Lancet Haematology最新文献

Background: Chronic lymphocytic leukaemia is the commonest leukaemia and is associated with profound immunosuppression. Bruton tyrosine kinase inhibitors (BTKi) have revolutionised chronic lymphocytic leukaemia management; however, therapy impairs vaccine-induced immunity. We evaluated whether a 3-week pause of BTKi treatment improved spike protein receptor binding domain (RBD) immunity to SARS-CoV-2 booster vaccination while maintaining disease control.

Methods: We performed an open-label, two-arm, parallel-group, randomised trial in secondary-care haematology clinics in 11 UK hospitals. Participants aged 18 years or older, diagnosed with chronic lymphocytic leukaemia, and currently taking BTKi therapy (frontline or relapsed setting) for at least 12 months were eligible. Participants were randomly allocated (1:1, by a centralised computer randomisation program, stratified by BTKi therapy line) to pause BTKi for 3 weeks, starting 6 days before their SARS-CoV-2 vaccination booster date, or to continue therapy as usual. Neither participants nor clinical staff were blinded but laboratory staff were. Intramuscular injection of either original BA.1 or original BA.4/5 bivalent mRNA vaccine (50 μg mRNA-1273 or 30 μg BNT162b2), or 5 μg protein-based Vidprevtyn Beta (Sanofi Pasteur, Lyon, France) were received according to the national vaccination programme schedule. The primary outcome measure was anti-spike-RBD-specific antibody titre 3 weeks after vaccination and analysis performed by intention to treat (as randomly allocated, irrespective of compliance) following trial completion. This trial is registered with ISRCTN, 14197181, and has been completed.

Findings: Between Oct 10, 2022, and June 8, 2023, 99 individuals (71 [72%] male and 28 [28%] female, with 89 [90%] of White ethnicity) were randomly allocated to groups pausing (n=50 [51%]) or continuing (n=49 [49%]) their BTKi therapy, and followed up for 12 weeks. At 3 weeks after vaccination, the geometric mean anti-spike-RBD-specific antibody titre was 218·8 U/mL (SD 122·9) in the continue group and 153·4 U/mL (103·2) in the pause group, with geometric mean ratio 1·104 (95% CI 0·565-2·158, p=0·77) using a mixed-effects model. The only serious adverse event during the 12-week follow-up was the death of one participant in the pause group due to COVID-19 infection 2 months after randomisation.

Interpretation: Although the study was slightly underpowered, the results suggest that pausing BTKi around the time of vaccination is not beneficial for immunity and should not be recommended in clinical practice.

Funding: National Institute for Health and Care Research.

Background: Crizanlizumab has previously shown efficacy as a potent disease-modifying therapy for alleviating vaso-occlusive crisis in sickle cell disease. The SUSTAIN study showed a reduction of vaso-occlusive crises in patients treated with 5 mg/kg crizanlizumab, compared with placebo. The STAND study aimed to evaluate the efficacy and safety of two doses (5·0 mg/kg and 7·5 mg/kg) of crizanlizumab in sickle cell disease. Herein, we report the primary analysis results of STAND.

Methods: STAND is a phase 3, multicentre, randomised, double-blind study of patients with sickle cell disease aged 12 years and older done at 65 sites in 21 countries. Patients were randomly assigned (1:1:1) to receive either 5·0 mg/kg of crizanlizumab, 7·5 mg/kg of crizanlizumab, or placebo, in addition to standard of care, for 1 year. The primary endpoint was the annualised rate of vaso-occlusive crises leading to a health-care visit over the first-year post-randomisation. The secondary objectives included assessing crizanlizumab's safety. The trial is registered at ClinicalTrials.gov (NCT03814746) and is ongoing.

Findings: Between July 26, 2019, and Aug 31, 2022, 252 patients were enrolled and treated. The primary analysis showed an adjusted annualised rate of vaso-occlusive crises of 2·49 (95% CI 1·90-3·26) in the crizanlizumab 5·0 mg/kg group, 2·04 (1·56-2·65) in the 7·5 mg/kg group, and 2·30 (1·75-3·01) in the placebo group. Ratios of adjusted annualised rates of vaso-occlusive crises leading to health-care visits were 1·08 (95% CI 0·76-1·55, p>0·999) for 5·0 mg/kg and 0·89 (0·62-1·27, p>0·999) for 7·5 mg/kg vs placebo. The incidence of adverse events was similar across treatment groups. Grade 3 or higher adverse events were observed less frequently in the placebo and crizanlizumab 7·5 mg/kg groups (27 [32%] of 85 and 32 [39%] of 83, respectively) than in the 5·0 mg/kg group (47 [56%] of 84). Serious adverse events (all grades) were also less frequent in the placebo and crizanlizumab 7·5 mg/kg groups (26 [31%] and 22 [27%], respectively) than in the 5·0 mg/kg group (35 [42%]).

Interpretation: The STAND study supports the safety and tolerability of crizanlizumab in the treatment of sickle cell disease. The primary analysis showed no significant difference in efficacy between crizanlizumab and placebo. Factors including the COVID-19 pandemic, global enrolment with varied patterns of health-care use and vaso-occlusive crisis management as well as the commercial availability of crizanlizumab might have influenced these results. The safety profile of crizanlizumab was consistent with that in previous reports, without new safety concerns.

Funding: Novartis Pharmaceuticals.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a condition in which a fetus is at risk for severe thrombocytopenia, possibly resulting in intracranial haemorrhage, due to maternal alloantibodies formed against human platelet antigens (HPAs). Currently, no FNAIT screening programme exists. Pregnancies at risk of FNAIT are identified in individuals who have previously given birth to a child with FNAIT. Management of the condition differs depending on the country. A panel of experts in obstetrics, neonatology, paediatrics, laboratory and transfusion medicine, haematology, health technology assessments, and population screening-related administration who are members of the FNAIT Modified Delphi Expert Group from Europe, the USA, Canada, and Australia, were invited to participate in this study. This Delphi study included three rounds of online questionnaires, which were formulated by professionals from the Dutch FNAIT centre of expertise in collaboration with co-authors, and one live meeting in Leiden, the Netherlands in April, 2023. Funding for the live meeting in Leiden was obtained from the Dutch Research Council. The final questionnaire had 35 statements on current management and a possible antenatal FNAIT screening programme. Answer options were: agree, disagree, neither agree or disagree, and not sufficient knowledge. Consensus threshold was set at 80%. After three rounds of questionnaires, consensus was reached on 25 (71%) of 35 statements. The experts agreed on the use of anti-HPA-1a antibody levels to identify high-risk FNAIT pregnancies, although a cutoff value was not defined. The panel achieved consensus on the design of a cost-effective screening programme based only on anti-HPA-1a antibody level measurement. International differences were observed in case of two aspects: addition of corticosteroids to intravenous immunoglobulins and delivery mode in FNAIT pregnancies. This Delphi study facilitated sharing of international knowledge, which enabled clarification of local policies related to perceived standards of care.