Manuel Pérez-Encinas

Clinical significance of CD56 expression in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens

The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56(+) (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56(+) APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56(+) APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56(-) APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56(+) APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin-derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.

Therapy-Related Myeloid Neoplasms in Patients With Acute Promyelocytic Leukemia Treated With All-Trans-Retinoic Acid and Anthracycline-Based Chemotherapy

PURPOSE We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR). PATIENTS AND METHODS From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy. RESULTS Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with > or = 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months. CONCLUSION t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.

Somatic mutations in calreticulin can be found in pedigrees with familial predisposition to myeloproliferative neoplasms

To the editor: JAK2 -V617F is the most frequently observed somatic mutation in patients with myeloproliferative neoplasms (MPNs).[1][1],[2][2] Recently, mutations in CALR were described in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) that were negative for JAK2 -

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.

Hydroxyurea-induced acute interstitial pneumonitis in a patient with essential thrombocythemia

Abstract Hydroxyurea is a drug widely used to control myeloproliferative disorders, due in part to its relative lack of severe side effects. We present a case of acute interstitial pneumonitis in a patient who was treated with hydroxyurea for essential thrombocythemia. The clinical course suggests that the interstitial pneumonitis was induced by hydroxyurea. This is the first case of hydroxyurea-induced acute interstitial pneumonitis reported in the literature.

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.

Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea.

Hematocrit control below 45% is associated with a lower rate of thrombosis in polycythemia vera. In patients receiving hydroxyurea, this target can be achieved with hydroxyurea alone or with the combination of hydroxyurea plus phlebotomies. However, the clinical implications of phlebotomy requirement under hydroxyurea therapy are unknown. The aim of this study was to evaluate the need for additional phlebotomies during the first five years of hydroxyurea therapy in 533 patients with polycythemia vera. Patients requiring 3 or more phlebotomies per year (n=85, 16%) showed a worse hematocrit control than those requiring 2 or less phlebotomies per year (n=448, 84%). There were no significant differences between the two study groups regarding leukocyte and platelet counts. Patients requiring 3 or more phlebotomies per year received significantly higher doses of hydroxyurea than the remaining patients. A significant higher rate of thrombosis was found in patients treated with hydroxyurea plus 3 or more phlebotomies per year compared to hydroxyurea with 0–2 phlebotomies per year (20.5% vs. 5.3% at 3 years; P<0.0001). In multivariate analysis, independent risk factors for thrombosis were phlebotomy dependency (HR: 3.3, 95%CI: 1.5–6.9; P=0.002) and thrombosis at diagnosis (HR: 4.7, 95%CI: 2.3–9.8; P<0.0001). The proportion of patients fulfilling the European LeukemiaNet criteria of resistance/intolerance to hydroxyurea was significantly higher in the group requiring 3 or more phlebotomies per year (18.7% vs. 7.1%; P=0.001) mainly due to extrahematologic toxicity. In conclusion, phlebotomy requirement under hydroxyurea therapy identifies a subset of patients with increased proliferation of polycythemia vera and higher risk of thrombosis.

A prognostic model for survival after salvage treatment with FLAG-Ida +/− gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia

The combination of fludarabine, cytarabine, idarubicin, and granulocyte colony‐stimulating factor (FLAG‐Ida) is widely used in relapsed/refractory acute myeloid leukaemia (AML). We retrospectively analysed the results of 259 adult AML patients treated as first salvage with FLAG‐Ida or FLAG‐Ida plus Gentuzumab‐Ozogamicin (FLAGO‐Ida) of the Programa Español de Tratamientos en Hematología (PETHEMA) database, developing a prognostic score system of survival in this setting (SALFLAGE score). Overall, 221 patients received FLAG‐Ida and 38 FLAGO‐Ida; 92 were older than 60 years. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 51%, with 9% of induction deaths. Three covariates were associated with lower CR/CRi: high‐risk cytogenetics and t(8;21) at diagnosis, no previous allogeneic stem cell transplantation (allo‐SCT) and relapse‐free interval <1 year. Allo‐SCT was performed in second CR in 60 patients (23%). The median overall survival (OS) of the entire cohort was 0·7 years, with 22% OS at 5‐years. Four independent variables were used to construct the score: cytogenetics, FLT3‐internal tandem duplication, length of relapse‐free interval and previous allo‐SCT. Using this stratification system, three groups were defined: favourable (26% of patients), intermediate (29%) and poor‐risk (45%), with an expected 5‐year OS of 52%, 26% and 7%, respectively. The SALFLAGE score discriminated a subset of patients with an acceptable long‐term outcome using FLAG‐Ida/FLAGO‐Ida regimen. The results of this retrospective analysis should be validated in independent external cohorts.

Clinical characteristics, prognosis and treatment of myelofibrosis patients with severe thrombocytopenia

Charles R. Jonassaint Amit Birenboim Dana Rae Jorgensen Enrico M. Novelli Andrea L. Rosso Center for Smart Technology and Behavioral Health, Department of Medicine, Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, USA, Department of Human Geography and Planning, Utrecht University, Utrecht, the Netherlands, Department of Epidemiology, School of Public Health, University of Pittsburgh, and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, USA E-mail: jonassaintcr@upmc.edu

Predictive factors for anemia response to erythropoiesis-stimulating agents in myelofibrosis

Erythropoiesis‐stimulating agents (ESAs) are commonly used to treat the anemia of myelofibrosis (MF), but information on the predictors of response is limited.