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ABSTRACT: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by expression of oncogenic fusion product BCR-ABL1, resulting from reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11.2)]. Previously perceived to confer poor outcome with at least 10 % lower chance of remission than standard-risk ALL. With the advent of targeted BCR-ABL specific tyrosine-kinase inhibitors (TKIs), higher remission rates were achieved, thus allowing more patients to proceed with the definitive treatment modality-allogeneic hematopoietic stem cell transplantation (alloHSCT). Prime challenges to treatment of Ph+ ALL include appropriate integration of TKIs into remission induction chemotherapeutic regimes, appropriate understanding and implementation of BCR-ABL monitoring for guiding therapeutic intervention(s), and minimizing transplant-related toxicities.
Current Hematologic Malignancy Reports 03/2013;
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P G Medd,
A J Peniket,
T J Littlewood,
R Pearce,
J Perry,
K E Kirkland,
B E Shaw,
M N Potter,
C F Craddock,
D W Milligan, A K Fielding,
D I Marks,
G Cook
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ABSTRACT: Myeloablative allo-SCT decreases relapse incidence (RI) in ALL. Reduced intensity conditioning (RIC) may extend allo-SCT to older and less fit patients. Sixty-nine ALL patients reported to the BSBMT underwent fludarabine-based RIC allo-SCT, 38 from unrelated donors (UD). Forty-four patients received alemtuzumab. ALL was in CR in 64 patients (93%). This was a second or third SCT in 23 patients. Two-year OS and PFS were 36% and 32%, respectively. In multivariate analysis male recipients demonstrated better OS and PFS (hazard ratio (HR)=0.42, P=0.008 and HR=0.45, P=0.012, respectively). Two-year TRM was 29%: higher with younger age (HR=0.97/year, P=0.041), female recipient (HR=2.55, P=0.049) and increasing grade of acute GVHD (HR=1.87, P=0.001). Two-year RI was 38% and was lower in patients with acute and chronic GVHD (HR=0.62 per increasing grade, P=0.035 and HR=0.52, P=0.025, respectively). Long-term ALL-free survival is achievable following fludarabine-based RIC allo-SCT. The association between GVHD and decreased RI suggests the presence of a GVL effect.Bone Marrow Transplantation advance online publication, 14 January 2013; doi:10.1038/bmt.2012.261.
Bone marrow transplantation 01/2013; · 3.00 Impact Factor
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F L Dignan,
D Greenblatt,
M Cox,
J Cavenagh,
H Oakervee,
J F Apperley, A K Fielding,
A Pagliuca,
G Mufti,
K Raj,
D I Marks,
P Amrolia,
A Peniket,
P Medd,
M N Potter,
B E Shaw,
J J Scarisbrick
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ABSTRACT: Extracorporeal photopheresis (ECP) has become a recognised treatment for steroid-refractory chronic GVHD (cGVHD), but the optimal frequency and duration of treatment are yet to be established. We report on 82 consecutive patients with mucocutaneous cGVHD who received a bimonthly regimen of ECP treatment for two consecutive days, which could be subsequently tapered to a monthly regimen depending on response. Patients were steroid-refractory, steroid-dependent or steroid-intolerant, and 29 (35%) had multiorgan involvement. The median duration of treatment was 330 days (42-987). The median number of ECP cycles was 15 (1.5-32). Response was assessed by clinical assessment and reduction in immunosuppression after 6 months. 69/82 (84%) had completed 6 months of ECP and 65/69 (94%) had ≥ 50% improvement in symptoms and signs of cGVHD. A total of 77% of patients who completed 6 months of ECP had a reduction in immunosuppression dose and 80% had decreased their steroid dose (27.5% stopped, 30% had ≥ 75% reduction, 17.5% had ≥ 50% reduction and 25% had <50% reduction). OS at 3 years from the start of ECP was 69%. This study reports the largest series of patients receiving bimonthly ECP treatment for cGVHD, and confirms that ECP allows successful reduction of immunosuppression.
Bone marrow transplantation 09/2011; 47(6):824-30. · 3.00 Impact Factor
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M Brüggemann,
A Schrauder,
T Raff,
H Pfeifer,
M Dworzak,
O G Ottmann,
V Asnafi,
A Baruchel,
R Bassan,
Y Benoit, [......],
R Pieters,
A Rambaldi,
J-M Ribera,
K Schmiegelow,
O Spinelli,
J Stary,
A von Stackelberg,
M Kneba,
M Schrappe,
J J M van Dongen
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ABSTRACT: Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 03/2010; 24(3):521-35. · 8.30 Impact Factor
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ABSTRACT: ALL in which the Philadelphia (Ph) chromosome is detected is one of the few diseases in which there is almost unequivocal agreement that a matched sibling allogeneic haematopoietic stem cell transplant in first CR is the most appropriate therapy for patients within certain age limits. Extension of allogeneic stem cell transplant to patients without matched sibling donors or to older individuals is increasingly possible due to unrelated donors, umbilical cord blood and reduced-intensity conditioning regimens. Here, we carefully review evidence supporting current practice and examine recent evidence relating to the use of newer allogeneic transplant technologies in Ph-pos ALL. We explore the burgeoning literature on the role of tyrosine kinase inhibitors in this disease and summarize their impact on the transplant practice.
Bone Marrow Transplantation 04/2008; 41(5):447-53. · 3.75 Impact Factor
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ABSTRACT: Avascular necrosis (AVN) is a serious complication of acute lymphoblastic leukaemia (ALL) therapy. Little is known of the scope and magnitude of this problem among adults with ALL. We analysed the incidence and risk factors for AVN in 1053 patients on the UKALLXII/ECOG2993 study. AVN affected 99 joints in 42 patients at a median of 2.2 years post-diagnosis, giving a crude incidence rate of 4.0%. Statistically significant risk factors for the development of AVN were age and treatment with chemotherapy. Patients receiving prolonged chemotherapy without stem cell transplant were at significantly greater risk of developing AVN than stem cell transplant recipients (P<0.00005). The actuarial incidence of AVN was 29% at 10 years in patients <20 years old compared to 8% at 10 years in those >20 years old; P=0.0004; odds ratio 0.28 (95% CI=0.14-0.56).
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2008; 22(2):308-12. · 8.30 Impact Factor
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ABSTRACT: Derivatives of the Edmonston-B strain of measles virus (MV-Ed) are safe, live attenuated measles virus (MV) vaccines that have been used worldwide for more than 30 years. The cytoreductive potential of MV-Ed has been investigated in murine models of both aggressive and indolent B-cell lymphoma in severe combined immunodeficient (SCID) mice. The rationale for these studies was generated by experience with viral fusogenic membrane glycoproteins as cytotoxic genes and the recognition of the potential of replicating viruses in the treatment of human malignancy. Intratumoral injection of both unmodified MV-Ed and a strain of MV-Ed genetically modified by the addition of a beta-galactosidase reporter gene (MVlacZ) induced regression of large established human lymphoma xenografts, in contrast to control therapy with UV-inactivated virus, in which all tumors progressed. The antitumor effect still occurred in the presence of passively transferred anti-MV antibody. Intravenous administration of MV also resulted in considerable slowing of tumor progression. Analysis of sections of residual tumor confirmed replication of MV within the tumors. Thus, the vaccine strain of MV mediates regression of large, established human B-cell lymphoma xenografts in SCID mice, and proof of principle is established that MV is oncolytic for lymphomas in vivo. Attenuated MVs may have value as a novel replicating-virus therapy for this group of disorders. (Blood. 2001;97:3746-3754)
Blood 07/2001; 97(12):3746-54. · 9.90 Impact Factor
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ABSTRACT: An important goal in cancer gene therapy is the development of novel targeted cytotoxic genes. The observation that transfection of a GaLV envelope glycoprotein lacking an R peptide into human cells results in considerable cell-cell fusion and subsequent cell death prompted us to explore the potential for using this fusogenic membrane glycoprotein (FMG) as a targeted cytotoxic gene. As proof of principle, we therefore displayed epidermal growth factor (EGF) on the N terminus of GaLV envelope glycoproteins both with and without an R peptide (GaLV R+ and GaLV R-). Transfection of the GaLVR+ envelope expression plasmids did not cause cell-cell fusion. The GaLV R+ envelopes were incorporated into retroviral vectors whose infectivity was investigated on EGF receptor-positive and -negative cells. The vector incorporating an N-terminally unmodified envelope was able to infect all human cell lines tested. Infectivity of the vector incorporating an envelope on which EGF was displayed was restricted on EGF receptor-positive cells (but not on EGF receptor-negative cells) and could be restored by protease cleavage of the displayed domain or competition with exogenous ligand. The cell-cell fusion capacity of the GaLV R- envelope glycoproteins (N-terminally unmodified and with N-terminal display of both EGF and insulin-like growth factor I [IGF-I]) was investigated by plasmid DNA transfection. While the N-terminally unmodified GaLV R- fused all human cell types tested, fusogenicity of GaLV R- on which EGF or IGF-I was displayed was considerably restricted on receptor-positive cells. "Reciprocal" competition experiments showed that fusogenicity could be restored by competition only with the relevant exogenous ligand. Thus the specificity of cell-cell fusion by a hyperfusogenic GaLV envelope glycoprotein can be regulated by N-terminal display of growth factor ligands. There is therefore significant potential for further development of the targeting of the cell-killing capability of this fusogenic viral glycoprotein by using strategies similar to those we have developed for the targeting of retroviral vectors.
Human Gene Therapy 05/2000; 11(6):817-26. · 4.22 Impact Factor
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ABSTRACT: We previously reported that retroviral vectors displaying epidermal growth factor (EGF) as part of a chimeric envelope glycoprotein are sequestered upon binding to EGF receptor (EGFR)-positive target cells, leading to loss of infectivity. In the current study, we have displayed stem cell factor (SCF) on beta-galactosidase-transducing ecotropic and amphotropic retroviral vector particles as a factor Xa protease-cleavable N-terminal extension of the envelope glycoprotein. Viral incorporation of the SCF chimeric envelopes was demonstrated by immunoblotting of pelleted virions and their specific attachment to Kit receptors was demonstrated by flow cytometry. Gene transfer studies showed that when SCF was displayed on an amphotropic envelope, the infectivity of the SCF-displaying vectors was selectively inhibited on Kit-expressing cells, but could be restored by adding soluble SCF to block the Kit receptors or by cleaving the displayed SCF domain from the vector particles with factor Xa protease. The host range properties of EGF-displaying and SCF-displaying vectors were then compared in cell mixing experiments. When EGFR-positive cancer cells and Kit-positive hematopoietic cells were mixed and exposed to the different engineered vector particles, the cancer cells were selectively transduced by the SCF-displaying vector and the hematopoietic cells were selectively transduced by the EGF-displaying vector. Retroviral display of polypeptide growth factors can therefore provide the basis for a novel inverse targeting strategy with potential use for selective transduction of hematopoietic or nonhematopoietic cells (eg, cancer cells) in a mixed cell population.
Blood 04/1998; 91(5):1802-9. · 9.90 Impact Factor
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D C Linch,
D W Milligan,
D A Winfield,
S M Kelsey,
S A Johnson,
T J Littlewood,
G M Smith,
R M Hutchinson,
A H Goldstone, A K Fielding,
G Vaughan Hudson
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ABSTRACT: We have undertaken a prospective randomized study in 90 patients with relapsed or resistant lymphomas to assess the value of G-CSF (lenograstim) in the acceleration of myeloid recovery after peripheral blood stem cell transplantation (PBSCT). A common regimen of cyclophosphamide 1.5 g/m2 on day 1 and lenograstim 263 microg s.c. on days 2-10 with two aphereses on days 10 and 11 was used for stem cell mobilization. 77% of patients achieved an adequate PBSC collection in two harvests (> 2 x 10(8) MNC/kg or > 2 x 10(6) CD34+ cells/kg). 65 patients went on to receive high-dose BEAM chemotherapy and engraftment data was available for 62. 34 patients had been randomized to receive lenograstim 263 microg/d s.c. and 28 to no growth factor. The median time to ANC > 0.5 x 10(9)/l was 9 d in the lenograstim arm versus 12.5 d in the no-lenograstim arm (P=0.0001). This was associated with a median duration of time in hospital post PBSCT of 13 d in the lenograstim arm versus 15.5 d in the no-lenograstim arm (P=0.0002). Median days to platelet independence, platelet transfusions, incidence of infection and red cell transfusion were the same in both arms. These data indicate that lenograstim significantly accelerated myeloid recovery after PBSCT and shortened the duration of hospital stay.
British Journal of Haematology 12/1997; 99(4):933-8. · 4.94 Impact Factor
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ABSTRACT: More frequent skewing of X-chromosome inactivation patterns (XCIPs) occurs in the white blood cells of elderly females; this study was performed to determine whether this occurs in myeloid or lymphoid lineages. XCIPs were analysed in purified neutrophils and T cells from 80 females > 75 years and the results were compared with 23 cord blood and 94 younger adult blood samples. The degree of XCIP skewing in cord blood and younger adult blood cells was similar, with 3-4% having > 90% expression of one allele. Skewing was markedly increased in the neutrophils of elderly females, with 33% having > 90% expression of one allele (P < 0.0001). Extreme skewing was present in only 9% of the elderly T-cell samples and no evidence of T-cell clonality was found by PCR analysis of the TCR gamma gene. The high level of acquired skewing of the XCIPs in myeloid cells of the elderly suggests that with time there is a change in stem cell usage with stochastic loss of some of the original stem cells. This has major implications for the use of XCIP analysis in the diagnosis of myeloid malignancies in the elderly and for gene therapy into haemopoietic stem cells.
British Journal of Haematology 09/1997; 98(3):512-9. · 4.94 Impact Factor
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BMJ 06/1997; 314(7091):1396-9. · 14.09 Impact Factor
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ABSTRACT: The use of genes or genetically modified cells for therapeutic benefit is likely to have a significant therapeutic role for patients with B cell lymphomas in the future. To date, most gene therapy strategies applicable to the therapy of these diseases have not reached the point of clinical study. Adoptive immunotherapy using donor leucocyte infusion to treat aggressive B cell neoplasms in immunosuppressed patients has, however, shown great promise clinically, and studies of idiotypic vaccination in patients with low grade B cell neoplasms are also under way. Results from in vitro and animal studies continue to suggest that it may become possible to use the immune system for therapeutic benefit, and many current basic research strategies in the gene therapy of B cell non-Hodgkin's lymphoma are based on immune modulation of T cells or tumour cells themselves. Other major approaches to gene therapy for B cell malignancies include the introduction of directly toxic or "suicide genes" into B cells or the chemoprotection of haemopoietic stem cells by the introduction of drug resistance genes. All of these approaches require efficient and accurate gene transfer as well as correct expression of the gene product within the target cell. Although some way from therapeutic use, specific targeting of gene delivery is an area of active investigation and will be of value in many of the gene therapy strategies applicable to B cell lymphomas.
Cancer surveys 01/1997; 30:327-42.
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ABSTRACT: Intermediate-dose salvage therapy is frequently given for relapsed and resistant lymphomas and is usually intensely myelosuppressive. In an attempt to reduce the haematological toxicity of miniBEAM, one of the commonly used salvage regimens, peripheral blood stem cell (PBSC) support was given to 21 consecutive patients who received miniBEAM chemotherapy. The outcome was compared with a non-randomised control group of consecutive patients who were similar to the supported group apart from the fact that it was not possible to collect PBSC before miniBEAM therapy. Apart from a small, marginally significant difference between the supported and unsupported groups in the number of days for which intravenous antibiotics were required, there were no other differences between the two groups in supportive care required and times to haematological recovery. In conclusion, PBSC support does not accelerate haematological recovery from miniBEAM therapy.
Bone Marrow Transplantation 10/1996; 18(3):507-11. · 3.75 Impact Factor
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ABSTRACT: To compare the results achieved with myeloablative therapy followed by either allogeneic bone marrow transplantation (alloBMT) or autologous bone marrow transplantation (ABMT) for patients with Hodgkin's disease (HD).
Of more than 1,200 patients with HD reported to the European Bone Marrow Transplantation (EBMT) registry, 49 underwent alloBMT. Of these, 45 with sufficient data were matched to 45 patients who underwent ABMT. The matching criteria were sex, age at time of transplantation, stage of disease at diagnosis, bone marrow involvement at diagnosis and at transplantation, year of transplantation, disease status at time of transplantation, time from diagnosis to transplantation, and conditioning regimen with or without total-body irradiation (TBI).
The 4-year actuarial probabilities of survival, progression-free survival (PFS), relapse, and non-relapse mortality were 25%, 15%, 61%, and 48% and 37%, 24%, 61%, and 27% after alloBMT and ABMT, respectively. The toxic death rate at 4 years was significantly higher for alloBMT patients (P = .04). For patients with sensitive disease at the time of transplantation, the 4-year actuarial probability of survival was 30% after alloBMT and 64% after ABMT (P = .007). This difference is mainly due to a higher transplant-related mortality rate after alloBMT (65% v 12%, P = .005). Acute graft-versus-host disease (aGVHD) > or = grade II was associated with a significantly lower risk of relapse, but also with a lower overall survival (OS) rate.
Based on this study, alloBMT from a human leukocyte antigen (HLA)-identical sibling donor does not appear to offer any advantage when compared with ABMT. A graft-versus-Hodgkin effect is associated with > or = grade II aGVHD, but its positive effect on relapse is largely offset by its toxicity. In most circumstances, alloBMT cannot be recommended for patients with HD.
Journal of Clinical Oncology 04/1996; 14(4):1291-6. · 18.37 Impact Factor
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New England Journal of Medicine 10/1995; 333(11):729; author reply 730. · 53.30 Impact Factor
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ABSTRACT: High-dose chemotherapy with autologous stem cell support is increasingly used in malignant disease. There are few data from randomized, controlled, clinical studies on which to base our approach, and many publications consist of retrospective analyses that do not help elucidate the overall role of high-dose therapy. There has been a rapid increase in the use of peripheral blood as a source of stem cells that may reduce the toxicity of the procedure, but this has spawned an enthusiasm for high-dose therapy particularly in conditions such as myeloma and solid tumors where, as yet, there are few clinical data to demonstrate survival benefit.
Current Opinion in Hematology 12/1994; 1(6):412-7. · 4.52 Impact Factor
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A K Fielding
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ABSTRACT: There is a well documented risk of late infection following both splenectomy and bone marrow transplantation. In asplenic patients, the phagocytic and antibody producing roles of the spleen are lost and there is a lifelong susceptibility to infection which may be overwhelming and fatal. Patients most at risk are children, those with underlying lymphoproliferative disorders and those receiving immunosuppressive therapy. Although it is hard to prove benefit from preventative strategies, patients are likely to benefit from prophylactic antibiotic therapy and from immunisation with pneumococcal, Haemophilus influenzae-B and meningococcal vaccine given prior to splenectomy. Following an allogeneic bone marrow transplant (BMT), recovery of immune function takes up to a year. During this time, patients are at high risk from cytomegalovirus (CMV) and varicella zoster virus (VZV) infections and also from pneumocystis pneumonia. Prophylactic medications are used to good effect. The major threat of late infection occurs in patients with chronic graft versus host disease (cGVHD)--there is increased susceptibility to bacterial, fungal and viral infections. Many patients without cGVHD recover immune function fully and many develop antibodies to specific recall antigens. This does not occur in all patients and although there is a low risk of infection with organisms against which vaccines are available. If it is not possible to measure specific antibody titres and consequently offer selective re-immunisation, then a universal vaccination strategy should be in force. Response to vaccines is likely to be poor before one year post BMT. For autologous transplant recipients, immune recovery is probably complete and routine re-immunisation is not likely to offer much benefit. For both asplenic and bone marrow transplant patients, education of patient and physician is important.
Blood Reviews 10/1994; 8(3):179-91. · 5.36 Impact Factor
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ABSTRACT: Bilateral iliac crest biopsies were performed at the time of bone marrow (BM) harvest in patients with poor-risk Hodgkin's disease (HD) undergoing autologous bone marrow transplantation (ABMT). 67 consecutive patients with normal trephine biopsies (58 unilateral; nine bilateral) taken 2 weeks prior to harvest were studied. Nine (13%) of patients had BM infiltration with HD on the harvest biopsies. These patients had all previously had only unilateral biopsies. Three patients did not proceed to ABMT because disease progression became clinically apparent, but the remaining six patients were infused with involved marrow. One patient died 6 weeks post ABMT, with no evidence of disease at post-mortem. One patient showed no response to ABMT and four patients either had a partial or complete response to ABMT. Of the responders, three patients are now in complete remission at 53, 39 and 33 months past ABMT.
British Journal of Haematology 08/1994; 87(3):647-9. · 4.94 Impact Factor
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ABSTRACT: Transplantation of mobilized peripheral blood progenitor cells has generally produced shortening of the period of posttransplant aplasia that is characteristic of bone marrow grafts. However, there has been no large prospective randomized study to compare these two sources of hematopoietic cells or to determine their relative merits. This issue is explored in this review.
Journal of Hematotherapy 02/1994; 3(4):299-304.
