Response loss and development of neutralizing antibodies during long-term treatment with romiplostim in patients with immune thrombocytopenia: a case series.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts resulting from both immune-mediated platelet destruction and inappropriate bone marrow platelet production. Therefore, in patients with ITP failing immunosuppressants/splenectomy, an alternative approach is to enhance platelet production stimulating thrombopoiesis. Studies on the development of recombinant thrombopoietins (rhTPO) were halted as a minority of patients developed an autoantibody that neutralized pegylated rhTPO and also cross-reacted with and neutralized endogenous TPO resulting in thrombocytopenia. Clinical use of romiplostim, a second-generation TPO-RAs, has shown that during long-term treatment, it may elicit the development of neutralizing antibodies to this agent resulting in acute thrombocytopenia. In our case series of 47 primary adult patients with ITP treated with romiplostim, 28 of 47 are evaluable for response loss. Among these, we observed eight patients who either progressively (3 of 8) or abruptly (5 of 8) lost response which accounts for a prevalence of 28.5%. Neutralizing antibody testing could be performed in 4 of 8 patients and 3 of 4 tested positive. These antibodies did not cross-react with endogenous TPO and retesting of 2 patients at 9 and 7 months yielded a negative result. At follow-up, 5 of 8 patients - including the 3 patients with neutralizing antibodies - went into long-term complete response when switched to a different therapy while 3 of 8 patients never regained a response on subsequent lines of therapy. Response loss does not seem to be so rare an event during romiplostim administration (28.5% in our series) and in a minority of patients, it can be associated with development of drug neutralizing antibodies. Although recognized by the manufacturer as a possible adverse event ensuing during romiplostim administration, development of neutralizing antibody in everyday clinical practice has so far not been specifically addressed in reports on romiplostim use outside controlled studies. Unfortunately, testing for these antibodies requires adhesion to strict procedures which is not easily accomplished in everyday clinical practice. This complexity represents a significant drawback in extending antibody testing to all patients who lose response to romiplostim.

Neurological symptoms in essential thrombocythemia: impact of JAK2V617F mutation and response to therapy.

Patients with essential thrombocythemia (ET) often suffer from neurological symptoms (NS) not ever resulting from previous thrombotic cerebral events (TCE). We reported NS occurred in 282 patients, in order to identify the factors influencing ET-related NS in the absence of TCE, and the response to therapy. Overall, 116 of 282 patients (41%) presented NS; 101 of them (87%) reported subjective transient and fluctuating NS, without concurrent TCE, which we defined as ET-related NS, by frequency: cephalalgia, chronic paresthesias, dizziness or hypotension, visual disturbances, and tinnitus. In univariate analysis, ET-related NS resulted more frequently in young people (P = 0.017) and in females (P = 0.025). We found a higher prevalence of JAK2V617F mutation in ET-related NS patients (P = 0.021). In multivariate analysis, gender (P = 0.024) and JAK2V617F mutation (P = 0.041) remained significantly associated with the development of ET-related NS, with a risk of about four times higher for JAK2V617F-mutated patients (OR = 3.75). Ninety-seven of 101 patients with ET-related NS received an antiplatelet (AP) agent at the time of NS, whereas only selected high-risk ET-related NS patients were treated with a cytoreductive drug, according to the published guidelines and similarly to patients without NS. We observed that only 32 of 97 (33%) patients with ET-related NS achieved a complete response after AP treatment. Among the 65 non-responder patients, 36 (55.4%) improved NS after the introduction of cytoreductive therapy; therefore, the addition of cytoreductive treatment should be considered in this setting.

Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia.

Developing optimal radiation-free central nervous system prophylaxis is a desirable goal in acute lymphoblastic leukemia, to avoid the long-term toxicity associated with cranial irradiation. In a randomized, phase II trial enrolling 145 adult patients, we compared intrathecal liposomal cytarabine (50 mg: 6/8 injections in B-/T-cell subsets, respectively) with intrathecal triple therapy (methotrexate/cytarabine/prednisone: 12 injections). Systemic therapy included methotrexate plus cytarabine or L-asparaginase courses, with methotrexate augmented to 2.5 and 5 g/m(2) in Philadelphia-negative B- and T-cell disease, respectively. The primary study objective was the comparative assessment of the risk/benefit ratio, combining the analysis of feasibility, toxicity and efficacy. In the liposomal cytarabine arm 17/71 patients (24%) developed grade 3-4 neurotoxicity compared to 2/74 (3%) in the triple therapy arm (P=0.0002), the median number of episodes of neurotoxicity of any grade was one per patient compared to zero, respectively (P=0.0001), and even though no permanent disabilities or deaths were registered, four patients (6%) discontinued intrathecal prophylaxis on account of these toxic side effects (P=0.06). Neurotoxicity worsened with liposomal cytarabine every 14 days (T-cell disease), and was improved by the adjunct of intrathecal dexamethasone. Two patients in the liposomal cytarabine arm suffered from a meningeal relapse (none with T-cell disease, only one after high-dose chemotherapy) compared to four in the triple therapy arm (1 with T-cell disease). While intrathecal liposomal cytarabine could contribute to improved, radiation-free central nervous system prophylaxis, the toxicity reported in this trial does not support its use at 50 mg and prompts the investigation of a lower dosage. (clinicaltrials.gov identifier: NCT-00795756).

A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy.

Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythaemia vera (PV), unresponsive to the maximum tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukaemiaNet response criteria were used to assess the primary endpoint after 12 weeks of treatment. Complete or partial response was observed in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, respectively. Control of pruritus was observed in 64% and 67% of patients in the 50 and 100 mg groups, respectively. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clinically effective in HC-unresponsive PV patients.

High cure rates in Burkitt lymphoma and leukemia: a Northern Italy Leukemia Group study of the German short intensive rituximab-chemotherapy program.

We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (≤ versus >60 years) and performance status (0-1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval ≤ 25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged ≤ 60 years with performance score 0-1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120.

CD20 expression has no prognostic role in Philadelphia-negative B-precursor acute lymphoblastic leukemia: new insights from the molecular study of minimal residual disease.

The prognostic significance of CD20 expression in acute lymphoblastic leukemia has been investigated in children and adults but is still a subject of debate. The aim of our study was to correlate CD20 expression with clinical-biological characteristics and outcome in 172 Philadelphia chromosome negative patients prospectively treated in a multicenter trial introducing the molecular evaluation of minimal residual disease for therapeutic purposes. We considered 20% as the threshold for CD20 positivity. Complete remission rate, minimal residual disease negativity rate at weeks 10, 16 and 22, and disease-free and overall survival were similar among CD20-positive and -negative patients, even considering minimal residual disease results and related therapeutic choices. Our study failed to demonstrate any prognostic significance for CD20 expression in Philadelphia chromosome negative acute lymphoblastic leukemia. This conclusion is supported for the first time by a comparable minimal residual disease response rate among CD20-positive and -negative and positive patients.

Quality of life in elderly patients with essential thrombocythaemia. An Italian multicentre study.

Essential thrombocythaemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts and increased incidence of thrombosis and haemorrhage. Median age at diagnosis is 65-70 years. Life expectancy is similar to that of the healthy population. Symptoms and complications may affect quality of life (QoL); in particular, in elderly patients ET may represent an additional burden. We performed a survey in 494 elderly ET patients to evaluate patient-reported outcomes (PROs). Comorbidities were present in 305 (62%) patients. Factorial analysis based on survey items representing psychological aspects of daily life identified an "attitude domain" with four clusters of patients: (A) very pessimistic (n = 99), (B) pessimistic (n = 101), (C) optimistic (n = 90), and (D) very optimistic (n = 107). Patients in cluster A had more comorbidities (p = 0.003) while patients in cluster D required fewer medical visits and were less disturbed by medications (p < 0.0001). Independent factors predicting Short-Form Health Survey, version 2 physical QoL were grade of optimism (p < 0.0001), gender (p = 0.007), and Charlson comorbidity index (p < 0.0001)). Grade of optimism and disturbances related to medication predicted mental QOL (p < 0.0001). In conclusion, physicians should take into consideration PROs, as "attitude" is associated with physical and mental QoL. Treatment should be tailored to patients' needs according to comorbidities, lifestyle, and psychological conditions.

High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study.

Therapeutic plasma exchange (PE) is the accepted therapy for thrombotic thrombocytopenic purpura (TTP). Because not all patients achieve remission, other treatment modalities have been used in addition to PE, but no randomized clinical trial evaluated their efficacy. The aim of this multicentric study was to compare the effectiveness of standard- versus high-dose methylprednisolone as an adjunctive treatment to PE in the acute phase of TTP. Sixty patients with idiopathic TTP were randomized to receive methylprednisolone 1 mg/kg/die intravenous or 10 mg/kg/die for 3 days, thereafter, 2.5 mg/kg/die in addition to PE. Both dosages of steroids were well tolerated. At the end of induction therapy (day 23), the percentage of patients failing to achieve complete remission was significantly higher in the standard dose (16 of 30) than in the high-dose group (seven of 30). Also, the number of cases without a good response at day 9 and the number of deaths were higher in the standard-dose arm, but the differences did not reach the statistical significance. Results of present study indicate that the association of PE with high-dose instead of standard-dose steroids reduces the percentage of TTP patients that fail to achieve complete remission.

Peg-filgrastim versus filgrastim after autologous stem cell tranplantation: case-control study in patients with multiple myeloma and review of the literature.

We investigated the effects of a single s.c. injection of peg-filgrastim in 32 patients with multiple myeloma who underwent autologous stem cell transplantation (AuSCT) as first line treatment. For comparison, 32 myeloma patients with similar characteristics and receiving standard daily administration of filgrastim were matched. Overall, there were no statistically significant differences between peg-filgrastim and filgrastim in terms of tolerability, marrow recovery, severity of neutropenia, incidence and duration of febrile neutropenia, documented infections and transfusions. However, some favourable trends or effects in favour of peg-filgrastim were observed. This was confirmed by a review of the published papers about this topic.

Lymphoproliferative disease and acquired C1 inhibitor deficiency.

Angioedema due to acquired deficiency of the C1-inhibitor is a bridging condition between autoimmunity and lymphoproliferation. We report 32 patients with acquired C1 inhibitor deficiency: 23 have anti C1-inhibitor autoantibodies; 13 have monoclonal gammopathies of unknown significance and 9 have non-Hodgkin's lymphoma. Our series suggest that different forms of B cell disorders coexist and/or evolve into each other in acquired angioedema.

Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial.

Purpose The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.

Corticosteroids can reverse severe imatinib-induced hepatotoxicity.

BACKGROUND: Imatinib can induce severe hepatotoxicity, in 1-5% of CML patients, many of whom need permanent imatinib discontinuation. DESIGN AND RESULTS: We report 5 CML patients who developed grade 3-4 hepatotoxicity after 2-8 months in imatinib. Different aetiologies of liver damage were ruled out and toxicity recurred in 2 patients with further attempts at low dose imatinib. In all patients prednisone or methylprednisolone at 25- 40 mg/day resolved hepatotoxicity in 3-8 weeks and allowed imatinib to be resumed at full doses. Corticosteroid were tapered off in 3-5 months without hepatotoxicity recurrence. CONCLUSIONS: Corticosteroid may avoid discontinuation for hepatotoxicity of the most effective anti-CML therapy.

Relationship between autoimmune phenomena and disease stage and therapy in B-cell chronic lymphocytic leukemia.

The aim of this multicenter GIMEMA study was to correlate autoimmune complications (AIC) in B-cell chronic lymphocytic leukemia (B-CLL) with stage and therapy. Autoimmune hemolytic anemia (129/194 cases) and autoimmune thrombocytopenia (35/194 cases) were typically present in advanced and multi-treated disease. Age over the median, stage C and first and second line therapy were identified as independent risk factors by multivariate analysis. In contrast, non-hematologic AIC (30/194 cases) and the presence of serological markers of autoimmunity were mostly observed in early B-CLL, suggesting different pathogenic mechanisms underlying hematologic and non-hematologic autoimmune phenomena in B-CLL.

CD34+ stem cell recovery after positive selection of "overloaded" immunomagnetic columns.

Techniques for CD34+ cell enrichment of hematopoietic progenitor cells in grafts destined for transplantation of certain patients with the aim of lowering the amount of infused T lymphocytes and subsequently decreasing the risk of graft versus host disease (GVHD) have been well developed. Adaptations of these techniques should be useful for isolation of other phenotypically defined stem cells. However, a major limitation of techniques now available consists of the number of total nucleated cells or phenotypically defined stem cells that can be processed in a single procedure. Here, we show that recommended levels are much lower than the levels of cells that can be effectively processed by immunomagnetic sorting. Twenty-nine procedures were performed using the Clini- MACS (Miltenyi Biotec) device, which is recommended for processing <6x10(10 )total nucleated cells or <6x10(8) CD34+ cells. Procedures were divided in groups according to their total cellular or CD34+ cell content. We achieved a median CD34+ cell recovery of 68.60% with a median purity of 98.56%, regardless of the loading dose when samples possessing 2-10x10(10) total nucleated cells and 0.8-12.5x10(8) CD34+ cells were applied to a single column. The median levels of CD3+ cells and CD19+ cells in the final product were depleted by 5 logs and 3.8 logs, respectively; no differences were noted when the initial loading dose was increased. Moreover, we found no correlation between the total number nucleated or CD34+ cells loaded and the resultant CD34+ cell recovery. In conclusion, levels of both total nucleated cells and CD34+ can be processed in a single procedure with satisfactory and similar CD34+ cell recovery when these columns are loaded with up to two times as many cells as recommended.

Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies.

Endothelial injury is the central factor in the events leading to thrombotic microangiopathy (TMA); however, the mechanisms involved are not fully understood. Here we investigate the role of neutrophils (PMNs) and of complement activation in inducing microvascular damage and loss of thromboresistance in TMA associated with ADAMTS-13 deficiency. PMNs isolated during the acute phase of the disease released excessive amounts of reactive-oxygen species (ROS), N-derived oxidants and proteinases and induced damage and thromboresistance loss in human microvascular endothelial cell line (HMEC-1) ex vivo. Endothelial cytotoxicity and thromboresistance loss was also induced by TMA serum. Complement-derived products were responsible for the above effects: in fact, TMA serum caused C3 and Membrane Attack Complex (MAC) deposition on HMEC-1 and its cytotoxic effect was abolished by complement inhibition. TMA serum caused surface expression of P-selectin on HMEC-1 which may promote PMN adhesion and resulted in increased PMN cytotoxicity, indicating that complement may have a role in PMN activation. In addition, TMA serum stimulated control PMNs to release ROS and proteinases, and to cause endothelial cell cytotoxicity. All of the above effects were abrogated by complement inactivation. These data document for the first time that complement-initiated PMN activation and endothelial injury may have a crucial role in microvascular thrombosis of TMA associated with ADAMTS-13 deficiency.

Feasibility of romiplostim discontinuation in adult thrombopoietin-receptor agonist responsive patients with primary immune thrombocytopenia: an observational retrospective report in real life clinical practice.

Thrombopoietin mimetics are new treatment options for patients with immune throm-bocytopenia (ITP). Because of their mechanism of action, long-term administration was envisioned in order to maintain effective thrombopoiesis. We report on 30 romiplostim treated patients: 13/27 responders (48%) achieved stable platelet counts on a mean romiplostim dose of 2.43 µg/kg and were able to stop romiplostim after a mean of 44.3 weeks (range 12-122) on therapy with sustained response maintained at a mean of 26 months (range 12-52). No bleeding events occurred during the observational period. No specific patient's features nor pattern of early response seemed to predict for sustained response. However, patients achieving safe platelet counts at lower dosages are probably worth a try of therapy tapering and discontinuation. Our observations support feasibility of romiplostim safe suspension in a relevant proportion of ITP patients.

Peripheral blood lymphocyte/monocyte ratio predicts outcome in follicular lymphoma and in diffuse large B-cell lymphoma patients in the rituximab era.

BACKGROUND: Diffuse large B-cell lymphoma is an aggressive lymphoma and a large number of studies have therefore focused on the search for prognostic factors. The same interest concerns FL, for which identification of patients candidates for watch and wait (W&W) strategy is still an option. Studies about the number and type of lymphocytes and monocytes detectable in patients with Hodgkin and non-Hodgkin lymphomas indicate they might affect the pathogenesis and prognosis of these diseases. LMR is recently under investigation as a new prognostic parameter in DLBCL; the role of this ratio in FL in the rituximab era is unknown. PATIENTS AND METHODS: We retrospectively analyzed 137 DLBCL and 132 FL patients referred to our institution; among FL pts, a W&W approach was performed at diagnosis for 42 patients. The remaining patients were treated with rituximab-containing therapy. We analyzed different LMR cutoff values at diagnosis and we wanted to investigate the prognostic effect among DLBCL and FL. RESULTS: We found that the most discriminative LMR was 2.4 for DLBCL and 2 for FL. Among DLBCL patients, an LMR value < 2.4 was associated with a worse 2-year progression-free survival (PFS), and we observed no difference in overall survival and complete response rate. Considering FL patients, LMR > 2 was associated with a longer time to treatment start compared with the LMR < 2 group (P = .0096). Among the 92 patients treated with rituximab chemotherapy, 2-year PFS was superior in the LMR > 2 group. CONCLUSION: LMR at diagnosis is a simple tool to better define long-term outcome of DLBCL and FL patients. The use of this tool might better define selection in FL of ideal candidates for W&W strategy.

Good Outcome for Very High Risk Adult B-cell Acute Lymphoblastic Leukaemia Carrying Genetic Abnormalities t(4;11)(q21;q23) or t(9;22)(q34;q11), if Promptly Submitted to Allogeneic Transplantation, after Obtaining a Good Molecular Remission.

BACKGROUND AND OBJECTIVES: Acute lymphoblastic leukaemia (ALL) carrying t(9;22) or t(4;11) genetic abnormalities represents a very high risk subtype of disease (VHR-ALL). Hematopoietic stem cell transplantation (HSCT) remains the best curative option not only for t(4;11) ALL, but also for t(9;22) ALL in the tyrosin-kinase inhibitors era. In the last years, low molecular level of minimal residual disease (MRD) before HSCT was reported as one of the best favourable indexes for survival in ALL. Here we observed that even these patients can show a favourable outcome if submitted to HSCT with very low MRD. METHODS: We considered 18 consecutive VHR-ALL patients eligible to HSCT. 16 of them were transplanted in first remission, as soon as possible, employing myelo-ablative conditioning regimens. Molecular MRD has been evaluated before and after HSCT. RESULTS: Immediately before HSCT, MRD revealed: complete molecular remission (MRD(neg)) for five patients, and a level <1×10(-3) for seven patients. 100 days after HSCT we had: MRD(neg) for seven patients and a decrease for all the others after HSCT. After the tapering of immunosuppressive drugs, 13 patients reached the MRD(neg) in a median time of 8 months (range 3-16). In the intention to treat analysis, 14/18 patients are alive and disease free at the date of analysis. Overall survival and event free survival is of 78% and 66% respectively, with an average follow-up of 45 months (range 6-84) since HSCT. CONCLUSION: Early transplantation with low MRD level seems to be correlated with a favourable outcome also in VHR-ALL.

Role of blood cells dynamism on hemostatic complications in low-risk patients with essential thrombocythemia.

Patients with essential thrombocythemia (ET) aged less than 60 years, who have not suffered a previous vascular event (low-risk patients), may develop thrombotic or hemorrhagic events. So far, it has not been possible to identify useful markers capable of predicting which of these patients are more likely to develop an event and therefore who needs to be treated. In the present study, we analysed the relationship between vascular complications and longitudinal blood counts of 136 low-risk ET patients taken over a sustained period of time (blood cells dynamism). After a median follow-up of 60 months, 45 out of 136 patients (33%) suffered 40 major thrombotic and 5 severe hemorrhagic complications. A total number of 5,781 blood counts were collected longitudinally. Thrombotic and hemorrhagic events were studied together (primary endpoint) but also separately (thrombotic alone = secondary endpoint; hemorrhagic alone = tertiary endpoint). The primary endpoint showed no significant association between platelet and WBC count at diagnosis and risk of any event (platelet, p = 0.797; WBC, p = 0.178), while Hb at baseline did show an association (p = 0.024). In the dynamic analysis with Cox regression model, where the blood count values were studied by time of follow-up, we observed that the risk for Hb was 1.49 (95% CI 1.13-1.97) for every increase of 1 g/dL, and that this risk then marginally decreased during follow-up. WBC was associated with an increased risk at baseline for every increase of 1 × 10(9)/L (hazard ratio (HR) 1.07, 95% CI 1.01-1.13, p = 0.034), the risk was stable during follow-up (HR 0.95, p = 0.187 at 60 months). Also, for each increment at baseline of 100 × 10(9) platelets/L, HR was increased by 1.08 (95% CI 0.97-1.22, p = 0.159) and decreases during follow-up. In conclusion, this study is the first to evaluate in ET low-risk patients, the risk of developing a thrombotic/hemorrhagic event considering blood counts over time. Overall our study shows that the risk changes over time. For example, the risk associated with WCC is not linear as previously reported. An interesting new finding is that PLT and even Hb contribute to the risk of developing vascular events. Future treatments should take into consideration these findings and aim to control all parameters over time. We believe this early study may help develop a dynamic analysis model to predict thrombosis in the single patient. Further studies are now warranted to further validate our findings.