Direct oral anticoagulants for the treatment of atrial fibrillation in patients with hematologic malignancies.

Atrial fibrillation (AF) is common in patients with cancer due to both the proinflammatory effect of neoplastic cells and to cardiotoxicity of anti-tumor therapies. Anticoagulation is still challenging in cancer patients due to increased bleeding risk related to specific neoplasms such us hematologic malignancies. The aim of this retrospective study was to evaluate the safety and the efficacy of direct oral anticoagulants (DOACs) in AF patients affected by hematologic neoplasms. We included 97 patients on active anticancer treatment. The median follow-up was 25 months (range 10-108). No thromboembolic complications occurred, while 14 bleeding events were recorded: 1 major, 12 clinical relevant non major bleeding and 1 minor bleeding. Although retrospective and with a small number of enrolled patients, our data support the efficacy and safety of DOACs in patients affected by hematologic malignancies suggesting caution to particular situations, such as thrombocytopenia.

Outcomes of long-term anticoagulant treatment for the secondary prophylaxis of splanchnic venous thrombosis.

BACKGROUND: Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA. METHODS: This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded. RESULTS: Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6 years (range 2-8) during VKA and 1.9 years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09). CONCLUSIONS: Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Single centre experience on Acquired Haemophilia A patients: Diagnosis, clinical management and analysis of factors predictive of response and outcome.

BACKGROUND: Acquired Haemophilia A (AHA) patients show a high response rate to immunosuppressive therapy (IST) but few information about predictors of response and outcome are reported. AIMS: We describe a large single-centre AHA cohort, investigating prognostic variables for the 'best response' (BR), time to BR (TTBR) and overall survival (OS). METHODS: A total of 61 patients were included, collecting data from clinical charts. RESULTS: A progressive increase in diagnoses, from 1978 to 2019, was observed. Fifty/56 patients (89%) underwent haemostatic therapy (rFVIIa 46%, aPCC 34%) with no significant differences in the response (rFVIIa 92.3% vs aPCC 100%) and no thromboembolic events. Sixty/61 patients underwent first-line IST with an initial response rate of 58.4%. The 12-months OS was 85%, the bleeding associated mortality rate 3% (2/61). The response rates at last observation were: CR 64%, PR 8%. We evaluated the influence of age, gender, associated conditions, IST, haemoglobin levels, FVIII:C, inhibitor titre on BR, TTBR and OS: post-partum AHA achieved the BR after a longer time than AHA related to other aetiologies or idiopathic (p = .05); in univariate analysis female sex (p = .03) and the achievement of BR (p = .001) had a positive impact on the OS while AHA secondary to neoplasms showed a shorter survival (p = .04); only the BR achievement remained significant in multivariate analysis (p = .02). CONCLUSIONS: Our data on response and survival confirmed those from the main registries. Post-partum AHA and BR achievement were significantly associated to a longer TTBR and a longer OS, respectively. Other predictors of outcome deserve to be explored in prospective studies.

Venous thromboembolism prophylaxis in patients with multiple myeloma: where are we and where are we going?

Venous thromboembolism is a common complication of patients with hematologic malignancies, due both to release of procoagulant factors by tumor cells and to external factors, such us drugs. In multiple myeloma patients, the risk is increased by use of immunomodulants, especially when associated to multidrug therapy, during the induction phase. Prevention of venous thromboembolism in myeloma patients is highly recommended but specific guidelines are still lacking. The most common approach is to stratify the thrombotic risk according to individual, myeloma-related and therapy-related risk factors and to use aspirin for all patients, except those with two or more thrombotic risk factors who should be treated with traditional oral or parenteral anticoagulant. A more controversial approach indicates for prophylaxis either anticoagulant or aspirin, regardless of risk stratification. Recent trials investigate prophylaxis in myeloma patients with direct oral anticoagulants, based on studies showing efficacy and safety of this new class of drugs in the treatment and prophylaxis of thrombosis in patients with any malignancy. The results of these trials are encouraging but they need to be confirmed by larger studies. An international consensus about best prophylaxis to prevent venous thromboembolism in patients with multiple myeloma on treatment is still missing. Therefore, thrombosis in multiple myeloma remains an ongoing issue.

Direct oral anticoagulants in patients with hematologic malignancies.

The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), which is considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation-therapy was maintained until the platelet count was ≥50 × 109 /L. In case of concomitant anticancer treatment and haemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135: 104/135 were on anticancer therapy. We did not observe either thrombotic or major haemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non-major (CRNM) in two patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent haemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs.

Satisfaction, quality of life and therapy adherence assessment in real life patients transitioning from vitamin K antagonists to direct oral anticoagulants.

Anticoagulant therapy has undergone a significant change since direct oral anticoagulants (DOACs) introduction. Their obvious advantages including the fixed dose, the few interactions and less frequent controls, have made them the first choice anticoagulant therapy. More and more patients have therefore switched from therapy with vitamin K antagonists (VKAs) to DOACs. Aim of our study was to assess the satisfaction, quality of life (QoL) and therapy adherence of patients who switched from VKA to DOACs therapy. This single center study evaluated satisfaction and QoL of 107 patients who switched from VKA to DOACs therapy through Anti-Clot Treatment Scale and SF-36 respectively. The questionnaires were administered before therapy change, after 3 months of DOACs therapy and then annually. We also evaluated DOACs therapy adherence with a questionnaire administered each visit and through the measures of DOACs plasma levels. Patients' satisfaction and QoL were high during VKA therapy, but with DOACs we observed an improvement after the first 3 months and then maintained over the time of DOACs therapy. DOACs adherence was excellent, also confirmed by DOACs plasma levels.

PICC-related upper deep venous thrombosis in patients with hematological malignancies. Management of anticoagulant therapy according to the platelet count.

Peripherally inserted central catheters (PICCs) for central venous access are frequently used in patients with hematological malignancies. Their use may be complicated by upper extremity deep venous thrombosis (UEDVT). Additionally, hematological patients are frequently thrombocytopenic and the optimal management of UEDVT in patients with thrombocytopenia is challenging and poorly standardized. We retrospectively analyzed 50 adult patients affected by hematological malignancies who presented a PICC-associated UEDVT. UEDVT treatment was compared in 3 groups: patients with a platelet count ≥ 50 × 109/l (group1) who underwent a therapeutic dose of low molecular weight heparin (LMWH) or fondaparinux 7.5 mg; patients with a platelet count < 50 × 109/l and ≥ 30 × 109/l (group 2) who were treated with a 50% reduced dose of LMWH or fondaparinux 5 mg; patients with platelets < 30 × 109/l (group 3) were observed and treated with anticoagulants when the count was > 30 × 109//l. At the onset of thrombosis, 36 patients were in group 1, 8 in group 2 and 6 in group 3. We observed no hemorrhagic or thrombotic complications related to the anticoagulant therapy; length of treatment was comparable between groups 1 and 2 (51 days group 1 vs 50 days group 2). Reduced doses of LMWH or fondaparinux may represent a safe and effective therapeutic approach in patients with moderate thrombocytopenia (< 50 × 109/l and ≥ 30 × 109/l) and a PICC-associated UEDVT.

Impact of exclusion criteria for the DASISION and ENESTnd trials in the front-line treatment of a 'real-life' patient population with chronic myeloid leukaemia.

Both Dasision and ENESTnd trials had many exclusion criteria, with a possible selection bias compared with the real-life. To address the impact of this bias on the first-line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase chronic myeloid leukaemia (CML) patients [M/F 108/99, median age 58.8 years, interquartile range 42.3-70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution, and evaluated how many of them would have been excluded from enrolment in the two trials. Twenty-eight patients (13.5%) should have been excluded by both trials because of polycomorbidities (12), severe cardiomyopathy (five), age > 80 with frailty (three), drug abuse (two) or other severe concomitant diseases (six). In addition, eight patients should have been excluded by Dasision due to isolated chronic obstructive broncopulmonar disease, and 19 patients should have been excluded by ENESTnd due to isolated diabetes (10), arrhythmia (four), acute myocardial infarction > 6 months before CML diagnosis (two), chronic pancreatic disease (two) and peripheral arterial obstructive disease (one). On the whole, 36 patients (17.4%) would have been excluded by Dasision trial and 47 (22.7%) by ENESTnd trial. The patients potentially not eligible for both trials were significantly older and with imatinib had a worse outcome compared with patients potentially eligible. Our data highlight that an automatic transposition of results available in clinical controlled trials into the frontline real-life management of CML patients should be regarded with caution. Copyright © 2015 John Wiley & Sons, Ltd.

Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment.

Nilotinib is currently approved for the treatment of chronic myeloid leukemia (CML) in chronic (CP) and accelerated phase (AP) after failure of imatinib and in newly diagnosed patients. Atherosclerotic events were retrospectively reported in patients with baseline cardiovascular risk factors during nilotinib treatment. We estimated the risk of developing atherosclerotic events in patients treated with second or first-line nilotinib, with a median follow-up of 48 months, by retrospectively applying the SCORE chart proposed by the European Society of Cardiology (ESC) and evaluating risk factors at baseline (diabetes, obesity, smoking, and hypertension). Overall, we enrolled in the study 82 CP patients treated frontline (42 CP patients at the dose of 600 mg BID) or after failure of other tyrosine kinase inhibitors (40 CP patients treated with 400 mg BID). The SCORE chart is based on the stratification of sex (male vs female), age (from 40 to 65 years), smoker vs non-smoker, systolic pressure (from 120 to 180 mm Hg), and cholesterol (measured in mmol/l, from 150 to 300 mg/dl). For statistical purposes, we considered patients subdivided in low, moderate, high (with a score >5), and very high risk. There were 48 males and 34 females, median age 51 years (range 22-84). According to WHO classification, 42 patients were classified as normal weight (BMI <25), 26 patients were overweight (BMI 26 ≤ 30), and 14 were obese (BMI >30). Retrospective classification according to the SCORE chart revealed that 27 patients (33 %) were in the low-risk category, 30 patients (36 %) in the moderate risk category, and 24 patients (29 %) in the high risk. As regards risk factors, we revealed that 17 patients (20.7 %) had a concomitant type II controlled diabetes (without organ damage), 23 patients (28 %) were smokers, 29 patients (35 %) were receiving concomitant drugs for hypertension, and 15 patients (18 %) had concomitant dyslipidemia. Overall, the cumulative incidence of atherosclerotic events at 48 months was 8.5 % (95 % CI, 4.55-14.07): None of the low-risk patients according to the SCORE chart experienced atherosclerotic events compared to 10 % in the moderate risk category and 29 % in the high risk (p = 0.002). Atherosclerotic-free survival was 100, 89, and 69 % in the low, moderate, and high-risk population, respectively (p = 0.001). SCORE chart evaluation at disease baseline could be a valid tool to identify patients at high risk of atherosclerotic events during nilotinib treatment.

Incidence of persistent/late chronic anemia in newly diagnosed patients with chronic myeloid leukemia responsive to imatinib.

In patients with chronic myeloid leukemia (CML) responsive to imatinib, it is still unknown whether the long-lasting treatment could induce the appearance of a persistent/late chronic anemia. To highlight this issue, we revised 128 patients with CML (M/F 64/64, median age at diagnosis 56.9 years, interquartile range 43.0-69.3) treated at our Institution with 1st line imatinib for at least 36 months and in stable complete cytogenetic response. At the 36th month of imatinib, a chronic anemia (Hb < 12 g/dl for > 6 months) was present in 38/128 patients (29.6%): the anemia was moderate (Hb > 8 ≤ 10 g/dl) in 12 patients (9.3%) and mild (Hb > 10 < 12 g/dl) in 26 patients (20.3%). All patients with persistent/late chronic anemia had a low reticulocyte count and 8/38 a condition of iron deficiency without clinical and instrumental signs of chronic blood loss. Four out of 38 patients (10.5%) needed red cell transfusions during the follow-up. At a landmark analysis from the 36th month of imatinib treatment, cumulative 4-year overall survival (OS) for patients with chronic anemia was 94.4% (CI 95% 83.8-100) compared to 93.5% (CI 95% 87.2-99.8) for patients without chronic anemia (P = 0.617). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in about 30% of our responsive patients: its occurrence does not seem to affect OS, but its real impact should be evaluated on a larger cohort of patients.

Secondary Prophylaxis of Venous Thromboembolism (VTE) with Low Dose Apixaban or Rivaroxaban: Results from a Patient Population with More than 2 Years of Median Follow-up.

Background: Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Nowadays, DOACs represent the gold standard for long-term anticoagulation, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit low-intensity apixaban and rivaroxaban are approved for clinical usage as secondary VTE prophylaxis, there are few literature data regarding their efficacy and safety with a long follow-up. Objectives: The aim of our study was to evaluate the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis in patients at high risk of VTE recurrence. Methods: We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily with a follow-up ≥ 12 months. Results: The examined patients were 323. The median low-dose DOAC administration time was 25.40 months (IQR 13.93-45.90). Twelve (3.7%) VTE recurrences were observed; 21 bleeding events were registered (6.5%), including one episode of Major bleeding (MB) (0.3%), 8 Clinically relevant nonmajor bleeding (CRNMB) (2.5%) and 12 minor bleeding (3.7%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between the rivaroxaban and apixaban groups. Patients included in the study for multiple episodes of VTE presented a significantly higher risk of a new VTE recurrence during low-intensity DOAC. Conclusions: Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis in patients at high risk of VTE recurrence; however, attention might be needed in their choice in such a scenario for patients who experienced multiple episodes of VTE.

Deferasirox treatment for myelodysplastic syndromes: "real-life" efficacy and safety in a single-institution patient population.

We here describe a single-institution experience on 40 patients with myelodysplastic syndromes (MDS) consecutively treated with deferasirox at the dose of 10-30 mg/kg/day according to Consensus Guidelines on Iron Chelation Therapy, outside of clinical trials. Serum ferritin (SF) was measured monthly, and safety assessment included monitoring of adverse events during treatment and of liver and renal parameters. Median SF at baseline of the 40 patients was 2,878 ng/ml. Median dose of deferasirox was 1,125 mg/day. At a median follow-up of 12 months of treatment, there was a significant reduction in SF from baseline, the median value being 1,400 ng/ml (p = 0.001). Interruptions due to toxicity were recorded in 40 % of patients: most common adverse events were diarrhoea (five patients, 12.5 %) and skin rash (four patients, 10 %). Seven patients had increased serum creatinine values >33 % above baseline, but there were no progressive increases. Four patients (three refractory anaemia and one refractory anaemia with excess blasts type 1) had a reduction of transfusion requirement (from a median of 5 to 1 unit/month) according to International Working Group 2006 criteria, with mean Hb value increasing from 8.5 to 10.5 g/dl, and mean Hb improvement being 2 g/dl (p = 0.02). No increased toxicity was noted when deferasirox was used concomitantly with azacitidine (eight patients who were intermediate 2 International Prognostic Scoring System risk) or lenalidomide (two patients with del(5q)). In conclusion, the oral iron chelator deferasirox is effective and safe when used in MDS patients with transfusion requirement, also if administered concomitantly with other drugs.

Secondary prophylaxis of venous thromboembolism with direct oral anticoagulants: comparison between patients with major congenital thrombophilia versus non-thrombophilic patients.

Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Congenital thrombophilia is a condition that predisposes to a higher incidence of VTE and often requires long-term anticoagulation for secondary prophylaxis. It is less clear the efficacy of DOACs in patients with major thrombophilia. The aim of our study was to evaluate the efficacy and safety of full and reduced DOACs dose for VTE secondary prophylaxis, in patients affected by major congenital thrombophilia compared to a control group of patients with idiopathic recurrent VTE without thrombophilia. We retrospectively evaluated consecutive patients who required long-term anticoagulation for recurrent VTE, treated with DOACs, and compared the outcomes between patients affected by major thrombophilia and the control group. The examined patients were 209. The median time of DOACs therapy was 20 months (range 6-90). Two (2.7%) thrombotic events were observed in the subset affected by major congenital thrombophilia (n = 72) and five (3.6%) in the control group (n = 137) (p 0.73). Four (5.5%) hemorrhagic events were reported in the group with major thrombophilia; 21 (15.3%) in the other group (p 0.039). No statistically significant differences were observed in terms of efficacy and safety between DOACs at full and reduced dose. Our data suggest that DOACs may be effective and safe in the secondary VTE prophylaxis in patients affected by major congenital thrombophilia, also at reduced dose.

D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506.