The online version of this article has a Supplementary Appendix. BackgroundFollowing a clinical evaluation of deferasirox (Exjade ® ) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged ≥2 years) with transfusional hemosiderosis from various types of anemia. Design and MethodsThe recommended initial dose was 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline. ResultsThe 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (-264 ng/mL; P<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (>5%) adverse events were gastrointestinal disturbances (28%) and skin rash (10%). ConclusionsAnalysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821).

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The identification of an acquired mutation of JAK2 in patients with myeloproliferative disorders has raised questions about the relationship between mutationpositive and mutation-negative subtypes, timing of the JAK2 mutation, and molecular mechanisms of disease progression. Here we demonstrate that patients with V617F ؊ essential thrombocythemia do not commonly progress to become V617F ؉ . Consistent with the concept of distinct pathogenetic mechanisms, we show that patients with and without the JAK2 mutation have different patterns of cytogenetic abnormality, with virtually all patients carrying the 20q deletion or trisomy 9 being V617F ؉ . We also investigated the existence of a "pre-JAK2 " phase by comparing the proportion of clonally derived granulocytes, estimated from X-chromosome inactivation patterns (XCIPs), with the proportion of V617F ؉ granulocytes.

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Several studies suggest an implication of transforming growth factor-␤1 (TGF-␤1) in the promotion of myelofibrosis associated with hematopoietic malignancies, but the involvement of this cytokine is not fully investigated. To test directly the impact of TGF-␤1 in the pathogenesis of myelofibrosis, bone marrow stem cells from homozygous TGF-␤1 null (TGF-␤1 ؊/؊ ) and wild-type (WT) littermates were infected with a retrovirus encoding the murine thrombopoietin (TPO) protein and engrafted into lethally irradiated wildtype hosts for long-term reconstitution. Over the 4 months of follow-up, TPO levels in plasma were markedly elevated in both groups of mice, and animals typically developed a myeloproliferative syndrome characterized by thrombocytosis, leukocytosis, splenomegaly, increased numbers of progenitors in blood, and extramedullary hematopoiesis. Severe fibrosis was observed in spleen and marrow from all the mice engrafted with WT cells. In contrast, none of the mice repopulated with TGF-␤1 ؊/؊ cells (chimerism > 70%) showed deposition of reticulin fibers at any time during the follow-up. In accordance with the development of fibrosis, latent TGF-␤1 levels in plasma and extracellular fluid of the spleen from mice engrafted with WT cells were increased 6-fold and 4-fold, respectively, over levels found in normal hosts, whereas no increase over baseline levels could be demonstrated in animals undergoing transplantation with TGF-␤1 ؊/؊ cells. These data provide evidence that TGF-␤1 produced by hematopoietic cells is pivotal for the pathogenesis of myelofibrosis that develops in mice with TPO overexpression. (Blood. 2002;100:3495-3503)

The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P ¼ 0.003). With a median follow-up of 39.2 months (6.3-67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P ¼ 0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P ¼ 0.014), and a worse progression-free survival (PFS) for T315I mutations (P ¼ 0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.

In myelodysplastic syndromes (MDS), anemia responds to recombinant human erythropoietin (rHuEPO) alone and in combination with recombinant human granulocyte-colony-stimulating factor (rHuG-CSF) in 10% to 20% and in 35% to 40% of patients, respectively. We randomly divided 60 patients with low-grade anemic MDS and serum EPO levels lower than 500 IU/L (500 mU/mL) into 2 groups: rHuEPO ؉ rHuG-CSF (arm A) and supportive care (arm B). After 12 weeks, those who had erythroid responses were given rHuEPO alone for 40 additional weeks.They were also given rHuG-CSF if they had relapses. A response was considered major if the hemoglobin (Hb) level was 115 g/L (11.5 g/dL) or higher and minor Hb increase was 15 g/L (1.5 g/dL) or more or if it remained stable without transfusion. Ten of 24 patients responded in arm A, and 0 of 26 responded in arm B (P ‫؍‬ .01). Eight patients in arm A continued rHuEPO therapy alone, and 6 had relapses. Responses were always restored when rHuG-CSF was reintroduced. IntroductionMyelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis, peripheral cytopenia, and increased risk for acute myelogenous leukemia (AML). Approximately two thirds of patients with MDS have anemia at diagnosis, and it develops in nearly all the rest as the disease progresses. Many MDS patients require frequent transfusions, leading to secondary hemochromatosis and risk for viral infections. In low-risk MDS, anemia is often the major clinical problem. Anemia significantly affects quality of life and causes significant morbidity in older patients. Cardiovascular diseases are often aggravated. Treatment of anemia with recombinant human erythropoietin (rHuEPO) alone is effective only in a small percentage of MDS patients. A meta-analysis of 205 patients with MDS showed that 16% responded to rHuEPO alone. 1 Patients who responded to treatment had no or limited transfusion requirements. Granulocytecolony-stimulating factor (G-CSF) and granulocyte macrophagecolony-stimulating factor (GM-CSF) increase neutrophil counts, do not increase the risk for leukemia, and have no effect on survival. [2][3][4] When combined with myeloid cytokines, rHuEPO can have synergistic effects on erythropoiesis in vitro. 5,6 Some clinical studies have shown that the combination of rHuG-CSF and rHuEPO has a better response rate (40%-50%) than rHuEPO alone. [7][8][9][10][11][12] However, none of these clinical trials were randomized, and cost analyses and quality-of-life evaluations are lacking. In one randomized study, the response rate was similar with GM-CSF plus EPO and with placebo 4 In these studies, only a small proportion of subjects with baseline serum EPO concentrations exceeding 500 IU/L (500 mU/mL) responded to treatment. 9 Therefore, we designed a multicenter randomized trial comparing treatment with rHuEPO plus rHuG-CSF and supportive care in patients with MDS who had serum EPO concentrations lower than or equal to 500 IU/L (500 mU/mL) to determine the effect of this Patients, materials...

The JAK2 V617F mutation has recently been described as an essential oncogenic event associated with polycythemia vera (PV), idiopathic myelofibrosis (IMF), and essential thrombocythemia. This mutation has been detected in all myeloid lineages but has not yet been detected in lymphoid cells. This raises the question whether this molecular event occurs in a true lymphomyeloid progenitor cell. In this work, we studied the presence of the mutation in peripheral