11 results on '"Tighe, Jane"'
Search Results
2. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma
- Author
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Morris, Emma, Thomson, Kirsty, Craddock, Charles, Mahendra, Prem, Milligan, Donald, Cook, Gordon, Smith, Graeme Murray, Parker, Anne, Schey, Steve, Chopra, Rajesh, Hatton, Christopher, Tighe, Jane, Hunter, Anne, Peggs, Karl, Linch, David, Goldstone, Anthony, and Mackinnon, Stephen
- Abstract
We report the outcomes after reduced-intensity conditioning allogeneic stem cell transplantation (RIT) for non-Hodgkin lymphoma (NHL) in 88 patients (low-grade NHL [LG-NHL], n = 41; high-grade NHL [HG-NHL], n = 37; mantle cell lymphoma [MCL], n = 10). Thirty-seven patients had previously received autografts, and 21 were in complete remission (CR) at transplantation. Conditioning therapy consisted of alemtuzumab, fludarabine, and melphalan. Sixty-five patients received peripheral blood stem cells (PBSCs) from HLA-identical siblings, and 23 received bone marrow (BM) from matched unrelated donors. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporin A. Grade III-IV acute GVHD developed in 4 patients, and chronic GVHD developed in 6 patients. With a median follow-up of 36 months (range, 18-60 months), the actuarial overall survival (OS) rates at 3 years were 34% for HG-NHL, 60% for MCL, and 73% for LG-NHL (P < .001). The 100-day and 3-year transplant-related mortality (TRM) rates for patients with LG-NHL were 2% and 11%, respectively, and were better (P = .01) than they were for patients with HG-NHL (27% and 38%, respectively). The actuarial current progression-free survival (PFS) rate at 3 years, including the rate for patients who achieved remission after donor lymphocyte infusion (DLI) for progression, was 65% for LG-NHL, 50% for MCL, and 34% for HG-NHL (P = .002). Twenty-one patients underwent DLI for matched related donor (MD)-persistent disease or relapse, and 15 underwent DLI for mixed hematopoietic chimerism. Patients who experienced relapses of LG-NHL and chronic lymphocytic leukemia (CLL) achieved excellent PFS with extremely low TRM and GVHD, even when matched related donors were unavailable. (Blood. 2004;104:3865-3871)
- Published
- 2004
- Full Text
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3. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma
- Author
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Morris, Emma, Thomson, Kirsty, Craddock, Charles, Mahendra, Prem, Milligan, Donald, Cook, Gordon, Smith, Graeme Murray, Parker, Anne, Schey, Steve, Chopra, Rajesh, Hatton, Christopher, Tighe, Jane, Hunter, Anne, Peggs, Karl, Linch, David, Goldstone, Anthony, and Mackinnon, Stephen
- Abstract
We report the outcomes after reduced-intensity conditioning allogeneic stem cell transplantation (RIT) for non-Hodgkin lymphoma (NHL) in 88 patients (low-grade NHL [LG-NHL], n = 41; high-grade NHL [HG-NHL], n = 37; mantle cell lymphoma [MCL], n = 10). Thirty-seven patients had previously received autografts, and 21 were in complete remission (CR) at transplantation. Conditioning therapy consisted of alemtuzumab, fludarabine, and melphalan. Sixty-five patients received peripheral blood stem cells (PBSCs) from HLA-identical siblings, and 23 received bone marrow (BM) from matched unrelated donors. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporin A. Grade III-IV acute GVHD developed in 4 patients, and chronic GVHD developed in 6 patients. With a median follow-up of 36 months (range, 18-60 months), the actuarial overall survival (OS) rates at 3 years were 34% for HG-NHL, 60% for MCL, and 73% for LG-NHL (P< .001). The 100-day and 3-year transplant-related mortality (TRM) rates for patients with LG-NHL were 2% and 11%, respectively, and were better (P= .01) than they were for patients with HG-NHL (27% and 38%, respectively). The actuarial current progression-free survival (PFS) rate at 3 years, including the rate for patients who achieved remission after donor lymphocyte infusion (DLI) for progression, was 65% for LG-NHL, 50% for MCL, and 34% for HG-NHL (P= .002). Twenty-one patients underwent DLI for matched related donor (MD)-persistent disease or relapse, and 15 underwent DLI for mixed hematopoietic chimerism. Patients who experienced relapses of LG-NHL and chronic lymphocytic leukemia (CLL) achieved excellent PFS with extremely low TRM and GVHD, even when matched related donors were unavailable. (Blood. 2004;104:3865-3871)
- Published
- 2004
- Full Text
- View/download PDF
4. Leukemic and Non-Leukemic Lymphocytes from Patients with Li Fraumeni Syndrome Demonstrate Loss of p53 Function, Bcl-2 Family Dysregulation and Intrinsic Resistance to Conventional Chemotherapeutic Drugs But Not Flavopiridol
- Author
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Pepper, Chris, Thomas, Alun, Hoy, Terry, Tighe, Jane, Culligan, Dominic, Fegan, Chris, and Bentley, Paul
- Abstract
Li Fraumeni syndrome (LFS) is characterised by a predisposition to the early onset of certain tumors and is associated with germline mutation of the anti-oncogene p53. In this study we analysed the in vitro responses of lymphocytes from two LFS patients to chemotherapeutic drugs in terms of apoptosis induction and the expression of key intracellular proteins that regulate this process. One of the LFS patients also suffered from B-cell chronic lymphocytic leukemia (B-CLL) and hence presented with a light-chain restricted B-cell lymphocytosis while the other patient had entirely normal blood counts. The B-lymphocytes from both LFS patients showed a marked degree of resistance to chlorambucil and fludarabine when compared to age-matched controls but were remarkably sensitive to the novel flavone, flavopiridol. Loss of function of p53 was demonstrated by a failure to induce Bax and p21 protein expression. In addition, altered basal expression patterns of Bcl-2 and Bax, two key regulators of apoptosis, were found in the LFS lymphocytes when compared with controls. These results suggest that LFS lymphocytes carrying a p53 mutation show intrinsic resistance to conventional chemotherapeutic drugs and this is associated with dysregulation of Bcl-2 family proteins. Furthermore, The innate resistance profile was similar in leukemic and non-leukemic lymphocytes and was therefore independent of genetic changes acquired during malignant transformation. Novel agents that induce p53-independent cell killing may be useful not only in the treatment of LFS-associated tumors but also drug resistant tumors in general where p53 and/or Bcl-2 family dysregulation is a feature.
- Published
- 2003
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5. Translocation Breakpoints Are Clustered on Both Chromosome 8 and Chromosome 21 in the t(8;21) of Acute Myeloid Leukemia
- Author
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Tighe, Jane E., Daga, Antonio, and Calabi, Franco
- Abstract
The t(8;21)(q22;q22) is consistently associated with acute myeloid leukemia (AML) M2. Recent data have suggested that breakpoints on chromosome 21 are clustered within a single intron of a novel gene, AML 1,just downstream of a region of homology to the runtgene of D melanogaster.In this report, we confirm rearrangement at the same location in at least 12 of 18 patients with t(8;21). Furthermore, we have isolated recombinant clones spanning the breakpoint regions on both the der(8) and the der(21) from one patient. By using α chromosome 8 probe derived from these clones, we show that t(8;21) breakpoints are also clustered on chromosome 8.
- Published
- 1993
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6. Alternative, Out-of-Frame runt/MTG8 Transcripts Are Encoded by the Derivative(8) Chromosome in the t(8;21) of Acute Myeloid Leukemia M2
- Author
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Tighe, Jane E. and Calabi, Franco
- Abstract
In the t(8;21) of acute myeloid leukemia (AMD M2, breakpoints are clustered on both chromosomes. The chromosome 21 breakpoint cluster region (bcr) falls within the runtlocus, in the intron immediately downstream of the exons encoding an evolutionary conserved domain (the runt box). Transcripts in which the runt box is fused in frame to a novel sequence derived from chromosome 8 (MTG8) have been previously identified and have been assumed to constitute a critical leukemogenic event. Here we show physical linkage of the chromosome 8 bcr to the MTG8locus. Unexpectedly, not only does the bcr map upstream of the most 5‘ MTG8exon found in runt/MTG8 fusion transcripts, but it also maps upstream of a further 5‘ exon. In addition, we demonstrate the presence of alternative transcripts, originating from the der(8) chromosome, in which runt is out of frame with MTG8. Thus, runt truncation per se, rather than its fusion to MTG8, may be the crucial leukemogenic event.
- Published
- 1994
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7. t(8;21) Breakpoints are Clustered between Alternatively Spliced Exons of MTG8
- Author
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Tighe, Jane E. and Calabi, Franco
- Abstract
1. The (8;21) translocation, which is consistently associated with a subgroup of acute myeloid leukaemia, involves two loci: runt on chromosome 21 and MTG8 on chromosome 8. 2. Breakpoints in runt fall within a single intron that is located immediately downstream of a phylogenetically conserved DNA-binding domain (the ‘runt box’). 3. We now show that most breakpoints on chromosome 8 fall within a region between two alternative 5′ MTG8 exons. Thus, we predict that chimaeric genes on both the derivative(8) and the derivative(21) chromosomes have the potential to be transcriptionally active.
- Published
- 1995
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8. A Phase 3 Pilot Study of Continuous Imatinib Versus Pulsed Imatinib with or without G-CSF in Patients with Chronic Phase CML Who Have Achieved a Complete Cytogenetic Response to Imatinib.
- Author
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Heaney, Nicholas, Drummond, Mark, Kaeda, Jaspal, Nicolini, Franck, Clark, Richard, Wilson, George, Shepherd, Pat, Tighe, Jane, McLintock, Lorna, Hughes, Timothy, and Holyoake, Tessa L.
- Abstract
Imatinib mesylate (IM) induces complete cytogenetic responses (CCR) in the majority of patients with CML in chronic phase (CP). Despite this reduction in disease burden many patients continue to have detectable Bcr-Abl transcripts in peripheral blood. We believe that IM-resistant Ph+ haemopoietic stem cells (HSC) contribute to this residual disease. IM has been shown to selectively target proliferating CML HSC, while simultaneously exerting an antiproliferative effect on the quiescent population-causing accumulation. We have previously characterised these quiescent cells and shown that intermittent in-vitro exposure of Ph+HSC to exogenous G-CSF leads to a reduction in number of quiescent and total HSC in culture (Clin Can Res 2006, 12: 626). This randomised, multi-centre, pilot phase 3 study was established to determine the safety and efficacy of combining G-CSF with IM in patients with CP CML who had achieved CCR on IM. 45 patients were equally randomised between 3 arms: continuous IM (cIM); pulsed IM (pIM 3 weeks IM and 1 week no drug); and pIM-G-CSF (pIM-G 3 weeks IM and 1 week G-CSF). The dose of IM administered was the dose on which the patient had achieved CCR. Patients had a median age of 59y (25–76y) and had been diagnosed with CML for a median of 36m (8–171m). 21 patients had prior IFN therapy with 4 autografted. Hasford scores were 36% low, 46% Intermediate, and 18% high. At baseline 25 patients had a major molecular response (MMR cIM 7, pIM 8, pIM-G 10). Patients were assessed monthly for 1 year with clinical examination, routine blood tests and Bcr-Abl Q-RT-PCR. Significant cardiovascular events were seen in 2 patients - 1 patient died of myocardial infarction (pIM-G) and 1 survived a stroke (cIM). There was a trend to less IM-associated side effects (diarrhoea, muscle cramps) in the experimental arms, though bony pain was reported in pIM-G (5 patients). Statistical analysis (ANCOVA) was performed on Bcr-Abl readings taken during the trial and no significant difference was detectable between the 3 arms. Further endpoint analyses showed that 4 achieved MMR (4 cIM) 21 maintained MMR (6 cIM, 6 pIM, 9 pIM-G) and 7 showed disease progression with loss of MMR (1 cIM, 2 pIM, 1 pIM-G) and/or loss of CCR (2 pIM, 1 pIM-G). 4 patients were withdrawn as a result of disease progression (3 pIM, 1 pIM-G). In conclusion both experimental arms appeared safe and well tolerated. In this pilot study there was no clear difference in efficacy when either pIM or pIM-G was compared to cIM, despite the 25% effective dose reduction of IM in the experimental arms. The absence of a clear benefit means that this approach cannot be recommended as an alternative to standard IM dosing, however may be applicable to a selected group of patients who cannot tolerate standard daily dosing.
- Published
- 2007
- Full Text
- View/download PDF
9. Eradication of Minimal Residual Disease with Alemtuzumab in Chronic Lymphocytic Leukemia Is Associated with Prolonged Survival and Is an Appropriate Theraputic Endpoint for Relapsed CLL.
- Author
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Sayala, Hazem A., Moreton, Paul, Kennedy, Ben, Lucas, Guy, Leach, Michael, Rassam, Saad M.B., Haynes, Andrew, Tighe, Jane, Oscier, David G., Fegan, Christopher, Rawstron, Andy C., and Hillmen, Peter
- Abstract
Eradication of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is emerging as a desirable therapeutic end point predicting for better outcome. The monoclonal antibody alemtuzumab (Mabcampath) is approved for patients with fludarabine refractory CLL. We previously published 91 patients with relapsed CLL (74 men and 17 women, median age 58 years [range, 32 to 75 years]; 44 fludarabine-refractory) who received a median of 9 weeks (range 1 to 16) of alemtuzumab, 30mg 3x a week after dose escalation, between 1996 and 2003. 84 patients had i.v. alemtuzumab and 7 received it subcutaneously. Responses to alemtuzumab according to NCI-WG criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 (19%) and no response (NR) in 42 (46%). Detectable CLL to a level of less than one CLL cell in 10,000 leucocytes, assessed by four-color MRD flow cytometry, was eradicated from the blood and marrow in 18 patients (20%). 8 of these 18 patients were fludarabine refractory. We report here the results of long term follow up of this cohort of patients after a median follow up of 77 months (range 5 to 123 months). Median survival was significantly longer in patients achieving MRD negative responses compared with those with detectable CLL at the end of therapy. The median survival for all 18 MRD negative responders has not been reached but was 87 months for the 8 fludarabine-refractory patients achieving MRD negativity. Overall survival for the 18 patients with MRD-negative remissions was 66% at 72 months (see Figure). MRD positive CR patients had a median survival of 56 months, MRD positive PR patients a median survival of 42 months and non-responders a median survival of 14 months. The median treatment-free interval prior to alemtuzumab for the 18 MRD negative patients was 8 months (range 4 to 35). Excluding planned stem cell transplantation performed in CR, the median time to next treatment for the 18 MRD negative patients was 114 months and 72% (13/18) have required no further therapy. Therefore alemtuzumab can induce MRD negative remissions in CLL resulting in a clear survival advantage with 66% of MRD negative patients alive 6 years after alemtuzumab. The markedly increased treatment-free survival and excellent survival for MRD negative patients strongly suggests that achieving an MRD negative remission is an appropriate therapeutic end-point in relapsed CLL. Figure Figure
- Published
- 2007
- Full Text
- View/download PDF
10. A Phase 3 Pilot Study of Continuous Imatinib Versus Pulsed Imatinib with or without G-CSF in Patients with Chronic Phase CML Who Have Achieved a Complete Cytogenetic Response to Imatinib.
- Author
-
Heaney, Nicholas, Drummond, Mark, Kaeda, Jaspal, Nicolini, Franck, Clark, Richard, Wilson, George, Shepherd, Pat, Tighe, Jane, McLintock, Lorna, Hughes, Timothy, and Holyoake, Tessa L.
- Abstract
Imatinib mesylate (IM) induces complete cytogenetic responses (CCR) in the majority of patients with CML in chronic phase (CP). Despite this reduction in disease burden many patients continue to have detectable Bcr-Abl transcripts in peripheral blood. We believe that IM-resistant Ph+ haemopoietic stem cells (HSC) contribute to this residual disease. IM has been shown to selectively target proliferating CML HSC, while simultaneously exerting an antiproliferative effect on the quiescent population-causing accumulation. We have previously characterised these quiescent cells and shown that intermittent in-vitro exposure of Ph+HSC to exogenous G-CSF leads to a reduction in number of quiescent and total HSC in culture (Clin Can Res 2006, 12: 626). This randomised, multi-centre, pilot phase 3 study was established to determine the safety and efficacy of combining G-CSF with IM in patients with CP CML who had achieved CCR on IM. 45 patients were equally randomised between 3 arms: continuous IM (cIM); pulsed IM (pIM 3 weeks IM and 1 week no drug); and pIM-G-CSF (pIM-G 3 weeks IM and 1 week G-CSF). The dose of IM administered was the dose on which the patient had achieved CCR. Patients had a median age of 59y (25–76y) and had been diagnosed with CML for a median of 36m (8–171m). 21 patients had prior IFN therapy with 4 autografted. Hasford scores were 36% low, 46% Intermediate, and 18% high. At baseline 25 patients had a major molecular response (MMR cIM 7, pIM 8, pIM-G 10). Patients were assessed monthly for 1 year with clinical examination, routine blood tests and Bcr-Abl Q-RT-PCR. Significant cardiovascular events were seen in 2 patients - 1 patient died of myocardial infarction (pIM-G) and 1 survived a stroke (cIM). There was a trend to less IM-associated side effects (diarrhoea, muscle cramps) in the experimental arms, though bony pain was reported in pIM-G (5 patients). Statistical analysis (ANCOVA) was performed on Bcr-Abl readings taken during the trial and no significant difference was detectable between the 3 arms. Further endpoint analyses showed that 4 achieved MMR (4 cIM) 21 maintained MMR (6 cIM, 6 pIM, 9 pIM-G) and 7 showed disease progression with loss of MMR (1 cIM, 2 pIM, 1 pIM-G) and/or loss of CCR (2 pIM, 1 pIM-G). 4 patients were withdrawn as a result of disease progression (3 pIM, 1 pIM-G). In conclusion both experimental arms appeared safe and well tolerated. In this pilot study there was no clear difference in efficacy when either pIM or pIM-G was compared to cIM, despite the 25% effective dose reduction of IM in the experimental arms. The absence of a clear benefit means that this approach cannot be recommended as an alternative to standard IM dosing, however may be applicable to a selected group of patients who cannot tolerate standard daily dosing.
- Published
- 2007
- Full Text
- View/download PDF
11. Eradication of Minimal Residual Disease with Alemtuzumab in Chronic Lymphocytic Leukemia Is Associated with Prolonged Survival and Is an Appropriate Theraputic Endpoint for Relapsed CLL.
- Author
-
Sayala, Hazem A., Moreton, Paul, Kennedy, Ben, Lucas, Guy, Leach, Michael, Rassam, Saad M.B., Haynes, Andrew, Tighe, Jane, Oscier, David G., Fegan, Christopher, Rawstron, Andy C., and Hillmen, Peter
- Abstract
Eradication of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL) is emerging as a desirable therapeutic end point predicting for better outcome. The monoclonal antibody alemtuzumab (Mabcampath) is approved for patients with fludarabine refractory CLL. We previously published 91 patients with relapsed CLL (74 men and 17 women, median age 58 years [range, 32 to 75 years]; 44 fludarabine-refractory) who received a median of 9 weeks (range 1 to 16) of alemtuzumab, 30mg 3x a week after dose escalation, between 1996 and 2003. 84 patients had i.v. alemtuzumab and 7 received it subcutaneously. Responses to alemtuzumab according to NCI-WG criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 (19%) and no response (NR) in 42 (46%). Detectable CLL to a level of less than one CLL cell in 10,000 leucocytes, assessed by four-color MRD flow cytometry, was eradicated from the blood and marrow in 18 patients (20%). 8 of these 18 patients were fludarabine refractory. We report here the results of long term follow up of this cohort of patients after a median follow up of 77 months (range 5 to 123 months). Median survival was significantly longer in patients achieving MRD negative responses compared with those with detectable CLL at the end of therapy. The median survival for all 18 MRD negative responders has not been reached but was 87 months for the 8 fludarabine-refractory patients achieving MRD negativity. Overall survival for the 18 patients with MRD-negative remissions was 66% at 72 months (see Figure). MRD positive CR patients had a median survival of 56 months, MRD positive PR patients a median survival of 42 months and non-responders a median survival of 14 months. The median treatment-free interval prior to alemtuzumab for the 18 MRD negative patients was 8 months (range 4 to 35). Excluding planned stem cell transplantation performed in CR, the median time to next treatment for the 18 MRD negative patients was 114 months and 72% (13/18) have required no further therapy. Therefore alemtuzumab can induce MRD negative remissions in CLL resulting in a clear survival advantage with 66% of MRD negative patients alive 6 years after alemtuzumab. The markedly increased treatment-free survival and excellent survival for MRD negative patients strongly suggests that achieving an MRD negative remission is an appropriate therapeutic end-point in relapsed CLL.
- Published
- 2007
- Full Text
- View/download PDF
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