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ABSTRACT: Alemtuzumab, a humanized anti-CD52, IgG1 monoclonal antibody, is used to reduce graft-versus- host disease (GVHD) and aid engraftment after allogeneic haemopoietic stem cell transplant (HSCT). Its associated low incidence of GVHD makes it an attractive alternative to anti-thymocyte globulin (ATG) in transplant conditioning regimen for severe aplastic anaemia (SAA). We have reviewed the use of alemtuzumab-based conditioning regimen for HSCT in SAA and show that it results in sustained haematological engraftment, a very low incidence of chronic GVHD without an increase in viral infections. Intriguingly, alemtuzumab appears to induce tolerance post-HSCT with the findings of stable mixed T cell chimerism with full donor myeloid chimerism and the absence of chronic GVHD, and which persist on withdrawal of post-graft immunosuppression. Finally, its low toxicity profile may permit future application of HSCT to older patients with SAA who fail to respond to immunosuppressive therapy.
International journal of hematology 04/2013; · 1.17 Impact Factor
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T M Westers,
R Ireland,
W Kern,
C Alhan,
J S Balleisen,
P Bettelheim,
K Burbury,
M Cullen,
J A Cutler,
M G Della Porta, [......],
D Subirá,
V Tindell,
T Vallespi,
P Valent,
V H J van der Velden,
T M de Witte,
D A Wells,
F Zettl,
M C Béné,
A A van de Loosdrecht
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ABSTRACT: Flow cytometry (FC) is increasingly recognized as an important tool in the diagnosis and prognosis of myelodysplastic syndromes (MDS). However, validation of current assays and agreement upon the techniques are prerequisites for its widespread acceptance and application in clinical practice. Therefore, a working group was initiated (Amsterdam, 2008) to discuss and propose standards for FC in MDS. In 2009 and 2010, representatives from 23, mainly European, institutes participated in the second and third European LeukemiaNet (ELN) MDS workshops. In the present report, minimal requirements to analyze dysplasia are refined. The proposed core markers should enable a categorization of FC results in cytopenic patients as 'normal', 'suggestive of', or 'diagnostic of' MDS. An FC report should include a description of validated FC abnormalities such as aberrant marker expression on myeloid progenitors and, furthermore, dysgranulopoiesis and/or dysmonocytopoiesis, if at least two abnormalities are evidenced. The working group is dedicated to initiate further studies to establish robust diagnostic and prognostic FC panels in MDS. An ultimate goal is to refine and improve diagnosis and prognostic scoring systems. Finally, the working group stresses that FC should be part of an integrated diagnosis rather than a separate technique.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(7):1730-41. · 8.30 Impact Factor
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W Nagi,
Z Y Lim,
P Krishnamurthy,
V Potter,
V Tindell,
L Reiff-Zall,
A Abdullah,
N Lea,
M Kenyon,
J Marsh,
A Y L Ho, G J Mufti,
A Pagliuca
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ABSTRACT: We report the results of 11 patients myelofibrosis, who have received a uniform alemtuzumab-based RIC HSCT. The median recipient age was 51 years. Stem cells were obtained from 8 full HLA-matched and 3 HLA-mismatched donors. The 2-year OS and TRM at 2-years was 46% and 54% with no disease relapse observed. For patients with a full HLA-matched donor, the 2-year TRM and OS was 37.5% and 62.5%. All 4 JAK2 V617F mutant positive patients achieved molecular remission after a median of 90 days post-transplant, and the median time to regression of bone marrow fibrosis was 180 days.
Leukemia research 06/2011; 35(8):998-1000. · 2.36 Impact Factor
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ABSTRACT: The Myelodysplastic Syndromes (MDS) represent a markedly heterogeneous group of haematopoietic stem cell disorders, with a
wide diversity in outcome. Whilst some cases of MDS carry an indolent course with prolonged survival, others may progress
rapidly to acute myeloid leukaemia (AML) and death. The pathophysiology of MDS remains poorly understood, in part due to the
heterogeneity of the disease. Several clonal karyotypic and genetic mutations are reported in MDS and likely to play a key
role in its pathogenesis. Moreover, defects in immune responses, both innate and adaptive, together with, or in the absence
of, altered cytokine/chemokine profiles are integral to the disease process. It is hypothesised that a combination of environmental
factors, genetic background and autoimmune responses play role in the pathogenesis of MDS (Fig.9.1). This chapter will focus
on the immunological aspects of MDS and provide the clinical evidence to support MDS as an autoimmune disorder.
03/2011: pages 145-157;
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ABSTRACT: The myelodysplastic overlap syndromes encompass a group of clonal neoplastic bone marrow disorders, which, at the time of
presentation, demonstrate clinical, morphological or laboratory findings in keeping with both the myelodysplastic syndromes
(MDS) and the myeloproliferative neoplasms (MPN) [1]. Cases present along a continuum, ranging from those with a predominant
dysplastic phenotype to others with predominant features of myeloproliferation such as a high white blood cell count (WBC)
and/or hepatosplenomegaly. One such disorder is chronic myelomonocytic leukaemia (CMML). The classification of CMML has caused
much controversy. Historically, the French-American-British (FAB) classification placed CMML in the MDS subgroup as it did
not contain a separate category for such overlap syndromes [2, 3]. However, while some cases of CMML present with a low WBC
and overt dysplasia, others present with a marked increase in the WBC count and organomegaly, more in keeping with the MPN.
As a result, the 3rd edition of the WHO classification of Tumours of Haematopoietic and Lymphoid Tissues recognised the need
to create a separate entity for such disorders. A subgroup termed the myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
was created and encompasses disorders with both dysplastic and proliferative features [1, 4].
03/2011: pages 159-173;
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ABSTRACT: Haematopoietic SCT (HSCT) offers the only potentially curative option in chronic myelomonocytic leukaemia (CMML). In this study, we report on single-centre results of 18 patients with CMML who have undergone allogeneic HSCT. The median age of patients was 54 years. Seven patients had AML, which had transformed from CMML. Overall, 11 patients received stem cells from an unrelated donor. A total of 15 patients received a T-cell-depleted fludarabine/BU-based reduced-intensity conditioning HSCT. The actuarial 3-year OS, non-relapse mortality (NRM) and relapse incidence for the cohort was 31±11%, 31±14% and 47±13%, respectively. Patients with favourable cytogenetics had a 3-year disease-free survival of 65±17%, whereas none of the seven patients with intermediate or poor risk cytogenetics survived beyond 2 years (P<0.01). No patients with favourable risk cytogenetics died from NRM causes, while the 2-year NRM for the intermediate/poor risk cytogenetics subgroup was 71±22% (P<0.02). In terms of disease status at transplantation, patients who had <5% BM blasts had a 3-year disease-free survival of 46.9±19% compared with those with >5% blasts at the time of transplantation (that is, 20.0±13%). Recipient age, type of conditioning regimen or stem cell dose did not have a significant impact on overall outcomes. Our data support existing evidence that allogeneic HSCT is a feasible therapeutic option for CMML, with the ability to attain long-term remission among patient subgroups.
Bone marrow transplantation 10/2010; 45(10):1502-7. · 3.00 Impact Factor
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ABSTRACT: Aliment Pharmacol Ther 31, 1330–1336SummaryBackground Occult myeloproliferative disorders (MPD) are present in 25% of patients with chronic portal, splenic and mesenteric venous thrombosis (PSMVT). A somatic mutation of JAK2 (JAK2V617F) can be used to identify patients with latent MPD.Aim We evaluated the prevalence and clinical significance of JAK2V617F in patients with chronic PSMVT.Methods Allele-specific polymerase chain reaction was performed to screen for JAK2V617F.Results Thirty-five patients were tested for JAK2V617F. The underlying pro-coagulant condition was MPD in seven of 35 (20.0%) patients; other aetiologies included hereditary thrombophilia (n = 5), chronic pancreatitis (n = 2), liver abscess (n = 1) and umbilical vein sepsis (n = 3). The remainder were labelled idiopathic, i.e. 17/35 (48.6%) patients. JAK2V617F was detected in 16/35 (45.7%) patients: seven of seven (100%) with MPD, two of 11 (18.1%) with non-MPD acquired conditions and seven of 17 (41.2%) with ‘idiopathic’ chronic PSMVT. Mean haemoglobin concentration (P = 0.04), haematocrit (P = 0.04), white cell count (P = 0.002) and platelet count (P = 0.05) were significantly higher in patients with JAK2V617F. None of the seven patients with latent MPD have progressed to overt MPD over median follow-up of 85 months.Conclusion JAK2V617F occurs in 41% of patients with idiopathic chronic portal, splenic and mesenteric venous thrombosis, confirming the presence of latent myeloproliferative disorders, and should form part of the routine pro-coagulant screen.
Alimentary Pharmacology & Therapeutics 05/2010; 31(12):1330 - 1336. · 3.77 Impact Factor
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ABSTRACT: DNA replication is tightly regulated, but paradoxically there is reported to be an excess of MCM DNA replication proteins over the number of replication origins. Here, we show that MCM levels in primary human T cells are induced during the G(0)-->G(1) transition and are not in excess in proliferating cells. The level of induction is critical as we show that a 50% reduction leads to increased centromere separation, premature chromatid separation (PCS) and gross chromosomal abnormalities typical of genomic instability syndromes. We investigated the mechanisms involved and show that a reduction in MCM levels causes dose-dependent DNA damage involving activation of ATR & ATM and Chk1 & Chk2. There is increased DNA mis-repair by non-homologous end joining (NHEJ) and both NHEJ and homologous recombination are necessary for Mcm7-depleted cells to progress to metaphase. Therefore, a simple reduction in MCM loading onto DNA, which occurs in cancers as a result of aberrant cell cycle control, is sufficient to cause PCS and gross genomic instability within one cell cycle.
Oncogene 05/2010; 29(26):3803-14. · 6.37 Impact Factor
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ABSTRACT: Occult myeloproliferative disorders (MPD) are present in 25% of patients with chronic portal, splenic and mesenteric venous thrombosis (PSMVT). A somatic mutation of JAK2 (JAK2V617F) can be used to identify patients with latent MPD.
We evaluated the prevalence and clinical significance of JAK2V617F in patients with chronic PSMVT.
Allele-specific polymerase chain reaction was performed to screen for JAK2V617F.
Thirty-five patients were tested for JAK2V617F. The underlying pro-coagulant condition was MPD in seven of 35 (20.0%) patients; other aetiologies included hereditary thrombophilia (n = 5), chronic pancreatitis (n = 2), liver abscess (n = 1) and umbilical vein sepsis (n = 3). The remainder were labelled idiopathic, i.e. 17/35 (48.6%) patients. JAK2V617F was detected in 16/35 (45.7%) patients: seven of seven (100%) with MPD, two of 11 (18.1%) with non-MPD acquired conditions and seven of 17 (41.2%) with 'idiopathic' chronic PSMVT. Mean haemoglobin concentration (P = 0.04), haematocrit (P = 0.04), white cell count (P = 0.002) and platelet count (P = 0.05) were significantly higher in patients with JAK2V617F. None of the seven patients with latent MPD have progressed to overt MPD over median follow-up of 85 months.
JAK2V617F occurs in 41% of patients with idiopathic chronic portal, splenic and mesenteric venous thrombosis, confirming the presence of latent myeloproliferative disorders, and should form part of the routine pro-coagulant screen.
Alimentary Pharmacology & Therapeutics 03/2010; 31(12):1330-6. · 3.77 Impact Factor
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ABSTRACT: We report on a retrospective analysis examining the influence of pre-transplant serum ferritin on transplant outcomes of 99 MDS patients receiving reduced intensity conditioning (RIC) HSCT. The median pre-transplant ferritin value was 1992 ng/ml (range: 6-9580 ng/ml). No patients received iron chelation therapy preceding transplantation. On univariate analysis, there was a strong correlation between a higher pre-transplant serum ferritin (>1500 ng/ml) and a significantly inferior 3-year OS (64.6+/-7.5% vs 39.6+/-7.3%, p=0.01). However, pre-transplant serum ferritin did not influence 3-year TRM (20.2+/-7% vs 27.4+/-7%, p=0.24). There was no difference in infection-related mortality, and incidence of acute or chronic GvHD between cohorts. On multivariate analysis, a raised serum ferritin (HR: 2.00, 95% CI: 0.97-3.57, p=0.03), and the presence of >5% bone marrow blasts at time of transplantation (HR: 2.14, 95% CI: 0.84-4.58, p=0.06) were independent predictors of an inferior overall survival. However, pre-transplant serum ferritin was not a significant predictor of disease-free survival, relapse or TRM. When compared with myeloablative regimens, RIC regimens may attenuate the impact of iron overload related end-organ toxicity. Prospective studies incorporating alternative biomarkers of iron metabolism alongside serum ferritin levels are needed to improve our understanding of the significance of iron overload in MDS patients undergoing allogeneic transplantation.
Leukemia research 11/2009; 34(6):723-7. · 2.36 Impact Factor
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ABSTRACT: We report a retrospective analysis of 128 consecutive patients with high-risk myelodysplastic syndrome (MDS) and AML who received an alemtuzumab-based reduced-intensity conditioning hematopoietic SCT (RIC HSCT). The median recipient age was 53 years (range 21-72 years). A total of 49 (38%) recipients had a sibling donor and 79 (62%) had a volunteer-unrelated donor. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was assigned to all patients with a score of 0 in 40 (31%), of 1-2 in 45 (35%) and >or=3 in 43 (34%) patients. The 3-year non-relapse mortality (NRM) was 31%, disease-free survival (DFS) was 41% and overall survival (OS) was 46%. The 3-year NRM for patients with a HCT-CI score of 0, 1-2 or >or=3 was 16, 24 and 42%, respectively. The 3-year DFS and OS by HCT-CI was 58 and 69% (score 0), 39 and 39% (score 1-2) and 24 and 32% (score >or=3), respectively. On multivariate analysis, HCT-CI was an independent variable affecting 3-year NRM, DFS and OS (P-value=0.04, 0.01 and <0.01, respectively). Although the disease stage at the time of transplant was an additional independent predictive variable on transplant outcomes, recipient age (>or<50 years) did not have a significant predictive impact. In MDS or AML patients with advanced disease receiving alemtuzumab-based RIC HSCT, the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant outcomes.
Bone marrow transplantation 09/2009; 45(4):633-9. · 3.00 Impact Factor
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Bone marrow transplantation 06/2009; 45(1):195-6. · 3.00 Impact Factor
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ABSTRACT: The prevalence of a novel somatic mutation (E17K) in the pleckstrin homology domain of AKT1 was investigated in pancreatic cancer using a quantitative pyrosequencing assay. This mutation was un-detectable in pancreatic cancer tissue samples (n=65) and pancreatic cell line (n=10) DNA suggesting that pancreatic cancer progression is mainly dependent on the K-Ras mutation.
Technology in cancer research & treatment 11/2008; 7(5):407-8. · 2.02 Impact Factor
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ABSTRACT: This multi-centre randomized study assessed the bioavailability of ganciclovir in patients undergoing alemtuzumab-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) after oral administration of valganciclovir. Patients were randomized to 2 groups receiving either oral valganciclovir (900 mg twice daily) or intravenous ganciclovir (5mg/kg twice daily) for 14 days. Twenty-seven patients were recruited and 18 patients (67%) completed allocated treatment resulting in clearance of cytomegolovirus (CMV) DNA load at a median of 14 days. The bioavailability of ganciclovir from valganciclovir was 73% (95% CI: 34-112%). The average exposure in the valganciclovir group (36.9+/-14.9 microg h/ml) was higher than the ganciclovir cohort (27.9+/-7.5 microg h/ml). When compared with intravenous ganciclovir, oral valganciclovir had high bioavailability in patients undergoing alemtuzumab-based RIC HSCT.
Leukemia research 10/2008; 33(2):244-9. · 2.36 Impact Factor
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B E Shaw, G J Mufti,
S Mackinnon,
J D Cavenagh,
R M Pearce,
K E Towlson,
J F Apperley,
R Chakraverty,
C F Craddock,
M A Kazmi,
T J Littlewood,
D W Milligan,
A Pagliuca,
K J Thomson,
D I Marks,
N H Russell
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ABSTRACT: Disease relapse following an allogeneic transplant remains a major cause of treatment failure, often with a poor outcome. Second allogeneic transplant procedures have been associated with high TRM, especially with myeloablative conditioning. We hypothesized that the use of reduced-intensity conditioning (RIC) would decrease the TRM. We performed a retrospective national multicentre analysis of 71 patients receiving a second allogeneic transplant using RIC after disease relapse following an initial allogeneic transplant. The majority of patients had leukaemia/myelodysplasia (MDS) (N=57), nine had lymphoproliferative disorders, two had myeloma and three had myeloproliferative diseases. A total of 25% of patients had unrelated donors. The median follow-up was 906 days from the second allograft. The predicted overall survival (OS) and TRM at 2 years were 28 and 27%, respectively. TRM was significantly lower in those who relapsed late (>11 months) following the first transplant (2 years: 17 vs 38% in early relapses; P=0.03). Two factors were significantly associated with a better survival: late relapse (P=0.014) and chronic GVHD following the second transplant (P=0.014). These data support our hypothesis that the second RIC allograft results in a lower TRM than using MA. A proportion of patients achieved a sustained remission even when relapsing after a previous MA transplant.
Bone marrow transplantation 09/2008; 42(12):783-9. · 3.00 Impact Factor
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Bone Marrow Transplantation 08/2008; 42(5):361-2. · 3.75 Impact Factor
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Bone Marrow Transplantation 06/2008; 41(9):831-2. · 3.75 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2008; 22(5):1084-7. · 8.30 Impact Factor
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Bone Marrow Transplantation 04/2008; 41(6):587-8. · 3.75 Impact Factor
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British Journal of Dermatology 02/2008; 158(1):172-4. · 3.67 Impact Factor
