Publications (13)102.77 Total impact
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Article: Defining the prognosis of early stage chronic lymphocytic leukaemia patients.
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ABSTRACT: Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n = 1154) with a median follow-up of 8 years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.British Journal of Haematology 12/2011; 156(4):499-507. · 4.94 Impact Factor -
Article: Aspergillus fumigatus osteomyelitis in a patient receiving alemtuzumab for B-cell chronic lymphocytic leukaemia.
British Journal of Haematology 02/2011; 153(2):147. · 4.94 Impact Factor -
Article: Phase II study of subcutaneous alemtuzumab without dose escalation in patients with advanced-stage, relapsed chronic lymphocytic leukaemia.
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ABSTRACT: This phase II study (n = 20) aimed to evaluate type, severity and duration of side-effects and efficacy following subcutaneous (SC) alemtuzumab, without dose-escalation, in advanced-stage relapsed chronic lymphocytic leukaemia (CLL) patients. Alemtuzumab 30 and 3 mg was administered SC simultaneously day 1, followed by 30 mg three times per week. Injection-site-reactions were recorded every 6-24 h until resolved using National Cancer Institute criteria and a new skin toxicity subscale. The first doses of 30 mg and 3 mg produced injection-site-reactions (all but one were grade 1/2) in 13/20 and 9/20 patients, respectively. The second dose (on day 3) resulted in skin-reactions in 10/20 patients and the third, fourth, fifth and sixth injections produced reactions in 6/20, 1/20, 2/20 and 0/20 patients, respectively. Mild "flu-like" symptoms occurred during week 1 in 10/20 patients. All side-effects had subsided by the sixth dose. 15/20 patients (75%) responded (12 partial responses, three complete responses) with a median time-to-treatment-failure of 20 months. Symptomatic cytomegalovirus-reactivation occurred in 6/20 patients. Two deaths occurred: one bacterial pneumonia and one adenovirus-infection. The present study showed how to assess cutaneous-toxicity in detail and that 30 mg alemtuzumab SC administered upfront was well tolerated. Optimized alemtuzumab therapy in properly selected patients may result in high efficacy even in advanced CLL. Our results need to be confirmed in extended studies.British Journal of Haematology 11/2008; 144(1):78-85. · 4.94 Impact Factor -
Article: Pyoderma gangrenosum complicating pegylated granulocyte colony-stimulating factor in Hodgkin lymphoma.
British Journal of Haematology 02/2006; 132(1):115-6. · 4.94 Impact Factor -
Article: No cardiac toxicity associated with alemtuzumab therapy for mycosis fungoides/Sézary syndrome.
Blood 06/2005; 105(10):4148-9. · 9.90 Impact Factor -
Article: Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival.
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ABSTRACT: To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 10(5) normal cells). Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.Journal of Clinical Oncology 06/2005; 23(13):2971-9. · 18.37 Impact Factor -
Article: Blood concentrations of alemtuzumab and antiglobulin responses in patients with chronic lymphocytic leukemia following intravenous or subcutaneous routes of administration.
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ABSTRACT: Alemtuzumab is a humanized anti-CD52 antibody licensed for refractory B-cell chronic lymphocytic leukemia (B-CLL), when given intravenously at 30 mg thrice weekly. However, the intravenous route is associated with infusion-related reactions and is inconvenient. We measured blood concentrations in 30 relapsed patients treated with intravenous alemtuzumab and in 20 patients from a previously untreated group who received similar doses subcutaneously. Highest trough samples in the intravenous group were less than 0.5 microg/mL to 18.3 microg/mL (mean 5.4 microg/mL). The cumulative dose required to reach 1.0 microg/mL was 13 mg to 316 mg (mean 90 mg). Higher blood concentrations correlated with the achievement of better clinical responses and minimal residual disease. The highest measured concentrations in the subcutaneous group were similar (0.6 microg/mL to 24.8 microg/mL, mean 5.4 microg/mL). However, the cumulative dose to reach 1.0 microg/mL was higher: 146 mg to 1106 mg (mean 551 mg). No antiglobulin responses were detected in 30 patients given intravenous alemtuzumab whereas 2 of 32 patients given subcutaneous alemtuzumab made substantial anti-idiotype responses. Thus, subcutaneous alemtuzumab achieved concentrations similar to those for intravenous alemtuzumab, although with slightly higher cumulative doses. Subcutaneous alemtuzumab is more convenient and better tolerated but may be associated with some patients forming anti-alemtuzumab antibodies, particularly those patients who were previously untreated.Blood 09/2004; 104(4):948-55. · 9.90 Impact Factor -
Article: Early prediction of outcome and response to alemtuzumab therapy in chronic lymphocytic leukemia.
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ABSTRACT: Alemtuzumab therapy is effective for some refractory chronic lymphocytic leukemia (CLL), but identifying responders requires at least 8 weeks of therapy. Early identification of nonresponders would minimize toxicity and/or facilitate more effective strategies. The aim of this study was to identify a minimally invasive method for early prediction of response and relapse. Flow cytometric monitoring was performed in 887 blood samples and 201 marrow samples from 43 patients undergoing intravenous alemtuzumab therapy. Although the absolute lymphocytosis was resolved in all patients by week 4, significant depletion of bone marrow tumor only occurred if circulating B-lymphocyte counts were persistently less than 0.001 x 10(9)/L, which was rare in nonresponders. The majority of patients (16/28) who did not benefit from a full course of therapy were identified with 100% positive predictive value using the following algorithm: peripheral B-cell count greater than 0.001 x 10(9)/L at week 2 with less than 1 log depletion of circulating B cells between weeks 2 and 4. Monitoring CLL levels after treatment identified patients at risk of early disease progression and could potentially improve patient management. During alemtuzumab therapy, bone marrow CLL depletion only occurs after abrogation of circulating tumor, requiring close monitoring of circulating B-cell levels. If validated in prospective studies, blood monitoring at 2 and 4 weeks may be used to optimize therapy.Blood 04/2004; 103(6):2027-31. · 9.90 Impact Factor -
Article: Management guidelines for use of alemtuzumab in B-cell chronic lymphocytic leukemia.
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ABSTRACT: An expert opinion roundtable held August 8-9, 2002, brought together clinicians with the most extensive experience with the use of alemtuzumab to pool knowledge and develop treatment goals and guidelines for optimal therapy. By sharing our collective experience, we have been able to formulate recommendations for current clinical practice, which are included in this report, and have emphasized results that have implications for future practice. Guidelines for the management of acute "first-dose" events, prophylaxis for infection, detection and treatment of cytomegalovirus reactivation, and hematologic support are presented, with emphasis on allowing patients to proceed smoothly through therapy while maximizing therapeutic benefit. Management of adverse events is facilitated by the predictable timing of their appearance. In general, hematologic adverse events are transient, manageable, and reversible. Clinicians should be cautious of prematurely terminating treatment at 4-6 weeks in patients whose disease responds to treatment. Although resolution of peripheral blood lymphocytosis occurs early in most patients, bone marrow is unlikely to be clear of disease. In particular, grade 4 neutropenia at this time is common and, because it is manageable, it is not an indication to discontinue treatment. The eradication of minimal residual disease from blood and bone marrow observed with alemtuzumab therapy is a major step forward in the treatment of B-cell chronic lymphocytic leukemia. Combination therapies such as alemtuzumab/fludarabine with the potential to maximize eradication at all disease sites should be systematically investigated. Because high response rates and few complications are observed in previously untreated patients, the use of alemtuzumab earlier in therapy may provide optimum benefit to patients.Clinical lymphoma 04/2004; 4(4):220-7. · 3.11 Impact Factor -
Article: Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion.
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ABSTRACT: Monoclonal chronic lymphocytic leukemia (CLL)-phenotype cells are detectable in 3.5% of otherwise healthy persons using flow cytometric analysis of CD5/CD20/CD79b expression on CD19-gated B cells. To determine whether detection of such CLL-phenotype cells is indicative of an inherited predisposition, we examined 59 healthy, first-degree relatives of patients from 21 families with CLL. CLL-phenotype cells were detected in 8 of 59 (13.5%) relatives, representing a highly significant increase in risk (P =.00002). CLL-phenotype cell levels were stable with time and had the characteristics of indolent CLL. Indolent and aggressive clinical forms were found in family members, suggesting that initiation and proliferation involves distinct factors. The detection of CLL-phenotype cells provides a surrogate marker of carrier status, potentially facilitating gene identification through mapping in families and direct analysis of isolated CLL-phenotype cells.Blood 11/2002; 100(7):2289-90. · 9.90 Impact Factor -
Article: Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts.
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ABSTRACT: Molecular and cellular markers associated with malignant disease are frequently identified in healthy individuals. The relationship between these markers and clinical disease is not clear, except where a neoplastic cell population can be identified as in myeloma/monoclonal gammopathies of undetermined significance (MGUS). We have used the distinctive phenotype of chronic lymphocytic leukemia (CLL) cells to determine whether low levels of these cells can be identified in individuals with normal complete blood counts. CLL cells were identified by 4-color flow cytometric analysis of CD19/CD5/CD79b/CD20 expression in 910 outpatients over 40 years old. These outpatients were age- and sex-matched to the general population with normal hematologic parameters and no evident history of malignant disease. CLL phenotype cells were detectable in 3.5% of individuals at low level (median, 0.013; range, 0.002- 1.458 x 10(9) cells/L), and represented a minority of B lymphocytes (median, 11%; range, 3%-95%). Monoclonality was demonstrated by immunoglobulin light-chain restriction in all cases with CLL phenotype cells present and confirmed in a subset of cases by consensus-primer IgH-polymerase chain reaction. As in clinical disease, CLL phenotype cells were detected with a higher frequency in men (male-to-female ratio, 1.9:1) and elderly individuals (2.1% of 40- to 59-year-olds versus 5.0% of 60- to 89-year-olds, P =.01). The neoplastic cells were identical to good-prognosis CLL, being CD5+23+20(wk)79b(wk)11a(-)22(wk)sIg(wk)CD38-, and where assessed had a high degree (4.8%-6.6%) of IgH somatic hypermutation. The monoclonal CLL phenotype cells present in otherwise healthy individuals may represent a very early stage of indolent CLL and should be useful in elucidating the mechanisms of leukemogenesis.Blood 08/2002; 100(2):635-9. · 9.90 Impact Factor -
Article: Campath-1H and fludarabine in combination are highly active in refractory chronic lymphocytic leukemia.
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ABSTRACT: Campath-1H (alemtuzumab) is the most effective monoclonal antibody in single-agent use in B-cell chronic lymphocytic leukemia (CLL) with reported response rates of 33% to 70%. Combination therapy is now the conventional treatment for most hematologic malignancies. Monoclonal antibody treatments may sensitize tumor cells to subsequent chemotherapy. We report the combination of Campath-1H with fludarabine in patients with CLL refractory to each agent used singly. Six patients who had received a median of 8 courses of fludarabine (range, 4-10 courses) and 16 weeks of Campath-1H (range, 8-32 weeks) were treated. Five patients responded, including one who had a complete response by National Cancer Institute criteria. The responses observed were better in each patient than responses after each agent used singly. Complete morphologic bone marrow responses were seen in 3 patients, including eradication of disease measured by sensitive flow cytometry in 2. Campath-1H combined with fludarabine is a highly promising novel therapy for refractory CLL.Blood 04/2002; 99(6):2245-7. · 9.90 Impact Factor -
Article: Immunological effects and safe administration of alemtuzumab (MabCampath) in advanced B-cLL.
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ABSTRACT: Alemtuzumab (MabCampath) can purge both B- and T-cells in a variety of clinical situations, as seen in the treatment of autoimmune disorders and of lymphoid malignancies such as B-cell chronic lymphocytic leukemia (B-CLL). One of the characteristics of advanced B-CLL is an increased susceptibility to infection, which may improve in patients whose disease responds to alemtuzumab, particularly when immune reconstitution by non-malignant stem cells is successful. However, at initiation of treatment, patients with advanced disease are likely to have poor immune function, and need careful management during and after treatment. Here, we present results showing the nature of immune reconstitution after alemtuzumab and the ways in which alemtuzumab may affect white cell counts during and after treatment. The management of B-CLL patients is discussed both in the context of minimizing acute "first-dose" events and with reference to the health risks already existing in this patient population. With protocols in place for dose escalation, for dose postponement in the event of cytopenia, and for anti-infective prophylaxis, alemtuzumab can be used effectively and safely in high-risk B-CLL patients.Medical Oncology 02/2002; 19 Suppl:S49-55. · 2.14 Impact Factor
Top co-authors
Top Journals
Institutions
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2011
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University Hospitals Of Leicester NHS Trust
Leicester, ENG, United Kingdom
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2005
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Leeds Teaching Hospitals NHS Trust
Leeds, ENG, United Kingdom
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2004
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University of Oxford
Oxford, ENG, United Kingdom -
University of Texas MD Anderson Cancer Center
Houston, TX, USA
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2002
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University of Leeds
Leeds, ENG, United Kingdom
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