J E Parker

King's College London, Londinium, England, United Kingdom

Are you J E Parker?

Claim your profile

Publications (8)31.94 Total impact

  • J E Parker, G J Mufti
    [Show abstract] [Hide abstract]
    ABSTRACT: The paradoxical occurrence of peripheral cytopenias despite a normo/hypercellular marrow in myelodysplastic syndromes (MDS) has been attributed to excessive intramedullary hematopoietic cell apoptosis. It has also been postulated that abrogation of programmed cell death (PCD) may underlie MDS transformation to acute myeloid leukemia (AML). Despite overwhelming evidence for a role of aberrant apoptosis in myelodysplasia, the molecular mechanisms responsible for such changes have not been elucidated. This paper summarizes current evidence implicating a role for altered PCD in MDS and outlines potential cellular mechanisms whereby hematopoietic progenitor cell apoptosis may be dysregulated.
    International Journal of Hematology 07/2001; 73(4):416-28. · 1.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We report our updated experience of allogeneic transplantation in lympho-proliferative disorders using a reduced-intensity conditioning regimen combining BEAM (plus fludarabine in three cases) with pre-transplant CAMPATH. Post-transplant donor lymphocytes have been infused for persisting disease or relapse, and both chimerism and minimal residual disease have been monitored utilizing molecular techniques. Thirty patients with median age 47.6 years underwent allogeneic transplantation for relapsed or high-risk lymphoproliferative disease using HLA-identical (sibling n = 25, unrelated n = 2) or one antigen mismatched sibling donors (n = 3). Twenty-one had NHL, three had HD and six had CLL/PLL. Stem-cell source was PBSC (n = 24), BM (n = 5) or both (n = 1) with a median CD34 dose of 4.5 x 10(6)/kg. GvHD prophylaxis was with CYA and MTX. Engraftment was prompt in the majority of patients, with a median of 15 days to both ANC > 0.5 and platelets > 20. There have been three transplant-related deaths secondary to viral pneumonitis or bacterial pneumonia. Seven patients developed Grade I-II acute GvHD post-transplant. Of 28 evaluable patients, 18 achieved a CR at assessment 2-3 months post-transplant and a further patient converted from PR to CR following DLI, to give an overall CR rate of 68%. Three patients had early progressive disease and six have relapsed from CR or progressed from PR (two of whom have achieved CR following DLI therapy). Overall survival is 67% and event-free survival 48% at 3 years. With a median follow-up of 1.3 years 57% of patients are currently alive and lymphoma-free. A molecular remission has been achieved in nine of 12 informative patients. These encouraging results show that this reduced-intensity conditioning regimen is effective, with a low-toxicity profile compared with conventional TBI-based conditioning, and certainly merits further evaluation in this setting.
    Cytotherapy 01/2001; 3(3):203-10. · 3.06 Impact Factor
  • J E Parker, G J Mufti
    [Show abstract] [Hide abstract]
    ABSTRACT: The paradox of peripheral cytopenias despite a normo/hypercellular marrow in MDS has been ascribed to excessive intramedullary hematopoietic cell apoptosis. Programmed cell death (PCD) in early disease might be triggered by the BM microenvironment, mediated either through inhibitory cytokines such as tumor necrosis factor alpha (TNF-alpha) or fas/fas ligand signaling or through a relative deficiency in hematopoietic growth factors. Intrinsic cellular defects giving rise to abnormalities in cell-cell or cell-stromal interaction, cell signaling or cell cycling may also underlie hematopoietic progenitor apoptosis. Alternatively, an early 'hit' in the multistep pathogenesis of MDS may result in a higher proliferative rate of the neoplastic clone. Increased apoptosis may thus represent a homeostatic process to control cell numbers. This paper shall summarize current evidence implicating a role for increased PCD in low risk MDS, outline possible etiologic factors and suggest potential therapeutic mechanisms whereby excessive hematopoietic progenitor cell apoptosis might be circumvented.
    Leukemia and Lymphoma 01/2001; 40(1-2):1-24. · 2.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone marrow CD34(+) cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia secondary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significantly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51.2% [25.2%-76. 6%]) compared with NBM (16.7% [3.4%-35.3%], P <.0001). In RA/RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5%-47.8%]; apoptosis:proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB, this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (40.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML was associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%]; P <.0001) and proliferation (16.8% [1.9%-75.8%); P =.04; ratio 1.69 [0.16-12.21]). Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl-2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P =.06), whereas disease progression was associated with significantly reduced ratios (1.16 [0.06-3.32]; P <.0001) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2/Bcl-X ratio were inversely correlated with both International Prognostic Scoring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend toward an association between Bcl-2-related protein expression and apoptosis (P =.07). This study indicates that MDS progression arises through multiple hits that alter levels of CD34(+) cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apoptosis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rather than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2-related protein ratios, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS. (Blood. 2000;96:3932-3938)
    Blood 12/2000; 96(12):3932-8. · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We performed flow cytometric analysis of CD34+ cell apoptosis in 59 patients with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) secondary to MDS (MDS-AML) using annexin V-FITC, which binds to exposed phosphatidylserine on apoptotic cells. Apoptosis was significantly increased in FAB subtypes RA, RARS and RAEB (<10% blasts) (56.5% (15.1-86.5%)) compared to normal controls (18.5% (3.4-33.4%), P<0.0001) and RAEB-t/MDS-AML (16% (2.1-43.2%), P<0.0001). There was no correlation between % apoptosis, Full blood count or cytogenetics in any disease category. Two-colour cytometric analysis of permeabilized CD34+ cells stained with antibodies to Bcl-2, Bcl-X (anti-apoptotic), Bax and Bad (pro-apoptotic), demonstrated significantly higher ratios of pro- v anti-apoptotic proteins in early MDS (2.47 (1.19-9.42) compared to advanced disease (1.14 (0.06-3.32), P=0.0001). Moreover, using repeated measures of variants (ANOVA), we found that variations between individual Bcl-2-related proteins differed significantly according to disease subtype (P<0.0005). Our results confirm that CD34+ cell apoptosis was significantly increased in MDS subtypes RA and RARS and fell with disease progression. Early MDS was also associated with a significantly higher CD34+ cell pro- v anti-apoptotic Bcl-2-family-protein ratio than advanced disease. Furthermore, patterns of expression of individual Bcl-2 related proteins differed significantly between different disease categories. However, no correlation between pro- v anti-apoptotic Bcl-2-family-protein ratios and the degree of apoptosis was observed.
    British Journal of Haematology 12/1998; 103(4):1075-82. · 4.94 Impact Factor
  • Source
    J E Parker, G J Mufti
    British Journal of Haematology 06/1998; 101(2):220-30. · 4.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy (de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (< 5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.
    British Journal of Haematology 12/1997; 99(4):939-44. · 4.94 Impact Factor
  • Leukemia Research - LEUK RES. 01/1997; 21(1).

Publication Stats

457 Citations
31.94 Total Impact Points

Institutions

  • 1997–2001
    • King's College London
      Londinium, England, United Kingdom
  • 1998
    • The Peninsula College of Medicine and Dentistry
      Plymouth, England, United Kingdom