BackgroundUsefulness of iron chelation therapy in myelodysplastic patients is still under debate but many authors suggest its possible role in improving survival of low-risk myelodysplastic patients. Several reports have described an unexpected effect of iron chelators, such as an improvement in hemoglobin levels, in patients affected by myelodysplastic syndromes. Furthermore, the novel chelator deferasirox induces a similar improvement more rapidly. Nuclear factor-κB is a key regulator of many cellular processes and its impaired activity has been described in different myeloid malignancies including myelodysplastic syndromes. Design and MethodsWe evaluated deferasirox activity on nuclear factor-κB in myelodysplastic syndromes as a possible mechanism involved in hemoglobin improvement during in vivo treatment. Forty peripheral blood samples collected from myelodysplastic syndrome patients were incubated with 50 μM deferasirox for 18h. ResultsNuclear factor-κB activity dramatically decreased in samples showing high basal activity as well as in cell lines, whereas no similar behavior was observed with other iron chelators despite a similar reduction in reactive oxygen species levels. Additionally, ferric hydroxyquinoline incubation did not decrease deferasirox activity in K562 cells suggesting the mechanism of action of the drug is independent from cell iron deprivation by chelation. Finally, incubation with both etoposide and deferasirox induced an increase in K562 apoptotic rate. ConclusionsNuclear factor-κB inhibition by deferasirox is not seen from other chelators and is iron and reactive oxygen species scavenging independent. This could explain the hemoglobin improvement after in vivo treatment, such that our hypothesis needs to be validated in further prospective studies.Key words: iron chelation therapy, nuclear factor-κB, myelodysplastic symdrome. Haematologica 2010;95(8):1308-1316. doi:10.3324/haematol.2009 Deferasirox is a powerful NF-κB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging Citation: Messa E, Carturan S, Maffè C, Pautasso M, Bracco E, Roetto A, Messa F, Arruga F, Defilippi I, Rosso V, Zanone C, Rotolo A, Greco E, Pellegrino RM, Alberti D, Saglio G, and Cilloni D. Deferasirox is a powerful NF-κB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging.

The Wilms' tumor gene WT1 is a reliable marker for minimal residual disease assessment in acute leukemia patients. The study was designed to demonstrate the potential use of WT1 to establish quality of remission in acute leukemia patients for early identification of patients at high risk of relapse. A prospective study based on a quantitative Real-Time PCR (TaqMan) assay in 562 peripheral blood samples collected from 82 acute leukemia patients at diagnosis and during follow-up was established. The evaluation of WT1 in peripheral blood samples after induction chemotherapy can distinguish the continuous complete remission patients from those who obtain only an "apparent" complete remission and who could relapse within a few months. WT1 helps identify patients at high risk of relapse soon after induction chemotherapy allowing post-induction therapy in high risk patients to be intensified. Key words: WT1, minimal residual disease, acute leukemia, RQ-PCRCitation: Cilloni D, Messa F, Arruga F, Defilippi I, Gottardi E, Fava M, Carturan S, Catalano R, Bracco E, Messa E, Nicoli P, Diverio D, Sanz MA, Martinelli G, Lo-Coco F, and Saglio G. Early prediction of treatment outcome in acute myeloid leukemia by measurement of WT1 transcript levels in peripheral blood samples collected after chemotherapy. Haematologica 2008 June; 93(6):921-924.

Transfusion-induced iron overload is a frequent problem that clinicians have to face in the treatment of patients affected by both myelodysplastic syndrome (MDS) and primary myelofibrosis (PMF). Different options are currently available for chelation therapy, e.g. oral once-daily administration of the iron chelator deferasirox. In 3 patients with MDS and 1 patient with PMF, deferasirox therapy resulted in an improvement in the hemoglobin level and a reduction in transfusion dependence. Our data open new insights regarding the benefit of iron chelation therapy not only for transfusional iron overload of myelodysplastic and myelofibrotic patients but also for the increase in hemoglobin levels. The biological mechanism of action of deferasirox, an effect which is not shared by other iron chelators, is still obscure and requires further investigations

Imatinib represents at present the most attractive therapy for BCR-ABL positive leukemias, even though a percentage of CML patients develop resistance to this compound. For these resistant patients a therapeutic approach based on a combination of drugs is more likely to be effective. In the last years, constitutive NF-jB/Rel activity has been demonstrated in several hematological malignancies. As a result, NFkB/Relblocking approaches have been proposed as antineoplastic strategies. Furthermore, the identification of specific kinases within the NF-jB activation pathway offers a selective target to address tailored therapies. In the current study, we show that the IKK inhibitor PS1145 is able to inhibit the proliferation of CML cell lines and primary BM cells. Moreover, the addition of Imatinib increases the effects of PS1145 in resistant cell lines and BM cells from resistant patients, with a further increase of apoptosis and inhibition of proliferation and colony growth. Our data provide the rational for a new therapeutic approach, which combines Imatinib and the IKK inhibitor PS1145 in CML resistant patients.

BACKGROUNDThe authors investigated the efficacy and safety of the histone deacetylase inhibitors valproic acid (VPA) and all‐trans retinoic acid (ATRA) as differentiation agents in a cohort of older, poor‐risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).METHODSTwenty older patients with recurrent or refractory AML or MDS were treated in a Phase II protocol with sequential VPA and ATRA therapy. VPA was started at a dose of 10 mg/kg per day and then escalated to achieve the serum concentration of 45–100 μg/mL. ATRA was added at 45 mg/square meters (sm) per day when VPA reached the target serum concentration. Only patients treated continuously for ≥ 2 months were considered evaluable.RESULTSHematologic improvement, according to World Health Organization criteria, was observed in 6 of 20 patients enrolled in the protocol but in 6 of 11 considered evaluable. In five patients, a major platelet response was observed, achieving platelet transfusion independence. Three of these five patients also exhibited a minor erythroid response. A sixth patient showed both a minor erythroid response and a platelet response. The median duration of response was 189 days (range, 63–550 days). No significant reduction in the blast count was observed. Grade 3 neurocortical toxicity was observed in four patients. Severe bone pain was experienced by 4 patients (2 Grade 4 and 2 Grade 3) and was associated with an increase in the peripheral blast cell count. Treatment with ATRA did not modify the response observed with VPA alone.CONCLUSIONSDifferentiation therapy with VPA was of clinical benefit in approximately 30% of elderly patients with AML and MDS of the refractory anemia with excess of blast type with unfavorable prognostic features. A striking platelet transfusion independence lasting several months may be obtained in some patients, reducing the burden of palliative care and improving the quality of life. Cancer 2005;. © 2005 American Cancer Society.