Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes.

ABSTRACT: Mutations in UBA1, which are disease-defining for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet polymerase chain reaction profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established World Health Organization (WHO) disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n = 2027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n = 12) and of unknown significance (n = 15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO 2016 criteria as MDS with multilineage dysplasia or MDS with single-lineage dysplasia. Patients had a median of 1 additional myeloid gene mutation, often in TET2 (n = 12), DNMT3A (n = 10), ASXL1 (n = 3), or SF3B1 (n = 3). Retrospective clinical review, where possible, showed that 82% (28/34) UBA1-mutant cases had VEXAS syndrome-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1 mutations in patients with MDS argues for systematic screening for UBA1 in the management of MDS.

Incidence, predictive factors, management, and survival impact of atrial fibrillation in non-Hodgkin lymphoma.

Atrial fibrillation (AF) and cancer are common disorders in the general population but there are few studies in patients with both diseases. More specifically, there are scarce data on AF in patients with non-Hodgkin lymphoma (NHL). We assessed the incidence, predictive factors, management, and survival impact of AF in a cohort of patients with NHL from a single institution between 2002 and 2016 (n = 747). Twenty-three patients were diagnosed with AF before and 40 after the diagnosis of NHL (of the later, 16 were secondary to an extracardiac comorbidity and 24 unrelated to any triggering event [primary AF]). The 5-year cumulative incidence of new-onset AF was 4% (95% confidence interval [CI] 3-6%). Age and hypertension were the only predictive factors for the development of AF. Management of AF was heterogeneous, primarily with anti-vitamin K agents but also antiplatelet therapy in a significant proportion of patients. Among the 63 patients, there were six episodes of ischemic stroke/transient ischemic attack and four venous thromboembolic events, with four major bleeding episodes. Overall survival (OS) was inferior in patients with AF (HR 0.1, 95% CI 0.01-0.7, p = 0.02), largely due to secondary AF. We conclude that the incidence of new-onset AF in NHL patients seemed somewhat higher than in the general population, although with similar predictive factors. The management was heterogeneous, and the risk of ischemic and hemorrhagic events did not seem higher than in cancer-free patients. Survival was particularly poor for patients with secondary AF.

Retinal vein occlusion and paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder associated with increased risk for thrombosis and reduced life expectancy. Retinal vein occlusion (RVO) is a frequent cause of vision loss but its relationship with PNH has not been studied systematically. Patients followed up for RVO in our ophthalmology department were screened for the presence of a PNH clone in peripheral blood by means of flow cytometry. The presence of other well-documented risk factors for RVO was also analyzed. In a series of 110 patients (54 males, median age of 67) we found no evidence of PNH. Most patients (97/110) had cardiovascular risk factors and/or hyperhomocysteinemia (67/110). Inherited thrombophilias were rare (three confirmed cases). Therefore, PNH does not appear to play a role in the development of RVO. However, this finding does not necessarily apply to young patients and/or those with no conventional risk factors for RVO, due to the low number of patients in these subgroups in our population.

Chronic myelomonocytic leukemia with ring sideroblasts/SF3B1 mutation presents with low monocyte count and resembles myelodysplastic syndromes with-RS/SF3B1 mutation in terms of phenotype and prognosis.

Introduction: Chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) with ring sideroblasts (RS) or SF3B1 mutation (MDS-RS/SF3B1) differ in many clinical features, but share others, such as anemia. RS and SF3B1 mutation can also be found in CMML. Methods: We compared CMML with and without RS/SF3B1 and MDS-RS/SF3B1 considering the criteria established by the 2022 World Health Organization classification. Results: A total of 815 patients were included (CMML, n=319, CMML-RS/SF3B1, n=172 and MDS-RS/SF3B1, n=324). The percentage of RS was ≥15% in almost all CMML-RS/SF3B1 patients (169, 98.3%) and most (125, 72.7%) showed peripheral blood monocyte counts between 0.5 and 0.9 x109/L and low risk prognostic categories. CMML-RS/SF3B1 differed significantly from classical CMML in the main clinical characteristics, whereas it resembled MDS-RS/SF3B1. At a molecular level, CMML and CMML-RS/SF3B1 had a significantly higher frequency of mutations in TET2 (mostly multi-hit) and ASXL1 (p=0.013) and CMML had a significantly lower frequency of DNMT3A and SF3B1 mutations compared to CMML/MDS-RS/SF3B1. Differences in the median overall survival among the three groups were statistically significant: 6.75 years (95% confidence interval [CI] 5.41-8.09) for CMML-RS/SF3B1 vs. 3.17 years (95% CI 2.56-3.79) for CMML vs. 16.47 years (NA) for MDS-RS/SF3B1, p<0.001. Regarding patients with CMML and MDS, both with SF3B1 mutation, survival did not significantly differ. CMML had a higher risk of transformation to acute myeloid leukemia (24% at 8 years, 95%CI 19%-30%). Discussion: CMML-RS/SF3B1 mutation resembles MDS-RS/SF3B1 in terms of phenotype and clearly differs from CMML. The presence of ≥15% RS and/or SF3B1 in CMML is associated with a low monocyte count. SF3B1 mutation clearly improves the prognosis of CMML.

HHV8 and EBV-negative primary effusion-based lymphoma: A case report of a new provisional entity and review of literature.

Key Clinical Message: HHV8- and EBV-negative primary effusion lymphoma is an extremely rare neoplasm involving body cavities without detectable tumor mass. It usually presents in elderly patients without known immunodeficiency. Compared to primary effusion lymphoma, it has a better prognosis.Primary effusion lymphoma (PEL) is a rare non-Hodgkin lymphoma confined exclusively to body cavities without detectable tumor masses. The term PEL-like is an entity similar to PEL in clinical presentation but without relation to human herpesvirus 8 (HHV8). We report a case of HHV8- and EBV-negative primary effusion-based lymphoma.

Refining the Limits of Borderline Lymphoproliferative Disorders.

BACKGROUND: The concept of borderline lymphoproliferative disorder (LPD) has not been clearly defined. METHODS: This study aimed to classify patients with leukemic LPD (n = 597, excluding hairy cell leukemia, mantle cell lymphomas, and CD10-positive LPDs) into CLL or non-CLL applying three diagnostic strategies (the D'Arena and CLLflow scores and CD43 expression) and to better characterize unclassified patients. RESULTS: Patients with concurring CLL-like (n = 441) or non-CLL like (n = 99) results with the three diagnostic strategies were determined to have CLL and non-CLL, respectively. Patients with discordant results (n = 57) were analyzed taking into consideration each individual cytometric marker and cytogenetic data: 41 were classified (11 CLL, 30 non-CLL) and 16 (2.7% of the entire series) could not and were considered borderline LPD. Excluding borderline LPD, the CLLflow score had the highest accuracy of the three strategies. With the addition of CD43 no patient was misclassified. With the aid of hierarchical clustering, 12 of the 16 borderline patients seemed to fall into two well-defined antigenic groups. None of the diagnostic strategies could reliably pick out borderline LPD. CONCLUSION: The combination of the CLLflow score and CD43 generally has a high diagnostic accuracy for leukemic LPD but it is not reliable to identify or diagnose borderline LPD. This latter group needs further study to determine its underlying biology. © 2018 International Clinical Cytometry Society.

Dabigatran for catastrophic antiphospholipid syndrome.

: Vitamin K antagonists (VKA) remain the treatment of choice for catastrophic antiphosphilipid syndrome (CAPS). However, when VKAs do not work for a specific patient, direct oral anticoagulants (DOAC) may be a valid therapeutic alternative. We present a patient with a psychiatric disorder and CAPS who was noncompliant to VKA and low-molecular-weight heparin. He was started on dabigatran and has remained thrombosis-free for 8 years. Due to CAPS he has developed progressive renal failure but dabigatran levels were within the expected range. In conclusion, this case report provides anecdotic evidence that dabigatran may be of use in patients with high-risk APS in whom VKA are not an option.

Venous thromboembolism in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia treated with lenalidomide: a systematic review.

Lenalidomide has been associated with an increased risk of venous thromboembolism (VTE) in multiple myeloma. It is unclear whether patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are also at such risk. We conducted a systematic review of the incidence of VTE in prospective trials of lenalidomide-treated patients with NHL or CLL. Sixty-eight unique reports were assessed for inclusion. For grade ≥3 VTE, 98 events were reported in 3043 patients (60 studies) (crude incidence: 3.22% [95% confidence interval: 2.6-3.9%]). For any grade VTE, 97 events were reported in 2244 patients (46 studies) (crude incidence: 4.32% [3.5-5.2%]). Subgroup analysis showed no difference based on histological subtype or use of prophylaxis. The study is at risk of bias, largely due to insufficient data from the individual studies. Within the limitations of this systematic review, we found a low risk of VTE in patients with NHL treated with lenalidomide.

Indications and use of, and incidence of major bleeding with, antithrombotic agents in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) and antithrombotic medication both increase the risk of bleeding. We set out to analyze the prevalence of use, indications and bleeding risk of antithrombotic therapy in patients with MDS in a retrospective, single-center study including all patients with MDS with >20 × 109/L platelets. 193 patients (59% male, median age 75 years) were included; 122 did not receive antithrombotic treatment, 51 received antiplatelet agents and 20 received anticoagulants. The cumulative incidence of major bleeding was higher in both the antiplatelet group (11.8% at 4 years, 95% confidence interval [95%CI]: 4.7-22.3%) and the anticoagulation group (21.2% at 4 years, 95%CI 6-42.5%) than in the control group (2.8% at 4 years 95%CI: 0.7-7.3%). The prevalence of use of antithrombotic medication in this cohort of patients with MDS was high and bleeding risk was increased in these patients.

[Comparison between phlebotomy and erythrocytapheresis of iron overload in patients with HFE gene mutations]. / Comparación de la flebotomía con eritrocitaféresis en la sobrecarga de hierro en portadores de mutaciones del gen HFE.

BACKGROUND AND OBJECTIVE: Large-volume erythrocytapheresis (EA) is an useful and speedy method to treat iron overload (IO). We assesed the efficacy of EA in patients with HFE gene mutations and IO compared to the classical phlebotomies. PATIENTS AND METHOD: Data from 9 patients with IO treated with EA, using a discontinuous flow cell separator as a single needle procedure, for a period of 2 years, were compared to 9 matched patients who underwent conventional phlebotomies. RESULTS: The mean volume of red blood cells removed in each EA was 275 ml, with a median reduction of 23 g/l for haemoglobin and 55 microg/l for serum ferritin levels (vs. 17 microg/l between phlebotomies). The liver function test returned to normal values in 4 out of 5 patients undergoing EA, but none of the phlebotomies. The time required to achieve iron depletion was 3 times shorter in EA group. CONCLUSIONS: EA is an effective and safe procedure that achieves iron depletion more quickly than manual phlebotomies. Nevertheless, to determine its cost-effectiveness, economical, prospective, randomized studies are warranted.

Different plasma markers of inflammation are influenced by immune recovery and cART composition or intensification in treated HIV infected individuals.

BACKGROUND: HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies. METHODS: Longitudinal plasma samples (0-48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis. RESULTS: At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040). CONCLUSIONS: The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers.