Brexucabtagene autoleucel in relapsed or refractory mantle cell lymphoma, intention-to-treat use in the DESCAR-T registry.

Not available.

Prognostic mortality factors in advanced light chain cardiac amyloidosis: A prospective cohort study.

AIMS: Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. METHODS AND RESULTS: This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT ≤ 107 ng/L and NT-proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT-proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT-proBNP then CB 4 µmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 µmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2-24]. At 1 year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11-18]) and stage 3, 6.6 months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. CONCLUSIONS: The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

Rate and characteristics of inflammatory neuropathies associated with brentuximab vedotin therapy.

BACKGROUND AND PURPOSE: Peripheral neuropathy is a frequent complication of brentuximab vedotin (BV), used in CD30+ lymphoma treatment. Classic BV-induced neuropathy (BV-CN) is a mild distal sensory axonal polyneuropathy. Severe BV-induced inflammatory neuropathies (BV-IN) have been described. BV-IN contribute to lymphoma-associated morbidity but might be immunotherapy-responsive. Our primary objective was to evaluate the rate of BV-IN. Our secondary objectives were to determine risk factors and warning signs. METHODS: We conducted a retrospective cohort study on all patients treated with BV at our center between April 2014 and September 2021. Clinical, biological, and electrophysiological data were collected. BV-induced neuropathy was defined as the occurrence of neuropathy up to 3 months after BV discontinuation. BV-IN was defined with criteria adapted from European Academy of Neurology/Peripheral Nerve Society 2021 electrodiagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. Other neuropathies were classified as BV-CN. RESULTS: Among 83 patients, 41 (49%) developed neuropathy: 35 BV-CN and 6 BV-IN. Thus, the rate of BV-IN was 7.2%. Compared to patients with BV-CN, no predisposing factor was identified. However, patients with BV-IN more frequently presented muscle weakness (67% vs. 5.7%, p < 0.05), gait disorders (83% vs. 20%, p < 0.05), or acute or subacute onset (67% vs. 14%, p < 0.05). BV-IN was frequently more severe (Common Terminology Criteria for Adverse Events grade ≥3; 50% vs. 0%, p < 0.05). Four patients were treated with immunotherapy. CONCLUSIONS: Brentuximab vedotin-induced neuropathy is an overlooked complication. Based on four easily identifiable "red flags", we provide an algorithm to help non-neurologist physicians that care for BV-treated patients to detect BV-IN. The aim of the algorithm is to decrease the diagnostic and management delay of this disabling neuropathy.

Transfusion needs after CAR T-cell therapy for large B-cell lymphoma: predictive factors and outcome (a DESCAR-T study).

ABSTRACT: Chimeric antigen receptor (CAR) T-cells targeting CD19 have been approved for the treatment of relapse/refractory large B-cell lymphoma. Hematotoxicity is the most frequent CAR T-cell-related adverse event. Transfusion support is a surrogate marker of severe cytopenias. Transfusion affects patients' quality of life, presents specific toxicities, and is known to affect immunity through the so-called transfusion-related immunomodulation that may affect CAR T-cell efficacy. We analyzed data from 671 patients from the French DESCAR-T registry for whom exhaustive transfusion data were available. Overall, 401 (59.8%) and 378 (56.3%) patients received transfusion in the 6-month period before and after CAR T-cell infusion, respectively. The number of patients receiving transfusion and the mean number of transfused products increased during the 6-month period before CAR T-cell infusion, peaked during the first month after infusion (early phase), and decreased over time. Predictive factors for transfusion at the early phase were age >60 years, ECOG PS ≥2, treatment with axicabtagene ciloleucel, pre-CAR T-cell transfusions, and CAR-HEMATOTOX score ≥2. Predictive factors for late transfusion (between 1 and 6 months after infusion) were pre-CAR T-cell transfusions, CAR-HEMATOTOX score ≥2, ICANS ≥3 (for red blood cells [RBC] transfusion), and tocilizumab use (for platelets transfusion). Early transfusions and late platelets (but not RBC) transfusions were associated with a shorter progression-free survival and overall survival. Lymphoma-related mortality and nonrelapse mortality were both increased in the transfused population. Our data shed light on the mechanisms of early and late cytopenia and on the potential impact of transfusions on CAR T-cell efficacy and toxicity.

Work and education interruption in long-term Hodgkin lymphoma survivors: an analysis among patients from nine EORTC-LYSA trials.

BACKGROUND: Disease-specific studies on the impact of Hodgkin lymphoma (HL) on education or work interruption and resumption are lacking. MATERIAL AND METHODS: In a cross-sectional study conducted among long-term HL survivors enrolled from 1964 to 2004 in nine randomised EORTC-LYSA trials, the interruption and resumption of education/work was investigated. Survivors alive 5-44 years after diagnosis who were studying or working at time of diagnosis were included (n = 1646). Patient and treatment characteristics were obtained from trial records. Education and work outcomes were collected using the Life Situation Questionnaire. Logistic regression was used to model education or work interruption; Cox regression was used to study resumption rates. RESULTS: Among survivors studying at time of diagnosis (n = 323), 52% (95% CI: 46-57%) interrupted their education; however, it was resumed within 24 months by 92% (95% CI: 87-96%). The probability of interruption decreased with time: the more recent the treatment era, the lower the risk (OR 0.70 per 10 years, 95% CI: 0.49-1.01). Treatment with radiotherapy (yes vs. no) was associated with a higher education resumption rate (HR 2.01, 95% CI 1.07-3.78) whereas age, sex, stage, radiotherapy field and chemotherapy were not.Among survivors working at time of diagnosis (n = 1323), 77% (95% CI: 75-79%) interrupted their work. However, it was resumed within 24 months by 86% (95% CI: 84%-88%). Women were more likely to interrupt their work as compared to men (OR 1.90, 95% CI: 1.44-2.51) and, when interrupted, less likely to resume work (HR 0.70, 95% CI: 0.61-0.80). Survivors with a higher educational level were less likely to interrupt their work (OR 0.68 for university vs. no high school, 95% CI: 0.46-1.03); and when interrupted, more likely to resume work (HR 1.50 for university vs. no high school, 95% CI: 1.21-1.86). Increasing age was also associated with lower resumption rates (HR 0.62 for age ≥50 vs. 18-29 years, 95% CI: 0.41-0.94). CONCLUSION: An interruption in education/work was common among long-term HL survivors. However, most of the survivors who interrupted their studies or work had resumed their activities within 24 months. In this study, no associations between survivors' characteristics and failure to resume education were observed. Female sex, age ≥50 years, and a lower level of education were found to be associated with not resuming work after treatment for HL.

Precision Medicine Approach Based on Molecular Alterations for Patients with Relapsed or Refractory Multiple Myeloma: Results from the MM-EP1 Study.

BACKGROUND: Despite that cytogenetic and molecular analysis of tumor cells can rapidly identify recurring molecular abnormalities, no personalized therapy is currently available in the setting of relapsed/refractory multiple myeloma (r/r MM). METHODS: MM-EP1 is a retrospective study aimed at comparing a personalized molecular-oriented (MO) versus a non-molecular-oriented (no-MO) approach in r/r MM. Actionable molecular targets and their associated therapies were the BRAF V600E mutation and BRAF inhibitors; t(11;14)(q13;q32) and BCL2 inhibitors; and t(4;14)(p16;q32) with FGFR3 fusion/rearrangements and FGFR3 inhibitors. RESULTS: One hundred three highly pretreated r/r MM patients with a median age of 67 years (range 44-85) were included. Seventeen (17%) patients were treated using an MO approach with BRAF inhibitors (vemurafenib or dabrafenib, n = 6), BCL2 inhibitor (venetoclax, n = 9), or FGFR3 inhibitor (erdafitinib, n = 2). Eighty-six (86%) patients received non-MO therapies. Overall response rate was 65% in MO patients versus 58% in the non-MO group (p = 0.053). Median PFS and OS were 9 and 6 months (HR = 0.96; CI95 = 0.51-1.78; p = 0.88) and 26 and 28 months (HR = 0.98; CI95 = 0.46-2.12; p = 0.98), respectively, in MO and no-MO patients. CONCLUSION: Despite the low number of patients treated with an MO approach, this study highlights the strengths and weakness of a molecular-targeted approach for the treatment of multiple myeloma. Widespread biomolecular techniques and improvement of precision medicine treatment algorithms could improve selection for precision medicine in myeloma.

Real-Life Evaluation of an Algorithm for the Diagnosis of Cardiac Amyloidosis.

OBJECTIVE: To evaluate the real-life use of a modified Gillmore algorithm with a "one-stop-shop" approach, bone scintigraphy (BS), a monoclonal gammopathy test (GT), a salivary gland biopsy (SGB), and genetic testing performed at the same time for the diagnosis of cardiac amyloidosis at the French National Reference Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil, France). METHODS: This retrospective cohort study included a total of 1222 patients with suspected amyloidosis who underwent BS and GT between June 2008 and May 2019. RESULTS: Of 1222 patients, 349 had no cardiac uptake on BS and negative GT (BS-/GT-), 276 were BS-/GT positive (GT+), 420 patients were BS+/GT-, and 177 were BS+/GT+. Our one-stop-shop check-up enabled us to diagnose 892 (72.9%) patients; 330 (27.0%) patients required additional examinations, such as mass spectrometry and/or a cardiac biopsy. This subset notably included 112 patients with amyloid light chain amyloidosis. More than 64% of the patients with transthyretin amyloidosis or another type of amyloidosis were diagnosed during the one-stop shop visit. Sensitivity and specificity of BS for transthyretin amyloidosis diagnosis was 99% and 96%, respectively. For amyloid light chain diagnosis, sensitivity and specificity were 100% and 76%, respectively, for GT and 54% and 100%, respectively, for SGB. Of 910 transthyretin genetic tests, 205 (17%) detected mutations. CONCLUSION: The results of our real-life cohort study confirmed the ability of a one-stop-shop approach with a modified Gillmore algorithm to diagnose cardiac amyloidosis and the interest of simultaneous testing for earlier diagnosis. The SGB has diagnostic value because it is easy, quick, and less invasive than a cardiac biopsy.

Employment situation among long-term Hodgkin lymphoma survivors in Europe: an analysis of patients from nine consecutive EORTC-LYSA trials.

PURPOSE: Little is known about the employment situation of long-term Hodgkin lymphoma (HL) survivors despite their young age at diagnosis and the favorable prognosis of the disease. In this cross-sectional study, we aim to describe the employment situation in a cohort of long-term HL survivors compared to the general population and investigate the associations with disease characteristics and treatment exposure. METHODS: HL survivors > 25 years (n = 1961) were matched 1:25 to controls (n = 49,025) from the European Union Labour Force Survey. Individual treatment information was obtained from trial records. Employment and socio-demographic characteristics were collected using the Life Situation Questionnaire. Logistic regression models were used to estimate associations between disease and treatment characteristics with employment status and work-related attitudes. RESULTS: At employment assessment, 69.7% of survivors (95% CI: 67.6-71.7%) were working; of these, 68.9% (95% CI: 66.3-71.3%) worked full-time, a figure comparable to that of controls (p value 0.17). The risk of not working was associated with increasing age at diagnosis, increasing age at survey, female sex, lower educational level, and relapse history. Of those who were at work during treatment, 16.8% (95% CI: 14.5-19.3%) stated their income had subsequently decreased, which was attributed to their HL by 65.4% (95% CI: 57.5-72.8). Among those not at work, 25.1% (95% CI: 20.7-29.8) survivors were disabled compared to only 14.5% (95% CI: 13.8-15.3%) of controls. CONCLUSIONS: In this cohort of HL survivors, employment status was comparable to that of the general population. However, increasing age at follow-up, female sex, lower educational level, and relapse history are risk factors for unemployment, a perceived decrease in income, and disability. IMPLICATIONS FOR CANCER SURVIVORS: To further improve follow-up care, special attention should be paid to these vulnerable subgroups.

Evaluation of a new ELISA assay for monoclonal free-light chain detection in patients with cardiac amyloidosis.

The causal protein of amyloid light-chain (AL) amyloidosis is a monoclonal immunoglobulin free light chain (mFLC), which must be quantified in the serum for patient diagnosis and monitoring. Several manufacturers commercialize immunoassays that quantify total kappa (κ) and lambda (λ) FLC, but results can differ greatly between these tests. Here, we compared a recently developed enzyme-linked immunosorbent assay (ELISA) (Sebia) with N-Latex immunonephelometry (Siemens) in 96 patients diagnosed with AL amyloidosis (histologically confirmed) and 48 non-AL patients sent to our referral center for suspicion of cardiac amyloidosis. ELISA free-light chain difference (dFLC) were lower than N-Latex values, and agreement between methods was reduced in the case of involved λ FLC. Diagnosis sensitivity and specificity were >85% with both assays. A receiver operating characteristic analysis indicated that ELISA performances could be improved by using a higher value for the lower limit of the κ/λ ratio. We also assessed Freelite (The Binding Site) in a subgroup of these same AL patients, including 18 cases with normal κ/λ ratio by at least one assay. Only two patients had normal κ/λ ratio with all three assays. Overall, ELISA demonstrated slightly lower sensitivity than N-Latex but may be an alternative to nephelometry/turbidimetry in certain difficult cases.

Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis.

Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a major advance in the treatment of relapsed/refractory aggressive B-cell lymphomas. However, a significant number of patients experience failure. Among 550 patients registered in the French registry DESCAR-T, 238 (43.3%) experienced progression/relapse, with a median follow-up of 7.9 months. At registration, 57.0% of patients presented an age-adjusted International Prognostic Index of 2 to 3, 18.9% had Eastern Cooperative Oncology Group performance status ≥2, 57.1% received >3 lines of treatment prior to receiving CAR T-cells, and 87.8% received bridging therapy. At infusion, 66% of patients presented progressive disease, and 38.9% had high lactate dehydrogenase (LDH). Failure after CAR T-cell treatment occurred after a median of 2.7 months (range: 0.2-21.5). Fifty-four patients (22.7%) presented very early failure (day [D] 0-D30); 102 (42.9%) had early failure (D31-D90), and 82 (34.5%) had late (>D90) failure. After failure, 154 patients (64%) received salvage treatment: 38.3% received lenalidomide, 7.1% bispecific antibodies, 21.4% targeted treatment, 11% radiotherapy, and 20% immunochemotherapy with various regimens. Median progression-free survival was 2.8 months, and median overall survival (OS) was 5.2 months. Median OS for patients failing during D0-D30 vs after D30 was 1.7 vs 3.0 months, respectively (P = .0001). Overall, 47.9% of patients were alive at 6 months, but only 18.9% were alive after very early failure. In multivariate analysis, predictors of OS were high LDH at infusion, time to CAR-T failure

Final results of brentuximab vedotin combined with ifosfamide-carboplatin-etoposide in first refractory/relapsed Hodgkin lymphoma: a lymphoma study association phase I/II study.

This phase I/II study assessed the combination of brentuximab vedotin (BV) with ifosfamide-carboplatin-etoposide (ICE) as a second-line therapy in refractory/relapsed (R/R) classical Hodgkin lymphoma (cHL) patients. Phase I study was designed to determine the maximum tolerated dose (MTD) of BV (10 patients) and phase II evaluated the rate of complete metabolic response (CMR) after 2 cycles of BV-ICE (42 patients). There were no dose-limiting toxicities (DLT) during phase I recommending BV 1.8 mg/kg for phase II. Twenty-six patients (61.9%) achieved CMR after 2 cycles of BV-ICE and 37 patients (88%) were transplanted. With a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) rate were 64.3% and 100%, respectively. Hematological toxicities (81%) and infections (21%) were the most frequent adverse event encountered BV-ICE regimen is feasible with manageable toxicities and could be an alternative to other salvage treatments. Trial Registration: ClinicalTrials.gov identifier: NCT02686346.

Heart Transplantation, Either Alone or Combined With Liver and Kidney, a Viable Treatment Option for Selected Patients With Severe Cardiac Amyloidosis.

Heart transplantation in cardiac amyloidosis (CA) patients is possible and generally considered for transplantation if other organs are not affected. In this study, we aimed to describe and assess outcome in patients following heart transplantations at our CA referral center. Methods: We assessed all CA patients that had heart transplantations at our center between 2005 and 2018. Patients with New York Heart Association status 3 out of 4, with poor short-term prognosis due to heart failure, despite treatment, and without multiple myeloma, systemic disease, severe neuropathic/digestive comorbidities, cancer, or worsening infections were eligible for transplantation. Hearts were transplanted by bicaval technique. Standard induction and immunosuppressive therapies were used. Survival outcome of CA patients after transplantation was compared with recipients with nonamyloid pathologies in France. Results: Between 2005 and 2018, 23 CA patients had heart transplants: 17 (74%) had light chain (light chain amyloidosis [AL]) and 6 (26%) had hereditary transthyretin (hereditary transthyretin amyloidosis [ATTRv]) CA. Also, 13 (57%) were male, and the mean age at diagnosis was 56.5 y (range, 47.7-62.8). Among AL patients, 13 had heart-only and 5 had heart-kidney transplantations. Among ATTRv patients, 1 had heart-only and 5 had heart-liver transplantations. The 1-y survival rate after transplantation was 78%, 70% with AL, and 100% with ATTRv. At 2 y, 74% were alive: 65% with AL and 100% with ATTRv. Conclusion: After heart transplantation, French CA and nonamyloid patients have similar survival outcomes. Among CA patients, ATTRv patients have better prognosis than those with AL, possibly due to the combined heart-liver transplantation. Selected CA patients should be considered for heart transplantations.

Revisiting the spectrum of IgM-related neuropathies in a large cohort of IgM monoclonal gammopathy.

INTRODUCTION: A significant number of patients with a peripheral neuropathy have IgM monoclonal gammopathy (IgM-MG). In this work, we encompassed the spectrum and outcome of IgM-related neuropathies (IgM-NP) in a large monocentric cohort of patients with IgM-MG. METHODS: We retrospectively reviewed the neurological and hematological findings and the course of neuropathy in all patients with IgM-MG over a five-year period in our center (Henri Mondor hospital, Assistance Publique Hôpitaux de Paris (APHP), France). RESULTS: Among 550 patients with IgM-MG, 83 patients (15%) had IgM-NP (55 males, mean age 67 y.o.). The median serum level of IgM-MG was 3.4 g/L, mostly kappa light chain component. The hematological diagnosis was Monoclonal Gammopathy of Undetermined Significance (MGUS) in 62 patients. Anti-MAG antibodies were detected in 38 patients with heterogeneous clinical and neurophysiological features. Four patients had neurolymphomatosis presenting as a non-length dependent predominantly motor neuropathy, which occurred long after the finding of IgM-MG and was responsive to hematological treatment. Five patients had an AL amyloid neuropathy revealed by a small fiber neuropathy. Finally, 30 patients were classified as "Neuropathy of Uncertain Relationship with the IgM" (NURIM) with characteristics close to those of an anti-MAG-NP at the time of diagnosis, except for the neurophysiological features with a predominant axonal pattern. CONCLUSION: This study emphasizes the wide spectrum of IgM-NP associated with a variety of hematological diagnoses. In particular, the course and prognosis vary considerably. In this setting, further studies are needed to unravel the group of patients classified as NURIM.

Anti-SARS-CoV-2 antibody response after 2 and 3 doses of BNT162b2 mRNA vaccine in patients with lymphoid malignancies.

OBJECTIVES: COVID-19 patients affected by haematological malignancies have a more severe course of the disease and higher mortality, prompting for effective prophylaxis. The present study aims to evaluate the humoral response after mRNA vaccination as well as the impact of a third vaccine dose in patients with lymphoid malignancies. METHODS: We conducted a single-centre study, evaluating the serological responses of mRNA vaccination amongst a cohort of 200 patients affected by lymphoid malignancies after two or three doses using an industrial SARS-CoV-2 serology assay for anti-receptor binding domain (RBD) Spike IgG detection and quantification. RESULTS: Among patients with plasma cell disorders, 59 of 96 (61%) had seroconversion (anti-RBD >50 AU/mL), and recent anti-CD38 therapies were associated with lower serological anti-RBD IgG concentrations (median IgG concentration 137 (IQR 0-512) AU/mL vs. 543 (IQR 35-3496) AU/mL; p < 0.001). Patients with B-cell malignancies had a lower seroconversion rate (20/84, 24%) mainly due to the broad usage of anti-CD20 monoclonal antibodies; only 2 of 53 (4%) patients treated by anti-CD20 antibodies during the last 12 months experienced a seroconversion. A total of 78 patients (44 with plasma cell disorders, 27 with B-cell malignancies, and 7 with other lymphomas) received a third dose of vaccine. The seroconversion rate and antibody concentrations increased significantly, especially in patients with plasma cell disorders, where an increment of anti-RBD IgG concentrations was observed in 31 of 44 (70%) patients, with an anti-RBD concentration median-fold increase of 10.6 (IQR 2.4-25.5). Its benefit in B-cell malignancies is uncertain, with only 2 of 25 (8%) patients having seroconverted after the vaccine booster, without increased median antibody concentration. DISCUSSION: A third mRNA vaccine dose significantly improved humoral responses among patients with plasma cell disorders, whereas the effect was limited among patients with B-cell malignancies.

Optimization of whole-body 2-[18F]FDG-PET/MRI imaging protocol for the initial staging of patients with myeloma.

OBJECTIVE: To determine the optimal 2-[18F]FDG-PET/MRI imaging protocol for the initial staging of patients with suspected or confirmed multiple myeloma. METHODS: Radiologists and nuclear medicine specialists reviewed all PET/MRI exams of 104 patients with a monoclonal gammopathy (MG). The presence of focal and diffuse bone marrow involvement (BMI) was assessed using 4 different image datasets: WB-MRI, PET, WB-PET/MRI, and WB-DCE-PET/MRI. A reference standard was established by a panel review of all baseline and follow-up imaging, and biological and pathological information. The diagnostic performance for each image dataset to detect BMI was evaluated and compared (Fisher's exact test). RESULTS: Sensitivity, specificity, and accuracy for focal BMI of WB-MRI was 87%, 97%, and 92%; of PET was 78%, 97%, and 95%; of WB-PET/MRI was 93%, 97%, and 95%; and of WB-DCE-PET/MRI was 93%, 97%, and 95%, respectively. WB-PET/MRI and WB-DCE-PET/MRI were statistically superior to PET (p = 0.036) without decreasing specificity. The sensitivity, specificity, and accuracy of WB-MRI for diffuse BMI detection was 91%, 80%, and 85%; of 3DT1-PET was 53%, 89%, and 74%; of WB-PET/MRI was 98%, 66%, and 79%; and of WB-DCE-PET/MRI was 98%, 59%, and 75%, respectively. PET lacked sensitivity compared to all other dataset studies (p < 0.0001). WB-MRI had the best accuracy without reaching statistical significance when compared to the other datasets. CONCLUSION: The WB-PET/MRI dataset including T1 and T2 Dixon, WB-DWI, and PET images provides optimal diagnostic performance to detect both focal lesions and diffuse BMI, with limited added value of WB-DCE for baseline staging of patients with MG. Key Points • The combination of morphological and functional MRI sequences and metabolic (2-[18F]FDG-PET) images increases the diagnostic performance of PET/MRI to detect focal bone lesions. • The adjunction of dynamic contrast-enhanced sequences did not improve diagnostic performance.

Echocardiographic Patterns of Left Ventricular Diastolic Function in Cardiac Amyloidosis: An Updated Evaluation.

AIMS: Multimodal imaging has allowed cardiac amyloidosis (CA) to be increasingly recognised as a treatable cause of heart failure with preserved ejection fraction, but its prognosis remains poor due to late diagnosis. To assess the left ventricular diastolic function (LVDF) patterns in a large contemporary CA cohort according to the current recommendations and to identify their determinants. METHODS AND RESULTS: We conducted a monocentric, observational study on a cohort of CA patients from a tertiary CA referral centre. Diastolic function was analysed using standard echocardiography and clinical, laboratory and survival parameters were collected. Four hundred and sixty-four patients with one of the three main type of CA were included: 41% had grade III diastolic dysfunction (restrictive mitral pattern), 25% had grade II diastolic dysfunction, and 25% had grade I diastolic dysfunction; 9% were unclassified. No difference was found between the main CA types. After multivariate analyses, grades II and III were independently associated with dyspnoea, elevated NT-proBNP, cardiac infiltration and systolic dysfunction (global longitudinal strain). Grade I patients had a better prognosis. CONCLUSIONS: All LVDF patterns can be observed in CA. One quarter of CA patients have grade I LVDF, reflecting the emergence of earlier stage-related phenotypes with a better prognosis.

Assessing Cardiac Amyloidosis Subtypes by Unsupervised Phenotype Clustering Analysis.

BACKGROUND: Cardiac amyloidosis (CA) is a set of amyloid diseases with usually predominant cardiac symptoms, including light-chain amyloidosis (AL), hereditary variant transthyretin amyloidosis (ATTRv), and wild-type transthyretin amyloidosis (ATTRwt). CA are characterized by high heterogeneity in phenotypes leading to diagnosis delay and worsened outcomes. OBJECTIVES: The authors used clustering analysis to identify typical clinical profiles in a large population of patients with suspected CA. METHODS: Data were collected from the French Referral Center for Cardiac Amyloidosis database (Hôpital Henri Mondor, Créteil), including 1,394 patients with suspected CA between 2010 and 2018: 345 (25%) had a diagnosis of AL, 263 (19%) ATTRv, 402 (29%) ATTRwt, and 384 (28%) no amyloidosis. Based on comprehensive clinicobiological phenotyping, unsupervised clustering analyses were performed by artificial neural network-based self-organizing maps to identify patient profiles (clusters) with similar characteristics, independent of the final diagnosis and prognosis. RESULTS: Mean age and left ventricular ejection fraction were 72 ± 13 years and 52% ± 13%, respectively. The authors identified 7 clusters of patients with contrasting profiles and prognosis. AL patients were distinctively located within a typical cluster; ATTRv patients were distributed across 4 clusters with varying clinical presentations, 1 of which overlapped with patients without amyloidosis; interestingly, ATTRwt patients spread across 3 distinct clusters with contrasting risk factors, biological profiles, and prognosis. CONCLUSIONS: Clustering analysis identified 7 clinical profiles with varying characteristics, prognosis, and associations with diagnosis. Especially in patients with ATTRwt, these results suggest key areas to improve amyloidosis diagnosis and stratify prognosis depending on associated risk factors.

History of extracardiac/cardiac events in cardiac amyloidosis: prevalence and time from initial onset to diagnosis.

AIMS: Cardiac amyloidosis (CA) has a poor prognosis which is aggravated by diagnostic delay. Amyloidosis extracardiac and cardiac events (AECE and ACE) may help improve CA diagnosis and typing. The aim of this study was to compare AECE and ACE between different CA types and assess their relationship with survival. METHODS AND RESULTS: This retrospective cohort study conducted in France from June 2008 to May 2019, at the Henry Mondor Hospital. This cohort included 983 patients with CA. Mean age at inclusion was 73.1 ± 11.4 years, 726 (75.1%) were male and the mean body mass index was 24.5 ± 4.1 kg/m2 . Among them, 321 had immunoglobulin light chain (AL) amyloidosis, 434 had wild-type transthyretin (ATTRwt), and 212 had hereditary transthyretin (ATTRv). The first AECE and/or ACE occurred at a mean age of 63 ± 11 years for AL and ATTRv, and 70 ± 12 years for ATTRwt (P < 0.01). The median (Q1-Q3) delay between declaration of the first events and diagnosis varied from 11.1 (5.9; 34.8) months for AL to 92.2 (39.0; 174.7) months for ATTRwt (P < 0.01). The nature of the onset of AECE or ACE varied based on amyloidosis type, heart failure symptoms for AL (26%) and integumentary symptoms for ATTRv with cardiologic or mixed phenotype (39%) and ATTRwt (42%). In AL and ATTRwt, a short delay between the onset of the first AECE or ACE and diagnosis was associated with reduced survival rate (log-rank test P-value <0.01). CONCLUSIONS: This study highlights the impact of amyloidosis type and evolution on diagnostic delay and on prognosis. Physicians must be aware and vigilant in front of extracardiac and cardiac events to considerably improve early diagnosis of amyloidosis.

Dexamethasone is associated with early deaths in light chain amyloidosis patients with severe cardiac involvement.

BACKGROUND: Cardiac light chain amyloidosis (AL-CA) patients often die within three months of starting chemotherapy. Chemotherapy for non-immunoglobulin M gammopathy with AL-CA frequently includes bortezomib (Bor), cyclophosphamide (Cy), and dexamethasone (D). We previously reported that NT-ProBNP levels can double within 24h of dexamethasone administration, suggesting a deleterious impact on cardiac function. In this study, we evaluate the role of dexamethasone in early cardiovascular mortality during treatment. METHODS AND FINDINGS: We retrospectively assessed 100 de novo cardiac AL patients (62% male, mean age 68 years) treated at our institute between 2009 and 2018 following three chemotherapy regimens: CyBorDComb (all initiated on day 1; 34 patients), DCyBorSeq (D, day 1; Cy, day 8; Bor, day 15; 17 patients), and CyBorDSeq (Cy, day 1; Bor, day 8; D, day 15; 49 patients). The primary endpoint was cardiovascular mortality and cardiac transplantation at days 22 and 455. At day 22, mortality was 20.6% with CyBorDComb, 23.5% with DCyBorSeq, and 0% with CyBorDSeq (p = 0.003). At day 455, mortality was not significantly different between regimens (p = 0.195). Acute toxicity of dexamethasone was evaluated on myocardial function using a rat model of isolated perfused heart. Administration of dexamethasone induced a decrease in left ventricular myocardium contractility and relaxation (p<0.05), supporting a potential negative inotropic effect of dexamethasone in AL-CA patients with severe cardiac involvement. CONCLUSION: Delaying dexamethasone during the first chemotherapy cycle reduces the number of early deaths without extending survival. It is clear that dexamethasone is beneficial in the long-term treatment of patients with AL-CA. However, the initial introduction of dexamethasone during treatment is critical, but may be associated with early cardiac deaths in severe CA. Thus, it is important to consider the dosage and timing of dexamethasone introduction on a patient-severity basis. The impact of dexamethasone in the treatment of AL-CA needs further investigation.