Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes

The introduction of reduced-intensity conditioning (RIC) has enabled the role of allogeneic transplantation to be re-evaluated in Hodgkin lymphoma (HL). While T-cell depletion reduces graft-versus-host disease (GvHD), it potentially abrogates graft-versus-tumour activity and increases infective complications. We compared the results in 67 sibling donor transplantations following RIC in multiply relapsed patients from two national phase II studies conditioned with fludarabine/melphalan. One used cyclosporine/alemtuzumab (MF-A, n = 31), the other used cyclosporine/methotrexate (MF, n = 36) as GvHD prophylaxis. There was a small excess of chemorefractory cases in the MF cohort (P = NS). MF-A resulted in significantly lower incidences of non-relapse mortality, acute and chronic GvHD, but no significant excess of relapse/progression. Post donor lymphocyte infusion (DLI) disease responses occurred in 8/14 (57%) and 6/11 (55%) patients in the MF-A and MF groups, respectively. Current progression-free survival (CPFS) was superior with MF-A (univariate analysis), with durable responses to DLI contributing to the favourable outcome (43% vs. 25%, P = 0.0356). Disease status at transplantation significantly influenced overall survival (P = 0.0038) and CPFS (P = 0.0014), retaining significance in multivariate analyses, which demonstrated a trend towards improved CPFS with T-cell depletion (P = 0.0939). These data suggest that alemtuzumab significantly reduced GvHD without resulting in a deleterious impact on survival outcomes following RIC in HL, and that durable responses to DLI may be more common following the inclusion of alemtuzumab in the conditioning protocol.     

Direct healthcare costs and predictors of costs in patients with primary Sjogren's syndrome

OBJECTIVES: To analyse the healthcare usage, direct healthcare costs and predictors of cost in primary Sj?gren's syndrome (PSS) in the UK and to compare the findings with the data from healthy control groups and rheumatoid arthritis (RA) patients. METHODS: A total of 129 patients with PSS (American-European criteria), 91 with RA and 92 controls, were included in the study. All groups were age-matched females and all completed questionnaires on health status (SF-36) and healthcare utilization (economic component of the Stanford Health Assessment Questionnaire). Annual direct healthcare costs were calculated (and expressed in 2004 UK pound sterling) and predictors of costs for each patient group were determined by regression analyses. Age, health status, disease duration and anti-Ro/La antibody positivity were used as potential predictor variables. RESULTS: Mean age was similar in the PSS (59.2 yrs, S.D. 11.6), RA (60.3 yrs, S.D. 10.5) and control groups (57.7 yrs, S.D. 12.5). The mean disease duration was 5.4 yrs (S.D. 4.8) in the PSS group and 13.4 yrs (S.D. 11.4) in the RA group. The mean annual total direct cost per patient [95% confidence interval (CI)] was 2188 pounds sterling (1831 and 2546 pounds sterling) in the PSS group, 2693 pounds sterling(2069 and 3428 pounds sterling) in the RA group and 949 pounds sterling (741 and 1156 pounds sterling) in the control group. The costs in the PSS group were greater than for the RA and control groups for visits to all healthcare professionals (total) as well as visits to the dentist, dental hospital and ophthalmologist. The costs in the PSS and RA groups were higher than in controls for diagnostic tests and visits to hospital and the accident and emergency (A&E) department. The PSS group also incurred higher costs than controls, but lower costs than the RA group, for visits to a rheumatologist, urine and blood tests, assistive devices and drug therapy. Regression analysis identified the SF-36 physical function subscale as the best predictor of costs in PSS patients as well as controls and the mental health subscale in RA patients. CONCLUSION: This is the first study to evaluate direct healthcare costs in patients with PSS. PSS has a significant impact on the healthcare system, similar to that of RA, by more than doubling costs compared with control patients.     

New guidelines on malaria prevention: A summary

Travellers to many tropical areas remain at risk of contracting malaria. Resistance of malaria parasites to a number of drugs continues to increase in degree and distribution, so that some older, trusted prophylactic drugs, such as chloroquine, are no longer useful in some parts of the world. Despite the introduction of new drugs and the reduction of malaria risk in some areas, such as parts of India, the number of people travelling continues to increase and malaria reports in the UK are not decreasing. New updated prevention guidelines from the Health Protection Agency Advisory Committee on Malaria Prevention (ACMP) in UK travellers (Chiodini P, Hill D, Lalloo D, Lea G, Walker E, Whitty C, et al. Guidelines for malaria prevention in travellers from the United Kingdom. London: Health Protection Agency; January 2007. Available from: http://www.hpa.org.uk/infections/topics_az/malaria/default.htm) aim to raise awareness of the risks of malaria and help UK travel health advisors in giving malaria prevention advice to all those who need it. Together with the ACMP malaria treatment guidelines it is hoped that the risk of illness and death from malaria in UK travellers can be reduced. This article summarises the new ACMP malaria prevention guidelines.     

The incidence of lymphoma in the UK haemophilia population between 1978 and 1999

OBJECTIVE: To determine the incidence of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) in the UK haemophilia population during the 22 year period 1978-1999. DESIGN AND METHODS: An analysis of patient data included on the UK Haemophilia Centre Doctors' Organisation lymphoma register. The number of cases of NHL and HD occurring in HIV-positive and negative patients in each 3-year period were compared with the expected incidence in the general male population. RESULTS: Eighty-nine cases of lymphoma were identified. Seventy-two cases (81%) occurred in HIV-positive patients (67 NHL, five HD), and 17 cases (19%) in HIV-negative patients (nine NHL, eight HD). The incidence of NHL in the HIV-positive cohort was significantly increased, with a ratio of observed to expected cases of 83.92 (P < 0.001) in the period 1985-1996. The ratio reduced to 42.15 during the period 1997-1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART). There was a significant excess of HD in HIV-positive patients, with an observed to expected ratio of 10.50 between 1985 and 1999 (based on five cases, P < 0.001). During the whole observation period, there was a significant excess of HD in HIV-negative patients, with an observed to expected ratio of 2.66 (based on eight cases, P < 0.05). CONCLUSION: The incidence of lymphoma is significantly higher in HIV-positive UK haemophilia patients compared with HIV-negative individuals. Since the introduction of HAART, the incidence of lymphoma has tended to fall in the HIV-positive group.     

Beliefs about antiretroviral therapy, treatment adherence and quality of life in a 48-week randomised study of continuation of zidovudine/lamivudine or switch to tenofovir DF/emtricitabine, each with efavirenz

Adherence may be facilitated by reducing perceptual and practical barriers to antiretroviral therapy (ART). Practical barriers include the complexity of daily dosing, while perceptual barriers include perceptions of the need for treatment and concerns about adverse effects. The study aim was to assess the effect of switching zidovudine plus lamivudine twice-daily (Combivir, CBV) to once-daily tenofovir DF plus emtricitabine (Truvada, TVD), each plus efavirenz (EFZ), on adherence, beliefs about ART and quality of life (QoL). Subjects stable on CBV + EFV were randomised 1:1 to continue this regimen or switch to TVD + EFV. Adherence was measured using the Medication Adherence Self-Report Inventory at 4, 12, 24 and 48 weeks. Beliefs about ART (perceptions of necessity and concerns about adverse effects), treatment intrusiveness and QoL were measured by questionnaire at baseline 4, 12, 24 and 48 weeks. Viral load was assessed at each visit. Two hundred and thirty-four subjects initiated treatment. At week 48, the proportion of subjects reporting high adherence (≥95% taken as prescribed) was significantly greater in the TVD arm (p=0.049). Low adherence (reporting taking <95% as prescribed, discontinuing the study or having missing data) was associated with doubts about necessity (p=0.020), stronger concerns about adverse effects (p=0.010), greater treatment intrusiveness (p=0.010) and poorer mental health related QoL (p=0.008). At week 48, both concerns about ART (p=0.038) and treatment intrusiveness (p=0.004) were lower among those who switched to TVD. Furthermore, there was a decline in both concerns about ART (p=0.007) and treatment intrusiveness (p=0.057) over the 48 weeks among those who switched to TVD. There were no significant differences in necessity beliefs, QoL or viral load between randomised groups. Switching from CBV to TVD may improve patient reported outcomes including slightly better adherence, a greater reduction in concerns about adverse effects and less treatment intrusiveness.     

A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial)

This prospective study aimed to develop reproducible diagnostic criteria for sporadic Burkitt lymphoma (BL), applicable to routine practice, and to evaluate the efficacy of dose-modified (dm) CODOX-M/IVAC in patients diagnosed using these criteria. The study was open to patients with an aggressive B-cell lymphoma with an MKI67 fraction approaching 100%. Immunophenotype and fluorescent in situ hybridization (FISH) were used to separate BL from other aggressive B-cell lymphomas. BL was characterized by the presence of a cMYC rearrangement as a sole cytogenetic abnormality occurring in patients with a germinal center phenotype with absence of BCL-2 expression and abnormal TP53 expression. A total of 128 patients were eligible for the study, of whom 58 were considered to have BL and 70 to have diffuse large B-cell lymphoma (DLBCL). There were 110 clinically fit patients who received dmCODOX-M (methotrexate, dose 3 g/m(2)) with or without IVAC according to risk group. The 2-year progression-free survival was 64% (95% confidence interval [CI] 51%-77%) for BL, 55% (95% CI 42%-66%) for DLBCL, 85% (95% CI 73%-97%) for low risk, and 49% (95% CI 38%-60%) for high-risk patients. The observed differences in outcome and other clinical features validate the proposed diagnostic criteria. Compared with the previous trial LY06 with full-dose methotrexate (6.7 g/m(2)), there was a reduction in toxicity with comparable outcomes. This study was registered at www.clinicaltrials.gov as NCT00040690.     

Subjective and Objective Measures of Dryness Symptoms in Primary Sjögren's Syndrome: Capturing the Discrepancy

Objective

To develop a novel method for capturing the discrepancy between objective tests and subjective dryness symptoms (a sensitivity scale) and to explore predictors of dryness sensitivity.

Methods

Archive data from the UK Primary Sjögren's Syndrome Registry (n = 688) were used. Patients were classified on a scale from ?5 (stoical) to +5 (sensitive) depending on the degree of discrepancy between their objective and subjective symptoms classes. Sensitivity scores were correlated with demographic variables, disease‐related factors, and symptoms of pain, fatigue, anxiety, and depression.

Results

Patients were on average relatively stoical for both types of dryness symptoms (mean ± SD ocular dryness ?0.42 ± 2.2 and ?1.24 ± 1.6 oral dryness). Twenty‐seven percent of patients were classified as sensitive to ocular dryness and 9% to oral dryness. Hierarchical regression analyses identified the strongest predictor of ocular dryness sensitivity to be self‐reported pain and that of oral dryness sensitivity to be self‐reported fatigue.

Conclusion

Ocular and oral dryness sensitivity can be classified on a continuous scale. The 2 symptom types are predicted by different variables. A large number of factors remain to be explored that may impact symptom sensitivity in primary Sjögren?s syndrome, and the proposed method could be used to identify relatively sensitive and stoical patients for future studies.

     

Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration

Aims/hypothesis We explored the epidemiology of hypoglycaemia in individuals with insulin-treated diabetes by testing the hypothesis that diabetes type and duration of insulin treatment influence the risk of hypoglycaemia. Materials and methods This was an observational study over 9–12 months in six UK secondary care diabetes centres. Altogether 383 patients were involved. Patients were divided into the following three treatment groups for type 2 diabetes: (1) sulfonylureas, (2) insulin for <2 years and (3) insulin for >5 years, and into two treatment groups for type 1 diabetes, namely <5 years disease duration and >15 years disease duration. Self-reported (mild and severe) and biochemical episodes (interstitial glucose <2.2 mmol/l using continuous glucose monitoring) were recorded. Results Mild hypoglycaemia in type 2 diabetic patients on insulin for <2 years was less frequent than in type 1 patients with <5 years disease duration (mean rate: 4 vs 36 episodes per subject-year, p < 0.001). In type 2 diabetic patients treated with sulfonylureas or insulin for <2 years, no differences were observed in the proportion experiencing severe hypoglycaemia (7 vs 7%, difference 0 [95% CI: −7 to 9%]), mild symptomatic (39 vs 51%, difference 12 [−3 to 25%]) or interstitial glucose <2.2 mol/l (22 vs 20%, difference 2 [−13 to 10%]). Severe hypoglycaemia rates were comparable in patients with type 2 diabetes on sulfonylureas or insulin < 2 years (0.1 and 0.2 episodes per subject-year) and far less frequent than in type 1 diabetes (<5 years group, 1.1; >15 years group, 3.2.episodes per subject-year). Conclusions/interpretation During early insulin use in type 2 diabetes, the frequency of hypoglycaemia is generally equivalent to that observed in patients treated with sulfonylureas and considerably lower than during the first 5 years of treatment in type 1 diabetes. UK Hypoglycaemia Study Group: For a list of the members of this group and their affiliations, see the Appendix. UK Hypoglycaemia Study Group: For a list of each author’s contribution to this study, see the Electronic supplementary material (ESM) which is available to authorised users at doi:. Send any feedback or comments on this article to Simon Heller at the Academic Unit of Diabetes, Endocrinology and Metabolism, School of Medicine and Biomedical Sciences, Room OU141, Beech Hill Road, Sheffield S10 2RX, UK. s.heller@sheffield.ac.uk.