Cardiac effects of deferasirox in transfusion-dependent patients with myelodysplastic syndromes: TELESTO study.

Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy.

BACKGROUND: The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis. METHODS: Expression of BRAF was analyzed by RT-qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK-8 assay. Network pharmacology and RNA-sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model. RESULTS: Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse. CONCLUSIONS: Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.

[Transfusions and iron chelation in myelodysplastic syndromes]. / Transfusions et chélation du fer dans les syndromes myélodysplasiques.

Iron overload (IO) is probably as toxic in elderly patients with low-risk myelodysplastic syndromes (MDS) as in young thalassemic patients. This impact is more difficult to demonstrate because of associated comorbidities. Cardiovascular disease increases vulnerability to the toxic effects of IO. In recent years, registry studies have shown a survival benefit of Iron Chelation Therapy (ICT) in these patients. These findings are now corroborated by an improvement in event-free survival in a single randomized study: the Telesto study. The EFS curves separate after two years of follow-up. This indicates inertia in the occurrence of complications. The benefits of ICT are also very slowly being revealed. It is possible to offer ICT to patients with transfusion-dependent MDS with a life expectancy of at least two years. In Telesto, patients had a serum ferritin (F) level of at least 1000ng/mL, recommendations using this F threshold as a trigger for chelation seem to be reinforced. It remains an open question whether chelation should be started earlier for effective suppression of IO-related oxidative stress. ICTs could be used in transfusion-dependent MDS patients with life expectancy greater than two years. including possibly higher risk patients responding to hypomethylating agents.

Prevalence and treatment of anemia and secondary iron overload in patients with a myelodysplastic syndrome: Real-world data from a multicenter cohort study.

BACKGROUND: anemia is the most common finding in patients with a myelodysplastic syndrome (MDS). Repetitive red blood cell (RBC) transfusions and disease-related low hepcidin levels induce secondary iron overload. Real-world data on the prevalence and treatment strategies of anemia and secondary iron overload in MDS patients, is limited. METHODS: three years of data on MDS diagnosis, anemia and ferritin management was collected in 230 MDS patients from seven non-academic hospitals in the Netherlands. Descriptive statistics and linear mixed models were used to analyze the data. RESULTS: transfusion dependent (TD) patients (n = 49) needed 1-3 RBC transfusions per month. Serum hemoglobin remained stable in both TD and transfusion-independent (TI) patients over 3 years. In the TD patients, serum ferritin increased 63 pmol/L/month. Overall, 19 (39%) were diagnosed with secondary hemochromatosis, of which 13 (68%) received chelation therapy with a heterogeneous response. CONCLUSIONS: mean hemoglobin remains stable over time in both TD and TI MDS patients. Approximately 40% of TD patients develop secondary hemochromatosis. Treatment and monitoring of secondary hemochromatosis as well as the response on chelation therapy vary substantially.

Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. PROCEDURE: We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4 years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor therapies. RESULTS: With a median follow-up of 41.6 months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II-IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025). CONCLUSIONS: Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.

Vitamin B6 Deficiency Anemia Attributed to Levodopa/Carbidopa Intestinal Gel Therapy for Parkinson's Disease: A Diagnostic Pitfall for Myelodysplastic Syndrome with Ring Sideroblasts.

Vitamin B6 (VB6) is essential to heme synthesis, and its deficiency can lead to anemia. VB6 deficiency anemia is typically microcytic, hypochromic, and sideroblastic. VB6 deficiency is a well-recognized complication of levodopa/carbidopa therapy, as metabolism of levodopa to dopamine is VB6-dependent, and carbidopa irreversibly forms bonds and deactivates VB6. We herein report a 75-year-old man with advanced Parkinson's disease who developed severe VB6 deficiency anemia due to levodopa/carbidopa intestinal gel therapy. His anemia was promptly resolved with simple oral supplementation of pyridoxal phosphate hydrate. VB6 deficiency anemia can mimic myelodysplastic syndrome and thus is an important differential diagnosis for patients administered levodopa/carbidopa.

Clonal cytopenia of undetermined significance and atypical Behçet's: the importance of zinc.

Atypical Behçet's is recognised in myelodysplastic syndrome (MDS) cases and is associated with trisomy 8. Clonal cytopenia of undetermined significance (CCUS) is recognised as a precursor to MDS. Our case describes the presentation of atypical Behçet's, in association with CCUS, post a Streptococcal infection. A mutation of a zinc finger RNA spliceosome, ZRSR2, is also described. Our patient initially presented with macrocytic anaemia, together with neutropenia and lymphocytopenia on routine monitoring. Later gastrointestinal symptoms together with oral and anal ulcerations developed. He was treated with oral zinc therapy and had resolution of recurrent oral ulcerations and significant reduction in severity of anal ulcerations. The functional impact of ZRSR2 mutation on spliceosome assembly is yet to be defined, but has been previously reported in CCUS with a clinical phenotype of macrocytic anaemia.

Impact of iron overload on poor graft function after allo-HSCT in a patient with transfusion-dependent low-risk MDS: A case report and literature review.

RATIONALE: Poor graft function (PGF) occurs in 5% to 27% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is associated with high life-threatening complications. The etiology of PGF is complex and multifactorial, and iron overload (IOL) is considered as a predictive factor. PATIENT CONCERN: A 45-years-old woman who was diagnosed as low-risk myelodysplastic syndrome in 2012 has been transfusion dependent and developed severe IOL. DIAGNOSES: Due to transfusion dependency and also ineffective erythropoiesis, this patient was diagnosed as IOL and developed PGF after allo-HSCT. INTERVENTIONS: Deferasirox (20mg/kg/d) was administered regularly after allo-HSCT for 2 years. OUTCOMES: Hematopoiesis was gradually recovered during iron chelation therapy treatment after allo-HSCT and PGF was reverted. LESSONS: IOL, as a prognostic factor for PGF, is a common problem in Transfusion dependent myelodysplastic syndrome patients undergoing HSCT. IOL issues should be considered at the time of diagnosis and throughout the treatment course for patients who are potential candidates for HSCT.

Intracellular ROS profile in hematopoietic progenitors of MDS patients: association with blast count and iron overload.

Objectives: Reactive oxygen species (ROS) are under scrutiny as a participant in the pathophysiology of myelodysplastic syndrome (MDS) and the progression of MDS to acute myeloid leukemia (AML). Measurement of intracellular ROS (iROS) is particularly important since iROS is a direct indicator of cellular health and integrity.Methods: We developed a technique to measure standardize iROS (siROS) level in lymphocytes and bone marrow (BM) CD34+ hematopoietic progenitors using the fluorescent probe dichlorofluorescein (DCF). We then quantified the siROS in 38 consecutive BM specimens from 27 MDS patients over the course of 10 months. Disease outcome of these patients were also assessed.Results: High serum ferritin, high blast count and poor IPSS were associated with inferior survival and AML progression in this cohort. High blast MDS patients had lower siROS in their BM CD34+ cells than those of low blast patients, consistent with increased reliance on glycolysis and enhanced ROS defense in high blast MDS. We also observed narrower siROS distribution in the BM CD34+ cells of high blast patients, suggesting that loss of heterogeneity in ROS content accompanies the clonal evolution of MDS. Furthermore, we observed a strong correlation between CD34+ cells siROS and serum ferritin level in high blast patients. In one case, iron chelation therapy (ICT) resulted in parallel decreases in serum ferritin and CD34+ cells siROS.Conclusion: Our findings established the siROS profile in early hematopoietic cells of MDS patients and its relationship with blast count and iron overload.

Association between red blood cell transfusion dependence and burden in patients with myelodysplastic syndromes: A systematic literature review and meta-analysis.

Myelodysplastic syndromes (MDS) are a group of malignant hematologic diseases characterized by ineffective hematopoiesis, which may lead to chronic anemia and transfusion dependency, with up to 30% of patients progressing to acute myeloid leukemia (AML). Studies suggest transfusion dependency may impact overall survival (OS); however, there is a lack of evidence concerning the association between transfusion status (TS) and OS in patients with MDS who become transfusion independent (TI) after treatment. In addition, the holistic impact of TS on other clinical, economic, and humanistic outcomes has not been well understood. We conducted a systematic literature review (SLR) to understand this impact. Ten studies were included and showed consistent decrease in OS in transfusion dependent (TD) compared with TI patients. These findings were confirmed by a meta-analysis (MA) reporting better OS prognosis for TI patients. A second SLR was conducted to understand the association between TS and other clinical, economic, and humanistic outcomes. Twenty-eight studies were included and showed better prognosis for other outcomes, including AML progression and leukemia-free survival for TI patients. Risk of AML progression and cumulative non-leukemic death assessed by the MA showed a trend toward worse prognosis and higher risk of AML progression for TD patients. Lower healthcare resource utilization, better quality of life, and reduced non-leukemic death for TI patients were observed. Studies not eligible for MA also showed better clinical, economic, and humanistic outcomes for TI patients. These findings contribute to understanding the association between transfusion dependence and OS among other outcomes in patients with MDS.

Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach.

The unraveling of the pathophysiology of acute myeloid leukemia (AML) has resulted in rapid translation of the information into clinical practice. After more than 40 years of slow progress in AML research, the US Food and Drug Administration has approved nine agents for different AML treatment indications since 2017. In this review, we detail the progress that has been made in the research and treatment of AML, citing key publications related to AML research and therapy in the English literature since 2000. The notable subsets of AML include acute promyelocytic leukemia (APL), core-binding factor AML (CBF-AML), AML in younger patients fit for intensive chemotherapy, and AML in older/unfit patients (usually at the age cutoff of 60-70 years). We also consider within each subset whether the AML is primary or secondary (therapy-related, evolving from untreated or treated myelodysplastic syndrome or myeloproliferative neoplasm). In APL, therapy with all-trans retinoic acid and arsenic trioxide results in estimated 10-year survival rates of ≥80%. Treatment of CBF-AML with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin (GO) results in estimated 10-year survival rates of ≥75%. In younger/fit patients, the "3+7" regimen (3 days of daunorubicin + 7 days of cytarabine) produces less favorable results (estimated 5-year survival rates of 35%; worse in real-world experience); regimens that incorporate high-dose cytarabine, adenosine nucleoside analogs, and GO are producing better results. Adding venetoclax, FLT3, and IDH inhibitors into these regimens has resulted in encouraging preliminary data. In older/unfit patients, low-intensity therapy with hypomethylating agents (HMAs) and venetoclax is now the new standard of care. Better low-intensity regimens incorporating cladribine, low-dose cytarabine, and other targeted therapies (FLT3 and IDH inhibitors) are emerging. Maintenance therapy now has a definite role in the treatment of AML, and oral HMAs with potential treatment benefits are also available. In conclusion, AML therapy is evolving rapidly and treatment results are improving in all AML subsets as novel agents and strategies are incorporated into traditional AML chemotherapy. LAY SUMMARY: Ongoing research in acute myeloid leukemia (AML) is progressing rapidly. Since 2017, the US Food and Drug Administration has approved 10 drugs for different AML indications. This review updates the research and treatment pathways for AML.

Iron Chelation in Transfusion-Dependent Patients With Low- to Intermediate-1-Risk Myelodysplastic Syndromes: A Randomized Trial.

Background: Iron chelation therapy (ICT) in patients with lower-risk myelodysplastic syndromes (MDS) has not been evaluated in randomized studies. Objective: To evaluate event-free survival (EFS) and safety of ICT in iron-overloaded patients with low- or intermediate-1-risk MDS. Design: Multicenter, randomized, double-blind, placebo-controlled trial (TELESTO). (ClinicalTrials.gov: NCT00940602). Setting: 60 centers in 16 countries. Participants: 225 patients with serum ferritin levels greater than 2247 pmol/L; prior receipt of 15 to 75 packed red blood cell units; and no severe cardiac, liver, or renal abnormalities. Intervention: Deferasirox dispersible tablets (10 to 40 mg/kg per day) (n = 149) or matching placebo (n = 76). Measurements: The primary end point was EFS, defined as time from date of randomization to first documented nonfatal event (related to cardiac or liver dysfunction and transformation to acute myeloid leukemia) or death, whichever occurred first. Results: Median time on treatment was 1.6 years (interquartile range [IQR], 0.5 to 3.1 years) in the deferasirox group and 1.0 year (IQR, 0.6 to 2.0 years) in the placebo group. Median EFS was prolonged by approximately 1 year with deferasirox versus placebo (3.9 years [95% CI, 3.2 to 4.3 years] vs. 3.0 years [CI, 2.2 to 3.7 years], respectively; hazard ratio, 0.64 [CI, 0.42 to 0.96]). Adverse events occurred in 97.3% of deferasirox recipients and 90.8% of placebo recipients. Exposure-adjusted incidence rates of adverse events (≥15 events per 100 patient treatment-years) in deferasirox versus placebo recipients, respectively, were 24.7 versus 23.9 for diarrhea, 21.8 versus 18.7 for pyrexia, 16.7 versus 22.7 for upper respiratory tract infection, and 15.9 versus 0.9 for increased serum creatinine concentration. Limitations: The protocol was amended from a phase 3 to a phase 2 study, with a reduced target sample size from 630 to 210 participants. There was differential follow-up between treatment groups. Conclusion: The findings support ICT in iron-overloaded patients with low- to intermediate-1-risk MDS, with longer EFS compared with placebo and a clinically manageable safety profile. Therefore, ICT may be considered in these patients. Primary Funding Source: Novartis Pharma AG.

Evolving therapies for lower-risk myelodysplastic syndromes.

The development in the therapeutic landscape of myelodysplastic syndromes (MDS) has substantially lagged behind other hematologic malignancies with no new drug approvals for MDS for 13 years since the approval of decitabine in the United States in 2006. While therapeutic concepts for MDS patients continue to be primarily defined by clinical-pathologic risk stratification tools such as the International Prognostic Scoring System (IPSS) and its revised version IPSS-R, our understanding of the genetic landscape and the molecular pathogenesis of MDS has greatly evolved over the last decade. It is expected that the therapeutic approach to MDS patients will become increasingly individualized based on prognostic and predictive genetic features and other biomarkers. Herein, we review the current treatment of lower-risk MDS patients and discuss promising agents in advanced clinical testing for the treatment of symptomatic anemia in lower-risk MDS patients such as luspatercept and imetelstat. Lastly, we review the clinical development of new agents and the implications of the wider availability of mutational analysis for the management of individual MDS patients.

Do Recent Randomized Trial Results Influence which Patients with Myelodysplastic Syndromes Receive Iron Chelation?

Iron overload (IOL) in patients with myelodysplastic syndromes (MDS) is mainly attributable to chronic transfusion therapy. The importance of iron chelation therapy (ICT) in MDS has been a matter of debate. The Telesto study, the only randomized, placebo-controlled trial of ICT with deferasirox in MDS, showed improved event-free survival with ICT in patients with lower-risk MDS. Although Telesto was not powered to detect differences between deferasirox and placebo for single-event categories of the composite primary endpoint for event-free survival, results are consistent with the view that iron-related cardiac dysfunction is ameliorated by ICT in elderly patients with MDS.

Iron Support in Erythropoietin Treatment in Myelodysplastic Syndrome Patients Affected by Low-Risk Refractory Anaemia: Real-Life Evidence from an Italian Setting.

Refractory anaemia (RA) among myelodysplastic syndrome (MDS) is associated with a partial functional iron deficit and may require transfusions. In low-risk lymphoma and solid tumour patients, iron support improves erythropoietin (EPO) cost-effectiveness in treating anaemia. The aim of this study is to see if oral sucrosomial iron support improves the cost-effectiveness of EPO treatment in MDS patients affected by low-risk RA. We treated patients with EPO only or with EPO plus oral sucrosomial iron or intravenous (i.v.) iron. The need for transfusions was lowest in the group taking oral iron (p = 0.016) or not receiving supplementation at all (p = 0.022). We compared costs of EPO with i.v. ferric gluconate or oral sucrosomial iron supplementation or no iron supplementation. The oral iron group had fewer side effects, fewer patient medical visits in the out-patient setting, and fewer transfusions; this led to higher savings on direct hospital costs and indirect patient costs (lost days at work) and translated into a 50% abatement of overall expenditures. EPO treatment-related expenditures in MDS-RA patients were lowest with oral sucrosomial iron supplementation (Sideral®), with a longer interval between EPO administration in maintenance treatment, quicker hemoglobin recovery, lower ferritin increase and fewer blood transfusions.

Iron chelation therapy for myelodysplastic syndrome: a systematic review and meta-analysis.

Iron overload remains a concern in myelodysplastic syndrome (MDS) patients especially those requiring recurrent blood transfusions. Whether iron chelating therapy (ICT) is beneficial to the long-term survival of myelodysplastic syndrome is still a controversial issue. Therefore, we conducted a systematic review and meta-analysis to clarify the relationship between ICT and long-term survival in patients with MDS. A total of 14 studies involving 7242 participants were identified; the outcomes revealed that for patients with MDS, ICT resulted in a lower risk of mortality compared to those with no ICT (HR 0.57; 95% CI 0.44-0.70; P < 0.001); what is more, ICT led to a lower risk of leukemia transformation (HR 0.70; 95% CI 0.52-0.93; P = 0.016). Results of subgroup analyses based on adequate ICT or any ICT, low/int-1 IPSS or unclassified IPSS and study types indicated that the ICT had a beneficial role in all these groups of patients.

Effect of iron chelation therapy on EPO-STAT5 signalling pathway and EPO resistance in iron-overloaded low-risk myelodysplastic syndrome patients.

Objectives: Background/aims: We aim to explore low-risk MDS patients' ESA response and the difference between iron-overloaded (IO) group and the control group in the expression of SOCS1, STAT5 and BCL2L1 which play a key role to EPO-STAT5 signal pathway.Methods: 56 low-risk MDS patients were divided into experimental group, IO patients; control group, non-IO patients. Among experimental group, 28 IO patients were treated with iron chelation therapy (ICT). SOCS1, phosphorylated STAT5 (p-STAT5) and BCL2L1 protein concentration in bone marrow supernatant have been analyzed by ELISA, STAT5a+b protein concentration in bone marrow mononuclear cells (BMMC) have been analyzed by Western blot, and mRNA expression of them have been detected in BMMC by RQ-PCR. The percentage of CD71+ cells in BMMC, apoptotic rate of CD71+ cells and ROS expression in CD71+ cells were detected by Flow cytometry.Results: Compared with the control group, the sEPO concentration, the efficacy of ESA and the expression of SOCS1, apoptotic rates of CD71+ cells and ROS expression in CD71+ cells in IO group were increased, the expression of STAT5 and BCL2L1 was reduced. Interestingly, after receiving ICT, some patients with EPO resistance have responded again to ESA treatment, with the decrease of the expression of SOCS1, apoptotic rates of CD71+ cells, ROS expression in CD71+ cells and the increase of the expression of STAT5 and BCL2L1.Conclusion: Iron overload can increase EPO resistance and the expression of SOCS1, inhibit the expression of STAT5 and BCL2L1. ICT could allivation of EPO resistance.

The impact of iron chelation therapy on patients with lower/intermediate IPSS MDS and the prognostic role of elevated serum ferritin in patients with MDS and AML: A meta-analysis.

Serum ferritin (SF) has been identified as a potential prognostic factor for patients undergoing stem cell transplantation, but the prognostic value of SF in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients and the impact of iron chelation therapy (ICT) on MDS patients are controversial. The present meta-analysis aimed to better elucidate these relationships.Three electronic databases were searched systematically to identify reports on the prognostic role of SF in MDS and AML patients, and those investigating the impact of ICT on prognosis of MDS patients. The hazard ratios (HRs) and its 95% confidence interval (95%CI) were extracted from the identified studies using Cox proportional hazard regression model for overall survival (OS) and progression of MDS to AML.Twenty reports including 1066 AML patients and 4054 MDS patients were included in present study. The overall pooled HRs for OS of AML and MDS patients with elevated SF prior to transplantation was 1.73 (1.40-2.14), subgroup analyses stratified by the cut-off value of SF ≥1400/1000 ng/mL showed that the pooled HRs were 1.45 (0.98-2.15) and 1.65 (1.30-2.10), respectively. The pooled HRs for ICT in MDS patients was 0.30 (0.23-0.40). For ICT, the pooled HRs for the progression of MDS to AML was 0.84 (0.61-1.61).SF has a negative impact on the OS of AML and MDS patients when it is higher than 1000 ng/mL. ICT can improve the OS of MDS patients with iron overload but it is not associated with the progression of MDS to AML.

Hematologic improvement with iron chelation therapy in myelodysplastic syndromes: Clinical data, potential mechanisms, and outstanding questions.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation.

Delayed time from RBC transfusion dependence to first cardiac event in lower IPSS risk MDS patients receiving iron chelation therapy.

Transfused MDS patients are at risk for iron overload (IOL). IOL may exacerbate congestive heart failure (CHF), coronary artery disease (CAD) and arrythmias (ARR). We retrospectively examined cardiac events (CE) in red blood cell (RBC) transfusion dependent (TD) lower IPSS risk MDS patients. Patients were censored at death or MDS progression. 151 MDS patients were lower IPSS risk and RBC TD. Median number of cardiac risk factors (RF) per patient was 1 (1-4). CE following RBC TD occurred in 48 (32%) and were: CHF, n = 20; CAD, n = 15; ARR, n = 11. In univariate analysis factors significant for time to (TT) CE were: age at 1st RBC transfusion; number of RBCU transfused while lower IPSS risk; received iron chelation therapy (ICT); MDS treatment received; and number of cardiac RF/patient (p ≤ 0.02). Receiving ICT remained significant for TTCE in multivariate analysis (p = 0.03). Median TTCE in patients not receiving and receiving ICT was 7.0 (0.1-65.0) and 20.0 (0.1-148.6) months, respectively (p = 0.02). For lower IPSS risk RBC transfusion dependent MDS patients, time to first cardiac event following RBC TD was significantly longer in patients receiving ICT. These results suggest ICT may delay cardiac events in transfused patients. The results should be confirmed in larger numbers in prospective analyses.