Carmen Burgaleta

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.

Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera

Criteria of response and definition of resistance and intolerance to hydroxyurea (HU) in polycythemia vera (PV) were proposed by the European LeukemiaNet (ELN). Such criteria were evaluated in 261 PV patients (median follow-up, 7.2 years) treated with HU for a median of 4.4 years. Complete response, partial response, and no response were observed in 24%, 66%, and 10% of patients, respectively. Achieving ELN response (complete or partial) or hematocrit response did not result in better survival or less thrombosis and bleeding. On the contrary, having no response in leukocyte count was associated with higher risk of death (HR, 2.7; 95% confidence interval [CI], 1.3%-5.4%; P = .007), whereas lack of response in platelet count involved a higher risk of thrombosis and bleeding. Resistance and intolerance to HU was registered in 11% and 13% of patients, respectively. Resistance to HU was associated with higher risk of death (HR, 5.6; 95% CI, 2.7%-11.9%; P < .001) and transformation (HR, 6.8; 95% CI, 3.0%-15.4%; P < .001). In summary, fulfilling the ELN definition for response to HU was not associated with a benefit in the clinical outcome in PV, whereas response in platelet and white blood cell counts were predictive of less thrombohemorrhagic complications and better prognosis, respectively. Resistance to HU was an adverse prognostic factor.

HCV‐associated thrombocytopenia: clinical characteristics and platelet response after recombinant α2b‐interferon therapy

Hepatitis C virus (HCV) has been proposed as a possible causative agent of chronic thrombocytopenia. We investigated HCV infection in a series of 51 unselected Spanish patients with chronic acquired thrombocytopenia. Anti‐HCV and HCV viraemia were detected in 13/51 (22·5%) of cases; this prevalence was particularly significant when compared with HCV seropositivity in age‐matched controls (0·4%). Anti‐HCV‐positive patients, four men and nine women with a median age of 59·3 years (range 36–72), had a mean platelet count of 55·8 × 109/l (range 12–96). Only one of our HCV‐positive thrombocytopenic patients had hypersplenism. Platelet‐associated IgG (PAIgG) was negative, as measured by immunofluorescent flow cytometric analysis in 11/13 HCV‐positive thrombocytopenic patients. Thus, thrombocytopenia in our HCV‐positive patients appeared to be non‐autoimmune mediated. In six patients, a trial of recombinant α2b‐interferon (IFN‐α) given at a dose of 3 MU three times per week for 6–24 months gave a durable (> 1 year) and significant increase in platelet count in all six patients. The maximum increase occurred after 6 months of IFN‐α therapy. In conclusion, the ability of IFN‐α to increase platelet counts in HCV‐positive thrombocytopenic patients supports mechanisms involving a direct role for HCV inhibiting platelet production.

Platelet dysfunction in primary thrombocythemia using the platelet function analyzer, PFA-100.

We measured platelet function by standard aggregometric tests and by the PFA-100 (Dade Behring, Newark, DE) in samples from 55 patients with primary thrombocythemia (PT) and 26 healthy volunteers. Platelet function was evaluated in platelet-rich plasma by aggregation tests. PFA-100 studies (closure time) were performed in citrated whole blood using collagen-adenosine diphosphate (ADP) and collagen-epinephrine cartridges. Plasma levels of von Willebrand factor (vWF) also were measured. The mean +/- SD closure time for patients vs volunteers for the collagen-epinephrine cartridge was prolonged (210.8 +/- 62.2 vs 118.1 +/- 19.6 seconds; P < .001); results were abnormal for 38 patients (69%). Results with the collagen-ADP cartridge also were abnormal in patients (134.3 +/- 58.4 seconds) vs volunteers (87.3 +/- 15.6 seconds; P < .001); closure time was prolonged in 23 patients (42%). A decreased response to epinephrine (38.4% +/- 34.2% vs 82.5% +/- 10.3%; P < .001), the main defect detected by platelet aggregation tests, affected 32 patients (58%). Platelet response to collagen also was abnormal (52.0% +/- 34.6% vs 86.0% +/- 10.1%; P < .01) but affected only 21 patients (38%). vWF levels for patients were normal. The results seem to confirm that platelet function in patients with PT is abnormal and show that platelet function can be assessed by an easy, reproducible, and sensitive method, the PFA-100. Closure time usually was prolonged; this feature could be applied in the diagnosis of PT.

Epidemiology and outcome of Rhodotorula infection in haematological patients.

Rhodotorula spp. are emergent opportunistic pathogens, particularly in haematological patients. However, no systematic review of this infection has been undertaken in this high‐risk patient group. The aim of this study was to review all reported cases of Rhodotorula infection to determine the epidemiology and outcome of this infection in this high‐risk population. The 29 reported cases were fungaemias. The most common underlying haematological disorder was the presence of acute leukaemia (65.5%). Rhodotorula mucilaginosa was the species found more frequently (79.3%). Most cases (58.6%) had several risk factors (≥3) simultaneously. The most common predisposing factors were the presence of central venous catheter (CVC, 100%) and neutropenia (62.1%). A substantial number of patients (81.5%) received antifungal treatment with amphotericin B. The overall mortality was higher (13.8%) than that described in non‐haematological patients (5.8% in solid‐organ neoplasms and 9% in AIDS or other chronic diseases). Patients with acute leukaemia had a higher mortality rate (15.7%) than patients with non‐Hodgkin’s lymphoma (0%). Our data suggest that patients with acute leukaemia might be managed as high‐risk patients and intensive measures might be taken. In addition, it appears that the subgroup of patients without acute leukaemia have a good outcome and might be managed as low‐risk patients with a less intensive approach.

Antiplatelet therapy versus observation in low-risk essential thrombocythemia with CALR mutation

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2V617F mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3–42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2V617F-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

Severe acute renal failure following high-dose methotrexate therapy in adults with haematological malignancies: a significant number result from unrecognized co-administration of several drugs

High-dose methotrexate (HDMTX, >1 g/m2) administered as an intravenous (i.v.) infusion is an important component in the treatment regimens for a variety of cancers [1]. HDMTX-associated severe acute renal failure (ARF) is an infrequent but serious complication because MTX is predominantly excreted in the urine. Data from a number of studies performed in the 1970s showed that a sustained elevation of serum MTX concentrations at 24 h (≥5 μmol/L), 48 h (≥1 μmo/L) and 72 h (≥0.1 μmo/L) after the start of the MTX infusion is considered to be toxic. The usual serum MTX level 48 h after HDMTX is <0.1 μmol/L. In the era of optimal supported care the incidence of grade 3–4 ARF after HDMTX has decreased from 10% to 0.6% in solid-cancer patients [2]. However, to our knowledge, the current incidence of HDMTX-associated severe ARF is unknown in adult haematological patients. As the doses of MTX used are generally smaller compared with those received by solid-cancer patients (e.g. patients with osteosarcoma receive a MTX dose >8 g/m2), the risk of severe ARF is perhaps lower. According to large case series, the reason why an individual patient comes down with who develop ARF after HDMTX and modern supported care remains unexplained in the majority of cases [1,3]. Nevertheless, the analysis of potential risk factors was not the main target in these studies; for this reason, these data should be carefully managed. To further define the incidence, predisposing factors and outcome of severe ARF occurring after HDMTX therapy in adults with haematological malignancies, we retro-

Dose‐adjusted EPOCH plus rituximab is an effective regimen in patients with poor‐prognostic untreated diffuse large B‐cell lymphoma: results from a prospective observational study

This study was designed to assess the efficacy and safety of an infusional DA‐EPOCH (dose‐adjusted etoposide/vincristine/doxorubicin/bolus cyclophosphamide/prednisone) and rituximab (DA‐EPOCH‐R) regimen for patients with poor prognosis diffuse large B‐cell lymphoma (DLBCL). Thirty‐three patients, aged 21–76 years, with an age‐adjusted International Prognostic Index (IPI) of 2 or 3, were enrolled, and 31/33 patients were evaluable for response. Consolidative radiation therapy was given to eight patients with bulky (≥10 cm) disease at presentation. Overall, 26 patients (83·8%) achieved a complete remission (CR), four patients (12·9%) achieved a partial remission, and one patient (3·2%) died during induction. Two patients relapsed (7·6%) within 15 months. Grade 3–4 neutropenia developed in 52% of cycles and neutropenic fever in 14% of cycles (51% of patients). The estimates for event‐free survival (EFS) and overall survival at 2 years were 68% and 75% respectively. The only factor related to poor EFS was the presence of three age‐adjusted IPI‐risk factors. We conclude that DA‐EPOCH‐R has clinically significant activity with a favourable toxicity profile for poor‐prognostic DLBCL patients. The administration of DA‐EPOCH‐R as an outpatient regimen by using a single portable infusion pump may be a feasible alternative to improve the compliance and to reduce the total cost of this very effective regimen.

Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm

This study aimed to assess the antitumour effects, molecular mechanisms of action, and potential synergy of ruxolitinib with sorafenib, KNK437, dasatinib, and perifosine, in Philadelphia‐negative chronic myeloproliferative neoplasms (MPN). Cytotoxic and cytostatic effects of the different compounds were determined in the JAK2 V617F‐positive cell lines, HEL and Ba/F3 JAK2V617F EPOR, and in primary mononuclear and bone marrow CD34‐positive cells from 19 MPN patients. Ruxolitinib [50% inhibitory concentration (IC50)PV = 15 nmol/l], as well as sorafenib ( IC50 PV=8μmol/l ), KNK437 ( IC50 PV=100μmol/l ), and perifosine ( IC50 PV=15μmol/l ), were able to inhibit proliferation in cell line models and in primary cells from MPN patients. Dasatinib, KNK437, and sorafenib showed a strong synergistic effect in combination with ruxolitinib [combination index (CI)PV < 0·3]. Western blot confirmed that ruxolitinib blocked ERK, and consequently STAT5 activation, sorafenib inhibited ERK, P38 and STAT5, dasatinib blocked SRC and STAT5, and KNK437 decreased the stability of the JAK2 protein, reducing its expression. Inhibiting JAK2‐related proliferative pathways has the potential to inhibit cell proliferation in MPNs. Furthermore, the combination of ruxolitinib with inhibitors that target these pathways has a strong synergistic effect, which may be due to decreased activation of the common effector, STAT5.

Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera.

The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra‐haematological toxicity (9%). With a median follow‐up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5–8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9–13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3–35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4–76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.