomly assigned (1:1), via computer-generated randomisation charts, to receive indefinite prednisolone maintenance alone (control group) or in combination with 12 months of thalidomide consolidation (thalidomide group) after autologous stem-cell transplantation. Randomisation was stratified by treating centre and pre-transplantation concentrations of β2 microglobulin. Patients and treating physicians were not masked to treatment allocation. Primary endpoints were progression-free survival and overall survival. Analysis was by intention to treat. Secondary endpoints were overall response to salvage therapy, incidence of second primary malignancy incidence, and cost-effectiveness. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12607000382471.

Findings: We randomly assigned 269 patients to the thalidomide (n=114) or control group (n=129). After a median follow-up of 5·4 years (IQR 3·1-7·2), estimated 5-year progression-free survival was 27% (95% CI 23-32) in the thalidomide group and 15% (11-18) in the control group (hazard ratio [HR] 0·16, 95% CI 0·044-0·58; p=0·0054) and 5-year overall survival was 66% (95% CI 61-70) and 47% (42-51), respectively (HR 0·12, 95% CI 0·028-0·56; p=0·0072). There was no difference in overall response to salvage therapy, survival post-progression, or incidence of secondary malignancies between the two groups. Incremental cost-effectiveness ratio was AUS$26 996 per mean life-year gained.

Interpretation: Consolidation therapy with thalidomide and prednisolone after autologous stem-cell transplantaion is an acceptable therapeutic approach when alternative drugs are not available.

Funding: Pharmion Corporation, Novartis Pharmaceuticals, Amgen Australia, The Merrin Foundation, and Alfred Health.
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http://dx.doi.org/10.1016/S2352-3026(14)00022-2DOI Listing
December 2014

Efficacy of dual PI-3K and mTOR inhibitors in vitro and in vivo in acute lymphoblastic leukemia.

Oncotarget 2014 Nov;5(21):10460-72

Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, Australia.

The major regulators of human acute lymphoblastic leukemia (ALL) cell growth and survival mediate their effects through the phosphoinositide 3-kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway. We have shown that the mTOR inhibitor everolimus extended survival in a non-obese diabetic/severe combined immune-deficient (NOD/SCID) mouse xenograft model of human ALL. Since PI-3K has mTOR dependent and independent functions we examined the effect of the dual PI-3K/mTOR inhibitors BEZ235 and BGT226. These agents inhibited the proliferation of ALL cell lines with a three log greater potency than everolimus. However, the induction of cell death differed, with BGT226 being cytotoxic in the low micromolar range while a two log higher concentration of BEZ235 was required to produce the same effect. While all three agents extended the survival of NOD/SCID mice engrafted with human ALL, the responses of individual xenografts varied. Although differential phosphorylation of AKT on Ser(473) and Thr(308) in response to everolimus exposure was observed, this did not entirely explain the different in vivo responses to the drugs. Our data suggests that while dual PI-3K/mTOR inhibitors may improve therapeutic outcomes for a subset of ALL patients, patient selection will be important, with some patients likely to respond better to single mTOR inhibition.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279386PMC
http://dx.doi.org/10.18632/oncotarget.2260DOI Listing
November 2014

A Phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia.

Leuk Lymphoma 2015 May 20;56(5):1406-15. Epub 2014 Nov 20.

Department of Clinical Haematology and BMT Service, The Royal Melbourne Hospital , Melbourne , Australia.

Acute myeloid leukemia (AML) blasts express high levels of interlekin-3 (IL-3) receptor-α (CD123). CSL360 is a recombinant, chimeric immunoglobulin G1 (IgG1), anti-CD123 monoclonal antibody (MoAb) that neutralizes IL-3 and demonstrates anti-leukemic activity in vitro. This phase 1 study assessed safety, pharmacokinetics and bioactivity of weekly intravenous CSL360 for 12 weeks in 40 patients with advanced AML across five dose levels (0.1-10.0 mg/kg). Other than mild infusion reactions, CSL360 was well tolerated. The maximal tolerated dose was not reached. The half-life was 4.9 days, and the area under the curve (AUC) and maximum concentration (Cmax) increased proportionally with dose. Doses ≥ 3.0 mg/kg resulted in complete saturation and down-regulation of CD123 and abolition of ex vivo proliferative responsiveness to IL-3, indicating adequate blockade of IL-3 signaling. Two patients responded, with one remaining in complete remission after 17 doses. CSL360 bound CD123 specifically, but did not induce anti-leukemic activity in most patients. While safe, MoAb blockade of CD123 function is insufficient as a therapeutic strategy.
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http://dx.doi.org/10.3109/10428194.2014.956316DOI Listing
May 2015

A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia.

Br J Haematol 2014 Dec 21;167(5):618-25. Epub 2014 Aug 21.

Department of Haematology, Westmead Hospital, Sydney, NSW, Australia.

Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment-related mortality. We conducted a placebo-controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 μg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0-4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662.
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http://dx.doi.org/10.1111/bjh.13086DOI Listing
December 2014

G-CSF: From granulopoietic stimulant to bone marrow stem cell mobilizing agent.

Cytokine Growth Factor Rev 2014 Aug 23;25(4):355-67. Epub 2014 Jul 23.

Department of Haematology, Westmead Hospital, Westmead, NSW, Australia.

G-CSF was among the first cytokines to be identified and rapidly transitioned into clinical medicine. Initially used to promote the production of neutrophils in patients with chemotherapy-induced neutropenia it helped to revolutionize the delivery of cancer therapy. Its ability to mobilize hematopoietic stem cells from the bone marrow into the blood was subsequently exploited, changing the face of hematopoietic stem cell transplantation. Today the knowledge gained in unraveling the mechanisms of stem cell mobilization by G-CSF is being explored as a means to increase chemosensitivity in hematological malignancies. This review provides a brief history of G-CSF and then focuses on recent advances in our understanding of G-CSF-induced stem cell mobilization and the potential clinical application of this knowledge in chemo-sensitization.
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http://dx.doi.org/10.1016/j.cytogfr.2014.07.011DOI Listing
August 2014

Silencer of death domains controls cell death through tumour necrosis factor-receptor 1 and caspase-10 in acute lymphoblastic leukemia.

PLoS One 2014 25;9(7):e103383. Epub 2014 Jul 25.

Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.

Resistance to apoptosis remains a significant problem in drug resistance and treatment failure in malignant disease. NO-aspirin is a novel drug that has efficacy against a number of solid tumours, and can inhibit Wnt signaling, and although we have shown Wnt signaling to be important for acute lymphoblastic leukemia (ALL) cell proliferation and survival inhibition of Wnt signaling does not appear to be involved in the induction of ALL cell death. Treatment of B lineage ALL cell lines and patient ALL cells with NO-aspirin induced rapid apoptotic cell death mediated via the extrinsic death pathway. Apoptosis was dependent on caspase-10 in association with the formation of the death-inducing signaling complex (DISC) incorporating pro-caspase-10 and tumor necrosis factor receptor 1 (TNF-R1). There was no measurable increase in TNF-R1 or TNF-α in response to NO-aspirin, suggesting that the process was ligand-independent. Consistent with this, expression of silencer of death domain (SODD) was reduced following NO-aspirin exposure and lentiviral mediated shRNA knockdown of SODD suppressed expansion of transduced cells confirming the importance of SODD for ALL cell survival. Considering that SODD and caspase-10 are frequently over-expressed in ALL, interfering with these proteins may provide a new strategy for the treatment of this and potentially other cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103383PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111576PMC
November 2015

mTOR inhibition by everolimus in childhood acute lymphoblastic leukemia induces caspase-independent cell death.

PLoS One 2014 11;9(7):e102494. Epub 2014 Jul 11.

Centre for Cancer Research, Westmead Millennium Institute, University of Sydney, Westmead, NSW, Australia.

Increasingly, anti-cancer medications are being reported to induce cell death mechanisms other than apoptosis. Activating alternate death mechanisms introduces the potential to kill cells that have defects in their apoptotic machinery, as is commonly observed in cancer cells, including in hematological malignancies. We, and others, have previously reported that the mTOR inhibitor everolimus has pre-clinical efficacy and induces caspase-independent cell death in acute lymphoblastic leukemia cells. Furthermore, everolimus is currently in clinical trial for acute lymphoblastic leukemia. Here we characterize the death mechanism activated by everolimus in acute lymphoblastic leukemia cells. We find that cell death is caspase-independent and lacks the morphology associated with apoptosis. Although mitochondrial depolarization is an early event, permeabilization of the outer mitochondrial membrane only occurs after cell death has occurred. While morphological and biochemical evidence shows that autophagy is clearly present it is not responsible for the observed cell death. There are a number of features consistent with paraptosis including morphology, caspase-independence, and the requirement for new protein synthesis. However in contrast to some reports of paraptosis, the activation of JNK signaling was not required for everolimus-induced cell death. Overall in acute lymphoblastic leukemia cells everolimus induces a cell death that resembles paraptosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0102494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094511PMC
March 2015

Sphingosine kinase 2 promotes acute lymphoblastic leukemia by enhancing MYC expression.

Cancer Res 2014 May 31;74(10):2803-15. Epub 2014 Mar 31.

Authors' Affiliations: Westmead Institute for Cancer Research, Westmead Millennium Institute, University of Sydney; Hematology Department, Westmead Hospital, Westmead, Sydney, New South Wales; and Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, South Australia, Australia

Sphingosine kinase 2 (SK2) may have utility as a prognostic marker in inflammatory diseases such as cancer in which it has been rationalized as a candidate therapeutic target. Here, we show that SK2 has an oncogenic role in acute lymphoblastic leukemia (ALL) by influencing expression of MYC. Genetic ablation of SK2 impaired leukemia development in a mouse model of ALL and pharmacologic inhibition extended survival in mouse xenograft models of human disease. SK2 attenuation in both the settings reduced MYC expression in leukemic cells, with reduced levels of acetylated histone H3 within the MYC gene associated with reduced levels of MYC protein and expression of MYC-regulated genes. Our results demonstrated that SK2 regulates MYC, which has a pivotal role in hematologic malignancies, providing a preclinical proof of concept for this pathway as a broad-based therapeutic target in this setting.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-2732DOI Listing
May 2014

Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning.

Biol Blood Marrow Transplant 2014 Jun 18;20(6):890-5. Epub 2014 Mar 18.

Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington, Seattle. Electronic address:

In a multicenter collaboration, we carried out T cell-replete, peripheral blood stem cell (PBSC) transplantations from related, HLA-haploidentical donors with reduced-intensity conditioning (RIC) and post-transplantation cyclophosphamide (Cy) as graft-versus-host disease (GVHD) prophylaxis in 55 patients with high-risk hematologic disorders. Patients received 2 doses of Cy 50 mg/kg i.v. on days 3 and 4 after infusion of PBSC (mean, 6.4 × 10(6)/kg CD34(+) cells; mean, 2.0 × 10(8)/kg CD3(+) cells). The median times to neutrophil (500/μL) and platelet (>20,000/μL) recovery were 17 and 21 days respectively. All but 2 of the patients achieved full engraftment. The 1-year cumulative incidences of grade II and grade III acute GVHD were 53% and 8%, respectively. There were no cases of grade IV GVHD. The 2-year cumulative incidence of chronic GHVD was 18%. With a median follow-up of 509 days, overall survival and event-free survival at 2 years were 48% and 51%, respectively. The 2-year cumulative incidences of nonrelapse mortality and relapse were 23% and 28%, respectively. Our results suggest that PBSC can be substituted safely and effectively for bone marrow as the graft source for haploidentical transplantation after RIC.
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http://dx.doi.org/10.1016/j.bbmt.2014.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451937PMC
June 2014

Antibody therapy for acute myeloid leukaemia.

Br J Haematol 2014 Feb 10;164(4):481-95. Epub 2013 Dec 10.

ANZAC Research Institute, University of Sydney, Concord, NSW, Australia; Department of Haematology, Concord Cancer Centre, Concord Repatriation General Hospital, Concord, NSW, Australia.

Novel therapies with increased efficacy and decreased toxicity are desperately needed for the treatment of acute myeloid leukaemia (AML). The anti CD33 immunoconjugate, gemtuzumab ozogamicin (GO), was withdrawn with concerns over induction mortality and lack of efficacy. However a number of recent trials suggest that, particularly in AML with favourable cytogenetics, GO may improve overall survival. This data and the development of alternative novel monoclonal antibodies (mAb) have renewed interest in the area. Leukaemic stem cells (LSC) are identified as the subset of AML blasts that reproduces the leukaemic phenotype upon transplantation into immunosuppressed mice. AML relapse may be caused by chemoresistant LSC and this has refocused interest on identifying and targeting antigens specific for LSC. Several mAb have been developed that target LSC effectively in xenogeneic models but only a few have begun clinical evaluation. Antibody engineering may improve the activity of potential new therapeutics for AML. The encouraging results seen with bispecific T cell-engaging mAb-based molecules against CD19 in the treatment of B-cell acute lymphobalstic leukaemia, highlight the potential efficacy of engineered antibodies in the treatment of acute leukaemia. Potent engineered mAb, possibly targeting novel LSC antigens, offer hope for improving the current poor prognosis for AML.
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http://dx.doi.org/10.1111/bjh.12691DOI Listing
February 2014

Alterations in chemokine receptor CCR5 expression on blood dendritic cells correlate with acute graft-versus-host disease.

Transplantation 2013 Oct;96(8):753-62

1 Flow Cytometry Unit, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead, New South Wales, Australia. 2 Dendritic Cell Biology and Therapeutics Group, ANZAC Medical Research Institute, Concord, New South Wales, Australia. 3 Blood and Marrow Transplant Service, Westmead Hospital, Westmead, New South Wales, Australia. 4 Address correspondence to: Kenneth F. Bradstock, M.B., B.S., P.hD., Haematology Department Westmead Hospital, Darcy Rd, Westmead, New South Wales, Australia 2145.

Background: Dendritic cells (DC) are important in the development of acute graft-versus-host disease (GVHD) after allogeneic hemopoietic cell transplantation (alloHCT). The trafficking of immature DC from blood to GVHD target organs is likely to be regulated by chemokine receptors.

Methods: We performed flow cytometry to document the expression of chemokine receptors on circulating DC and correlated the findings after alloHCT with occurrence of acute GVHD.

Results: In normal individuals, plasmacytoid DC (pDC) expressed high levels of CCR5, whereas the major CD16 myeloid DC subpopulation lacked CCR5. However, its expression on CD16 cells was induced by culture in allogeneic mixed lymphocyte reaction supernatant, an effect largely mediated by interferon-γ. CCR5 was expressed on a significant proportion of CD16 DC in 42 alloHCT patients, whereas it was down-regulated on pDC. The maximum percentage of CCR5CD16 DC, at any time after transplantation, correlated with acute GVHD, whereas the minimum CCR5 on pDC showed a similar correlation. Before developing signs of GVHD, the maximum percentage CCR5CD16 DC was higher in patients with GVHD grades II to IV than in GVHD grades 0 and I, whereas the minimum percentage CCR5 on pDC was lower in GVHD grades II to IV than in GVHD grades 0 and I. CCR5 levels more than 20.5% on CD16 myeloid DC and less than 22.6% on CD123 pDC correlated with subsequent GVHD grades II to IV with high sensitivities and specificities.

Conclusions: These observations may reflect DC activation and altered homing during the alloimmune response and could allow early diagnosis and therapeutic intervention before the clinical diagnosis of GVHD.
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http://dx.doi.org/10.1097/TP.0b013e31829e6d5bDOI Listing
October 2013

Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial.

Lancet Infect Dis 2013 Jun 30;13(6):519-28. Epub 2013 Apr 30.

Infectious Diseases Unit, Alfred Health, and Department of Infectious Diseases, Central Clinical School, Monash University, Melbourne, VIC, Australia.

Background: Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients.

Methods: In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered with ClinicalTrial.gov, number NCT00163722.

Findings: 240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4-26; p=0·002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0·11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0·20).

Interpretation: Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients.

Funding: Australian National Health and Medical Research Council, Cancer Council New South Wales, Pfizer, Merck, Gilead Sciences.
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http://dx.doi.org/10.1016/S1473-3099(13)70076-8DOI Listing
June 2013

Oncogenic properties of sphingosine kinases in haematological malignancies.

Br J Haematol 2013 Jun 25;161(5):623-38. Epub 2013 Mar 25.

Westmead Institute for Cancer Research, Westmead Millennium Institute, The University of Sydney, Sydney, NSW, Australia.

The sphingosine kinases (SphKs) have relatively recently been implicated in contributing to malignant cellular processes with particular interest in the oncogenic properties of SPHK1. Whilst SPHK1 has received considerable attention as a putative oncoprotein, SPHK2 has been much more difficult to study, with often conflicting data surrounding its role in cancer. Initial studies focused on non-haemopoietic malignancies, however a growing body of literature on the role of sphingolipid metabolism in haemopoietic malignancies is now emerging. This review provides an overview of the current state of knowledge of the SphKs and the bioactive lipid sphingosine 1-phosphate (S1P), the product of the reaction they catalyse. It then reviews the current literature regarding the roles of S1P and the SphKs in haemopoietic malignancies and discusses the compounds currently available that modulate sphingolipid metabolism and their potential and shortcomings as therapeutic agents for the treatment of haematological malignancies.
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http://dx.doi.org/10.1111/bjh.12302DOI Listing
June 2013

Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells.

J Biol Chem 2013 Mar 18;288(12):8679-90. Epub 2013 Jan 18.

Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.

Natural killer (NK) cell recognition of the nonclassical human leukocyte antigen (HLA) molecule HLA-E is dependent on the presentation of a nonamer peptide derived from the leader sequence of other HLA molecules to CD94-NKG2 receptors. However, human cytomegalovirus can manipulate this central innate interaction through the provision of a "mimic" of the HLA-encoded peptide derived from the immunomodulatory glycoprotein UL40. Here, we analyzed UL40 sequences isolated from 32 hematopoietic stem cell transplantation recipients experiencing cytomegalovirus reactivation. The UL40 protein showed a "polymorphic hot spot" within the region that encodes the HLA leader sequence mimic. Although all sequences that were identical to those encoded within HLA-I genes permitted the interaction between HLA-E and CD94-NKG2 receptors, other UL40 polymorphisms reduced the affinity of the interaction between HLA-E and CD94-NKG2 receptors. Furthermore, functional studies using NK cell clones expressing either the inhibitory receptor CD94-NKG2A or the activating receptor CD94-NKG2C identified UL40-encoded peptides that were capable of inhibiting target cell lysis via interaction with CD94-NKG2A, yet had little capacity to activate NK cells through CD94-NKG2C. The data suggest that UL40 polymorphisms may aid evasion of NK cell immunosurveillance by modulating the affinity of the interaction with CD94-NKG2 receptors.
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http://dx.doi.org/10.1074/jbc.M112.409672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605686PMC
March 2013