Introduction
Pembrolizumab is a humanised monoclonal antibody targeting the receptor programmed cell death protein-1 (PD-1), with anti-tumour activity demonstrated for many malignancies. Such immune ...checkpoint inhibitors are associated with many immune-related adverse events including rash, colitis, hepatitis, pneumonitis, endocrinopathy and, rarely, haematological adverse events, including immune-related thrombocytopenia.
Case report
We report a 60-year-old female with metastatic non-small cell lung cancer treated with pembrolizumab every three weeks. Following her fifth cycle, she presented to our hospital with community-acquired pneumonia. Thrombocytopenia developed the next day and, after detailed investigations, thrombotic thrombocytopenic purpura was diagnosed.
Management and outcome
Pembrolizumab was immediately ceased and plasma exchange commenced along with IV methylprednisolone 250 mg daily for three days followed by oral prednisolone. After five days of plasma exchange, platelet counts normalised and haemolytic anaemia resolved.
Discussion
Acquired thrombotic thrombocytopenic purpura is an autoimmune disorder caused by an inhibitory autoantibody against ADAMTS-13. While most cases of acquired thrombotic thrombocytopenic purpura are idiopathic, certain conditions (e.g. bacterial infection, autoimmune disorders, malignancies) and medications are associated with thrombotic thrombocytopenic purpura. Other potential causes were eliminated in our patient. As acquired thrombotic thrombocytopenic purpura is an autoimmune disorder, pembrolizumab, given its unique mechanism of action and association with immune-related adverse events, is believed to be implicated in the development of thrombotic thrombocytopenic purpura. This case is one of only two linking anti-PD-1 therapy to thrombotic thrombocytopenic purpura development (the other occurring in a patient on nivolumab plus ipilimumab). Thrombotic thrombocytopenic purpura is life-threatening and clinicians are advised to be aware of its possible occurrence in immune checkpoint inhibitor-treated patients.
Introduction Endovascular abdominal aortic aneurysm (AAA) repair (EVAR) has been associated with lower operative mortality and morbidity than open surgery but comparable long-term mortality and ...higher delayed complication and reintervention rates. Attention has therefore been directed to identifying preoperative and operative variables that influence outcomes after EVAR. Risk-prediction models, such as the EVAR Risk Assessment (ERA) model, have also been developed to help surgeons plan EVAR procedures. The aims of this study were (1) to describe outcomes of elective EVAR at the Royal Brisbane and Women's Hospital (RBWH), (2) to identify preoperative and operative variables predictive of outcomes after EVAR, and (3) to externally validate the ERA model. Methods All elective EVAR procedures at the RBWH before July 1, 2009, were reviewed. Descriptive analyses were performed to determine the outcomes. Univariate and multivariate analyses were performed to identify preoperative and operative variables predictive of outcomes after EVAR. Binomial logistic regression analyses were used to externally validate the ERA model. Results Before July 1, 2009, 197 patients (172 men), who were a mean age of 72.8 years, underwent elective EVAR at the RBWH. Operative mortality was 1.0%. Survival was 81.1% at 3 years and 63.2% at 5 years. Multivariate analysis showed predictors of survival were age ( P = .0126), American Society of Anesthesiologists (ASA) score ( P = .0180), and chronic obstructive pulmonary disease ( P = .0348) at 3 years and age ( P = .0103), ASA score ( P = .0006), renal failure ( P = .0048), and serum creatinine ( P = .0022) at 5 years. Aortic branch vessel score was predictive of initial (30-day) type II endoleak ( P = .0015). AAA tortuosity was predictive of midterm type I endoleak ( P = .0251). Female sex was associated with lower rates of initial clinical success ( P = .0406). The ERA model fitted RBWH data well for early death (C statistic = .906), 3-year survival (C statistic = .735), 5-year survival (C statistic = .800), and initial type I endoleak (C statistic = .850). Conclusions The outcomes of elective EVAR at the RBWH are broadly consistent with those of a nationwide Australian audit and recent randomized trials. Age and ASA score are independent predictors of midterm survival after elective EVAR. The ERA model predicts mortality-related outcomes and initial type I endoleak well for RBWH elective EVAR patients.
Background: Systemic AL Amyloidosis is characterized by deposition by amyloid fibrils of light chains produced by clonal plasma cells. New combination therapies have substantially prolonged the life ...expectancy of patients with AL Amyloidosis . Still the prognosis of the disease in the majority of the patients is dismal and Quality of Life (QoL) issues should be included in clinicians' primary objectives. Nowadays, patient-reported outcome measures (PROMs) are considered one of the most responsive tools that can guide personalized interventions to optimize QoL in parallel with therapeutic interventions. The aim of this metanalysis was to establish which PROMs have been utilized in studies on AL Amyloidosis and evaluate their validity.
Methods: Two independent investigators (S.B.; C.K.) systemically reviewed PubMed, Medline and EMBASE databases for publications up to May 2021 on PROMs employed to report QoL outcomes in AL Amyloidosis. The identified PROMs were subsequently assessed for their validity in this context against COSMIN (Consensus-based Standards for the selection of health Measurement Instruments) quality criteria.
Results:
Of the 246 publications originally retrieved, only 57 were further analysed as 92 were duplicates, 11 were irrelevant to AL Amyloidosis, 56 did nor refer to QOL and 13 reported QOL without using QOLQs, 13 were case-reports and 4 were review articles. These included 47 observational studies and 10 prospective clinical trials. In these, thirteen different PROMs were used on occasion to report QOL outcomes (SF-36; EQ-5D-3L; FACT-G; PROMIS-GH); HPRSS; DT; EORTC QLQ-C30; KCCQ-12; GAF; SWLS; STAI; CESD; MDASI) with SF-36 being the most popular (35/ 58 publications). All of them are traditionally validated in similar to AL Amyloidosis diseases (e.g. Multiple Myeloma) or in its complications (e.g. Congestive Heart Failure). In the absence of face-validity studies, the content validity of these PROMs was assessed against QOL aspects identified in literature by open questionnaires (Table 1). The outcome of the intensive analysis of these studies showed that the QoLQ fail to cover the broad spectrum of disease symptoms and current therapy-related toxicity. Furthermore, there is limited if any evidence for the validation of these tools in this context (Table 2). COSMIN criteria were met only for SF-36 and PROMIS-GH as regards internal consistency (Cronbach's a>70).
Conclusions: This literature review reveals that commonly applied PROMs in studies on AL Amyloidosis do not represent the impact of this complex disease and its treatment on QoL issues. Thus, there is a need to develop a new, well-validated, disease-specific PROM that can facilitate the approval of new treatments and the adjustment of therapy-intensity according to its toxicity and QoL.
Display omitted
No relevant conflicts of interest to declare.
To assess the ability of cardiovascular magnetic resonance (CMR) to (i) measure changes in response to chemotherapy; (ii) assess the correlation between haematological response and changes in ...extracellular volume (ECV); and (iii) assess the association between changes in ECV and prognosis over and above existing predictors.
In total, 176 patients with cardiac AL amyloidosis were assessed using serial N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography, free light chains and CMR with T1 and ECV mapping at diagnosis and subsequently 6, 12, and 24 months after starting chemotherapy. Haematological response was graded as complete response (CR), very good partial response (VGPR), partial response (PR), or no response (NR). CMR response was graded by changes in ECV as progression (≥0.05 increase), stable (<0.05 change), or regression (≥0.05 decrease). At 6 months, CMR regression was observed in 3% (all CR/VGPR) and CMR progression in 32% (61% in PR/NR; 39% CR/VGPR). After 1 year, 22% had regression (all CR/VGPR), and 22% had progression (63% in PR/NR; 37% CR/VGPR). At 2 years, 38% had regression (all CR/VGPR), and 14% had progression (80% in PR/NR; 20% CR/VGPR). Thirty-six (25%) patients died during follow-up (40 ± 15 months); CMR response at 6 months predicted death (progression hazard ratio 3.82; 95% confidence interval 1.95-7.49; P < 0.001) and remained prognostic after adjusting for haematological response, NT-proBNP and longitudinal strain (P < 0.01).
Cardiac amyloid deposits frequently regress following chemotherapy, but only in patients who achieve CR or VGPR. Changes in ECV predict outcome after adjusting for known predictors.
Summary
Systemic AL amyloidosis is an incurable condition with various presentations and may cause multiple complications related to organ involvement. As survival has improved, disease and ...therapy‐related quality of life (QoL) is becoming an increasingly important treatment endpoint. We review the literature summarising the utilised QoL questionnaires (QLQs) and assess their validity according to COSMIN (Consensus‐based Standards for the Selection of Health Measurement Instruments) standards. Thirteen retrospective observational studies and thirty‐two prospective clinical trials were analysed. Most QLQs are generic or only validated in populations with distinct complications of the disease. None meet ‘strong evidence’ for validation in this context. There is a need to develop a disease‐specific QLQ, which could inform treatment choices and facilitate the approval of novel therapies.
Abstract
Aims
To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine ...serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease.
Methods and results
A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM.
Conclusion
The NBDC for ATTR-CM are highly specific 97% (95% CI 0.91-0.99) in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.
Structured Graphical Abstract
Structured Graphical Abstract
A real-world analysis of 3354 patients referred to specialist centres with suspected or proven cardiac amyloidosis showed that the non-biopsy diagnostic criteria for ATTR-CM remain highly specific with inclusion of refined cut-offs for sFLC ratio in CKD, as long as the diagnostic algorithm is carefully adhered to and technical considerations are met. Legend: AL, light chain amyloidosis; ATTR, transthyretin amyloidosis; ATTR-CM, transthyretin amyloid cardiomyopathy; CA, cardiac amyloidosis; IFE, immunofixation electrophoresis; CA, cardiac amyloidosis; CMR, cardiac magnetic resonance; NBDC, non-biopsy diagnostic criteria; eGFR, estimated glomerular filtration rate; MG, monoclonal gammopathy; sFLC, serum free light chains; TTR, transthyretin.
Binary cardiac response assessment using cardiac biomarkers is prognostic in light chain amyloidosis. Previous studies suggested four-level cardiac responses using N-terminal prohormone of brain ...natiuretic peptide improves prognostic prediction. This study was designed to validate graded cardiac response criteria using N-terminal prohormone of brain natiuretic peptide/brain natiuretic peptide.
This retrospective, multicenter study included patients with light chain amyloidosis who achieved at least a hematologic partial response (PR) and were evaluable for cardiac response. Four response criteria were tested on the basis of natriuretic peptide response depth: cardiac complete response (CarCR), cardiac very good partial response (CarVGPR), cardiac PR (CarPR), and cardiac no response (CarNR). Response was classified as best response and at fixed time points (6, 12, and 24 months from therapy initiation). The study primary outcome was overall survival.
651 patients were included. Best CarCR, CarVGPR, CarPR, and CarNR were achieved in 16%, 26.4%, 22.9%, and 34.7% of patients, respectively. Patients in cardiac stage II were more likely to achieve CarCR than patients in cardiac stage IIIA and IIIB (22%
13.5%
3.2%;
< .001). A deeper cardiac response was associated with a longer survival (5-year overall survival 93%, 79%, 65%, and 33% for CarCR, CarVGPR, CarPR, and CarNR, respectively;
< .001). Fixed time-point analyses and time-varying covariates Cox regression analysis, to minimize survivorship bias, affirmed the independent survival advantage of deeper cardiac responses. Four-level response performed better than two-level response as early as 12 months from therapy initiation.
Graded cardiac response criteria allow better assessment of cardiac improvement compared with the traditional binary response system. The study re-emphasizes the importance of early diagnosis, which increases the likelihood of deep cardiac responses.
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