Obese patients with atrial fibrillation are more efficiently protected from thrombosis under warfarin or xabans compared to non-obese patients; a systematic review and Meta-analysis of six randomized controlled trials.

INTRODUCTION: Recommendations about proper anticoagulation in obese patients, body mass index (BMI) > 30 kg/m2, are not yet clearly defined. Obese patients were included in randomized controlled trials comparing new anticoagulants (NOACs) with warfarin in patients with atrial fibrillation or thromboembolism. METHODS: We performed a medline search entering proper criteria and finally 6 post-hoc analysis of RCTs, reporting outcome according to BMI, were included in this meta-analysis. Two major outcomes were considered end points in our meta-analysis; thrombosis, including ischemic cerebral events (transient or not) and venous thrombosis (DVD) /pulmonary embolism (PE) and bleeding, including major bleeding and clinically relevant non-major bleeding. RESULTS: In the NOACs treated group, thrombosis occurred less frequently in obese vs non-obese patients; RR and 95 % CI 0,75 (0,58-0,97), p = 0,03, while low heterogeneity was observed (I2= 40 %). In the warfarin treated subgroup there was statistically significant difference with less thrombotic events occurring in the obese vs non-obese patients; RR and (95 % CI) 0,80 (0,66-0,98), p = 0,03, and heterogeneity was low (I2 = 24 %). This protective effect called the obesity paradox is limited to obese patients anticoagulated for non-valvular atrial fibrillation (NVAF); RR (95 % CI) was 0,70 (0,58-0,85) p = 0,03 and I2 = 24 %. Bleeding events were similar under both NOACs and warfarin in obese vs non-obese analysis. CONCLUSIONS: Obese patients anticoagulated for NVAF with either standard dose of xabans or INR guided warfarin are more efficiently protected against thrombosis compared to non-obese patients.

A personalized stepwise dynamic predictive algorithm of the time to first treatment in chronic lymphocytic leukemia.

Personalized prediction is ideal in chronic lymphocytic leukemia (CLL). Although refined models have been developed, stratifying patients in risk groups, it is required to accommodate time-dependent information of patients, to address the clinical heterogeneity observed within these groups. In this direction, this study proposes a personalized stepwise dynamic predictive algorithm (PSDPA) for the time-to-first-treatment of the individual patient. The PSDPA introduces a personalized Score, reflecting the evolution in the patient's follow-up, employed to develop a reference pool of patients. Score evolution's similarity is used to predict, at a selected time point, the time-to-first-treatment for a new patient. Additional patient's biological information may be utilized. The algorithm was applied to 20 CLL patients, indicating that stricter assessment criteria for the Score evolution's similarity, and biological similarity exploitation, may improve prediction. The PSDPA capitalizes on both the follow-up and the biological background of the individual patient, dynamically promoting personalized prediction in CLL.

Estimated glomerular filtration rate independently predicts outcome of azacitidine therapy in higher-risk Myelodysplastic syndromes. Results from 536 patients of the Hellenic National Registry of Myelodysplastic and Hypoplastic syndromes.

Higher-risk Myelodysplastic syndromes (MDS) patients undergoing treatment with 5-azacytidine (AZA) are typically elderly with several comorbidities. However, the effect of comorbidities on the effectiveness and safety of AZA in real-world settings remains unclear. We analyzed data from 536 AZA-treated patients with higher-risk MDS, Myelodysplastic/Myeloproliferative neoplasms and low blast count Acute Myeloid Leukemia enrolled to the Hellenic National Registry of Myelodysplastic and Hypoplastic Syndromes. Multivariate analysis adjusted also for the International Prognostic Scoring System (IPSS), its revised version (IPSS-R) and the French Prognostic Scoring System (FPSS), demonstrated independent associations of overall and leukemia-free survival with estimated glomerular filtration rate (eGFR) <45 mL min-1 /1.73 m2 (P = .039, P = .023, respectively), ECOG performance status <2 (P = .015, P = .006), and presence of peripheral blood blasts (P = .008, P = .034), while secondary MDS also correlated with significantly shorter leukemia-free survival (P = .039). Addition of eGFR <45 mL min-1 /1.73 m2 , in IPSS-R and FPSS increased the predictive power of both models. Only FPSS ≤2 and eGFR <45 mL min-1 /1.73 m2 predicted worse response to AZA in multivariate analysis, whereas eGFR <45 mL min-1 /1.73 m2 correlated significantly with death from hemorrhage (P = .003) and cardiovascular complications (P = .006). In conclusion, in the second largest real-world series of AZA-treated MDS patients, we show that an eGFR <45 mL min-1 /1.73 m2 is an independent predictor of worse response and survival. This higher cut-off, instead of the commonly used serum creatinine >2 mg/dL, can be utilized as a more precise indicator of renal comorbidity during AZA therapy. Incorporation of eGFR in the prognostic assessment of AZA-treated MDS patients may prove useful not only in routine practice, but also for the appropriate patient stratification in clinical trials with AZA combinations.

Epigenetic therapy of myelodysplastic syndromes connects to cellular differentiation independently of endogenous retroelement derepression.

BACKGROUND: Myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML) are characterised by abnormal epigenetic repression and differentiation of bone marrow haematopoietic stem cells (HSCs). Drugs that reverse epigenetic repression, such as 5-azacytidine (5-AZA), induce haematological improvement in half of treated patients. Although the mechanisms underlying therapy success are not yet clear, induction of endogenous retroelements (EREs) has been hypothesised. METHODS: Using RNA sequencing (RNA-seq), we compared the transcription of EREs in bone marrow HSCs from a new cohort of MDS and chronic myelomonocytic leukaemia (CMML) patients before and after 5-AZA treatment with HSCs from healthy donors and AML patients. We further examined ERE transcription using the most comprehensive annotation of ERE-overlapping transcripts expressed in HSCs, generated here by de novo transcript assembly and supported by full-length RNA-seq. RESULTS: Consistent with prior reports, we found that treatment with 5-AZA increased the representation of ERE-derived RNA-seq reads in the transcriptome. However, such increases were comparable between treatment responses and failures. The extended view of HSC transcriptional diversity offered by de novo transcript assembly argued against 5-AZA-responsive EREs as determinants of the outcome of therapy. Instead, it uncovered pre-treatment expression and alternative splicing of developmentally regulated gene transcripts as predictors of the response of MDS and CMML patients to 5-AZA treatment. CONCLUSIONS: Our study identifies the developmentally regulated transcriptional signatures of protein-coding and non-coding genes, rather than EREs, as correlates of a favourable response of MDS and CMML patients to 5-AZA treatment and offers novel candidates for further evaluation.