Publications by authors named "Stella Bowcock"

23 Publications

  • Page 1 of 1

Anti-bacterial antibodies in multiple myeloma patients at disease presentation, in response to therapy and in remission: implications for patient management.

Blood Cancer J 2020 11 4;10(11):114. Epub 2020 Nov 4.

Institute of Immunology and Immunotherapy, Clinical Immunology Service, University of Birmingham, Birmingham, UK.

Multiple myeloma (MM) is associated with increased risk of infection, but little is known regarding antibody levels against specific bacteria. We assessed levels of polyclonal immunoglobulin and antibacterial antibodies in patients recruited to the TEAMM trial, a randomised trial of antibiotic prophylaxis at the start of anti-myeloma treatment. Polyclonal IgG, IgA and IgM levels were below the reference range in 71%, 83% and 90% of 838 MM patients at diagnosis. Anti-vaccine targeted tetanus toxoid antibodies were protective in 95% of 193 healthy controls but only 41% of myeloma patients. In healthy controls, protective antibodies against 6/12 pneumococcal serotypes, haemophilus and meningococcus A were present in 67%, 41% and 56% compared to just 15%, 21% and 17% of myeloma patients. By 1 year, myeloma patients IgG levels had recovered for 57% of patients whilst the proportion with protective levels of IgG against thymus-dependent protein antigen tetanus toxoid had changed little. In contrast the proportions of patients with protective levels against thymus independent polysaccharide antigens pneumococcus, haemophilus and meningococcus had fallen from 15 to 7%, 21 to 0% and 17 to 11%. Findings highlight the need for strategies to protect patients against bacterial infections during therapy and vaccination programmes during remission.
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http://dx.doi.org/10.1038/s41408-020-00370-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642409PMC
November 2020

Survival trends in elderly myeloma patients.

Eur J Haematol 2021 Jan 29;106(1):126-131. Epub 2020 Oct 29.

London School of Hygiene and Tropical Medicine, London, UK.

Objective: Myeloma is primarily a disease of the elderly, but older patients experience poorer outcomes. Effective treatments may not be offered to older patients over fears about toxicity, particularly for those with comorbidities. We aimed to characterise the trend in survival disparity between older and younger patients and assess to what extent comorbidity might explain these disparities.

Methods: We examined records for 56 010 patients diagnosed with myeloma in England between 1998-2014. The Hospital Episode Statistics database provided information on comorbidity. Net survival was estimated for each diagnosis period. Adjusted excess hazard ratios for the effect of age were estimated using flexible parametric models.

Results: Net survival increased for all age groups over the study period. However, older patients experienced a higher risk of death from their disease consistent between 1998 and 2014. Adjusting for comorbidity made little difference to the estimates.

Conclusion: Factors other than comorbidity must explain the poorer survival experience of elderly patients. Treatment data were not examined and should be employed by future population studies. Inconsistent treatment of elderly patients with myeloma may be prevented by further use of pragmatic clinical trials which are inclusive of older adults, and also wider utilisation of frailty scores.
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http://dx.doi.org/10.1111/ejh.13530DOI Listing
January 2021

Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.

Br J Haematol 2021 Mar 15;192(6):997-1005. Epub 2020 Aug 15.

Department of Haematological Medicine, King's College Hospital NHS Trust, London, UK.

Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression.
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http://dx.doi.org/10.1111/bjh.17044DOI Listing
March 2021

Levofloxacin prophylaxis in patients with myeloma - Authors' reply.

Lancet Oncol 2020 02;21(2):e69

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

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http://dx.doi.org/10.1016/S1470-2045(20)30020-6DOI Listing
February 2020

Prophylactic levofloxacin to prevent infections in newly diagnosed symptomatic myeloma: the TEAMM RCT.

Health Technol Assess 2019 11;23(62):1-94

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Background: Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as . There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial.

Objectives: To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients.

Design: Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio.

Setting: A total of 93 NHS hospitals throughout England, Northern Ireland and Wales.

Participants: A total of 977 patients with newly diagnosed symptomatic myeloma.

Intervention: Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year.

Main Outcome Measures: The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond.

Results: In total, 977 patients were randomised (levofloxacin,  = 489; placebo,  = 488). A total of 134 (27%) events (febrile episodes,  = 119; deaths,  = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes,  = 91; deaths,  = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86;  = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; -trend of 0.06). There was no difference in new acquisitions of , methicillin-resistant and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival ( = 0.94).

Limitations: Short duration of prophylactic antibiotics and cost-effectiveness.

Conclusions: During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04).

Trial Registration: Current Controlled Trials ISRCTN51731976.

Funding Details: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta23620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859427PMC
November 2019

Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.

Lancet Oncol 2019 12 23;20(12):1760-1772. Epub 2019 Oct 23.

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma.

Methods: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35.

Findings: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group.

Interpretation: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy.

Funding: UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S1470-2045(19)30506-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891230PMC
December 2019

Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in adults with haematological malignancies: a phase 3, randomised, clinical trial and post-hoc efficacy analysis.

Lancet Infect Dis 2019 09 6;19(9):988-1000. Epub 2019 Aug 6.

CureVac, Tübingen, Germany.

Background: The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments.

Methods: In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1-2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18.

Findings: Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p<0·0001) in all patients, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. Humoral and cell-mediated immune responses persisted above baseline until month 13 in all strata and, as expected, vaccine was more reactogenic than placebo (within 7 days after vaccination pain was reported by 221 [79·5%] of 278 vaccine group participants and 45 [16·4%] of 274 placebo group participants; fatigue was reported by 162 [58·3%] of 278 vaccine group participants and 102 [37·2%] of 274 placebo group participants). Incidences of unsolicited or serious adverse events, potential immune-mediated diseases, disease-related events, and fatal serious adverse events were similar between the groups.

Interpretation: The immunocompromised adult population with haematological malignancies is at high risk for herpes zoster. The adjuvanted recombinant zoster vaccine, which is currently licensed in certain countries for adults aged 50 years and older, is likely to benefit this population.

Funding: GlaxoSmithKline Biologicals SA.
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http://dx.doi.org/10.1016/S1473-3099(19)30163-XDOI Listing
September 2019

Unplanned admissions for patients with myeloma in the UK: Low frequency but high costs.

J Bone Oncol 2019 Aug 7;17:100243. Epub 2019 Jun 7.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Rd, Oxford OX3 7LD, UK.

Background: Multiple myeloma (MM) is associated with high healthcare resource utilisation and increasing hospitalisation rates. The aim of this study was to characterise the hospital use by patients with MM in the English National Health Service (NHS).

Methods: Routinely-collected aggregate data about all NHS-funded hospital admissions of patients with MM were analysed. Data were obtained from the English Hospital Episodes Statistics on admissions between 1 April 2014 and 31 March 2018.

Results: A total of 754,345 admissions were reported over four years, equivalent to a mean of 188,586 admissions per year. Of the 41,845 patients admitted during this period, 42% were women and 58% men. From the total admissions, 90% were elective and 10% unplanned. Mean annual estimated costs over the period were £46 million for elective and £56 million for unplanned admissions. The number of elective admissions increased by 4.5% with costs increasing 1.5% per year; for unplanned admissions, these figures were 4.1% and 9.0%, respectively.

Conclusions: MM is associated with a significant number of hospital admissions and NHS costs. The majority of the hospital admissions are elective, but the highest burden in terms of costs relates to unplanned admissions, with numbers increasing over time.
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http://dx.doi.org/10.1016/j.jbo.2019.100243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579752PMC
August 2019

Cryptococcosis in late stage multiple myeloma: consider it.

Br J Haematol 2017 03 20;176(5):687. Epub 2017 Jan 20.

Department of Haematological Medicine, King's College Hospital NHS Trust, Princess Royal Hospital, Orpington, London, Kent, UK.

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http://dx.doi.org/10.1111/bjh.14496DOI Listing
March 2017

Guidelines for screening and management of late and long-term consequences of myeloma and its treatment.

Br J Haematol 2017 Mar 20;176(6):888-907. Epub 2017 Jan 20.

University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

A growing population of long-term survivors of myeloma is now accumulating the 'late effects' not only of myeloma itself, but also of several lines of treatment given throughout the course of the disease. It is thus important to recognise the cumulative burden of the disease and treatment-related toxicity in both the stable and active phases of myeloma, some of which is unlikely to be detected by routine monitoring. We summarise here the evidence for the key late effects in long-term survivors of myeloma, including physical and psychosocial consequences (in Parts 1 and 2 respectively), and recommend the use of late-effects screening protocols in detection and intervention. The early recognition of late effects and effective management strategies should lead to an improvement in the management of myeloma patients, although evidence in this area is currently limited and further research is warranted.
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http://dx.doi.org/10.1111/bjh.14514DOI Listing
March 2017

Outcome for patients with relapsed/refractory aggressive lymphoma treated with gemcitabine and oxaliplatin with or without rituximab; a retrospective, multicentre study.

Leuk Lymphoma 2017 09 16;58(9):1-9. Epub 2017 Jan 16.

b Department of Haematology , King's College Hospital , London , UK.

The treatment of relapsed aggressive lymphoma remains a challenge. Platinum-containing chemotherapy is standard of care. Gemcitabine/oxaliplatin (Gem-Ox) with or without rituximab (R) is an outpatient regimen with a favorable toxicity profile. This retrospective 'real world' study reports outcomes for 44 unselected patients with relapsed/refractory aggressive lymphoma treated with Gem-Ox ± R. 41% had primary refractory disease. The overall response rate (ORR) was 43% with a complete response (CR) of 30%. Response to the prior treatment regimen significantly affected the ORR with only 8% achieving CR if prior remission was <12 months. Grade 3-4 hematological toxicity was common and 22% had febrile neutropenia. Eight patients proceeded to stem cell transplant. Overall, outcomes remain poor with a median overall survival of 8 months. In this high-risk group of patients, Gem-Ox ± R results in similar responses to other more toxic, inpatient regimens and should therefore be considered as second line therapy in relapsed lymphoma.
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http://dx.doi.org/10.1080/10428194.2016.1276288DOI Listing
September 2017

Time to redefine Myeloma.

Br J Haematol 2015 Oct 27;171(1):1-10. Epub 2015 Jul 27.

Department of Haematology, University Hospitals Bristol Foundation Trust, Bristol, UK.

In November 2014 the International Myeloma Working Group (IMWG) revised the definition of multiple myeloma, such that asymptomatic patients with newly diagnosed multiple myeloma without any of the traditional 'CRAB' (hypercalcaemia, renal impairment, anaemia, bone disease) end organ damage criteria but with one of three new criteria would be recommended to start treatment. Previously, the standard of care for such patients was expectant management. These three new criteria are: greater than 60% clonal plasma cells on bone marrow biopsy, a serum free light chain (sFLC) ratio of >100 (the involved sFLC must be >100 mg/l) and greater than one unequivocal focal lesion on advanced imaging (low dose whole body computerized tomography, magnetic resonance imaging, (18) F fluorodeoxyglucose positron emission tomography). Although this would appear to affect a small number of patients, the impact of these changes are broad, leading to an increased use of advanced imaging, a debate around the management of patients previously diagnosed with smouldering myeloma, changed terminology and clinical trial design and an extension of the use of biomarkers. For the first time the philosophy of treatment in myeloma will change from treatment initiation only being triggered by overt end organ damage to an era where sub clinical risk factors will also be taken into account.
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http://dx.doi.org/10.1111/bjh.13620DOI Listing
October 2015

Ultra low dose thalidomide in myeloma revisited.

Br J Haematol 2010 Jul 21;150(2):232-4. Epub 2010 Mar 21.

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http://dx.doi.org/10.1111/j.1365-2141.2010.08182.xDOI Listing
July 2010

High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities.

Ann Hematol 2003 Dec 10;82(12):759-65. Epub 2003 Oct 10.

Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, London, UK.

Abnormalities of the p53 gene are known to confer detrimental effects in chronic lymphocytic leukaemia (CLL) and are associated with short survival. We have used high dose methylprednisolone (HDMP) to treat 25 patients with advanced refractory CLL of whom 45% had p53 abnormalities shown by one or more methods: flow cytometry, fluorescent in situ hybridisation and direct DNA sequencing. Fifteen were resistant to fludarabine and 16 were non-responders to their most recent therapy. Methylprednisolone had a cytotoxic effect on lymphocytes from 95% of cases assessed by an ex vivo apoptotic drug sensitivity index (DSI). HDMP was given alone or in combination with other drugs: vincristine, CCNU, Ara-C, doxorubicin, mitoxantrone and chlorambucil, according to the results of DSI. Three patients were treated twice and each treatment was analysed separately. The overall response rate was 77% with a median duration of 12 months (range 7 -23+). Responders included 5/10 with abnormal p53, of which two achieved nodular PR. Patients with p53 abnormalities fared worse than those with normal p53. There were no differences in response according to whether HDMP was used alone or in combination. Nine of the 22 evaluable patients (3 NR and 6 PR) have died from progressive disease or transformation. Main toxicity was infection in 7/25 patients. Event free and overall survival were significantly better in responders vs non-responders ( P>0.0001 and P=0.04 respectively). Patients with a DSI of 100% to steroids had a better overall and event free survival, but this was not statistically significant. This study demonstrates that HDMP alone or in combination with other agents is a useful treatment strategy in refractory CLL including patients with p53 abnormalities.
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http://dx.doi.org/10.1007/s00277-003-0710-5DOI Listing
December 2003

Thromboembolism in patients on thalidomide for myeloma.

Hematology 2002 Feb;7(1):51-3

Department of Haematology, Queen Mary's Sidcup NHS Trust, Sidcup, Kent, DA14 6LT, UK.

Seven cases of thromboembolism were found amongst 23 patients treated with thalidomide for myeloma over a total of 141.5 patient treatment months. Five thromboembolic events were venous (two severe) and two arterial. A historical control of 18 similar patients not given thalidomide had one thromboembolism over 289 months. We found no underlying thrombophilic tendency in the affected patients. We suggest that the thalidomide may predispose to thromboembolism at even lower doses than previously reported (mean dose 150 mg). The two most severe thromboses occurred on 100 mg thalidomide alone, not associated with chemotherapy or glucocorticoids. We raise the possibility that arterial thromboembolism may also occur in association with thalidomide. Some patients continued thalidomide after the event, together with warfarin, with no further thromboembolism.
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http://dx.doi.org/10.1080/10245330290020126DOI Listing
February 2002