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Sally Moore,
Sangeeta Atwal,
Sajitha Sachchithanantham,
Matthew Streetly,
Iftekhar Khan,
Laura Percy,
Santosh Narat, Shirley D'Sa,
Neil Rabin,
Rosalynd Johnston,
Steve Schey,
Kwee Yong
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ABSTRACT: OBJECTIVES: Bortezomib is an effective anti-myeloma therapy but clinical benefit can be limited by neurotoxicity. In newly diagnosed, older patients, modification of the bi-weekly dosing schedule to weekly regimens improves tolerability whilst maintaining efficacy. There is less information on the efficacy and tolerability of weekly bortezomib regimens in the relapsed/refractory setting. Here we report our experience of weekly intravenous bortezomib in clinical practice in relapsed/refractory patients. METHODS: We analyzed fifty-two patients who received weekly bortezomib for relapsed/refractory MM. RESULTS: Thirty-one percent of patients received bortezomib beyond first relapse. Almost all (94%) also received steroids and 48% also received an alkylator. The median cumulative dose was 22.6mg/m(2) , and median length of treatment was 164 days. Three patients reported grade 2 sensory neuropathy, one reported grade 3 motor neuropathy. There were no grade 4 neuro-toxicities. Eighty-three percent achieved a PR or greater, and the median PFS for the whole group was 13 months. One year PFS and OS were 53% (95% CI 39-66.6%) and 78% (95% CI 66.7-89.6%) respectively. CONCLUSIONS: Weekly intravenous bortezomib when used in combination with steroids ± alkylator is effective in relapsed/refractory MM, producing outcomes comparable to bi-weekly regimens, and with lower rates of peripheral neuropathy. © 2013 John Wiley & Sons A/S.
European Journal Of Haematology 01/2013; · 2.61 Impact Factor
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ABSTRACT: The use of consolidation or maintenance to improve disease response, and hence clinical outcome, following autologous stem cell transplantation (ASCT) remains the subject of intense clinical research. We carried out a single-arm study to assess the toxicity and efficacy of a short block of consolidation therapy with cyclophosphamide, low dose thalidomide and dexamethasone (CTD) in patients within 6 months following ASCT, as part of frontline therapy for symptomatic multiple myeloma. Forty-five patients who had not progressed were enrolled on the study, and 43 completed treatment on protocol. This regimen was well tolerated soon after ASCT, with only grade 1/2 toxicity apart from neutropenia, and no long-term sequelae. Importantly, CTD consolidation improved the depth of response in treated patients, increasing the complete/very good partial response rate from 44% at 3 months, to 72% at 12 months, which was significantly higher compared with a historical group of control patients (P = 0·002). There was a trend to longer progression-free survival that favoured the study group. Consolidation therapy did not adversely affect subsequent disease response to salvage therapies at relapse. We conclude that CTD consolidation may be a useful, non-toxic and cost-effective strategy to deepen disease response following ASCT, and deserves further study in a randomized trial.
British Journal of Haematology 06/2012; 158(4):499-505. · 4.94 Impact Factor
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ABSTRACT: A significant minority of patients with diffuse large B-cell lymphoma (DLBCL) who enter a complete remission following standard first-line immunochemotherapy will relapse. A primary aim of follow-up is to detect early relapse, with the hope of improving outcome following salvage chemotherapy. It is often routine to measure lactate dehydrogenase (LDH) as part of follow-up; however, the evidence for the utility of LDH as a predictor for relapse is scant. A retrospective analysis of the LDH results recorded during the follow-up of 102 patients with DLBCL who achieved a CR following treatment was undertaken in order to determine the utility of LDH as a predictor for relapse (median follow-up 24 months). Despite the fact that the sensitivity of LDH was 69% (95% confidence interval [CI] 39-91), the positive predictive value (PPV) of a raised LDH was only 9/63, 14% (95% CI 6.7-25). Furthermore, in eight of the nine patients who had a raised LDH prior to relapse, symptoms suggestive of relapse were documented simultaneously. As the PPV of a raised LDH is so low and because a raised LDH may cause unnecessary worry, leading to unnecessary radiological investigations, routine evaluation of LDH in patients with DLBCL who achieve CR and who are asymptomatic is not recommended.
Leukemia & lymphoma 03/2012; 53(10):1949-52. · 2.40 Impact Factor
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Journal of Neurology 09/2011; 259(3):571-3. · 3.47 Impact Factor
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John A Snowden,
Sam H Ahmedzai,
John Ashcroft, Shirley D'Sa,
Timothy Littlewood,
Eric Low,
Helen Lucraft,
Rhona Maclean,
Sylvia Feyler,
Guy Pratt,
Jennifer M Bird
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ABSTRACT: Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate-induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011.
British Journal of Haematology 07/2011; 154(1):76-103. · 4.94 Impact Factor
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Jennifer M Bird,
Roger G Owen, Shirley D'Sa,
John A Snowden,
Guy Pratt,
John Ashcroft,
Kwee Yong,
Gordon Cook,
Sylvia Feyler,
Faith Davies,
Gareth Morgan,
Jamie Cavenagh,
Eric Low,
Judith Behrens
British Journal of Haematology 07/2011; 154(1):32-75. · 4.94 Impact Factor
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Journal of the Peripheral Nervous System 12/2010; 15(4):366-8. · 2.80 Impact Factor
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Praxis 08/2010; 99(17):1043-6.
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BMJ (Clinical research ed.). 01/2010; 340:c63.
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ABSTRACT: In 2001, reference to the use of imaging in the British Committee for Standards in Haematology guidelines for the diagnosis and management of myeloma was confined to the standard use of plain X-rays in the diagnostic skeletal survey and emergency use of computed tomography (CT) and magnetic resonance (MR) imaging in the setting of cord compression. Since then, there has been a steady rise in interest in the use of various imaging techniques in the management of myeloma. The purpose of imaging in the management of myeloma includes the assessment of the extent and severity of the disease at presentation, the identification and characterisation of complications, and the assessment of response to therapy. Plain radiography, CT, and MR imaging are generally established examination techniques in myeloma whilst positron emission tomography (PET) and (99)Technetium sestamibi (MIBI) imaging are promising newer scanning techniques under current evaluation. These stand-alone imaging guidelines discuss recommendations for the use of each modality of imaging at diagnosis and in the follow up of patients with myeloma.
British Journal of Haematology 05/2007; 137(1):49-63. · 4.94 Impact Factor
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ABSTRACT: This study aimed to determine the outcome of patients with relapsed or refractory lymphoma who have an inadequate response to first-line salvage therapy (1 degrees ST) and who subsequently receive a second-line salvage regimen (2 degrees ST) with the intention of ultimately proceeding to high-dose therapy. The outcome of 57 patients [Hodgkin's Lymphoma 17, histologically-aggressive non-Hodgkin's Lymphoma (NHL) 26, histologically-indolent NHL 14] who received more than one modality of conventional-dose salvage therapy was analysed. Sixteen patients had a partial response (PR) to 1 degrees ST, but subsequently received 2 degrees ST because the PR was judged to be inadequate (iPR) because of persisting disease bulk or marrow infiltration. Of these 16 patients, 10 (63%) continued to respond to 2 degrees ST. Of the 15 patients who had stable disease following 1 degrees ST, 5 (33%) responded to 2 degrees ST. Only one of the 24 (4%) with progressive disease (PD) following 1 degrees ST, responded to 2 degrees ST. 25 of the 57 patients ultimately underwent stem cell transplantation. The 2-year progression-free survival (PFS) and the 3-year overall survival (OS) for all patients was 24% and 31%, respectively. Long-term survival was highly dependent on response to 1 degrees ST (P = 0.0001); in patients with PD following 1 degrees ST, the PFS and OS at 3 years was only 4%. This analysis indicates that patients with malignant lymphomas, who have PD on 1 degrees ST, are not rescued by subsequent salvage regimens. They should either be treated palliatively or novel approaches should be explored.
British Journal of Haematology 09/2005; 130(3):363-72. · 4.94 Impact Factor
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ABSTRACT: The feasibility and efficacy of a triple regimen of oral weekly cyclophosphamide, monthly pulsed dexamethasone and low-dose Thalidomide (CDT) was studied in 52 patients with relapsed or refractory multiple myeloma (MM). All 52 patients were evaluable for response with a median follow up of 18 (4-29) months. About 17% achieved complete response (CR), 62% partial response (PR), 11% minimal response (MR), 6% stable disease (SD) and 4% progressive disease (PD), resulting in an objective response rate (>/=MR) of 90%. Subsequent to successful response, nine patients received high-dose therapy (HDT) followed by stem cell transplantation (SCT) and 34 received thalidomide monotherapy as maintenance. Response rate was not influenced by disease status, prior HDT or age. The regimen was successfully delivered to all patients except for one patient who developed abnormal liver function at 7 weeks. Infective complications were minimal and there were no infection-related deaths. The estimated overall and event-free survival (EFS) at 2 years was 73% and 34%, respectively, and the median time to progression has not been reached. We conclude that the CDT regimen is safe, well tolerated and effective in patients with relapsed and refractory myeloma.
British Journal of Haematology 06/2005; 129(6):763-70. · 4.94 Impact Factor
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Shirley D'Sa,
Kwee Yong,
Chara Kyriakou,
Soumo Bhattacharya,
Karl S Peggs,
Barbara Foulkes,
Michael J Watts,
Stuart J Ings,
Kirit M Ardeshna,
Anthony H Goldstone,
Catherine D Williams
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ABSTRACT: Myeloma remains incurable with a median survival of 4 years, but outcome can be improved by the use of high-dose therapy. We used the etoposide, methylprednisolone, cytarabine and cisplatin (ESHAP) regimen as second-line therapy in 42 newly diagnosed myeloma patients who had failed vincristine, adriamycin and dexamethasone (VAD)- type therapy (n = 36), responded to first-line treatment but persisted in having significant residual marrow plasmacytosis (n = 5) or failed prior stem cell harvesting (n = 1), with the dual aim of improving disease response and mobilizing peripheral blood stem cells. Fourteen of 21 (67%) patients with no change or progressive disease after VAD responded to ESHAP; seven of 12 (58%) patients with minor response converted to partial response. Marrow plasmacytosis fell from a median of 52% at diagnosis to 23.5% after primary therapy and to15% after ESHAP. ESHAP chemotherapy was well-tolerated. There were 11 admissions due to febrile neutropenia (n = 7), nausea and vomiting (n = 2), pneumonia (n = 1) and perforated bowel (n = 1). Renal function deteriorated in 13 of 42 patients after ESHAP, but none required renal support. ESHAP mobilization was performed in 32 patients of whom 87% achieved a CD34(+) yield >2 x 10(6)/kg. In all, 38 patients proceeded to high-dose therapy. The overall survival for all patients was 62% at 4 years following ESHAP. We conclude that ESHAP has acceptable toxicity and efficient stem cell mobilizing capability, effectively cytoreduced this chemoresistant group of patients, and did not appear to adversely affect transplant outcome.
British Journal of Haematology 06/2004; 125(6):756-65. · 4.94 Impact Factor
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Shirley D'Sa,
Karl Peggs,
Arnold Pizzey,
Stephanie Verfuerth,
Dharsha Thuraisundaram,
Michael Watts,
Harry White,
Geoff Hale,
Herman Waldmann,
Anthony Goldstone,
Stephen Mackinnon,
Kwee Yong
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ABSTRACT: Immune reconstitution after conventional allogeneic transplantation is a major determinant of survival. We conducted a detailed investigation of T- and B-cell immune reconstitution and clinical outcome in 19 patients with multiple myeloma undergoing reduced-intensity stem cell transplantation using in vivo T-cell depletion with alemtuzumab. These patients experienced delayed T-cell recovery, particularly in the naïve (CD45 RA+) CD4 compartment. T-cell receptor spectratype analysis showed a reduced repertoire diversity, which improved rapidly after the administration of donor leucocyte infusions and subsequent conversion to full donor T-cell chimaerism. Post-transplant recovery of CD19+ B cells was also delayed for up to 18 months. Spectratype analysis of IgH CDR3 repertoire revealed a gradual normalization in IgM spectratype complexity by 6-12 months after transplant. There was a high incidence of viral infection, particularly cytomegalovirus reactivation, but the regimen-related mortality was low, perhaps because of the very low incidence of acute graft-versus-host disease (GVHD; grade I-II skin GVHD was seen in 5/19 patients). Over 80% of all patients have relapsed at a median of 283 (range 153-895) d after transplant, suggesting that the initially low rate of GVHD comes at a high price with regard to the desired graft-versus-myeloma effect.
British Journal of Haematology 11/2003; 123(2):309-22. · 4.94 Impact Factor
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Karl S Peggs,
Stephen Mackinnon,
Catherine D Williams, Shirley D'Sa,
Dharsha Thuraisundaram,
Charalampia Kyriakou,
Emma C Morris,
Geoff Hale,
Herman Waldmann,
David C Linch,
Anthony H Goldstone,
Kwee Yong
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ABSTRACT: Reduced-intensity conditioning regimens allow application of allogeneic stem cell transplantation to greater numbers of patients with myeloma by reducing transplantation-related mortality. We prospectively evaluated the role of an approach incorporating in vivo T-cell depletion and subsequent adjuvant donor lymphocyte infusions (DLIs) as part of front-line therapy for chemotherapy-sensitive multiple myeloma. Twenty patients with HLA-matched related (n = 12) or unrelated (n = 8) donors entered the study. None had previously undergone autologous transplantation. Acute graft-versus-host disease (GVHD) following transplantation was minimal (3 grade II and no grade III or IV). Nonrelapse mortality rate was relatively low (15%) compared with conventional myeloablative allogeneic transplantation series, although it remained significantly higher than in the autologous setting. Disease responses by 6 months posttransplantation were modest (2 in complete remission, 4 in partial remission, 2 were minimally responsive, 6 had no change, 3 had progressive disease, and 3 were not evaluable). Fourteen patients received escalating-dose DLI for residual/progressive disease. Three developed acute GVHD and 2 developed limited chronic GVHD. Seven demonstrated further disease responses, which appeared to be more common in those developing GVHD (5 of 5 versus 2 of 9; P =.02). All responses were associated with conversion from mixed to full donor T-cell chimerism. Response durations were disappointing (5 <12 months) and progression often occurred despite persisting full donor chimerism. Two-year estimated overall survival and current progression-free survival rates (intention to treat with DLI from 6 months) were 71% and 30%, respectively. The current approach incorporating T-cell depletion appears excessively immunosuppressive despite attempts to restore immune function with DLI. Dose escalation failed to allow convincing dissociation of graft-versus-myeloma from GVHD. Attempts to hasten immune reconstitution and to focus and amplify appropriate components of allogeneic T-cell responses will be required to increase complete remission rates and response durations.
Biology of Blood and Marrow Transplantation 05/2003; 9(4):257-65. · 3.87 Impact Factor
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ABSTRACT: T-cell receptor (TCR) BV spectratyping provides information concerning immune reconstitution complementary to that derived from monoclonal antibody analysis of surface antigen expression. However, the most appropriate way to analyse and represent these data, the number of subfamilies that should be analysed, and the effects of CD4/8 ratio on observed diversity, remain unclear. A diversity scoring system was developed based on analysis of 11 cord blood (CB) and 12 normal adult BV spectratypes. CB subfamily spectratypes demonstrated minor deviations from a Gaussian pattern consistent with current knowledge about germline TCR rearrangements. Diversity scores were significantly lower in myeloma patients than normal adults (P < 0.001) and fell significantly following stem cell transplantation (P = 0.003). Subsequently increasing diversity was not detected by two previously described complexity scoring systems. The CD4/8 ratio was neither the major determinant of the absolute diversity score nor of the change in score for individual patients, suggesting that analysis of unselected mononuclear cells can provide information largely independent of CD4/8 ratios. There was a relatively low correlation between individual subfamily scores and overall diversity score. The novel and objective diversity scoring system described appears better able to document changes in spectratype patterns than previously described techniques and should aid the standardization of reporting.
British Journal of Haematology 02/2003; 120(1):154-65. · 4.94 Impact Factor
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Supratik Basu,
Judith Behrens,
Mark Drayson, Shirley D'Sa,
Graham Jackson,
Atul Mehta,
Guy Pratt,
Hamish Ross,
Simon Rule,
Diana Samson,
Charles Singer,
Alastair Smith
