Thrombotic risk and features of patients with inferior vena cava agenesis: a multicentre, retrospective, observational study.

BACKGROUND: Inferior vena cava agenesis (IVCA) is a rare anomaly predisposing affected people to lower-limb venous thrombosis with low frequency of pulmonary embolism. Antenatal thrombosis and inherited thrombophilia have been suggested as causes of IVCA. However, there is little evidence on the clinical course and management of this condition. We designed a patient registry to assess the thrombotic risk and features of IVCA. METHODS: In this this multicentre, retrospective, observational study, we included patients with IVCA diagnosed by routine imaging from 20 hospitals in Spain (n=18), Portugal (n=1), and Italy (n=1). Patients were identified from a systematic search in radiology databases using data extraction software (cohort A) and alternative searches in medical records for confirmed IVCA (cohort B; option allowed when systematic approaches were unapplicable). Primary outcomes were clinical and imaging features, thrombotic risk, phenotype of IVCA-associated thrombosis, anticoagulant treatment, and the results of thrombophilia testing. FINDINGS: We included patients with IVCA diagnosed by routine imaging studies done between Jan 1, 2010, and Dec 31, 2022. In the systematic search, 4 341 333 imaging exams were screened from the radiology databases of eight centres. 122 eligible patients were enrolled in cohort A. A further 95 patients were identified by screening medical records at 12 centres, of whom 88 were eligible and included in cohort B, making a combined cohort of 210 patients. 96 (46%) of 210 patients were female and 200 (95%) were European or Hispanic. 60 (29%) of 210 patients had hepatic IVC interruption, whereas 150 (71%) had extrahepatic IVCA. In cohort A, 65 (53%) of 122 patients had venous thrombosis, with an estimated annual risk of 1·15% (95% CI 0·89-1·46). Extrahepatic IVCA was associated with a greater risk of venous thrombosis than hepatic IVCA (56 [67%] of 84 patients vs nine [24%] of 38 patients, odds ratio 5·31, 95% CI 2·27-12·43; p<0·0001). Analysis of 126 patients with venous thrombosis pooled from cohorts A and B showed early-onset (median age 34·6 years, IQR 23·3-54·3) and recurrent events (50 [40%] of 126 patients). Patients with extrahepatic IVCA had greater proportions of lower-limb venous thrombosis (95 [87%] of 109 vs nine [53%] of 17, p=0·0010) and recurrence (48 [44%] of 109 vs two [12%] of 17, p=0·015), but lower rates of pulmonary embolism (10 [10%] of 99 vs four [33%] of 12, p=0·044) than did patients with hepatic IVCA. 77 (63%) of 122 patients with thrombosis underwent indefinite anticoagulation. 32 (29%) of 111 patients (29 [34%] of 86 with thrombosis) had coexisting thrombophilias. The recurrence risk was lower for patients receiving indefinite anticoagulation (adjusted odds ratio 0·24, 95% CI 0·08-0·61; p=0·010), and greater for thrombophilias (3·19, 1·09-9·32; p=0·034). INTERPRETATION: This evaluation of a large patient cohort demonstrates the high thrombotic burden of IVCA. We have identified two distinct forms of IVCA, hepatic and extrahepatic, suggesting different underlying mechanisms. Beyond clinical characterisation, we draw attention to this orphan disease and highlight the need for its study and improved care. FUNDING: Spanish Society of Thrombosis and Haemostasis, Instituto de Salud Carlos III, FEDER, Fundación Séneca.

High penetrance of inferior vena cava system atresia in severe thrombophilia caused by homozygous antithrombin Budapest 3 variant: Description of a new syndrome.

Atresia of inferior vena cava (IVC) is a rare congenital malformation associated with high risk of venous thrombosis that still has unknown etiology, although intrauterine IVC thrombosis has been suggested to be involved. The identification of IVC atresia in a case with early idiopathic venous thrombosis and antithrombin deficiency caused by the homozygous SERPINC1 c.391C > T variant (p.Leu131Phe; antithrombin Budapest 3) encouraged us to evaluate the role of this severe thrombophilia in this vascular abnormality. We have done a cross-sectional study in previously identified cohorts of patients homozygous for the Budapest 3 variant (N = 61) selected from 1118 patients with congenital antithrombin deficiency identified in two different populations: Spain (N = 692) and Hungary (N = 426). Image analysis included computed tomography and phlebography. Atresia of the IVC system was observed in 17/24 cases (70.8%, 95% confidence interval [CI]: 48.9%-87.3%) homozygous for antithrombin Budapest 3 with available computed tomography (5/8 and 12/16 in the Spanish and Hungarian cohorts, respectively), 16 had an absence of infrarenal IVC and one had atresia of the left common iliac vein. All cases with vascular defects had compensatory mechanisms, azygos-hemiazygos continuation or double IVC, and seven also had other congenital anomalies. Short tandem repeat analysis supported the specific association of the IVC system atresia with SERPINC1. We show the first evidence of the association of a severe thrombophilia with IVC system atresia, supporting the possibility that a thrombosis in the developing fetal vessels is the reason for this anomaly. Our hypothesis-generating results encourage further studies to investigate severe thrombophilic states in patients with atresia of IVC.

Treatment with daratumumab in patients with relapsed/refractory AL amyloidosis: a multicentric retrospective study and review of the literature.

Management of patients with relapsed or refractory (R/R) AL amyloidosis is complex. Some initial reports have shown positive results with daratumumab in heavily pre-treated AL amyloidosis patients. In this retrospective multicentric study, 38 patients (mean age 64 ± 9 years) with R/R AL amyloidosis treated with daratumumab were included. Cardiac and renal involvement was present in 76 and 74% of patients, and 42% had ≥3 organs involved. Median number of previous lines of therapy was 2 (range 1-8). Overall hematological response was 72%, including 28% complete responses. The median time to first hematological response was 2 weeks. A high-quality response (≥very good partial response) was obtained in 65% of patients who had never achieved such depth of response previously. Hematological responses were more frequent among patients receiving daratumumab as second-line therapy compared to subsequent therapies (92 vs. 61%). Cardiac and renal organ response rates were 37 and 59%. At 12 months, overall and progression-free survival were 59% (95%CI: 0.36-0.77) and 52% (95%CI: 0.29-0.70), respectively. Daratumumab is a safe and effective drug in the treatment of R/R AL amyloidosis and should be considered early in the course of the disease.

Risk of, and survival following, histological transformation in follicular lymphoma in the rituximab era. A retrospective multicentre study by the Spanish GELTAMO group.

The diagnostic criteria for follicular lymphoma (FL) transformation vary among the largest series, which commonly exclude histologically-documented transformation (HT) mandatorily. The aims of this retrospective observational multicentre study by the Spanish Grupo Español de Linfoma y Transplante Autólogo de Médula Ósea, which recruited 1734 patients (800 males/934 females; median age 59 years), diagnosed with FL grades 1-3A, were, (i) the cumulative incidence of HT (CI-HT); (ii) risk factors associated with HT; and (iii) the role of treatment and response on survival following transformation (SFT). With a median follow-up of 6·2 years, 106 patients developed HT. Ten-year CI-HT was 8%. Considering these 106 patients who developed HT, median time to transformation was 2·5 years. High-risk FL International Prognostic Index [Hazard ratio (HR) 2·6, 95% confidence interval (CI): 1·5-4·5] and non-response to first-line therapy (HR 2·9, 95% CI: 1·3-6·8) were associated with HT. Seventy out of the 106 patients died (5-year SFT, 26%). Response to HT first-line therapy (HR 5·3, 95% CI: 2·4-12·0), autologous stem cell transplantation (HR 3·9, 95% CI: 1·5-10·1), and revised International Prognostic Index (HR 2·2, 95% CI: 1·1-4·2) were significantly associated with SFT. Response to treatment and HT were the variables most significantly associated with survival in the rituximab era. Better therapies are needed to improve response. Inclusion of HT in clinical trials with new agents is mandatory.