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See detailErythropoietin therapy after allogeneic hematopoietic cell transplantation : a prospective randomized trial
JASPERS, Aurélie ULg; Baron, Frédéric ULg; WILLEMS, Evelyne ULg et al

in Blood (2014), 124

We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (n=131) were ... [more ▼]

We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (n=131) were randomized (1:1) between no treatment (control arm) or erythropoietin (Neorecormon®) at 500 U/kg/week (EPO arm). Patients were also stratified in 3 cohorts: patients undergoing myeloablative HCT with rhEPO to start on day 28, patients given nonmyeloablative HCT (NMHCT) with rhEPO to start on day 28, and patients also given NMHCT but with rhEPO to start on day 0. The proportion of complete correctors (i.e. achieving Hb ≥ 13 g/dL) before day 126 post-transplant (primary endpoint) was 8.1% in the control arm (median not reached) and 63.1% in the EPO arm (median time 90 days) (p<0.001). Hb levels were higher and transfusions requirements decreased (p<0.001) in the EPO arm, but not during the first month in the nonmyeloablative cohort starting rhEPO on day 0. There was no difference in rates of thrombo-embolic events or other complications between the 2 arms. This is the first randomized trial to demonstrate that rhEPO therapy hastens erythroid recovery and decreases transfusion requirements when started one month after allogeneic HCT. There was no benefit to start rhEPO earlier after NMHCT. [less ▲]

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See detailGalectins in cancer: jacks of all trades
Heusschen, Roy ULg; Schulkens, Iris; Muller, Joséphine ULg et al

in International Journal of Molecular Medicine (2014)

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See detailLarge-Scale Clinical Expansion of Mesenchymal Stem Cells in the GMP-Compliant, Closed Automated Quantum® Cell Expansion System: Comparison with Expansion in Traditional T-Flasks
LECHANTEUR, Chantal ULg; Baila, Stefano; Janssen, Michel Etienne et al

in Journal of Stem Cell Research & Therapy (2014), 4(8),

Objectives: Significant advances have been achieved regarding the knowledge of the immunoregulatory properties of mesenchymal stem cells (MSC). We are currently involved in several clinical protocols ... [more ▼]

Objectives: Significant advances have been achieved regarding the knowledge of the immunoregulatory properties of mesenchymal stem cells (MSC). We are currently involved in several clinical protocols evaluating these properties in different settings including hematopoietic cells or solid organ transplantation, and severe or refractory autoimmune disorders. Considering the large number of ex-vivo expanded cells required for these clinical protocols (MSC dose varies from 1 to 4x10-6 MSC/kg patient per infusion), we evaluated the Quantum® device, a GMPcompliant, functionally closed, automated hollow fiber bioreactor system and compared it with our traditional clinical culture system in flasks. Methods: Primary and pre-enriched MSC expansions were simultaneously conducted in both culture systems and evaluated in terms of expansion rates and compliance with quality specifications and ISCT-release criteria. Due to practical considerations, most of the experiments conducted in the bioreactor (P1 and P2 expansions) used thawed MSC. These were compared with both fresh and thawed MSC expansions in flasks. Results: The Quantum® device reproducibly produced therapeutic MSC doses that fulfill ISCT-release criteria, are sterile, devoid of mycoplasma and endotoxin, have normal karyotypes and demonstrate immunosuppressive and differentiation capacities in vitro. Cells also grew faster in the bioreactor than in flasks during passage P1 (doubling time 40 compared to 56 hours in flasks) and P2 expansions but not during the primary expansion phase (P0). Seeding 20x10-6 thawed P2-preselected cells on the device allowed us to harvest 110-276x10-6 MSC after a 7 day expansion; seeding 50x10-6 cells resulted in 291-334x10-6 MSC harvested. Conclusion: In conclusion, the Quantum® device is an excellent system to produce a clinical dose of MSC but cost-effectiveness varies as a function of the manufacturing strategy in place. For our particular situation, the use of the Quantum device didn't result in a cost saving solution. [less ▲]

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See detailCellular immunotherapy in multiple myeloma : lessons from preclinical models
Binsfeld, Marilène ULg; Fostier, K.; Muller, Joséphine ULg et al

in Biochimica et Biophysica Acta - Reviews on Cancer (2014), 1846

The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and ... [more ▼]

The majority of multiple myeloma patients relapse with the current treatment strategies, raising the need for alternative therapeutic approaches. Cellular immunotherapy is a rapidly evolving field and currently being translated into clinical trials with encouraging results in several cancer types, including multiple myeloma. Murine multiple myeloma models are of critical importance for the development and refinement of cellular immunotherapy. In this review,we summarize the immune cell changes that occur inmultiplemyelomapatients and we discuss the cell-based immunotherapies that have been tested in multiple myeloma, with a focus on murine models. [less ▲]

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See detailHuman bone marrow, umbilical cord or liver mesenchymal stromal cells fail to improve liver function in a model of CCl4-induced liver damage in NOD/SCID/IL-2Ry(null) mice
BRIQUET, Alexandra ULg; GREGOIRE, Céline ULg; Comblain, Fanny ULg et al

in Cytotherapy (2014), 16

Background aims. Transplantation is the gold standard procedure for treating acute and chronic end-stage liver diseases. Given the shortage of organs, the development of cellular sources other than human ... [more ▼]

Background aims. Transplantation is the gold standard procedure for treating acute and chronic end-stage liver diseases. Given the shortage of organs, the development of cellular sources other than human liver is urgent. The main objective of this project was to examine the effect of mesenchymal stromal cell (MSC) (bone marrow, umbilical cord and liver MSCs) intravenous injection on liver regeneration in a model of hepatic damage in NOD/SCID/IL non-obese diabetic/severe combined immunodeficient/Interleukin-2Rg(null) (NSG) mice. Methods. Mice received 3 intraperitoneal injections of CCl4 Carbon tetrachloride per week for 4 weeks. Forty-eight hours after the last injection of CCl4, mice received 500,000 MSCs or phosphate-buffered saline by intravenous injection. We examined hepatic damage by means of quantitative image analysis and blood enzyme analysis 24 h, 1 week or 8 weeks after MSC or phosphate-buffered saline injection. We also examined MSC homing by means of real-time polymerase chain reaction of human albumin. Results. We adapted a model of liver injury in immunodeficient mice. In this model, accumulation of collagen in newly formed scar septa was apparent up to 8 weeks after CCl4 treatment. Human albumin DNA was found in all organs tested. However, intravenous MSC injection, even after CXCR4 C-X-C chemokine receptor type 4 transduction and whatever the origin of MSCs, failed to improve liver damage. Conclusions. In this liver injury model, MSCs were propagated in various tissues, particularly filtering organs. For the treatment of hepatic damage, intravenous administration of moderate doses of MSCs does not appear to be effective. Yet, this adapted liver injury model is appropriate for investigating engraftment of human cells. [less ▲]

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See detailMesenchymal stromal cell therapy in conditions of renal ischaemia/reperfusion.
Erpicum, Pauline; Detry, Olivier; Weekers, Laurent et al

in Nephrology Dialysis Transplantation (2014), 29

Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbi-mortality. AKI treatment mostly relies on supportive manoeuvres in the absence of ... [more ▼]

Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbi-mortality. AKI treatment mostly relies on supportive manoeuvres in the absence of specific target-oriented therapy. The pathophysiology of AKI commonly involves ischaemia/reperfusion (I/R) events, which cause both immune and metabolic consequences in renal tissue. Similarly, at the time of kidney transplantation (KT), I/R is an unavoidable event which contributes to early graft dysfunction and enhanced graft immunogenicity. Mesenchymal stromal cells (MSCs) represent a heterogeneous population of adult, fibroblast-like multi-potent cells characterized by their ability to differentiate into tissues of mesodermal lineages. Because MSC have demonstrated immunomodulatory, anti-inflammatory and tissue repair properties, MSC administration at the time of I/R and/or at later times has been hypothesized to attenuate AKI severity and to accelerate the regeneration process. Furthermore, MSC in KT could help prevent both I/R injury and acute rejection, thereby increasing graft function and survival. In this review, summarizing the encouraging observations in animal models and in pilot clinical trials, we outline the benefit of MSC therapy in AKI and KT, and envisage their putative role in renal ischaemic conditioning. [less ▲]

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See detailImmunosuppresseurs dans la prévention de la réaction du greffon contre l'hôte : rapport de la SFGM-TC
Belaiche, S.; Yafour, N.; Balcaen, S. et al

in Pathologie Biologie (2014), 62

In the attempt to harmonize dinical practîces between different French transplantation centers, the Frenell Society of Bane Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual ... [more ▼]

In the attempt to harmonize dinical practîces between different French transplantation centers, the Frenell Society of Bane Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and taak place in September 2013 in Lille. Here we report our recommendatÎons regarding the use of immunosuppressive treatment in the prevention of graft versus hast disease: repOlt by the SFGM-TC. [less ▲]

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See detailIron sucrose - characteristics, efficacy and regulatory aspects of an established treatment of iron deficiency and iron-deficiency anemia in a broad range of therapeutic areas
JASPERS, Aurélie ULg; Beguin, Yves ULg

in Expert Opinion on Pharmacotherapy (2014), 15

Introduction: Iron is a key element in the transport and utilization of oxygen and a variety of metabolic pathways. Iron deficiency is a major cause of anemia and can be associated with fatigue, impaired ... [more ▼]

Introduction: Iron is a key element in the transport and utilization of oxygen and a variety of metabolic pathways. Iron deficiency is a major cause of anemia and can be associated with fatigue, impaired physical function and reduced quality of life. Administration of oral or intravenous (i.v.) iron is the recommended treatment for iron-deficiency anemia (IDA) in different therapeutic areas. Areas covered: This article provides an overview of studies that evaluated i.v. iron sucrose for anemia and iron status management, either alone or in combination with erythropoiesis-stimulating agents, across various diseases and conditions. Expert opinion: Iron sucrose is an established, effective and well-tolerated treatment of IDA in patients with acute or chronic conditions such as chronic kidney disease, inflammatory bowel disease, pregnancy (second and third trimester), postpartum period, heavy menstrual bleeding and cancer who need rapid iron supply and in whom oral iron preparations are ineffective or not tolerated. Available data on patient blood management warrant further studies on preoperative iron treatment. First experience with iron sucrose follow-on products raises questions about their therapeutic equivalence without comparative clinical data in newly diagnosed patients or patients on existing chronic treatment. [less ▲]

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See detailUpfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome : a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire
Damaj, Gandhi; Mohty, Mohammad; Robin, Marie et al

in Biology of Blood & Marrow Transplantation (2014), 20

Cytoreduction before allogeneic stem cell transplantation (allo-SCT) for patients with myelodysplastic syndromes remains a debatable issue. After excluding patients who had received preconditioning ... [more ▼]

Cytoreduction before allogeneic stem cell transplantation (allo-SCT) for patients with myelodysplastic syndromes remains a debatable issue. After excluding patients who had received preconditioning induction chemotherapy, we analyzed 128 consecutive patients with myelodysplastic syndrome who received reducedintensity or nonmyeloablative conditioning (RIC/NMA) allo-SCT. Among them, 40 received azacitidine (AZA) before transplant (AZA group) and 88 were transplanted up front (best supportive care [BSC] group). At diagnosis, 55 patients had intermediate 2 or high-risk scores per the International Prognostic Scoring System and 33 had a high cytogenetic risk score. Progression to a more advanced disease before allo-SCT was recorded in 22 patients. Source of stem cells were blood (n ¼ 112) or marrow (n ¼ 16) from sibling (n ¼ 78) or HLA-matched unrelated (n ¼ 50) donors. With a median follow-up of 60 months, 3-year overall survival, relapse-free survival, cumulative incidence of relapse, and nonrelapse mortality were, respectively, 53% versus 53% (P ¼ .69), 37% versus 42% (P ¼ .78), 35% versus 36% (P ¼ .99), and 20% versus 23% (P ¼ .74), for the AZA group and BSC group, respectively. Multivariate analysis confirmed the absence of statistical differences in outcome between the AZA and BSC groups, after adjusting for potential confounders using the propensity score approach. The absence of cytoreduction before RIC/NMA allo-SCT did not seem to alter the outcome. However, our results emphasize the need to perform prospective protocols to delineate the role of debulking strategy and to identify subsets of patients who may benefit from this approach. [less ▲]

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See detailA propos de l'encéphalopathie du nouveau-né
Battisti, Oreste ULg; Beguin, Yves ULg

in Percentile (2014), 19

Editorial sur l'hypoxie périnatale et les cellules souches.

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See detailVaccination guidelines in hematopoietic transplant patients : recommendations from the BHS Transplant Committee
Moors, I.; Schoemans, H.; Callens, S. et al

in Belgian Journal of Hematology (2014), 6

Over the past years, hematopoietic stem cell transplantation (HSCT) is increasingly used as a consolidation therapy in several haematological diseases and solid tumours. In the post-transplantation period ... [more ▼]

Over the past years, hematopoietic stem cell transplantation (HSCT) is increasingly used as a consolidation therapy in several haematological diseases and solid tumours. In the post-transplantation period, the immunity of HSCT recipients is impaired due to toxicity of the pre-HSCT treatment (chemo- and/or radiotherapy) and the conditioning regimen with reset of the immune system and – in case of allogeneic stem cell transplantation – possible graft-versus-host-disease (GVHD) and use of immunosuppressive drugs. This leads to a considerably increased risk of infections, with higher morbidity and mortality in these patients. Therefore, prevention of infections, through antibiotic prophylaxis, life style adjustments, germfree nutrition and revaccination, is of major importance to improve outcomes. In this article we present the Belgian guidelines for vaccination after hematopoietic stem cell transplantation, based on available data in the literature and international guidelines, taking into account the availability of vaccines and - if applicable - their reimbursement in Belgium. We present a general vaccination schedule for post-HSCT patients, a proposition for pre-transplant vaccination and donor vaccination, and an overview of special indications such as travel vaccinations and vaccinations of close contacts and health care workers, with guidelines for titer follow up. [less ▲]

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See detailA European patient record study on diagnosis and treatment of chemotherapy-induced anaemia
Ludwig, H.; Aapro, M.; Bokemeyer, C. et al

in Supportive Care in Cancer (2014), 22

Purpose – Patients with cancer frequently experience chemotherapy‐induced anaemia (CIA) and iron deficiency (ID). Erythropoiesis‐stimulating agents (ESA), iron supplementation and blood transfusions are ... [more ▼]

Purpose – Patients with cancer frequently experience chemotherapy‐induced anaemia (CIA) and iron deficiency (ID). Erythropoiesis‐stimulating agents (ESA), iron supplementation and blood transfusions are available therapies. This study evaluated routine practice in CIA management. Methods – Medical oncologists and/or haematologists from nine European countries (n=375) were surveyed on their last five cancer patients treated for CIA (n=1730). Information was collected on tests performed at diagnosis of anaemia, levels of haemoglobin (Hb), serum ferritin and transferrin saturation (TSAT), and applied anaemia therapies. Results – Diagnostic tests and therapies for CIA varied across Europe. Anaemia and iron status were mainly assessed by Hb (94%) and ferritin (48%) measurements. TSAT was only tested in 14%. At anaemia diagnosis, 74% of patients had Hb ≤10g/dL, including 15% with severe (Hb <8g/dL) anaemia. Low iron levels (ferritin ≤100ng/mL) were detected in 42% of evaluated patients. ESA was the most commonly used treatment (63%) and 30% of ESA‐treated patients also received iron supplementation. Most iron‐treated patients (74%) received an oral iron; intravenous iron was administered to 26%. 52% of patients received transfusions and in 76% of these, transfusions formed part of a regular anaemia treatment regimen. Management practices were similar in 2009 and 2011. Conclusion – Management of anaemia and iron status in patients treated for CIA varies substantially across Europe. Iron status is only assessed in half of the patients. In contrast to clinical evidence, iron treatment is underutilised and mainly based on oral iron supplementation. Implementation of guidelines needs to be increased, particularly the minimisation of blood transfusions. [less ▲]

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See detailThinking out of the box - New approaches to controlling GVHD
Baron, Frédéric ULg; Humblet-Baron, Stéphanie; Ehx, Grégory ULg et al

in Current Hematologic Malignancy Reports (2014), 9

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD ... [more ▼]

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD prophylaxis regimens continue to bebased on the combination of a calcineurin inhibitor with an antimetabolite, while first line treatmentsstill relies on high-dose corticosteroids. Further, no second line treatment has emerged thus far in acute or chronic GVHD patients who failed on corticosteroids. After briefly reviewing current standards of GVHD prevention and treatment, this article will discuss recent approaches that might change GVHD prophylaxis / treatment in the next decades, with a special focus on recently developed immunoregulatory strategies based on infusion of mesenchymal stromal or regulatory T-cells, or on injection of lowdose interleukin-2. [less ▲]

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See detailGalectin expression in the multiple myeloma microenvironment
Muller, Joséphine ULg; CAERS, Jo ULg; Binsfeld, Marilène ULg et al

in Belgian Journal of Hematology (2014)

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See detailEstablishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation.
Binsfeld, Marilène ULg; BEGUIN, Yves ULg; Belle, Ludovic et al

in Belgian Journal of Hematology (2014)

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See detailMultiple myeloma cells instruct myeloid-derived suppressor cells to release pro-angiogenic cytokines
Binsfeld, Marilène ULg; Heusschen, Roy ULg; Lamour, Virginie et al

in Belgian Journal of Hematology (2014)

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See detailHemolytic crisis induced by rasburicase administration revealing G-6-PD deficiency.
SID, Sélim ULg; Dugauquier, D.; DE PRIJCK, Bernard ULg et al

in Belgian Journal of Hematology (2014)

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See detailAntithymocyte globulin before allogeneic stem cell transplantation for progressive myelodysplastic syndrome : a study from the French Society of Bone Marrow Transplantation and Cellular Therapy
Duléry, Rémy; Mohty, Mohamad; Duhamel, Alain et al

in Biology of Blood & Marrow Transplantation (2014), 20

We investigated the impact of rabbit antithymocyte globulins (ATG) on patient outcomes after allogeneic stem cell transplantation (allo-SCT) for progressive myelodysplastic syndrome (MDS). Of the 242 ... [more ▼]

We investigated the impact of rabbit antithymocyte globulins (ATG) on patient outcomes after allogeneic stem cell transplantation (allo-SCT) for progressive myelodysplastic syndrome (MDS). Of the 242 consecutive patients who underwent allo-SCT for progressive MDS between October 1999 and December 2009, 93 received ATG (ATG group) at the median dose of 5 mg/kg, whereas 149 patients did not (no-ATG group). Donors were sibling (n ¼ 153) or HLA-matched unrelated (n ¼ 89). Patients received blood (n ¼ 90) or marrow (n ¼ 152) grafts after either myeloablative (n ¼ 109) or reduced-intensity (n ¼ 133) conditioning. Three-year overall and event-free survival, nonrelapse mortality, relapse, and chronic graft-versus-host disease (GVHD) development were not significantly different between the 2 groups. In contrast, acute grade II to IV GVHD occurred more often in the no-ATG group (55% of the patients) than in the ATG group (27%, P < .0001). Similar results were observed with acute grade III to IV GVHD (28% and 14% in the no-ATG group and ATG group, respectively; P ¼ .009). In multivariate analysis, after adjustment with propensity score, the absence of ATG was the strongest parameter associated with an increased risk of acute grade II to IV GVHD (hazard ratio, 2.13; 95% confidence interval, 1.35 to 3.37; P ¼.001]. ATG had no impact on overall and event-free survival or cumulative incidence of the relapse. In conclusion, the addition of ATG to allo-SCT conditioning did not increase the incidence of relapse of patients with progressive MDS. The incidence of acute GVHD was decreased without compromising outcomes. [less ▲]

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See detailAdequate iron chelation therapy for at least six months improves survival in transfusion-dependent patients wih lower risk myelodysplastic syndromes
Delforge, Michel; Selleslag, Dominik; BEGUIN, Yves ULg et al

in Leukemia Research (2014), 38

Background: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of ironoverload and associated organ damage, and death. Emerging evidence indicates that iron chelation ther ... [more ▼]

Background: Most patients with myelodysplastic syndromes (MDS) require transfusions at the risk of ironoverload and associated organ damage, and death. Emerging evidence indicates that iron chelation ther-apy (ICT) could reduce mortality and improve survival in transfusion-dependent MDS patients, especiallythose classified as International Prognostic Scoring System (IPSS) Low or Intermediate-1 (Low/Int-1).Methods: Follow-up of a retrospective study. Sample included 127 Low/Int-1 MDS patients from 28 centersin Belgium. Statistical analysis stratified by duration (≥6 versus <6 months) and quality of chelation (adequate versus weak). Results: Crude chelation rate was 63% but 88% among patients with serum ferritin ≥1000 g/L. Of the 80chelated patients, 70% were chelated adequately mainly with deferasirox (26%) or deferasirox followingdeferoxamine (39%). Mortality was 70% among non-chelated, 40% among chelated, 32% among patientschelated ≥6 m, and 30% among patients chelated adequately; with a trend toward reduced cardiacmortality in chelated patients. Overall, median overall survival (OS) was 10.2 years for chelated and 3.1years for non-chelated patients (p < 0.001). For patients chelated ≥6 m or patients classified as adequatelychelated, median OS was 10.5 years. Mortality increased as a function of average monthly transfusionintensity (HR = 1.08, p = 0.04) but was lower in patients receiving adequate chelation or chelation ≥6 m(HR = 0.24, p < 0.001). Conclusion: Six or more months of adequate ICT is associated with markedly better overall survival. Thissuggests a possible survival benefit of ICT in transfusion-dependent patients with lower-risk MDS. [less ▲]

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