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Between 2002 and 2008, a number of consensus statements and guidelines were developed by various groups around the world to educate healthcare professionals on the treatment of myelodysplastic syndromes (MDS), including the management of transfusional iron overload with iron chelation therapy. Guidelines have been developed by The Italian Society of Hematology, The UK MDS Guidelines Group, The Nagasaki Group, The National Comprehensive Cancer Network, and The MDS Foundation. These guidelines show that the approaches to managing iron overload in patients with MDS are region specific, differing in their recommendations for when iron chelation therapy should be initiated and strategies for the ongoing management of iron overload. The guidelines all agree that red blood cell transfusions are clinically beneficial to treat the symptomatic anemia in MDS, and that patients with low-risk MDS receiving transfusions are the most likely to benefit from iron chelation therapy.

The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR 4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR 4.5 . Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR 4.5 . The Kaplan–Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR 4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.

Iron overload (IOL) starts to develop in MDS patients before they become transfusion-dependent because ineffective erythropoiesis suppresses hepcidin production in the liver and thus leads to unrestrained intestinal iron uptake. However, the most important cause of iron overload in MDS is chronic transfusion therapy. While transfusion dependency by itself is a negative prognostic factor reflecting poor bone marrow function, the ensuing transfusional iron overload has an additional dose-dependent negative impact on the survival of patients with lower risk MDS. Cardiac dysfunction appears to be important in this context, as a consequence of chronic anemia, age-related cardiac comorbidity, and iron overload. Another potential problem is iron-related endothelial dysfunction. There is some evidence that with increasing age, high circulating iron levels worsen the atherosclerotic phenotype. Transfusional IOL also appears to aggravate bone marrow failure in MDS, through unfavorable effects on mesenchymal stromal cells as well a hematopoietic cells, particularly erythroid precursors. Patient series and clinical trials have shown that the iron chelators deferoxamine and deferasirox can improve hematopoiesis in a minority of transfusion-dependent patients. Analyses of registry data suggest that iron chelation provides a survival benefit for patients with MDS, but data from a prospective randomized clinical trial are still lacking.

Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m 2 per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French–American–British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21·1 months (IQR 15·1–26·9), median overall survival was 24·5 months (9·9–not reached) for the azacitidine group versus 15·0 months (5·6–24·1) for the conventional care group (hazard ratio 0·58; 95% CI 0·43–0·77; stratified log-rank p=0·0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50·8% (95% CI 42·1–58·8) of patients in the azacitidine group were alive compared with 26·2% (18·7–34·3) in the conventional care group (p<0·0001). Peripheral cytopenias were the most common grade 3–4 adverse events for all treatments. Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care. Celgene Corporation.

We analysed 3,748 patients with myelodysplastic syndromes (MDS) to evaluate the prevalence and prognostic relevance of bone marrow (BM) iron accumulation at the time of initial diagnosis, its relationship with serum ferritin (SF), and its impact on overall survival (OS). Cytomorphological and/or histopathological BM iron assessment revealed that approximately 50% of patients already had increased iron stores at diagnosis. Elevated BM iron was significantly associated with more severe anaemia, higher SF levels, and lower transferrin levels. BM iron accumulation likely reflects prolonged ineffective erythropoiesis with increased intestinal iron absorption prior to transfusion dependency. Survival analyses demonstrated that increased BM iron adversely affected OS particularly in patients with MDS with increased blasts (MDS IB), whereas no significant effect was observed in lower-blast MDS. Multivariate Cox regression identified age and WHO subtype as the strongest prognostic factors overall, with SF as an independent predictor of OS; notably, in MDS IB, cytomorphological BM iron content emerged as the strongest independent prognostic parameter. These findings support a role for iron-induced oxidative stress in promoting genomic instability and disease progression in higher-risk MDS. We conclude that assessment of BM iron content and serum ferritin at diagnosis provides important prognostic information and should be incorporated into the initial evaluation of MDS patients.

The constitutively active BCR-ABL tyrosine kinase is the cause of chronic myeloid leukemia. Imatinib is the first small synthetic molecular inhibitor of the BCR-ABL tyrosine kinase with clinical activity in chronic-phase myeloid leukemia. This 5-year follow-up of patients with the disease who began continuous treatment with imatinib reports that the drug can induce durable hematologic and cytogenetic responses in a high proportion of patients. This 5-year follow-up of patients with chronic myeloid leukemia who began continuous treatment with imatinib reports that the drug can induce durable hematologic and cytogenetic responses in a high proportion of patients. Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expansion of a clone of hematopoietic cells that carries the Philadelphia chromosome (Ph). 1 The Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11). 2 The molecular consequence of this translocation is a novel fusion gene, BCR-ABL, which encodes a constitutively active protein, tyrosine kinase. 3 – 5 Imatinib (Gleevec, Novartis; formerly called STI571) is a relatively specific inhibitor of the BCR-ABL tyrosine kinase and has efficacy in CML. 6 – 11 Before the availability of imatinib, interferon alfa plus cytarabine was considered standard therapy for patients . . .

X-linked sideroblastic anemia (XLSA) is a hereditary disorder affecting heme biosynthesis, caused by mutations in the ALAS2 gene, which encodes the erythroid-specific enzyme 5-aminolevulinate synthase. This enzyme, which requires pyridoxal 5’-phosphate (PLP) as a cofactor, catalyzes the first and rate-limiting step of heme synthesis in erythroid cells. XLSA is characterized by hypochromic microcytic anemia and ring sideroblasts in bone marrow, with most patients showing variable degrees of response to pyridoxine supplementation; however, female carriers of ALAS2 mutations often present a distinct clinical phenotype. A comprehensive review of the literature reveals over 100 distinct ALAS2 mutations linked to XLSA in more than 240 families. Here, we report seven new patients (four female cases) initially diagnosed with various conditions, later confirmed to have X-linked Sideroblastic Anemia due to ALAS2 mutations through genetic analysis. Among these, five represent novel ALAS2 mutations, including the first ever reported stop-loss mutation in ALAS2 associated with XLSA rather than X-linked dominant protoporphyria (XLDPP). Computational modelling of six reported cases revealed that four mutations significantly impact protein structure, conformation and cofactor interaction, consistent with our enzymatic assays demonstrating reduced ALAS2 activity. Furthermore, X-chromosome studies in female probands revealed a pronounced skewing of X-chromosome, which may provide an explanation for their distinct clinical manifestations in females.

Over the history of myelodysplastic neoplasms (MDS), an increasing number of treatment modalities have become available. It is therefore important to assess whether these developments have translated into improved overall survival (OS) for patients. We analyzed data from 1,147 patients in the German MDS registry and observed a progressive improvement in median survival across three diagnostic periods: until 2000 (20 months), 2001–2010 (31 months), and after 2011 (57 months). Patients treated with allogeneic stem cell transplantation (SCT) had the best prognosis with a median survival of 108 months. Over time, both the proportion of patients undergoing allogeneic SCT (6.3% vs. 22.1% vs. 40.0%) and the median age at transplantation (36.5 vs. 52 vs. 61 years) increased. Notably, OS also improved among patients treated with best supportive care (BSC) alone (17 vs. 31 vs. 64 months; p  < 0.001). Multivariate analysis demonstrated that the period of first diagnosis had an independent positive effect on survival. The underlying reasons for this improvement remain unclear, but a multifactorial origin—including improved supportive measures and greater eligibility for allogeneic SCT—must be considered.

Many patients with myelodysplastic syndromes (MDS) become dependent on blood transfusions and develop transfusional iron overload, which is exacerbated by increased absorption of dietary iron in response to ineffective erythropoiesis. However, it is uncertain whether there is an association among iron accumulation, clinical complications, and decreased likelihood of survival in MDS patients. Here, we discuss our current understanding of the effects of transfusion dependency and iron overload in MDS, indicate our knowledge gaps, and suggest that particular emphasis should be placed on further characterizing the role of redox-active forms of labile iron, which may be as important as the total iron burden.

IntroductionPatients undergoing chemotherapy often experience side effects during treatment, including psychological distress and symptoms of anxiety and depression. Interventions during chemotherapy that divert attention from potentially aversive environmental factors have been demonstrated to have a beneficial impact on these symptoms. Virtual reality (VR) offers the potential to visually and audibly disengage from the surrounding environment and can create an alternative sense of presence. This could facilitate the implementation of active guided interventions that may prove more effective than receptive interventions, such as listening to music. The present study examines the feasibility, acceptance and effectiveness of a VR intervention and a music intervention during chemotherapy.MethodsThe single-centre three-arm, randomised-controlled trial investigates the efficacy of a VR mindfulness intervention and a music intervention in patients with cancer undergoing chemotherapy at the University Hospital Düsseldorf, Germany. Patients were randomly assigned to receive either (a) the VR mindfulness intervention, (b) the receptive music intervention or (c) the standard care (control group) in two consecutive chemotherapy sessions. A comprehensive psychological assessment and self-ratings using visual analogue scales will be conducted with situational anxiety as the primary outcome measure. Additionally, secondary measures will be employed to assess cancer-related anxiety, self-efficacy and chemotherapy-related side effects. Furthermore, salivary cortisol, heart rate and blood pressure will be recorded. At the end of the study, an evaluation questionnaire will be completed. It is planned to enrol 82 patients.Ethics and disseminationThe study has been approved by the ethics committee of the medical faculty of the Heinrich-Heine-University Düsseldorf (2022-1880). Written informed consent is obtained from the patients prior to participation. The results will be published in international scientific, peer-reviewed journals. Conference presentations are also planned.Trial registration numberGerman Clinical Trials Register (DRKS00029738).