Iron Chelation in Patients with Myelodysplastic Syndromes and Myeloproliferative Neoplasms-Real-World Data from the German Noninterventional Study EXCALIBUR.

Myelodysplastic syndromes and myeloproliferative neoplasms both represent hematologic diseases associated with bone marrow failure often resulting in anemia. For those patients, transfusion of red blood cell (RBC) units is essential but results in iron overload (IOL) that may affect various organ functions. Therefore, iron chelation therapy plays a major role in anemic patients, not only because it reduces IOL, but also because it may improve hematopoietic function by increasing hemoglobin or diminishing the requirement for RBC transfusions. To assess the utility, efficacy, and safety of the different iron chelation medications approved in Germany, as well as to examine the effect of chelation on hematopoietic insufficiency, a prospective, multicenter, noninterventional study named EXCALIBUR was designed. In total, 502 patients from 106 German hospitals and medical practices were enrolled. A large proportion of patients switched from a deferasirox dispersible tablet to a deferasirox-film-coated tablet, mainly because of more convenient application, which was reflected in the treatment satisfaction questionnaire for medication scores. Iron chelation was effective in lowering serum ferritin levels, with the observed adverse drug reactions being in line with the known safety profile. Hematologic response occurred in a few patients, comparable to other studies that examined hematologic improvement in patients with MDS.

Myelodysplastic Syndromes: New Methods of Diagnosis, Prognostication, and Treatment

BACKGROUND: Myelodysplastic syndromes (MDS) are malignant diseases arising from hematopoietic stem cells. Their overall incidence is 4 cases per 100 000 persons per year, and they are usually diagnosed when evaluating cytopenia. The median survival time is three years. Myelodysplastic syndromes take a variable course; one-quarter of patients go on to develop acute leukemia. METHODS: This review is based on publications retrieved by a selective search of the literature from 2013 to 2022, including relevant guidelines, in the PubMed database. The time period was chosen to reflect developments since the publication of the latest EHA guidelines in 2013. RESULTS: The gold standard of diagnosis is cytomorphology of the blood and bone marrow, supplemented by banding cytogenetics, histomorphology, and somatic mutation analyses. The new classification proposed by the WHO incorporates the molecular and cytogenetic findings. The Molecular International Prognostic Scoring System (IPSS-M), which takes somatic mutations into account, is now available as an aid to prognostication. Quality of life evaluation with standardized instruments is helpful in many ways. Low-risk patients are treated supportively with erythrocyte transfusions and iron chelation therapy. Erythropoietin-a can be given to patients whose erythropoietin level is less than 200ng/mL, lenalidomide to those with a 5q deletion, and luspatercept to those with an SF3B1 mutation. High-risk patients should be evaluated as early as possible for allogeneic hematopoietic stem cell transplantation with curative intent. 5-azacytidine improves outcomes in patients for whom stem cell transplantation is not suitable. CONCLUSION: Once a precise diagnosis has been established, new prognostic instruments such as the IPSS-M enable risk-adapted treatment based on the biological aspects of the patient's disease as well as his or her age and comorbidities.

Wilm's Tumor 1-guided preemptive treatment with hypomethylating agents for molecular relapse of AML and MDS after allogeneic transplantation.

Hypomethylating agents (HMA) for relapsed acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after allogeneic transplantation (allo-SCT) are most effective when used at the stage of molecular relapse. As Wilm's Tumor 1 (WT1)- expression has proven to serve as broadly applicable, sensitive and specific minimal residual disease (MRD) marker, we measured WT1-expression in 35 AML and MDS patients using a standardized assay for the guidance of therapy with HMA and donor lymphocyte infusions (DLI). Molecular relapse was detected in median 168 days post-transplant prompting therapy with a median of six HMA cycles and at least one DLI (n = 22, 63%). Hereby, 13 patients (37%) achieved major response (=MRD- complete remission [CR]), and 7 patients (20%) achieved minor response (=MRD+ CR), whereas 15 patients (43%) progressed into hematologic relapse. Two-year overall survival (OS) rate was 35% including 11 patients (31%) with ongoing MRD- remission for a median of 21 months. Patients with the major response after six cycles had significantly better OS suggesting that those not achieving MRD negativity after six cycles are candidates for alternative therapies. Combining MRD-monitoring of WT1-expression and preemptive therapy with HMA and DLI appears as a practicable and efficient approach for imminent relapse after allo-SCT.

Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry.

Iron overload due to red blood cell (RBC) transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome (MDS) patients. Many studies have suggested improved survival after iron chelation therapy (ICT), but valid data are limited. The aim of this study was to assess the effect of ICT on overall survival and hematologic improvement in lower-risk MDS patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival (OS), treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2,200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for OS for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative RBC transfusions, Revised-International Prognostic Scoring System (IPSS-R), and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, RBC transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R, and, in addition, corrected for cumulative RBC transfusions and presence of ringed sideroblasts, demonstrated a significantly improved OS for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve OS and hematopoiesis in transfused lower-risk MDS patients. This trial was registered at clinicaltrials.gov identifier: 00600860.

Treatment of Anemia in Transfusion-Dependent and Non-Transfusion-Dependent Lower-Risk MDS: Current and Emerging Strategies.

Myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders with a highly diverse clinical course. For lower-risk MDS patients, therapeutic objectives aim to correct chronic anemia and improve/maintain health-related quality of life (HRQoL). However, disease burden is often insufficiently recognized, and although some patients do not respond/lose response to standard treatment, many are treated late. This is the case for non-transfusion-dependent patients with symptomatic anemia, in whom delayed treatment initiation may lead to unnecessary morbidity. Current active treatment options for lower-risk MDS are limited. Standard care for lower-risk 5q deletion [del(5q)] MDS patients with anemia remains supportive, consisting of red blood cell (RBC) transfusions, iron chelation therapy, and treatment with erythropoiesis-stimulating agents (ESAs) in the case of low serum erythropoietin levels. Response rates to ESAs range from 15% to 63%, whereas 56% to 67% of patients with del(5q) MDS achieve RBC transfusion independence with lenalidomide. Treatment options for patients' refractory to ESAs and/or lenalidomide, however, are limited. Frequent transfusions are associated with profound clinical, HRQoL, and economic consequences for transfusion-dependent patients. This review focuses on the multiple unmet clinical needs that exist in the treatment of anemia associated with lower-risk MDS and the current and future treatment options that may improve disease management and patient outcomes.

Sorafenib and azacitidine as salvage therapy for relapse of FLT3-ITD mutated AML after allo-SCT.

OBJECTIVE: Patients with acute myeloid leukemia (AML) carrying FLT3-ITD mutations (FLT3-ITD+) who relapse after allogeneic transplantation (allo-SCT) have a very dismal prognosis with the currently available treatment options. METHODS: We treated eight patients with FLT3-ITD+ AML who had relapsed in median 91 d (range, 28-249) following allo-SCT with a combination of the multikinase inhibitor sorafenib and the DNA methyltransferase inhibitor azacitidine (Aza). RESULTS: Patients received a median of five cycles of Aza (range, 2-9) and sorafenib with a median daily dosage of 750 mg (range 400-800) for 129 d (range, 61-221). Six of eight patients received donor lymphocyte infusions (DLI) with a median number of two DLI per patient (range, 1-4). Following this treatment, four patients (50%) achieved a complete remission and three of them a complete molecular remission. Median duration of CR was 182 d (range, 158-406), and two patients remain in ongoing remission for 406 and 168 d. Median overall survival was 322 d (range, 108-574 d) with three patients being currently alive. CONCLUSION: Taken together, the combination of sorafenib, Aza, and DLI shows promising efficacy and deserves further evaluation in larger patient groups.

Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry.

Baseline characteristics, disease-management and outcome of 1000 lower-risk myelodysplastic syndrome (MDS) patients within the European LeukaemiaNet MDS (EUMDS) Registry are described in conjunction with the validation of the revised International Prognostic Scoring System (IPSS-R). The EUMDS registry confirmed established prognostic factors, such as age, gender and World Health Organization 2001 classification. Low quality of life (EQ-5D visual analogue scale score) was significantly associated with reduced survival. A high co-morbidity index predicted poor outcome in univariate analyses. The IPSS-R identified a large group of 247 patients with Low (43%) and Very low (23%) risk score within the IPSS intermediate-1 patients. The IPSS-R also identified 32 High or Very high risk patients within the IPSS intermediate-1 patients. IPSS-R was superior to the IPSS for predicting both disease progression and survival. Seventy percent of patients received MDS-specific treatment or supportive care, including red blood cell transfusions (51%), haematopoietic growth factors (58%) and iron chelation therapy (8%), within 2 years of diagnosis; while 30% of the patients only required active monitoring. The IPSS-R proved its utility as a more refined risk stratification tool for the identification of patients with a very good or poor prognosis and in this lower-risk MDS population.

Improved survival in MDS patients receiving iron chelation therapy - a matched pair analysis of 188 patients from the Düsseldorf MDS registry.

MDS patients are prone to develop transfusional iron overload. Iron overload may partly explain why transfusion dependency is associated with a decreased likelihood of survival. Our matched-pair analysis included 94 patients on long-term chelation therapy and 94 matched patients without it. All patients had iron overload, defined as serum ferritin (SF) above 1000 ng/ml or a history of multiple transfusions and SF ≥ 500 ng/ml. Median SF was 1954 ng/ml in chelated and 875 ng/ml in non-chelated patients. The difference in median survival (74 vs. 49 months, respectively; p=0.002) supports the idea that iron chelation therapy is beneficial for MDS patients.

Red blood cell transfusion dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de novo myelodysplastic syndrome (MDS).

The prognosis of patients with de novo myelodysplastic syndrome (MDS) who are red blood cell transfusion-dependent (TD) and receive supportive care is inferior to that of patients who do not require transfusions. Whether TD also affects outcome after allogeneic transplantation is unknown. Consequently, in 172 de novo MDS patients (median age, 51 years), we analyzed the impact of TD on outcome after high-dose conditioning and allogeneic peripheral blood stem cell transplantation (PBSCT). With a median follow-up of 37 months, the probability of 3-year overall survival (OS) did not differ significantly between patients who were TD and those who were not TD before PBSCT (P=.1); however, transfusion burden, as reflected by ferritin levels, was correlated with a greater probability of severe acute graft-versus-host disease (aGVHD; P=.03) and a higher comorbidity index (P=.01), and OS was inferior in those patients with a ferritin level>1000 microg/L before PBSCT (P=.03). In multivariate analysis, only marrow myeloblast count (P=.01) and comorbidity index (P=.001) had a significant impact on OS. Our data do not identify TD as an independent negative prognostic factor for outcome after allogeneic PBSCT' however, iron overload (presumably transfusion-related) may contribute to poor transplantation success by adding to the overall comorbidities. Whether clinical intervention in the form of iron chelation can improve the outcome of allogeneic PBSCT in TD patients with MDS remains to be determined.