Background: Acute myeloblastic leukemia (AML) usually presents with cytopenias, although its degree is variable and in some cases it is non-existent. We herein highlight the existence of “de novo” AML patients that debut with a normal or elevated platelet count. Aims: Our aim was to evaluate the prognostic impact of a platelet count over >300 x109/L at diagnosis. Methods: One hundred and twenty-eight adult patients from nine tertiary centers of Spain, with a diagnostic of non-promyelocytic AML between 2000 and 2021, were included. Two groups were defined based on platelet count at diagnosis: those who debuted with a platelet count over >300 x109/L and those who debuted with a lower platelet count. Patients were also distributed in two different groups according to whether they received intensive chemotherapy treatment. We used the Kaplan-Meier and the Cox method to analyze overall survival (OS), with a two-sided P value ≤ 0.15 for a factor in the univariate analysis to be included in the multivariate regression, where a P value ≤ 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software (IBM SPSS Statistics 21, IBM Corporation, Chicago, IL). Results: A total of 128 patients were included. The median age at diagnosis was 65 y.o (25-89). Eighty patients (62.5%) had received an intensive regimen. Patients were considered upon platelet count: higher or less than 300 x109/L. We found significant differences in the white blood cells (WBC) count (19.9x109/L vs 5.3x109/L, p= 0.047), the percentage of patients who responded to treatment and in those who achieved complete remission, (56.0% vs 87.0%, p=0.004 and 44 .0% vs 80.4%, p=0.002, respectively). Figure 1 shows how presenting a platelet count over 300 x109/L was an adverse prognostic factor only in the group that received an intensive regimen. Within this group, only the age (p=0.079), the blast count (%) in bone marrow (p=0.05) and belong to intermediate-adverse European LeukemiaNet-2017 (ELN2017) risk group (p=0.008), were significantly associated with a shorter OS in the univariate analysis When confronting these variables with the presence of a platelet count at diagnosis over 300x109/L, only intermediate-adverse ELN2017 risk group and the platelet count remained significant for a shorted OS (p=0,023, HR 2.17, 95%CI 1.11-4.24 and p=0.025, HR 3.50, 95% CI 1.16-10.54, for platelet count and ELN risk group, respectively). Image:Summary/Conclusion: In “de novo” AML patients treated with an intensive regimen, an unusually high platelet count is related to a worse prognosis. In those patients, a specific molecular study focused on megakaryopoiesis could be of interest.

Background:Telomere length (TL) is shortened with every cell division. Critically short telomeres are associated with genetic instability. In chronic myeloid leukemia (CML), increased cellular turnover of clonal BCR‐ABL1‐positive hematopoietic stem and progenitor cells leads to significantly shortened telomeres in myeloid cells from peripheral blood (PB). Retrospective studies have related accelerated telomere shortening in CML to disease stage, clinical risk score at diagnosis as well as cytogenetic remission.So far, no study has considered the possible association between TL at diagnosis of CML and the achievement of deep molecular response (DMR) with imatinib (IM) treatment.Aims:To explore if TL at diagnosis of CML is predictive of DMR achievement with IM as first‐line treatment.Methods:Samples from 100 patients with de novo CML at diagnosis of three different Catalan hospitals between 2004 and 2016 were included. Three patients were considered as missing due to no valid PCR results. All patients provided informed consent. Patients’ median age was 49 yrs (range 24–80 yrs) and 59% were males. Thirty‐one (38%) patients had the e13a2 p210 BCR‐ABL1 isoform whereas 51 (62%) had the e14a2 isoform. According to Sokal and ELTS scores, 48(50%) and 52(60%) patients were low risk, 30(32%) and 24(28%) were intermediate risk while 17(18%) and 10(12%) were high risk, respectively.Patients were treated with first line IM 400 mg QD orally. For the molecular response (MR) analysis, only response to IM was considered. Response during the first year was assessed according to European Leukemia Net 2013 guidelines. DMR was defined as MR4.0 or MR4.5 The median time from IM start to MR4.0 achievement was 16.1 months (5.5, 100.7). Follow‐up was at least 24 months for all patients.For TL determination, DNA was extracted from PB or bone marrow cells. TL was analysed by monochrome multiplex quantitative polymerase chain reaction and the results were expressed as the standardized T/S ratio. Age adaptation of TL, indicated as ΔTL (delta‐TL), was performed using data from 107 healthy controls (age range 16–84 years). The ΔTL for every patient was calculated subtracting the subject's linear predicted TL (linear regression analysis of healthy controls) from the observed TL.Results:Healthy controls showed the expected decline in TL with increasing age (R2 = 0.1693), which was not detectable in CML (R2 = 0.0002), suggesting that telomeres are not age‐dependent in CML at diagnosis.Analysing the clinical data, no significant correlation between ΔTL and clinical prognostic scores (Sokal and ELTS, with p = 0.816 and p = 0.314, respectively) was observed, nor between ΔTL and p210 BCR‐ABL1 onco‐protein isoforms (e13a2 and e14a2, p = 0.981).Finally, focusing on the ΔTL representing the difference between TL expected by age and TL determined in the CML cells, patients with lower ΔTL at diagnosis were significant associated with achievement of MR4.0 and MR4.5 (HR [95%CI]: 0.24 [0.1, 0.74], p = 0.013 and 0.23 (0.1, 0.76), p = 0.016, respectively). In addition, when patients were stratified according to median value of ΔTL (0.40), those with ΔTL<0.40 significantly achieved MR4.0 earlier than patients with ΔTL>0.40 (median in months [95%CI]: 21 [8.2, 33.7] vs 46.2 [23.6, 68.8], p = 0.034) (Fig1).Summary/Conclusion:TL at diagnosis of CML is a predictive biomarker of DMR achievement with IM as first‐line treatment. Acknowledgements: FIS (AES 2016) PI16/01200 and FEHH.image

Background:Thrombopoietin receptor agonists (TPO‐RA) are a well‐established treatment in patients with primary immune thrombocytopenia (ITP). Sustained treatment‐free responses (TFR) after TPO‐RA discontinuation in adult ITP have been reported; yet, to date there are no predictors to identify in which patients this approach is likely to be successful.Aims:To evaluate clinical predictors of TFR in a real world cohort of ITP patients treated with TPO‐RA.Methods:Patients aged >18 years with primary ITP who had initiated TPO‐RA (eltrombopag [EPG] or romiplostim [ROM]) treatment between January 2012 and December 2014 were included in this retrospective, multicenter study from 19 secondary and tertiary Spanish hospitals. Data on patient characteristics, history of disease and previous therapies, TPO‐RA administration, response and discontinuation were collected from medical records.Results:A total of 121 patients with a median age of 63 years (range 19–96 years), 59% females initiated TPO‐RA as long‐term therapy (ROM 54; EPG 67). Sixty‐eight percent of the patients treated with TPO‐RA met criteria for chronic, 16% for newly diagnosed and 16% for persistent ITP. The median time on TPO‐RA treatment was 35.2 months (1 to 67.3 months), and the median follow‐up from start of TPO‐RA until collection of data was 44.9 months (23.8 to 67.5 months). A total of 39 patients (32.2%) switched TPO‐RA during follow‐up. The most frequent cause for switching was lack of efficacy (48.7% of cases ‐in 89.5% the initial TPO‐RA was EPG‐). Due to switching the exposure to both TPO‐RAs was similar during follow‐up; 80 patients received ROM and a similar number was treated with EPG, with total exposure (years) of 161.0, and 168.3, respectively.During follow‐up almost one half of the patients (46.3%, n = 56) tapered‐off the TPO‐RA; 10 out of the 37 cases that discontinued ROM had previously received EPG, and 4 out of the 19 that stopped EPG had switched from ROM. After a median of 432 days (29–1344) under TPO‐RA treatment, 35 patients (28.9%) maintained TFR defined as platelet counts >50x109/l for more than 6 months. In 4 of these 35 cases, TPO‐RAs were reintroduced due to loss of response after a median TFR of 20.5 months. Potential predictors of TFR in the remaining 31 patients (25.6%) with sustained platelet counts in the absence of any agent meant to increase platelet count (median 32 months, 8–217) were analyzed. No specific patient feature (e.g. age, comorbidities, ITP duration, previous treatments), bleeding, previous therapies nor phase of disease seemed to consistently predict for sustained response off therapy. However, univariate analysis (Chi‐square) did identify statistically significant predictors of TFR. Interestingly, while the specific TPO‐RA that was discontinued did not influence the probability to achieve TFR, receiving ROM as first TPO‐RA was positively associated with TFR (P = 0.010), while switching TPO‐RA negatively predicted sustained platelet responses (P = 0.002). In multivariate analysis with logistic regression both variables predicted significantly higher odds of TFR (Table 1).Summary/Conclusion:Platelet response following TPO‐RA cessation is sustained in 25.6% of adult patients with primary ITP. Although published studies have not identified a predictive factor of sustained response after TPO‐RA discontinuation, in this long‐term follow up analysis, ROM as first TPO‐RA being administered, and no need of TPO‐RA switching are factors that positively correlate with the probability to achieve TFR.image

Background:To date there are no head‐to‐head randomized controlled trials comparing romiplostim (ROM) with eltrombopag (ELT) for the management of patients with primary immune thrombocytopenia (ITP). Having different routes of administration, which is the best choice of a thrombopoietin receptor agonist (TPO‐RA) for an individual patient is not clear.Aims:To analyze biological and clinical factors leading physicians and/or patients to the use of a particular TPO‐RA.Methods:We collected retrospectively the clinical data of 146 adult primary ITP patients who had initiated treatment with ROM or ELT between January 2012 and December 2014. Data on patient characteristics were collected from medical records in a multicenter study from 19 secondary and tertiary Spanish hospitals.Results:A minority of patients (n = 25) started TPO‐RA as short‐term therapy with an intention to treat of <2 months (14 ROM, 11 ELT). The most frequent single indication for a transient use of TPO‐RA was to increase platelet counts before a scheduled surgery; all patients (n = 6) received ROM in this scenario. No differences were observed between ROM and ELT in terms of sex, baseline platelet counts, time to achieve platelets >50x109/l, nor maximal platelet counts after short‐time TPO‐RA treatment. The majority of patients (n = 121, median age 63 years; range 19–96 years; 58.7% female) initiated TPO‐RA as long term treatment (ROM 54; ELT 67). Sixty‐eight percent of the patients met criteria for chronic, 16% for newly diagnosed and 16% for persistent ITP. There was a trend towards a preferential use of ELT in patients ≥65years (52.2% vs. 35.2% for ROM, P = 0.061). Neither gender, liver disease, history of previous neoplasia or vascular events, phase of the disease, or responses to earlier lines of therapy associated with the choice of TPO‐RA. We assessed the bleeding severity both at diagnosis and before initiation of TPO‐RA therapy according to the Page score (Br J Haematol. 2007;138:245–8). In univariate analysis, ROM was preferentially given to patients presenting with bleeding symptoms at diagnosis (66.7% of those receiving ROM) compared to 41.8% of bleeders among those receiving ELT (P = 0.006). The cumulative bleeding scale at diagnosis was also higher in those patients elected for treatment with ROM than ELT (median bleeding score at diagnosis 2 vs. 0, p = 0.003). At the time when TPO‐RA was initiated, the risk of hemorrhage (platelet counts 18x109/l vs. 25 x109/l for ROM and ELT, respectively; P = 0.014), and bleeding manifestations (bleeding score of 1 and 0 for ROM and ELT, respectively; P = 0.037) were also correlated with the selection of TPO‐RA. Additionally, six months before the start of TPO‐RA, the requirement for hospital care (emergency treatment or hospital admission) was higher in patients that were subsequently treated with ROM than those elected for ELT (55.6% vs. 31.8%, P = 0.009). In multivariate analysis with logistic regression, platelet counts before TPO‐RA and the need for hospital care 6 months before TPO‐RA correlated with the selection of TPO‐RA (Table 1).Summary/Conclusion:Our study shows a trend towards the use of ELT in older patients, but no influence of other patient characteristics, or previous therapies on the choice of TPO‐RA. While previous indirect data comparing ROM and ELT suggest that there is no substantial difference in the efficacy of these agents, real world data from this analysis indicates that the risk and severity of bleeding before starting TPO‐RA influences the selection of TPO‐RA in the clinical practice.image

Background:Thrombopoietin‐receptor‐agonists (TPO‐RA) are effective treatments of immune thrombocytopenia (ITP). Previous long‐term TPO‐RA clinical trials have shown that thrombotic events occurred in 6% of TPO‐RA‐treated ITP patients, with thrombotic events appearing to be more frequent in patients of older age and having at least 1 general risk factor for thrombosis.Aims:To evaluate the prevalence of venous and arterial thrombosis in patients with primary ITP during treatment with TPO‐RA.Methods:Multicenter retrospective study that included 121 adult primary ITP patients from 19 secondary and tertiary Spanish hospitals who had initiated treatment with Romiplostim (ROM) or Eltrombopag (ELT) as long‐term therapy between January 2012 and December 2014. Information on patient characteristics was collected from medical records to assess and compare risk factors of ITP patients with and without vascular events (VE).Results:A total of 121 patients (median age 63 years, range 19–96 years; 68% chronic phase), initiated TPO‐RA (ROM 54; EPG 67). During a 329.3 patient‐year time under treatment (exposure to ROM and ELT of 161.03 and 168.27 patient‐year, respectively) 15 patients experienced 17 vascular episodes (9 arterial, 8 venous). One patient presented antiphospholipid antibodies, five had been diagnosed with neoplasia, one with vascular peripheral disease, two with hypothyroidism –one of whom also had renal disease‐. Seven events occurred with ROM, and 10 with ELT. The annualized risk was 4.2 and 5.9 VE/100 patient‐years in ROM and ELT treated patients, respectively (median 5.2). Most VE occurred in the first year of TPO‐RA therapy (median 276 days; 5–1183), with a trend toward earlier events under ROM than ELT (127 days vs 360 days, respectively; p = 0.070). In the case of ischemic events the median time to arterial events was 165 vs. 606 days in ROM and ELT treated patients; P = 0.029. There were no significant differences in the 15 patients vs. the 106 patients that did not suffer from vascular events in terms of gender, age, diabetes, hypertension, previous vascular events, nor time on prednisone as 1st line therapy. In patients experiencing VE on TPO‐RA, a significant association with previous splenectomy (53.3% vs. 25.5%, P = 0.026), and chronic phase of the disease (93.3% vs. 64.1%, P = 0.024) compared with those not having such characteristic was detected. Surprisingly previous malignancy significantly associated with VE under TPO‐RA treatment (33% vs. 2.8%, P = 0.000009). All patients were reported to have sustained complete remission of previous neoplasias (1 colon carcinoma; 1 Burkitt lymphoma; 1 bladder cancer; 1 breast cancer; 1 patient with history of thyroid, breast and ovarian tumors) and were not receiving antineoplastic therapies. In multivariate analysis with logistic regression only previous malignancy predicted significantly higher odds of VE (Table 1).Summary/Conclusion:In this study, we describe an annualized risk of 5.2 vascular events/100 patient‐years in TPO‐RA treated patients. Venous and arterial thromboembolism are not frequent complications in ITP patients under TPO‐RA, except in particular settings, such as in splenectomized and chronic patients. Our data revealed a novel association of history of previous neoplasia with thrombotic events in patients with TPO‐RA. These results suggest that a history of prior cancer should be systematically screened before TPO‐RA initiation, and if so, alternative therapy should be considered; however, due to the limited sample size, further research is warranted.image

Recombinant factor VIIa (rfVIIa) has been widely used for the treatment and prevention of bleeding episodes in haemophiliacs with high-titre inhibitors. High single doses are the treatment of choice for joint and muscle bleeds in those patients. There are only a few reports on the value of rfVIIa in cirrhotic patients with haemostatic impairment but this drug can consistently correct the prothrombin time in these individuals. We report a case of a good response to a single high dose of rfVIIa in a patient with advanced liver disease who suffered from severe refractory postoperative haematuria.