Lancet Haematology最新文献

The increasing use of immunotherapeutic approaches, cellular therapies, and targeted agents is rapidly and profoundly changing the treatment paradigms of haematological malignancies. These novel therapies are increasingly incorporated into earlier lines of treatment. Some are administered for a fixed duration, often with curative intent, whereas others are administered chronically for disease control. The associated acute, mid-term, and long-term toxic effects can differ markedly from conventional cytotoxic chemotherapy and radiotherapy. Accumulating clinical experience and data enable identification of class-specific effects and development of consensus-based guidelines for toxicity management. In this third paper in the Series on adverse event reporting, we build on our emerging understanding of toxicity profiles of novel treatments to propose an actionable framework for improved assessment, reporting, and critical appraisal of treatment tolerability. We discuss recent insights regarding second cancers and the relevance of infectious complications, explore tolerability aspects of time-limited treatments, and suggest approaches to address gaps in tolerability assessment.

Incorporating patient-generated data into drug development is crucial for assessing the tolerability of treatments, particularly in patients with haematological malignancies, some of whom receive high-intensity, short-duration treatments and others who endure chronic therapies for months to years at a time. With increasing use of novel therapies such as oral targeted agents and immunotherapy, including chimeric antigen receptor T-cell therapy and bispecific antibodies across different haematological malignancies, new types of toxicity assessment techniques that harness patient-generated data, including patient-reported outcomes (PROs) are required to fully evaluate short-term and long-term side-effects. In this second paper in this Series, we describe progress in PRO implementation in clinical trials and outline future directions for use of patient-generated data, including PRO implementation in early-phase trials, novel PRO-based endpoints in haematology trials, and updated PRO measures that reflect treatment advances across haematological malignancies.

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.

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.

Background: In low-income and middle-income counties (LMICs), the outcome of relapsed or refractory B-cell malignancies is poor due to the absence of effective therapies. We report the results of a phase 1/2 study of a novel humanised anti-CD19 4-1BB chimeric antigen receptor (CAR) T-cell therapy, talicabtagene autoleucel, for patients with relapsed or refractory B-cell malignancies.

Methods: This open-label, multicentre, phase 1/2 study was done at six tertiary cancer centres in India. Phase 1 was a single-centre study done in Tata Memorial Hospital, India, in patients aged 18 years or older with relapsed or refractory B-cell lymphomas. Phase 2 was a single-arm, multicentre, basket trial done in five tertiary cancer centres in patients aged 15 years and older with relapsed or refractory B-cell acute lymphoblastic leukaemia or B-cell lymphoma. Eligible patients had a life expectancy of 12 weeks or more, an ECOG performance status of 0-1 (phase 1) or 0-2 (phase 2), and an adequate organ function. Patients underwent apheresis to obtain at least 1 × 10⁹ lymphocytes to manufacture CAR T cells. Lymphodepletion therapy was done with cyclophosphamide 500 mg/m² and fludarabine 30 mg/m² for 3 days or bendamustine 90 mg/m² for 2 days. Patients were then infused intravenously with talicabtagene autoleucel 1 × 10⁷-5 × 10⁹ CAR T cells in a fractionated schedule (10%, 30%, and 60%, on days 0, 1, and 2, respectively) during phase 1 or at least 5 × 10⁶ CAR T cells per kg (up to 2 × 10⁹ CAR T cells) on day 0 during phase 2. The primary endpoints were safety (phase 1) and overall response rate (phase 2). The efficacy analysis was done in the efficacy evaluable cohort (all patients who received the target dose and 3 days of lymphodepletion therapy). The safety analysis was done in the safety population (all patients who received talicabtagene autoleucel). The trials are registered with Clinical Trial Registry-India (CTRI/2021/04/032727 and CTRI/2022/12/048211), and enrolment is closed.

Findings: Of 64 patients, 14 were enrolled in phase 1 (from May 11, 2021, to May 13, 2022) and 50 were enrolled in phase 2 (Dec 27, 2022, to Aug 31, 2023). The median age of the overall cohort was 44 years (IQR 27-57), and 49 (77%) of 64 patients were male and 15 (23%) were female. In phase 1, no dose-limiting toxicities occurred at doses of 2 × 10⁶-17 × 10⁶ CAR T cells per kg. A dose of at least 5 × 10⁶ CAR T cells per kg was chosen for phase 2 based on a complete response in three of seven patients at this dose. The most common grade 3 or worse toxicities were haematological events: anaemia (35 [61%] of 57 patients), thrombocytopenia (37 [65%] patients), neutropenia (55 [96%] patients, and febrile neutropenia (27 [47%]) patients). There were two treatment-related deaths, one due to febrile neutrope