Edurne Sarrate

Expression of CD43 in chronic lymphoproliferative leukemias

CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B‐cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies.

Consistency of the Moreau CLL score

The Moreau score is essential for the diagnosis of B‐cell lymphoproliferative disorders (B‐LPD).

Usefulness of the CLLflow score: USEFULNESS OF THE CLLflow SCORE

The CLLflow score was recently suggested as an improvement over the Moreau score (MS) for the diagnosis and classification of B‐cell lymphoproliferative disorders (B‐LPD).

Applicability of the results of thrombophilia studies in clinical practice

The factor V G1691A (factor V Leiden, FVL) and factor II G20210A gain-of-function mutations are the most frequent forms of inherited thrombophilia [1,2]. However, considering their prevalence in the healthy Caucasian population (3–10% depending on the region), the increase in thromboembolic risk is merely 3–5 times that of non-carriers and the large majority of carriers will not suffer any thromboembolic event [1,3]. Therefore, screening for the presence of FVL and G20210A is controversial, particularly in patients without a strong personal or familial history of thrombosis and those in whom the results would not have therapeutic implications. Thrombophilia studies are particularly prone to bias because they are largely case-control studies or case series. Furthermore, the penetrance of thrombosis in patients with gain-of-function genetic mutations (both FVL and G20210A) is greatly determined by thrombotic history. Since testing is largely done because of a thrombotic history (both personal or familial), these mutations might appear thrombogenic where thrombogenicity is largely (although not entirely) conferred by a history of a thrombotic event itself, rather than in themutation. This notion has recently become more generalized and expert opinion now suggests stringent criteria for testing [4]. Indeed, in the 2016 meeting of the American society of Hematology, Dr Middledorp reviewed the evidence and concluded [5], in line with current guidelines, that an essential criteria for testing is a therapeutic implication, which is rarely present. The results of our own experience, in a tertiary healthcare center, seem to show that these recommendations are not followed (Table 1). Although we have not tested healthy individuals, the prevalence in other series from the Northwestern coast of the Mediterranean is 1.6– 5.8% for FVL [1,6] and 3–6.5% for G20210A [2,7]. Therefore, the prevalence of FVL and G20210A in patients in whom a thrombophilia study was ordered is only slightly higher than in the general population, seemingly indicating that the clinical threshold for ordering these tests is very low.

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.

The case for lymphoma-specific survival

In their recent perspective, Cheah and Seymour [1] assessed the scarce evidence available on treatment criteria for relapsed follicular lymphoma (FL). We applaud their effort in broaching such a difficult subject because, in contrast to treatment-naïve patients, high-quality evidence is largely lacking in the relapsed setting. In the introduction, the authors claim that ‘...the natural history [of FL] is marked by successive lines of therapy resulting in progressively shorter periods of disease-free survival followed ultimately by the development of either chemo-refractoriness, large cell transformation, or death from treatment related toxicities.’ This claim, which we have made in the past ourselves [2], is supported by classical studies such as those by Johnson et al. [3], Weisdorf et al. [4], and Gallagher et al. [5], which included mostly patients treated with single alkylating agents or alkylator-based chemotherapy. At present, it has become clear that FL is a very heterogeneous disease, and that the different prognostic subgroups can largely be drawn based on response to first-line immunochemotherapy (ICT). Thus, patients with poor response to frontline ICT have a poorer response to subsequent lines of therapy as well as a shorter overall survival (OS) [6–8], and they also seem to have notably higher rates of histological transformation (HT). Although it is unclear whether there is a late plateau in the HT curves [9]; HT is more frequent [7,8] and aggressive [10,11] shortly after diagnosis. Conversely, patients with remission persisting 2 years after diagnosis (or perhaps as early as 1 year) can expect to live as long as the general population [12], which seems to indicate that their risk of death from either the disease or toxicity is lower. In a recent study analyzing the outcome of FL patients based on their response to front-line ICT [7], we found that most patients with ICT-refractory disease were dead at the time of analysis (31/53, 58%), mostly due to lymphoma (27/31, 87%) while only a minority of ICT-sensitive patients had died (35/290, 12%), 14 (40%) due to lymphoma and 10 (29%) due to toxicity (unpublished data). Importantly, however, a majority of patients remained alive. With this background, we believe it would be interesting to assess lymphoma-specific survival in studies with long-term follow-up. Lymphoma-specific survival is the time from diagnosis until death due to lymphoma (although it is also important to record deaths due to toxicity [13]). While progression-free survival (PFS; the time from diagnosis until progression or death by any cause) and OS (the time from diagnosis until death by any cause) remain the most relevant and informative endpoints, it is also essential to learnwhat patients with FL currently die from (as compared to the general population), in order to assess whether any specific early interventions or targeted follow-up are warranted. The patients in our study died mostly of lymphoma or treatment-related toxicities, but the median follow-up was relatively short (4 years in living patients), and it is conceivable that causes of death differ in patients with longer remissions. Indeed, in a recent study, El-Galaly et al. [11] estimated death due to lymphoma to be 13% at 10 years, although themedian follow-up of their studywas less than 6 years and the entire populationwas managed initially by watchful waiting. One of the concerns of lymphoma-specific survival is the problem of determining the cause of death [13], particularly in patients with long remissions and those lost to follow-up. Similarly, late infectious complications, secondary cancers, and cardiovascular deaths may be only partly due to treatment toxicity. However, other endpoints also involve a best medical guess. In particular, PFS puts a specific date on progression, when that is a continuous process. Furthermore, progression can be detected earlier or later depending on how close the follow-up visits are or how sensitive (PET vs. CT scans) or frequent image testing is carried out. Although flawed, lymphoma-specific survival might also provide important clues into a relevant problem.

Triple therapy with dual antiplatelet treatment and direct oral anticoagulants

In their recent review, Dezsi et al. [1] summarize the evidence on antithrombotic treatment in patients with atrial fibrillation (AF) who have undergone percutaneous coronary intervention (PCI)with stenting, arguably themost common clinical situation requiring triple therapy (dual antiplatelet [DAPT] and anticoagulant treatment). This topic is of renewed relevance since the introduction of direct oral anticoagulants (DOACs), which are now commonly employed for stroke prevention in AF. Their use as part of triple therapy is less well-established due to both a lack of evidence in this setting aswell as evidence of increasedbleedingwith limited benefit in patients with acute coronary syndrome [2,3]. Furthermore, the evidence on the use of (and the optimal length of) triple therapy for non-coronary stenting (such as endovascular treatment of cerebral arterial aneurysms) is also scarce, and is likely to remain so due to insufficient number of patients for large trials. Therefore, we believe the study by Dans et al. [4], who analyzed the subgroup of patients receiving antiplatelet therapy in the RE-LY (Dabigatran versuswarfarin in patientswith atrial fibrillation) study [5], is of great practical value. In their otherwise clearly written and well-documented review, Dezsi et al. [1] failed to underscore its importance (although they did refer to the study). The case for dabigatran 110 mg b.i.d., over other DOACs as part of triple therapy inpatientswithAF is two-fold. First, unlike in thepivotal studies for all other DOACs, patients treated with DAPT were not excluded from the RE-LY study [5]. Although there were less than 1000 patients with DAPT, the net benefit was maintained with dabigatran 110 mg b.i.d, as shown by the aforementioned study by Dans et al. [4]. Secondly, patients in the RE-LY study [5] were randomized to any of the 2 dabigatran doses (150 mg or 110 mg b.i.d) or warfarin. Conversely, in the pivotal trials with apixaban and rivaroxaban there was only one dose for any patient (based on renal function for rivaroxaban and renal function, weight and age for apixaban). This means that low dose apixaban [6] (which is 50% that of the standard dose) and low dose rivaroxaban [7] (or very low dose rivaroxaban [8]) have not been shown to protect young patients and/or thosewith normal renal function from stroke, unlike dabigatran 110 mg b.i.d. The ESC guidelines recommend using the lowest effective dose for stroke prevention [9] but for apixaban and rivaroxaban only one dose has been tested for any particular age and degree of renal failure. In the case of edoxaban, patients were also randomized to one of twodoses but the lowdose (30/15mgq.d)was less effective than warfarin for the prevention of ischemic stroke [10]. In conclusion, we think that dabigatran 110mg b.i.d is generally the most evidence-based option for patients without renal failure in need of triple therapy.

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.

Hemorragia intracraneal durante el tratamiento con apixabán

latente y con un título de anticuerpos reagínicos (VDRL/RPR) superior a 1:325. Con las limitaciones del escaso número de pacientes y el carácter retrospectivo del estudio, y habida cuenta de las con5. Sun JJ, Wang ZY, Shen JY, Shen YZ, Liu L, Wang JR, et al. Serum TRSUT titer ≥ 1:16 predictor for neurosyphilis among HIV-infected patients with concurrent syph and no neurological symptoms. Medicine (Baltimore). 2015;94:e2023.

Número de pacientes necesario a tratar con anticoagulantes orales directos con respecto a warfarina en la fibrilación auricular

RE-LY2 Ensayo clínico 18.113 Dabigatrán 150 mg/12 h vs. warfarina 1,11 vs. 1 HR: 0,66 p < 0,001 Dabigatrán 110 mg/12 h vs. warfarina 1,53 vs. 1 HR: 0,91 p = 0,34 ROCKET-AF3 Ensayo clínico 14.264 Rivaroxabán vs. warfarina 2,1 vs. 2, HR: 0,88 p = 0,12 ARISTOTLE4 Ensayo clínico 18.201 Apixabán vs. warfarina 1,27 vs. 1 HR: 0,79 p = 0,01 Graham et al.5, 2015 Vida real 134.414 Dabigatrán (150 o 75 mg/12 h) vs. warfarina 1,13 vs. 1 HR: 0,8 ( p = 0,02d Yao et al.6, 2016b Voda real 125.243 Dabigatrán (150 o 75 mg/12 h) vs. warfarina 1,18 vs. 1 HR: 0,98 p = 0,88 Apixabán (5 o 2,5 mg/12 h) vs. warfarina 1,33 vs. 1 HR: 0,67 p = 0,04 Rivaroxabán (20 o 15 mg/24 h) vs. warfarina 1,26 vs. 1 HR: 0,93 p = 0,56