Are CAR-T therapies living up to their hype?: A study using real-world data in two cohorts to determine how well they are actually working in practice compared with bone marrow transplants

With the increasing use of new regulatory tools, like the Food and Drug Administration's breakthrough designation, there are increasing challenges for European health technology assessors (HTAs) to make an accurate assessment of the long-term value and performance of chimeric antigen receptor T-cell (CAR-T) therapies, particularly for orphan conditions, such as acute lymphoblastic leukaemia. The aim of this study was to demonstrate a novel methodology harnessing longitudinal real-world data, extracted from the electronic health records of a medical centre functioning as a clinical trial site, to develop an accurate analysis of the performance of CAR-T compared with the next-best treatment option, namely allogeneic haematopoietic cell transplant (HCT). The study population comprised 43 subjects in two cohorts: 29 who had undergone HCT treatment and 14 who had undergone CAR-T therapy. The 3-year relapse-free survival probability was 46% (95% CI: 08% to 79%) in the CAR-T cohort and 68% (95% CI: 46% to 83%) in the HCT cohort. To explain the lower RFS probability in the CAR-T cohort compared with the HCT cohort, the authors hypothesised that the CAR-T cohort had a far higher level of disease burden. This was validated by log-rank test analysis (p=0.0001) and confirmed in conversations with practitioners at the study site. The authors are aware that the small populations in this study will be seen as limiting the generalisability of the findings to some readers. However, in consultation with many European HTAs and regulators, there is broad agreement that this methodology warrants further investigation with a larger study

Bacterial Infections Complicating Tongue Piercing

Tongue piercing has become an increasingly popular form of body art. However, this procedure can occasionally be complicated by serious bacterial infections. The present article reports a case of prosthetic valve endocarditis caused by a Gemella species in a patient with a pierced tongue, and reviews 18 additional cases of local and systemic bacterial infections associated with tongue piercing. Infections localized to the oral cavity and head and neck region included molar abscess, glossal abscess, glossitis, submandibular lymphadenitis, submandibular sialadenitis, Ludwig’s angina and cephalic tetanus. Infections distal to the piercing site included eight cases of infective endocarditis, one case of chorioamnionitis and one case of cerebellar abscess. Oropharyngeal flora were isolated from all cases. While bacterial infections following tongue piercing are rare, there are reports of potentially life-threatening infections associated with the procedure. Both piercers and their clients should be aware of these potential complications, and standardized infection prevention and control practices should be adopted by piercers to reduce the risk.Peer Reviewe

Bacterial infections complicating tongue piercing

Tongue piercing has become an increasingly popular form of body art. However, this procedure can occasionally be complicated by serious bacterial infections. The present article reports a case of prosthetic valve endocarditis caused by a Gemella species in a patient with a pierced tongue, and reviews 18 additional cases of local and systemic bacterial infections associated with tongue piercing. Infections localized to the oral cavity and head and neck region included molar abscess, glossal abscess, glossitis, submandibular lymphadenitis, submandibular sialadenitis, Ludwig’s angina and cephalic tetanus. Infections distal to the piercing site included eight cases of infective endocarditis, one case of chorioamnionitis and one case of cerebellar abscess. Oropharyngeal flora were isolated from all cases. While bacterial infections following tongue piercing are rare, there are reports of potentially life-threatening infections associated with the procedure. Both piercers and their clients should be aware of these potential complications, and standardized infection prevention and control practices should be adopted by piercers to reduce the risk

Bendamustine plus rituximab for the treatment of Waldenström Macroglobulinaemia: patient outcomes and impact of bendamustine dosing

Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinaemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicentre, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p<0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% vs 82%, respectively (p=0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000mg/m2 compared with those receiving 800-999mg/m2 (p=0.04). In the relapsed cohort, those who received doses of <600mg/m2 had poorer PFS outcomes compared with those who received ≥600mg/m2 (p=0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings. This article is protected by copyright. All rights reserved

Bendamustine plus rituximab for the treatment of Waldenström Macroglobulinemia: patient outcomes and impact of bendamustine dosing

Bendamustine and rituximab (BR) therapy is commonly used in the treatment of Waldenström Macroglobulinemia (WM). The impact dose of Bendamustine dose on response and survival outcomes is not well-established, and the impact of its use in different treatment settings is not clear. We aimed to report response rates and survival outcomes following BR, and clarify the impact of depth of response and bendamustine dose on survival. A total of 250 WM patients treated with BR in the frontline or relapsed settings were included in this multicenter, retrospective cohort analysis. Rates of partial response (PR) or better differed significantly between the frontline and relapsed cohorts (91.4% vs 73.9%, respectively; p < 0.001). Depth of response impacted survival outcomes: two-year predicted PFS rates after achieving CR/VGPR vs PR were 96% versus 82%, respectively (p = 0.002). Total bendamustine dose was predictive of PFS: in the frontline setting, PFS was superior in the group receiving ≥1000 mg/m 2 compared with those receiving 800–999 mg/m 2 (p = 0.04). In the relapsed cohort, those who received doses of <600 mg/m 2 had poorer PFS outcomes compared with those who received ≥600 mg/m 2 (p = 0.02). Attaining CR/VGPR following BR results in superior survival, and total bendamustine dose significantly impacts response and survival outcomes, in both frontline and relapsed settings

Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping

A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP)-based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in "functional regions" within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332