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1.  Persistence of Recipient Human Leucocyte Antigen (HLA) Antibodies and Production of Donor HLA antibodies Following Reduced Intensity Allogeneic Haematopoietic Stem Cell Transplantation 
British journal of haematology  2014;166(3):425-434.
The effects of reduced intensity conditioning (RIC) on human leucocyte antigen (HLA)-alloimmunization and platelet transfusion refractoriness (PTR) following allogeneic haematopoietic stem cell transplantation (Allo-HSCT) are unknown. We studied HLA-alloantibodies in a cohort of 16 patients (8 HLA-alloimmunized with pre-transplant histories of PTR and 8 non-alloimmunized controls) undergoing Allo-HSCT using fludarabine/cyclophosphamide-based RIC. Pre- and post-transplant serum samples were analysed for HLA-antibodies and compared to myeloid, T-cell and bone marrow plasma cell chimaerism. Among alloimmunized patients, the duration that HLA-antibodies persisted post-transplant correlated strongly with pre-transplant HLA-antibody mean fluorescence intensity (MFI) and PRA levels (Spearman’s rank correlation = 0.954 (p=0.0048) and 0.865 (p=0.0083) respectively). Pre-transplant MFI >10,000 was associated with post-transplant HLA antibody persistence >100 days (p=0.029). HLA-antibodies persisted ≥100 days in 3/8 patients despite recipient chimaerism being undetectable in all lympho-haematopoietic lineages including plasma cells. Post-transplant de-novo HLA-antibodies developed in 3 control patients with 2 developing PTR; the donors for 2 of these patients demonstrated pre-existing HLA-antibodies of equivalent specificity to those in the patient, confirming donor origin. These data show HLA-antibodies may persist for prolonged periods following RIC. Further study is needed to determine the incidence of post-transplant PTR as a consequence of donor–derived HLA alloimmunization before recommendations on donor HLA-antibody screening can be made.
PMCID: PMC4174569  PMID: 24750103
HLA antibodies; platelets; allogeneic bone marrow transplantation
2.  Comparison of the Prognostic Utility of the Revised International Prognostic Scoring System and the French Prognostic Scoring System in Azacitidine-Treated Patients with Myelodysplastic Syndromes 
British journal of haematology  2014;166(3):352-359.
The revised International Prognostic Scoring System (IPSS-R) was developed in a cohort of untreated myelodysplastic syndromes (MDS) patients. A French Prognostic Scoring System (FPSS) was recently reported to identify differential survival among azacitidine-treated patients with high-risk MDS. We applied the FPSS and IPSS-R to 150 patients previously randomized to azacitidine monotherapy or a combination of azacitidine with entinostat (a histone deacetylase inhibitor). Neither score predicted response but both discriminated patients with different overall survival (OS) (median OS, FPSS: 9.7, 14.7, and 25.3 months, P=0.018; IPSS-R: 12.5, 11.3, 20.8, and 36 months, P=0.005). Statistical analysis suggested no improvement in OS prediction for the FPSS over the IPSS-R in azacitidine-treated patients.
PMCID: PMC4299460  PMID: 24712482
Myelodysplastic syndromes (MDS); azacitidine; Revised International Prognostic Scoring System (IPSS-R); French Prognostic Scoring System (FPSS); prognostic models
3.  R-CHOP with Iodine-131 Tositumomab Consolidation for Advanced Stage Diffuse Large B-Cell Lymphoma (DLBCL): SWOG S0433 
British journal of haematology  2014;166(3):382-389.
Radiolabelled antiCD-20 antibodies have demonstrated single agent activity in relapsed diffuse large B-cell lymphoma (DLBCL). The S0433 clinical trial enrolled patients with newly diagnosed, advanced stage or bulky stage II, histologically confirmed DLBCL. Patients received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), two cycles of CHOP, then iodine-131 tositumomab radioimmunotherapy consolidation 30–60 days after completion of chemotherapy. The primary endpoint was two-year progression-free survival (PFS). Eighty-four eligible patients were enrolled, and 56 patients completed the entire course of protocol treatment. Of the 84 patients evaluable for treatment response, 72 (86%, 95% confidence interval [CI]: 76%–92%) achieved a partial response (n=21) or a confirmed (n=41) or unconfirmed (n=10) complete response to therapy. With a median follow-up of 3.9 years, the 2-year PFS estimate is 69% and the 2-year overall survival estimate is 77%. Rituximab levels at time of radioimmunotherapy did not correlate with toxicity or outcome. Twenty percent of patients had double hit features (MYC+; BCL2+) by immunohistochemistry, and had inferior outcome. These current results suggest that the incorporation of novel agents earlier in therapy may ultimately have greater impact in DLBCL, as early progressions, deaths and declining performance status during CHOP chemotherapy limited the number of patients who ultimately could benefit from radioimmunotherapy consolidation.
PMCID: PMC4107050  PMID: 24749780
lymphoma; chemotherapeutic approaches; diffuse large B cell lymphoma; radioimmunotherapy; pharmacotherapeutics
4.  Progress in Central Nervous System Lymphomas 
British journal of haematology  2014;166(3):311-325.
Until recently, primary central nervous system lymphoma (PCNSL) was associated with a uniformly dismal prognosis. It is now reasonable to anticipate long-term survival and possibly cure for a significant proportion of patients diagnosed with PCNSL. Accumulated data generated over the past ten years has provided evidence that long-term progression-free survival (PFS) can reproducibly be attained in a significant fraction of PCNSL patients that receive dose-intensive chemotherapy consolidation, without whole brain radiotherapy. One consolidative regimen that has reproducibly demonstrated promise is the combination of infusional etoposide plus high-dose cytarabine (EA), administered in first complete remission after methotrexate, temozolomide and rituximab-based induction. Given evolving principles of management and the mounting evidence for reproducible improvements in survival rates in prospective clinical series, our goal in this review is to highlight and update principles in diagnosis, staging and management as well as to review data regarding the pathogenesis of central nervous system lymphomas, information that is likely to constitute a basis for the implementation of novel therapies that are requisite for further progress in this unique phenotype of non-Hodgkin lymphoma.
PMCID: PMC4107064  PMID: 24837460
Primary CNS Lymphoma; High-Dose Chemotherapy; Rituximab; Tumour Microenvironment
5.  Outpatient Bendamustine and Idarubicin for Upfront Therapy of Elderly acute myeloid leukaemia/myelodysplastic syndrome: A Phase I/II Study using an Innovative Statistical Design 
British journal of haematology  2014;166(3):375-381.
Combinations of agents may improve outcomes among elderly acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) patients. We performed an adaptive phase I/II trial for newly-diagnosed AML or high-risk MDS patients aged ≥ 50 years using a Bayesian approach to determine whether 1 of 3 doses of bendamustine (45, 60, 75 mg/m2 days 1–3), together with idarubicin (12 mg/m2 days 1–2), might provide a complete response (CR) rate ≥ 40% with <30% grade 3–4 non-haematological toxicity. We treated 39 patients (34 AML; 5 MDS with >10% marrow blasts; median age 73 years). None of the 3 bendamustine doses in combination with idarubicin met the required CR and toxicity rates; the 75 mg/m2 dose because of excess toxicity (2 of 3 patients) and the 60 mg/m2 dose because of low efficacy (CR rate 10/33), although no grade 3–4 non-haematological toxicity was seen at this dose. Median survival was 7.2 months. All patients began treatment as outpatients but hospitalization was required in 90% (35/39). Although we did not find a dose of bendamustine combined with idarubicin that would provide a CR rate of >40% with acceptable toxicity, bendamustine may have activity in AML/MDS patients, suggesting its addition to other regimens may be warranted.
PMCID: PMC4107117  PMID: 24749757
AML; bendamustine; MDS; elderly; bayesian
7.  Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma 
British journal of haematology  2015;169(2):219-227.
Sixty-four transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1–28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28-day cycles (CYKLONE regimen). Carfilzomib was dose-escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide-related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression-free survival and overall survival at 24 months was 76% and 96%, respectively (median follow-up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.
PMCID: PMC4521972  PMID: 25683772
myeloma therapy; multiple myeloma; clinical trials; clinical studies; experimental therapies
8.  Measuring T cell immunity to influenza vaccination in children after haemopoietic stem cell transplantation 
British journal of haematology  2004;127(3):322-325.
Quantitative assessment of immunogen-specific T cell responses may provide a meaningful surrogate marker of functional immunity in patients following haemopoietic stem cell transplantation (HSCT). We developed a flowcytometric assay to quantify antigen-specific T cell immunity to influenza-A and studied the T cell response to influenza vaccination in five children, 3–21 months post-HSCT. All patients showed an increase in influenza-A-specific CD4+ immunity following vaccination while none had a detectable IgG response to the vaccine. This assay proved sufficiently sensitive to evaluate changes in T cell memory in immunocompromised individuals and could be used to better characterize post-HSCT immune reconstitution.
PMCID: PMC4516023  PMID: 15491293
BMT; T cells; vaccines; clinical studies; flow cytometry
9.  Comparative proteomics reveals deficiency of SLC9A1 (sodium/hydrogen exchanger NHE1) in β-adducin null red cells 
British journal of haematology  2011;154(4):492-501.
Spherocytosis is one of the most common inherited disorders, yet presents with a wide range of clinical severity. While several genes have been found mutated in patients with spherocytosis, the molecular basis for the variability in severity of haemolytic anaemia is not entirely understood. To identify candidate proteins involved in haemolytic anaemia pathophysiology, we utilized a label-free comparative proteomic approach to detect differences in red blood cells (RBCs) from normal and β-adducin (Add2) knock-out mice. We detected seven proteins that were decreased and 48 proteins that were increased in β-adducin null RBC ghosts. Since haemolytic anaemias are characterized by reticulocytosis, we compared reticulocyte-enriched samples from phenylhydrazine-treated mice with mature RBCs from untreated mice. Among the 48 proteins increased in Add2 knockout RBCs, only 11 were also increased in reticulocytes. Of the proteins decreased in Add2 knockout RBCs, α-adducin showed the greatest intensity difference, followed by SLC9A1, the sodium-hydrogen exchanger previously termed NHE1. We verified these mass spectrometry results by immunoblot. This is the first example of SLC9A1deficiency in haemolytic anaemia and suggests new insights into the mechanisms leading to fragile RBCs.
PMCID: PMC4515348  PMID: 21689084
red blood cell; reticulocyte; adducin; SLC9A1; label-free proteomics
10.  JAK2-V617F-mediated signalling is dependent on lipid rafts and statins inhibit JAK2-V617F-dependent cell growth 
British journal of haematology  2012;160(2):177-187.
Aberrant JAK2 signalling plays an important role in the aetiology of myeloproliferative neoplasms (MPNs). JAK2 inhibitors, however, do not readily eliminate neoplastic MPN cells and thus do not induce patient remission. Further understanding JAK2 signalling in MPNs may uncover novel avenues for therapeutic intervention. Recent work has suggested a potential role for cellular cholesterol in the activation of JAK2 by the erythropoietin receptor and in the development of an MPN-like disorder in mice. This study demonstrates for the first time that the MPN-associated JAK2-V617F kinase localizes to lipid rafts and that JAK2-V617F-dependent signalling is inhibited by lipid raft disrupting agents, which target membrane cholesterol, a critical component of rafts. We also show for the first time that statins, 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, widely used to treat hypercholesterolaemia, induce apoptosis and inhibit JAK2-V617Fdependent cell growth. These cells are more sensitive to statin treatment than non-JAK2-V617F-dependent cells. Importantly, statin treatment inhibited erythropoietin-independent erythroid colony formation of primary cells from MPN patients, but had no effect on erythroid colony formation from healthy individuals. Our study is the first to demonstrate that JAK2-V617F signalling is dependent on lipid rafts and that statins may be effective in a potential therapeutic approach for MPNs.
PMCID: PMC4505927  PMID: 23157224
JAK2-V617F; statin; lipid raft; myeloproliferative neoplasms; cholesterol
11.  HSP70 inhibition reverses cell adhesion mediated and acquired drug resistance in multiple myeloma 
British journal of haematology  2008;142(4):551-561.
Heat shock proteins (HSPs) are a super family of highly conserved molecular chaperone proteins, which are induced in response to stress. HSP70 has been demonstrated to inhibit apoptosis induced by a number of chemotherapeutic agents. Previous investigations have suggested the development of drug resistance in multiple myeloma (MM) cells after adhesion to stroma. This study used MM cell lines and primary plasma cells to determine if HSP70 had a role in development of chemo resistance. Adhesion of MM cells to either bone marrow stromal cells or fibronectin (FN) enhanced HSP70 expression. Inhibition of the HSP70 expression decreased 8226 cell adhesion to stroma or FN and induced more apoptosis in FN-adhered 8226 cells than in suspension cultures at 24 h. Further, HSP70 inhibitors enhanced melphalan-induced apoptosis and reversed melphalan-induced cell adhesion-mediated drug resistance (CAM-DR) phenotype. In addition, compared to parental cells, KNK-437, a heat shock factor inhibitor caused more apoptosis in melphalan-resistant 8226/LR5 cells and sensitized them to melphalan. Primary CD138 positive cells showed high expression of HSPA4 mRNA, and KNK-437 caused apoptosis in these cells. In conclusion, our data suggest inhibition of HSP70, reduced adhesion and caused apoptosis of both acquired and de novo drug resistant MM cells.
PMCID: PMC4503206  PMID: 18503584
HSP70; multiple myeloma; drug resistance; adhesion; cell adhesion mediated resistance
12.  The effect of secondary prophylaxis versus episodic treatment on the range of motion of target joints in patients with haemophilia 
British journal of haematology  2013;161(3):424-433.
This study prospectively compared the effect of secondary prophylaxis to episodic treatment on target joint (TJ) range of motion (ROM), number of joint haemorrhages and new TJ development in patients with moderate or severe haemophilia. Two-hundred and eighty-six males, 17% in prophylaxis, 83% in episodic treatment group, participating in the Centers for Disease Control and Prevention's Universal Data Collection project, fulfilled inclusion criteria: age >2 years at enrolment, free of TJs at enrolment, developed at least one TJ after enrolment, and received either prophylaxis or episodic treatment continuously for two follow-up visits after TJ development. The outcomes of interest – percentage change in TJ ROM, number of joint haemorrhages and new TJ development, were modelled using multivariate linear, Poisson and logistic regression techniques respectively. Individuals who received secondary prophylaxis in comparison to episodic treatment were younger at TJ development (P < 0·01); there was no difference in the decrease in TJ ROM between the two groups (P = 0·9). Factors significantly associated with a higher rate of haemarthroses included episodic treatment, severe haemophilia, age >5 years at TJ development, obesity and inhibitor negative status. Secondary prophylaxis significantly decreased haemarthroses but was not associated with a significant improvement in TJ ROM or with new TJ development.
PMCID: PMC4494109  PMID: 23432684
secondary prophylaxis; episodic treatment; haemophilia; range of motion; target joint
13.  A Cross-sectional Study of Bleeding Phenotype in Haemophilia A Carriers 
British journal of haematology  2015;170(2):223-228.
Haemophilia A carriers have historically been thought to demonstrate normal haemostasis. However, recent data demonstrates that despite normal factor VIII, haemophilia A carriers demonstrate an increased bleeding tendency. We tested the hypothesis that obligate haemophilia carriers demonstrate an increase in bleeding symptoms. A cross sectional study was performed comparing haemophilia A carriers to normal women. Questionnaire assessment included a general bleeding questionnaire, condensed MCMDM-1VWD bleeding assessment tool and Pictorial Bleeding Assessment Chart (PBAC). Laboratory assessment included complete blood count, prothrombin time, activated partial thromboplastin time, fibrinogen activity, FVIII activity (FVIII:C), von Willebrand factor antigen level, ristocetin cofactor, platelet function analyser-100™ and ABO blood type. 44 haemophilia A carriers and 43 controls were included. Demographic features were similar. Laboratory results demonstrated a statistically significant difference only in FVIII:C (82.5 versus 134%, p value < 0.001). Carriers reported a higher number of bleeding events, and both condensed MCMDM-1 VWD bleeding scores (5 versus 1, p value < 0.001) and PBAC scores (423 versus 182.5, p value = 0.018) were significantly higher in carriers. Haemophilia A carriers exhibit increased bleeding symptoms when compared to normal women. Further studies are necessary to fully understand the bleeding phenotype in this population and optimize clinical management.
PMCID: PMC4490107  PMID: 25832012
coagulation; haemostasis; Haemophilia; factor VIII
14.  Temporal Definition of Haematopoietic Stem Cell Niches in a Large Animal Model of In Utero Stem Cell Transplantation 
British journal of haematology  2014;166(2):268-278.
The fetal sheep model has served as a biologically relevant and translational model to study in utero haematopoietic stem cell transplantation (IUHSCT), yet little is known about the ontogeny of the bone marrow (BM) niches in this model. Because the BMmicroenvironment plays a critical role in the outcome of haematopoietic engraftment, we have established the correlation between the fetal-sheep and fetal-human BM niche ontogeny, so that studies addressing the role of niche development at the time of IUHSCT could be accurately performed. Immunofluorescence confocal microscopic analysis of sheep fetal bone from gestational days (gd) 25-68 showed that the BM microenvironment commences development with formation of the vascular niche between 25-36 gd in sheep; correlating with the events at 10-11 gestational weeks (gw) in humans. Subsequently, between 45-51 gd in sheep (~14 gw in humans), the osteoblastic/endosteal niche started developing, the presence of CD34+CD45+ cells were promptly detected, and their number increased with gestational age. IUHSCT, performed in sheep at 45 and 65 gd, showed significant haematopoietic engraftment only at the later time point, indicating that a fully functional BM microenvironment improved engraftment. These studies show that sheep niche ontogeny closely parallels human, validating this model for investigating niche influence/manipulation in IUHSCT engraftment.
PMCID: PMC4079736  PMID: 24673111
In utero; Transplantation; Niche; Haematopoietic; Vascular; Osteoblast
15.  Acute Myeloid Leukaemia (AML) with t(6;9)(p23;q34) is Associated with Poor Outcome in Childhood AML Regardless of FLT3-ITD Status: A Report from the Children’s Oncology Group 
British journal of haematology  2014;166(2):254-259.
Acute myeloid leukaemia (AML) with t(6;9)(p23;q34) is a rare subtype associated with FLT3-internal tandem duplication (ITD) and poor outcomes. The clinical outcomes of paediatric patients with t(6;9) with and without FLT3-ITD treated on six consecutive cooperative trails were evaluated. In contrast to patients without t(6;9), those with t(6;9) had a significantly lower complete remission rate, higher relapse rate (RR), and poor overall survival (OS). Within t(6;9) patients, those with and without FLT3-ITD had an OS of 40% and 27% respectively (p>0.9), demonstrating that t(6;9) is a high-risk cytogenetic feature in paediatric AML and its clinical impact is independent of the presence of FLT3-ITD.
PMCID: PMC4079767  PMID: 24661089
acute myeloid leukaemia; paediatric; t(6;9)(p23;q34); FLT3-ITD; clinical outcome
16.  Donor-derived myelodysplastic syndrome and acute leukaemia after allogeneic haematopoietic stem cell transplantation: incidence, natural history and treatment response 
British journal of haematology  2014;166(2):209-212.
Donor-derived myelodysplastic syndrome/acute leukaemia (DD-MDS/AL) is a rare life-threatening complication of allogeneic haematopoietic stem cell (HSC) transplantation. However, it is unknown whether the risk differs by HSC source. Therefore, we evaluated the incidence of DD-MDS/AL in 2390 engrafted patients. With a median follow-up of 7·1 years (1–20·8), the incidence of DD-MDS/AL was 0·53% (95% confidence interval (CI), 0·01–1·41%], 0·56% (95%CI, 0·01–1·36%) and 0·56% (95%CI, 0·01–1·10%) in recipients of bone marrow (n = 1117), peripheral blood (n = 489) and umbilical cord blood (UCB, n = 784), respectively. While follow-up is shorter in recipients of UCB and peripheral blood, incidence of DD-MDS/AL is, thus far, similar between HSC sources.
PMCID: PMC4098791  PMID: 24661075
donor-derived leukaemia; haematopoietic cell transplantation
17.  The BTK Inhibitor Ibrutinib (PCI-32765) Blocks Hairy Cell Leukaemia Survival, Proliferation and BCR Signalling: A New Therapeutic Approach 
British journal of haematology  2014;166(2):177-188.
B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins (A, G, and M) and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL.
PMCID: PMC4104473  PMID: 24697238
Hairy Cell Leukaemia (HCL); B cell receptor (BCR); microenvironment; BTK; ibrutinib
18.  Loss of function tp53 mutations do not accelerate the onset of myc-induced T-ALL in the zebrafish 
British journal of haematology  2014;166(1):84-90.
The TP53 tumour suppressor is activated in response to distinct stimuli, including an ARF-dependent response to oncogene stress and an ATM/ATR-dependent response to DNA damage. In human T-cell acute lymphoblastic leukaemia (T-ALL), TP53-dependent tumour suppression is typically disabled via biallelic ARF deletions. In murine models, loss of Arf (Cdkn2a) or Tp53 markedly accelerates the onset of Myc-induced lymphoblastic malignancies. In zebrafish, no ARF ortholog has been identified, but the sequence of ARF is very poorly conserved evolutionarily, making it difficult to exclude the presence of a zebrafish ARF ortholog without functional studies. Here we show that tp53 mutations have no significant influence on the onset of myc-induced T-ALL in zebrafish, consistent with the lack of additional effects of Tp53 loss on lymphomagenesis in Arf-deficient mice. By contrast, irradiation leads to complete T-ALL regression in tp53 wild-type but not homozygous mutant zebrafish, indicating that the tp53-dependent DNA damage response is intact. We conclude that tp53 inactivation has no impact on the onset of myc-induced T-ALL in the zebrafish, consistent with the lack of a functional ARF ortholog linking myc-induced oncogene stress to tp53-dependent tumour suppression. Thus, the zebrafish model is well suited to the study of ARF-independent pathways in T-ALL pathobiology.
PMCID: PMC4234197  PMID: 24690081
Myc; Tp53; ARF; tumour suppression; T-cell acute lymphoblastic leukaemia
19.  Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease 
British journal of haematology  2007;139(3):434-438.
Impaired bone formation contributes to the lack of bone healing in multiple myeloma and there is a need for agents with bone anabolic properties to reverse the bone deficit in patients. Bortezomib, a proteasome inhibitor with antitumour efficacy in myeloma patients, enhanced new bone formation in mouse calvarial cultures; this effect was blocked by dickkopf 1(Dkk1), an antagonist of Wnt signalling implicated in myeloma bone disease. Bortezomib inhibited Dkk1 expression in calvariae and bone marrow-derived stromal cells, suggesting a novel mechanism by which bortezomib exerts its effects in bone. Clinical trials in patients with myeloma bone disease are needed to validate these results.
PMCID: PMC4482356  PMID: 17910634
bortezomib; osteoblast; myeloma; Dkk1; bone
20.  CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: a prognostic parameter with therapeutic potential 
British journal of haematology  2008;140(5):537-546.
In vitro studies have demonstrated that surface expression of CD49d on chronic lymphocytic leukaemia (CLL) B cells facilitates leukaemic cell– stromal interactions by binding to fibronectin. This interaction reduces both spontaneous and drug-induced apoptosis. The present study measured CD49d expression by flow cytometry in a cohort of untreated CLL patients previously accrued to a prospective observational study and evaluated the relationship with overall survival (OS). Among the 158 CLL patients tested, the percentage of leukaemic B cells expressing CD49d ranged from 0 to 100%. When all risk factors were treated as continuous variables, CD49d expression showed moderate correlation with expression of ZAP-70 (r = 0.54; P < 0.0001) and CD38 (r = 0.58; P < 0.0001) but not % IGHV mutation. As a continuous variable, CD49d expression strongly correlated with OS (P < 0.0001). Recursive partitioning analysis suggested the 45% threshold of CD49d expression best predicted OS. Multivariate analysis, controlling for disease stage, ZAP-70, IGHV status and fluorescent in situ hybridization defects identified CD49d as an independent predictor of OS and was a better predictor of clinical outcome than ZAP-70, IGHV, or cytogenetics. This observational cohort study suggests that CLL B-cell expression of CD49d is an easily measurable and independent predictor of OS and CD49d expression in CLL. Importantly, anti-CD49d antibodies are already approved for treatment of other human diseases. Clinical testing of anti-CD49d therapy in CLL appears warranted.
PMCID: PMC4477272  PMID: 18275431
chronic lymphocytic leukaemia; stromal cells; therapy; prognostic factors; CD49d
21.  Gender, Race, and Diet Affect Platelet Function Tests in Normal Subjects Contributing to a High Rate of Abnormal Results 
British journal of haematology  2014;165(6):842-853.
To assess sources of variability in platelet function tests in normal subjects, 64 healthy young adults were tested on 2–6 occasions at 2 week intervals using 4 methods: platelet aggregation (AGG) in platelet-rich plasma (PRP) in the Bio/Data PAP-4 Aggregometer (BD) and Chrono-Log Lumi-Aggregometer (CL); and AGG in whole blood (WB) in the CL and Multiplate Platelet Function Analyzer (MP), with ATP release (REL) in CL-PRP and CL-WB. Food and medication exposures were recorded prospectively for 2 weeks prior to each blood draw. At least one AGG abnormality was seen in 21% of 81 drug-free specimens with CL-PRP, 15% with CL-WB, 13% with BD-PRP, and 6% with MP-WB, increasing with inclusion of REL to 28% for CL-PRP and 30% for CL-WB. Epinephrine AGG and REL were significantly reduced in males (P<0.0001). Ristocetin AGG and collagen and thrombin REL were significantly reduced in Blacks (P<0.0001). One-third of specimens drawn following flavonoid-rich food exposures had aberrant results, compared to 8.5% of specimens without such exposures (P=0.0035). PRP tests had less intra-individual variation than WB tests. Gender, race, diet, and test system affected results of platelet function testing in healthy subjects, suggesting caution when interpreting the results of platelet function testing in patients.
PMCID: PMC4477706  PMID: 24617520
Platelets; platelet function tests; platelet aggregation; ristocetin; flavonoids
22.  Circulating CD52 and CD20 levels at end of treatment predict for progression and survival in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab (FCR) 
British journal of haematology  2009;148(3):386-393.
CD52 and CD20 antigens are important therapeutic targets for the monoclonal antibodies (mAbs) alemtuzumab and rituximab respectively. Circulating CD52 (cCD52) and CD20 (cCD20) have prognostic utility in lymphoid malignancies. The efficacy of mAb therapy in patients with chronic lymphocytic leukaemia (CLL) may be adversely affected by cCD52 or cCD20. In this report, blood and bone marrow (BM) cCD52 and cCD20 were measured at response assessment in previously treated (N = 235) patients with CLL who received fludarabine, cyclophosphamide, and rituximab (FCR). Univariate and multivariate statistical models evaluated correlations of pre- and response variables with progression-free (PFS) and overall survival (OS). Response variables included 1996 National Cancer Institute-Working Group (NCI-WG) response, polymerase chain reaction (PCR) for immunoglobulin heavy chain (IGHV) in BM, and cCD52 and cCD20 levels (blood and BM) at response assessment. Using multivariate analysis, response blood and BM cCD52, blood cCD20, and NCI-WG response were significant independent predictors of PFS. At the time of response assessment, BM cCD52 correlated with OS in univariate analysis. cCD52 and cCD20, therefore appear useful in predicting survival and may be important for monitoring patients following salvage FCR (fludarabine, cyclophosphamide, rituximab) therapy. These data further indicate that plasma may be a good target to evaluate for minimal residual disease using cCD52/cCD20 levels.
PMCID: PMC4476391  PMID: 19895616
CD20; CD52; CLL; fludarabine; cyclophosphamide and rituximab; salvage
23.  The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population 
British journal of haematology  2014;165(6):832-835.
The influence of genetic variation on warfarin dose requirement is limited for paediatric patients. We performed a retrospective, cross-sectional study to examine the effect of variant CYP2C9 and VKORC1 genotypes on warfarin dose in 100 children. Those with VKORC1 genotype AA required 48% of the dose of homozygous wild-type (GG, p<0.0001). Patients with any variant CYP2C9 allele required 71% of the dose for wild-type (p=0.001). The effect of variant VKORC1 alleles tended to vary with age, suggesting developmental ontogeny may influence warfarin sensitivity. Age, CYP2C9 genotype, VKORC1 genotype and age:VKORC1 interaction accounted for 53% of warfarin dose variability.
PMCID: PMC4043918  PMID: 24601977
warfarin; paediatrics; pharmacogenomics; CYP2C9; VKORC1
24.  LMO2 and BCL6 are Associated with Improved Survival in Primary Central Nervous System Lymphoma 
British journal of haematology  2014;165(5):640-648.
Primary central nervous system lymphoma (PCNSL) is an aggressive sub-variant of non-Hodgkin lymphoma (NHL) with morphological similarities to diffuse large B-cell lymphoma (DLBCL). While methotrexate (MTX)-based therapies have improved patient survival, the disease remains incurable in most cases and its pathogenesis is poorly understood. We evaluated 69 cases of PCNSL for the expression of HGAL (also known as GCSAM), LMO2 and BCL6 – genes associated with DLBCL prognosis and pathobiology, and analysed their correlation to survival in 49 PCNSL patients receiving MTX-based therapy. We demonstrate that PCNSL expresses LMO2, HGAL(also known as GCSAM) and BCL6 proteins in 52%, 65% and 56% of tumours, respectively. BCL6 protein expression was associated with longer progression-free survival (, p=0.006) and overall survival (OS, p=0.05), while expression of LMO2 protein was associated with longer OS (p=0.02). Further research is needed to elucidate the function of BCL6 and LMO2 in PCNSL.
PMCID: PMC4123533  PMID: 24571259
PCNSL; HGAL; BCL6; LMO2; prognosis
25.  Bruton tyrosine kinase inhibitors: a promising novel targeted treatment for B cell lymphomas 
British journal of haematology  2013;163(4):436-443.
Constitutive or aberrant signalling of the B cell receptor signalling cascade has been implicated in the propagation and maintenance of a variety of B cell malignancies. Small molecule inhibitors of Bruton tyrosine kinase (BTK), a protein early in this cascade and specifically expressed in B cells, have emerged as a new class of targeted agents. There are several BTK inhibitors, including ONO-WG-307, LFM-A13, dasatinib, CC-292, and PCI-32765 (ibrutinib), in preclinical and/or clinical development of which ibrutinib is currently in phase III trials. Recent clinical data suggest significant activity of ibrutinib as a first in class oral inhibitor of BTK. This review provides an overview of ongoing clinical studies of BTK inhibitors.
PMCID: PMC4444436  PMID: 24111579
Bruton tyrosine kinase; B cell receptor signalling; refractory non-Hodgkin lymphoma; ibrutinib; CC-292

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