Juan-Carlos Hernández-Boluda

Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia

The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 low-risk patients with ET treated with antiplatelet drugs as monotherapy (n = 198) or followed with careful observation (n = 102). Follow-up was 802 and 848 person-years for antiplatelet therapy and observation, respectively. Rates of thrombotic events were 21.2 and 17.7 per 1000 person-years for antiplatelet therapy and observation, respectively (P = .6). JAK2 V617F-positive patients not receiving antiplatelet medication showed an increased risk of venous thrombosis (incidence rate ratio [IRR]: 4.0; 95% CI: 1.2-12.9; P = .02). Patients with cardiovascular risk factors had increased rates of arterial thrombosis while on observation (IRR: 2.5; 95% CI: 1.02-6.1; P = .047). An increased risk of major bleeding was observed in patients with platelet count greater than 1000 x 10(9)/L under antiplatelet therapy (IRR: 5.4; 95% CI: 1.7-17.2; P = .004). In conclusion, antiplatelet therapy reduces the incidence of venous thrombosis in patients with JAK2-positive ET and the rate of arterial thrombosis in patients with associated cardiovascular risk factors. In the remaining low-risk patients, this therapy is not effective as primary prophylaxis of thrombosis, and observation may be an adequate option.

Darbepoetin-alpha for the anaemia of myelofibrosis with myeloid metaplasia

Darbepoetin‐α, a novel hyperglycosylated erythropoiesis‐stimulating protein, was administered to 20 patients with myelofibrosis with myeloid metaplasia and anaemia. The initial weekly dose, 150 μg, was increased to 300 μg when no response was observed after 4–8 weeks. Eight patients (40%) responded to treatment, including six complete and two partial responses, and five maintained their response at a median follow‐up of 12 months (range 4–22). Univariate analysis indicated that older age was the only factor associated with a favourable response to treatment (P = 0.006). None of the patients with appropriate serum erythropoietin levels responded. Treatment was usually well tolerated.

Correlation between genetic polymorphisms of the hOCT1 and MDR1 genes and the response to imatinib in patients newly diagnosed with chronic-phase chronic myeloid leukemia

The association between seven polymorphisms in the genes hOCT1 and MDR1, encoding for imatinib transporter proteins, and the response to imatinib 400mg/daily was investigated in 65 patients newly diagnosed with chronic-phase chronic myeloid leukemia. The AA genotype at the rs6935207 hOCT1 polymorphic locus was not detected in patients with inadequate response to imatinib. The CC genotype at the rs1045642 (C3435T) MDR1 locus was associated with primary failure, whereas a T allele at the rs2032582 (G2677T/A) MDR1 locus seemed to protect from primary failure. Beside, the MDR1 haplotype 1236T-2677G-3435C was more frequently found in patients primarily resistant to imatinib.

Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia

Standardized criteria of response to treatment and a unified definition of resistance/intolerance to hydroxycarbamide (HC) in essential thrombocythaemia (ET) have been proposed by the European LeukaemiaNet (ELN). We have retrospectively evaluated such criteria in 166 ET patients treated with HC for a median of 4·5 years. Overall, 134 patients achieved a complete clinicohaematological response (CR) and 25 a partial response. Thirty‐three patients met at least one of the ELN criteria defining resistance (n = 15) or intolerance (n = 21) to HC. Fifteen cases developed anaemia with thrombocytosis, which was associated with a high incidence of myelofibrosis and death from any cause. Other definitions of resistance were less useful. Factors determining the thrombotic risk were a history of prior thrombosis and a baseline leucocyte count >10 × 109/l. Of note, patients achieving a CR, even if sustained during the entire follow‐up, did not benefit from a lower incidence of thrombosis or an improved survival. In conclusion, most ET patients respond to HC, but the achievement of response, as defined by the ELN, does not correlate with the patients’ outcome. The best discriminating ELN criterion of resistance to HC was the detection of anaemia, which also identified a subgroup of patients with poor prognosis.

Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group

Background Despite the favorable results of imatinib front line in chronic-phase chronic myeloid leukemia there is room for improvement. Design and Methods Early intervention during imatinib therapy was undertaken in 210 adults with chronic-phase chronic myeloid leukemia less than three months from diagnosis (Sokal high risk: 16%). Patients received imatinib 400 mg/day. At three months, dose was increased if complete hematologic response was not achieved. At six months, patients in complete cytogenetic response were kept on 400 mg and the remainder randomized to higher imatinib dose or 400 mg plus interferon-alfa. At 18 months, randomized patients were switched to a 2nd generation tyrosine kinase inhibitor if not in complete cytogenetic response and imatinib dose increased in non-randomized patients not in major molecular response. Results Seventy-two percent of patients started imatinib within one month from diagnosis. Median follow-up is 50.5 (range: 1.2–78) months. At three months 4 patients did not have complete hematologic response; at six months 73.8% were in complete cytogenetic response; among the remainder, 9 could not be randomized (toxicity or consent withdrawal), 17 were assigned to high imatinib dose, and 15 to 400 mg + interferon-alpha. The low number of randomized patients precluded comparison between the two arms. Cumulative response at three years was: complete hematologic response 98.6%, complete cytogenetic response 90% and major molecular response 82%. On an intention-to-treat basis, complete cytogenetic response was 78.8% at 18 months. At five years, survival was 97.5%, survival free from accelerated/blastic phase 94.3%, failure free survival 82.5%, and event free survival (including permanent imatinib discontinuation) 71.5%. Conclusions These results indicate the benefit of early intervention during imatinib therapy (ClinicalTrials.gov Identifier: NCT00390897).

A polymorphism in the XPD gene predisposes to leukemic transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera

Patients with essential thrombocythemia (ET) and polycythemia vera (PV) have an increased incidence of acute myeloid leukemia and new nonhematologic malignancies compared with the general population. However, information on the factors determining the risk for such complications is limited. In the present study, we investigated whether constitutional genetic variations in DNA repair predispose to leukemic transformation and new nonmyeloid neoplasias in patients with ET and PV. Case-control studies for predisposition to both types of malignancies were nested in a cohort of 422 subjects diagnosed with ET or PV during the period 1973-2010 in several institutions in Spain. A total of 64 incidence cases of leukemia and 50 cases of primary nonmyeloid cancers were accrued. At conditional regression analysis, the Gln/Gln genotype in the XPD codon 751 showed the strongest association with both leukemic transformation (odds ratio [OR] = 4.9; 95% confidence interval [95% CI], 2.0-12) and development of nonmyeloid malignancies (OR = 4.2; 95% CI, 1.5-12). Additional predictive factors were exposure to cytoreductive agents for leukemic transformation (OR = 3.5; 95% CI, 2.0-6.2) and age for nonmyeloid malignancies (OR = 2.0; 95% CI, 1.4-2.8). These findings provide further evidence about the contribution of inherited genetic variations to the pathogenesis and clinical course of myeloproliferative neoplasms.

The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis

Myelofibrotic transformation is a well-recognized complication of essential thrombocythemia (ET) and polycythemia vera (PV).[1][1],[2][2] However, information is scarce on the life expectancy and prognostic factors of patients developing this complication.[1][1],[3][3]–[5][4] Prognostic models

Survivin expression in the progression of chronic myeloid leukemia: A sequential study in 16 patients

An increase in the proliferation and resistance to apoptosis of leukemic cells has been found in chronic myeloid leukemia (CML) as the disease evolves from the chronic phase to blast crisis (BC). To contribute to a better knowledge of the molecular mechanisms involved in such biological abnormality, the expression of the survivin gene was studied by quantitative real-time polymerase chain reaction (PCR) in the chronic phase of CML and at BC in 16 patients in whom sequential RNA samples from the 2 phases of the disease were available. Survivin was significantly overexpressed in both the chronic phase and BC as compared with granulocytes from controls. In BC, survivin expression was 7-fold higher than in the chronic phase, with such an increase being more pronounced in the myeloid (17-fold) than in the lymphoid cases (3-fold) (P = 0.03). Cell proliferation was significantly increased at BC, with Ki-67 expression being 2.8-fold higher than in the chronic phase. Despite the overexpression of both survivin and Ki-67 at BC, no significant correlation between their expression levels was observed. These data support a possible role for survivin overexpression in the pathogenesis of the progression of CML. However, further studies are required to elucidate the possible prognostic importance of such biological findings in this disease.

Cytoreduction plus low-dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high-risk essential thrombocythaemia: an observational study.

The effectiveness of low‐dose aspirin in the primary prevention of thrombosis in patients with high‐risk essential thrombocythaemia (ET) treated with cytoreductive drugs is not well established. The risk‐benefit balance of low‐dose aspirin plus cytoreductive therapy compared with cytoreduction alone was retrospectively analysed in 247 patients with high‐risk ET without prior thrombosis. Follow‐up was 763 and 685 person‐years for cytoreduction plus low‐dose aspirin and cytoreduction alone, respectively. The rate of thrombosis was not significantly reduced in patients on cytoreduction plus aspirin (14·4 events per 1000 person‐years) when compared with those on cytoreduction alone (24·8 events per 1000 person‐years; P = 0·2). However, in the subgroup of patients older than 60 years, the addition of low‐dose aspirin was associated with a significantly lower rate of thrombosis (8·6 vs. 29·2 thrombosis per 1000 person‐years for combined treatment and cytoreduction alone, respectively, P = 0·02). The rate of major bleeding was significantly higher with combined therapy than with cytoreduction alone both in the whole series (14·4 vs. 1·4 haemorrhagic events per 1000 person‐years, respectively, P = 0·006) and in the subgroup of patients older than 60 years. In conclusion, low‐dose aspirin benefits high‐risk ET patients older than 60 years receiving cytoreductive therapy as primary prophylaxis of thrombosis.

Oral anticoagulation to prevent thrombosis recurrence in polycythemia vera and essential thrombocythemia.

It is unclear whether anticoagulation guidelines intended for the general population are applicable to patients with polycythemia vera (PV) and essential thrombocythemia (ET). In the present study, the risk of thrombotic recurrence was analyzed in 150 patients with PV and ET treated with vitamin K antagonists (VKA) because of an arterial or venous thrombosis. After an observation period of 963 patient-years, the incidence of re-thrombosis was 4.5 and 12 per 100 patient-years under VKA therapy and after stopping it, respectively (P < 0.0005). After a multivariate adjustment for other prognostic factors, VKA treatment was associated with a 2.8-fold reduction in the risk of thrombotic recurrence. Notably, VKA therapy offset the increased risk of re-thrombosis associated with a prior history of remote thrombosis. Both the protective effect of VKA therapy and the predisposing factors for recurrence were independent of the anatomical site involved in the index thrombosis. Treatment periods with VKA did not result in a higher incidence of major bleeding as compared with those without VKA. These findings support the use of long-term anticoagulation for the secondary prevention of thrombosis in patients with PV and ET, particularly in those with history of remote thrombosis.