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Anemic patients with lower risk myelodysplastic syndromes are frequently treated with erythropoiesis stimulating agents (ESA), eventually in combination with granulocyte colony stimulating factor (G-CSF). However, the evidence for the efficacy of a combined treatment remains controversial. The goal of our analysis was to assess the available evidence for a combined treatment. We performed a systematic review and identified only nine eligible studies. In two randomized controlled trials (n = 98), erythroid response rates were 33% and 40% after low-/standard-doses of ESA alone (10,000-30,000 rHuEPO equivalents/week) versus 65% and 73% after combination treatment. In seven trials with sequential drug administration (n = 393), erythroid response rates ranged from 12% to 71% after full-doses of ESA alone (60,000-80,000 rHuEPO equivalents/week) and from 35% to 74% after combination therapy. Our analysis supports an additional efficacy of G-CSF added to low-/standard-dose ESA, but the available data remains controversial, if G-CSF is added to full-dose ESA.

Iron overload (IOL) due to transfusion-dependent anemia is a serious adverse effect in patients with myelofibrosis (MF). Recent studies have shown that the oral iron chelator deferasirox may prevent multiple organ damage due to IOL in MF. However, it is not clear whether deferasirox may contribute to revert transfusion-dependent anemia. Here, we present a patient with transfusion-dependent intermediate-2 MF according to the International Prognostic Scoring System treated with ruxolitinib in combination with deferasirox. In addition to a reduced serum ferritin level, the patient required less blood transfusions, ultimately resulting in long-lasting transfusion-free survival.

The experiments were conceived, designed and performed by Augusta Di Savino, Antonietta Palmieri, Marco De Gobbi. RNA extraction from patients' bone marrow samples was performed by Alessandro Volpengo, Francesca Crasto, Roberta Lorenzatti and Enrico Gottardi. Clinical data was provided by Valentina Gaidano, Paolo Nicoli, Patrizia Scaravaglio, Daniela Cilloni and Marco De Gobbi. Statistical analysis was performed by Augusta Di Savino and Alessandro Manello. Data were analysed and the manuscript was reviewed by Augusta Di Savino, Daniela Cilloni, Giuseppe Saglio and Marco De Gobbi. The paper was written by Augusta Di Savino, Daniela Cilloni and Marco De Gobbi

Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis that results in peripheral cytopenias. Anemia is the most common symptom of MDS and the majority of patients become transfusion-dependent with the risk of iron overload, which may lead to cardiac, hepatic and endocrine complications. Deferasirox is an orally available iron chelator administered once-daily in transfusion-dependent patients with various chronic anemias. Its efficacy has been established in controlled clinical trials. In the present study, we describe our experience with 55 consecutive MDS patients [International Prognostic Scoring System risk score of low (n=32) or intermediate-1 (n=23)] treated with deferasirox in a routine clinical setting following Consensus Guidelines on Iron Chelation Therapy. According to WHO classifications, patients had refractory anemia (n=30), refractory anemia with ringed sideroblasts (n=16), refractory cytopenia with multilineage dysplasia (n=8) or refractory cytopenia with multilineage dysplasia and ringed sideroblasts (n=1). The median monthly transfusion requirement at baseline was 3 units. Patients received a starting dosage of 10 mg/kg/day, subsequently titrated according to serum ferritin (SF) levels which were measured monthly. Safety assessment included monitoring of liver and renal parameters and recording adverse events (AE) during treatment. At the baseline, the mean ± SD SF level was 2,362±172 ng/ml and after 24 months, the mean ± SD decrease in SF was 1,679±209 ng/ml. Sixteen patients had sustained hematological improvement meeting International Working Group 2006 criteria. One patient became transfusion-independent. No severe AE were reported. In conclusion, deferasirox therapy was effective and safe in reducing transfusional iron overload and it reduces transfusion requirement in a subset of patients.

Summary We previously reported a 60% erythroid response rate with recombinant erythropoietin + 13-cis retinoic acid + dihydroxylated vitamin D3 in 63 elderly myelodysplastic patients (median age 75 years) with unfavourable features for response to erythropoietin alone [70% transfusion-dependent, 35% refractory anaemia with ring sideroblasts/refractory anaemia with excess of blasts type 1 (RAEB1), 70% with International Prognostic Scoring System (IPSS) Intermediate-1 or -2]. This report updates that case study at a 7-year follow-up, and compared the impact on overall survival of erythroid response to known prognostic factors. The erythroid response duration (median 17 months; 22 in non-RAEB patients, with 20% patients in response after 6 years of therapy) was longer than in most studies with erythropoietin alone. Overall survival (median 55 months in non-RAEB, 15 in RAEB1 patients) was negatively affected by RAEB1 diagnosis, IPSS and WPSS intermediate scores and transfusion-dependence. In the multivariate analysis, erythroid response maintained an independent positive impact on survival, particularly in non-RAEB patients in the first 3 years from diagnosis (90% survival compared to 50% of non-responders). In conclusion, the long-term follow-up confirmed the achievement, by our combined treatment, of fairly long-lasting erythroid response in the majority of MDS patients with unfavourable prognostic features for response to erythropoietin: this translated in a survival benefit that was independent from other prognostic features.

Anemia in MDS with 5q deletion was generally considered, until the advent of lenalidomide, unresponsive to available treatments. We analyzed erythroid response to erythropoetin (EPO) or darbepoetin (DAR) and thalidomide in MDS with 5q deletion treated by French centers (GFM) and in whom karyotype was successfully performed. Of 345 patients treated with EPO or DAR+/-G-CSF, 48 had 5q deletion. The response rate was 46% (31% major, 15% minor) according to International Working Group (IWG) 2000 criteria versus 64% in patients without 5q deletion (p=0.03). According to IWG 2006 criteria, the response rate in patients with 5q deletion was 39% versus 52% in patients without 5q deletion (p=0.10). Mean duration of response was 14 months versus 25 months (IWG 2000) and 13 months versus 27 months (IWG 2006) in 5q deletion and non-5q deletion patients (p=0.019 and 0.003, respectively). Of 120 MDS treated with thalidomide, all of whom had successful cytogenetic analysis, 37% of the 24 patients with 5q deletion responded (IWG 2000 criteria, 20% major, 17% minor) with a mean duration of 9.5 months, versus 32% (18% major, 14% minor) in MDS without 5q deletion and a mean response duration of 9 months (p=NS). Our results confirm that response rates to EPO or DAR and thalidomide are clearly inferior to those obtained with lenalidomide.

Background The efficacy of erythropoietic-stimulating agents (ESA) in chronic myelomonocytic leukemia (CMML) is unknown. Our objective was to analyze erythroid response (ER) and overall survival (OS) in a series of 94 patients with CMML treated with ESA. Methods We analyzed a series of 94 patients with CMML treated with ESA included in the Spanish and Dusseldorf-MDS registries. Findings ER was observed in 64% of patients and red blood cell (RBC) transfusion independence in 31%. The median duration of ER was 7 months (range, 0–88). CPSS and EPO level were significantly associated with ER in multivariate analysis (P = 0.003). Considering only patients with CPSS low- or intermediate-1-risk group, the absence of RBC transfusion dependence and erythropoietin (EPO) level predicted ER (P = 0.003 and P = 0.008, respectively). In multivariate analysis, only the EPO level retained its prognostic value (P = 0.029). Achievement of ER correlated with a better survival since ER evaluation (P = 0.016). Interpretation The CPSS and EPO levels are adequate tools to select CMML patients with symptomatic anemia who may benefit from treatment with ESA. A significant ER to ESA is expected in anemic patients with low/intermediate-1 CMML risk by the CPSS and a low endogenous serum EPO level.

Deferasirox (DFX) is an orally administered iron chelator approved for use in patients with transfusion-dependent iron overload due to myelodysplastic syndromes (MDS). The safety and efficacy of DFX has been explored in clinical trial settings, but there is little data on unselected patients with MDS. The aim of this study was to retrospectively evaluate the safety, compliance, efficacy and effect on haematopoiesis of DFX in a large 'real-world' MDS population. One hundred and eighteen patients with transfusion-dependent MDS were treated with DFX across 11 centres in Italy. Serum ferritin levels, haematological response, dosing, adverse events and transfusion dependence were recorded at baseline, 3, 6, 12 and 24 months following initiation of treatment. DFX reduced mean serum ferritin levels from 1790 to 1140 ng/mL (P < 0.001), with 7.1% of patients achieving transfusion independence. Significant haematological improvement was seen in erythroid (17.6%), platelet (5.9%) and neutrophil counts (7.1%). Adverse events were reported in 47.5% of patients, including gastrointestinal and renal toxicity. Regression analysis showed that higher starting doses of DFX are associated with transfusion independence at 24 months. DFX is a safe, effective treatment for transfusion-dependent MDS that can lead to transfusion independence and haematological improvement in a subset of patients.

Summary. Treatment with recombinant human erythropoietin (rHuEpo) improves anaemia in approximately 20% of patients with myelodysplastic syndromes (MDS). We investigated the potential advantage of a prolonged administration of rHuEpo to achieve higher erythroid response rates (RR) in 281 MDS patients: 118 with refractory anaemia (RA), 77 with refractory anaemia and ringed sideroblasts (RARS), 59 with refractory anaemia with excess of blasts and blast count 150 U/l at baseline predicted for non-response. The median duration of response was 68 weeks and the overall risk of leukaemic transformation was 21·7%. These results suggest that prolonged administration of rHuEpo produces high and long-lasting erythroid RR in MDS patients with low blast counts, particularly in those with pretreatment serum Epo levels of < 150 U/l and good cytogenetic prognosis.

Evaluation of erythropoietic regeneration in horses is difficult unless serial bone marrow aspirates are performed. To investigate the acute and chronic erythropoietic regenerative response of equine bone marrow following acute removal or loss of blood, sequential bone marrow aspirates over 4 weeks were taken from the sternum of five horses from which 20 ml kg -1 of blood had been removed. We found that the total number of erythroid cells counted (expressed as a percentage of the total number of erythroid and myeloid cells counted) expanded initially by 13·7 per cent within 3 days after blood removal, the erythroid response peaking by 9 days with a further 13·5 per cent increase. This peak coincided with the lowest M:E ratio. Concomitantly, a shift from proliferative phase cells to maturing phase cells occurred, which appeared to persist beyond 31 days post collection. Thus, we found that the equine bone marrow mounted a regenerative erythropoietic response more slowly than previously determined and, also, regeneration of the erythroid compartment was incomplete 31 days after blood removal of this magnitude.

Thirteen patients with low-to-intermediate risk myelodysplastic syndrome (MDS) received recombinant erythropoietin (r-EPO) at the single, weekly dose of 40.000 U for at least 8 weeks. Five patients (38.4%) achieved a major erythroid response (increased haemoglobin levels > 2 g/dl and/or transfusion independence), which is currently maintained after 3-11 months, without modification of r-EPO dose. This study suggests that 40.000 U r-EPO given once a week may be at least as effective as the more frequent (daily or three times a week) administrations of the drug usually employed in MDS patients.

We describe a low-risk myelodysplastic syndrome patient who did not respond to erythropoietin alone, but who did show a major erythroid response to combination therapy consisting of erythropoietin and moxifloxacin. This observation was exclusively empirical. The immunomodulatory effects of moxifloxacin may explain the synergy with erythropoietin.

NF-kB is reported to be constitutively activated in a percentage of high-risk myelodysplastic syndrome carrying cytogenetic aberrations. Only few data are reported on the use of proteasome inhibitors in this subset of patients. We performed a study on efficacy and safety of bortezomib as a single agent in patients with myelodysplastic syndromes (MDS). Bortezomib was administered at 1.3mg/m(2) with a 1, 4, 8, 11-day schedule every 28 days, in 19 patients with IPSS low/intermediate 1 or intermediate2/high risk. Six out of 19 patients received all planned eight cycles. Hematologic toxicity was recorded in all patients, especially grade 3/4 neutropenia and grade 3/4 thrombocytopenia; non-hematologic side effects were recorded in 7 patients, but events were all of grade 1/2 toxicity. According to IWG 2006 criteria, 4 out of 19 patients (21%) achieved erythroid response and 9 patients (47%) showed stable disease. In patients with erythroid response bone marrow WT1 levels decreased from a median of 109 copies at baseline to a median of 14 copies at the end of treatment, whereas in patients with stable disease, median WT1 copies increased either in bone marrow and peripheral blood. In conclusion, bortezomib used alone in MDS shows modest hematologic efficacy but appears to affect the WT1 gene expression, which is typically increased in these diseases.

Patients with myelodysplastic syndromes (MDS) often develop anaemia resulting in frequent transfusions and fatigue. Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anaemia. This single-arm, phase 2 study examined the efficacy of darbepoetin alfa 500 microg every 3 weeks (Q3W) for treating anaemia in low-risk MDS patients (after 6 weeks, poor responders received darbepoetin alfa 500 microg every 2 weeks). The primary end-point was the incidence of erythroid responses (International Working Group criteria) after 13 weeks of therapy. Secondary end-points included the incidence of erythroid responses at weeks 28 and 55, [or weeks 27 and 53 for dose escalations to every two weeks (Q2W)], and safety parameters. Analyses were stratified by the patient's previous ESA therapy status [ESA-naïve (n = 144) vs. prior ESA-treated (n = 62)]. After 13 weeks of therapy, 49% of ESA-naïve patients and 26% of prior ESA-treated patients achieved a major erythroid response. After 53/55 weeks, 59% of ESA-naïve patients and 34% of prior ESA-treated patients achieved a major erythroid response; 82% of ESA-naïve patients and 55% of prior ESA-treated patients achieved target haemoglobin of 110 g/l. Thromboembolic or related adverse events occurred in 2% of patients; no pulmonary embolisms were reported. In conclusion, darbepoetin alfa, 500 microg Q3W appeared well tolerated and increased haemoglobin levels in low-risk MDS patients.

Refractory anaemia associated with excessive intramedullary erythroid apoptosis and dysplasia is a major feature of myelodysplastic syndromes (MDS). Recombinant human erythropoietin (specifically, epoetin alfa [EPO]) has been used in the therapy of MDS for many years. Initially, the erythroid response rates were modest, as EPO was used in all subgroups of MDS patients without discretion. However, with increased sophistication in patient selection and response evaluation criteria, there has been a significant improvement in the response rates to EPO therapy. This review discusses the evolution of therapeutic strategies incorporating EPO for the treatment of MDS.

Thrombocytosis is not a frequent event in myelodysplasia (MDS) and is observed mainly in 5q- syndrome and MDS/myeloproliferative (MPD) overlap syndromes. The pathogenetic mechanism of thrombocytosis in 5q- has not been fully elucidated to-date. Bortezomib is a proteasome inhibitor which seems to be effective in MDS. We present here the first case in the literature with MDS/MPD syndrome, sole 5q- anomaly and thrombocytosis in which bortezomib administration normalized platelet count, produced a major erythroid response, and reduced levels of interleukin-6 (IL-6) and TNF-alpha while increased levels of IL-4 in the bone marrow plasma. The study of such cases will reveal the exact role of bortezomib in the management of MDS/MPD.

1721 The Nordic scoring system is commonly used to predict response to ESA's in MDS patients and is comprised of two weighted elements, patient's endogenous erythropoietin levels and transfusion dependency status, and three predictive categories of ESA response rates (E. Hellstrom-Lindberg et al., BJH 1997). We set out to validate the Nordic scoring system using the modified IWG erythroid response criteria for MDS 2006 (BD Cheson et al. Blood 2006) and identify any other clinical elements of prognostic importance. Methods: We conducted a retrospective review of 135 patients in a prospectively maintained MDS database of 400+ patients enrolled between the years of 2005 and 2012. Patients flagged as having had previous ESAs were included and categorized as ESA naive erythropoietin (EP), ESA naive darbepoetin (DP), ESA non-naive EP and ESA non-naive DP. Nordic scores were calculated (when possible) using patient transfusion status and erythropoietin levels preceding ESA use, and actual response rates were determined using electronic medical records and transfusion histories. We recorded doses and schedules and evaluated the impact of WHO classification (3 groups) and IPSS risk score (L, Int-1 and Int-2) on overall response as well. We excluded patients who converted to AML during ESA trial, Jehovah witnesses and those with high risk MDS. We did not calculate Nordic scores in patients concurrently on ESA when referred to our center. Results: The patient population had a median age of 76 with 59% male. Out of 135 patients, 90 were put on EP, 35 put on DP and 10 put on both, with DP following EP in the 10 patients. Starting dose for most EP patients (59%) was 40,000 units q week with escalation to 60,000 units in non/suboptimal responders. GCSF was added concurrently in 36 (27%) patients. Starting dose for 71% of DP patients was 500 ug q3 weeks with increase to Q2 weeks for suboptimal response. The Nordic score was ‘calculatable’ in 109 patients pre ESA. [Table 1][1] summarizes the response rates by Nordic score, IPSS transfusion dependence and type of ESA. [Figures 1][2] and [2][3] depict response rates by ESA exposure and by WHO categories 1–3(see legend). We were not able to accurately document response durations. Conclusions: The Nordic scoring system is still valid for predicting response to ESA using IWG erythroid response criteria 2006 with slightly lower response rates at the highest score of > +1 than previously reported of 74%. We observed higher erythroid response rates in EP treated (42%) versus DP treated (31%) patients even after adjusting for Nordic scores. As expected, transfusion dependent MDS patients had lower responses to ESA than those independent of transfusions. | Patient Categories[*][4] | Sample size | Response (%) | |:------------------------:| ----------- | ------------ | | All patients | 135 | 39 | | Nordic scores | | | | >+1 | 65 | 54 | | -1 to +1 | 42 | 31 | | +1 | 37 | 62 | | Nordic -1 to +1 | 34 | 38 | | DP | 45 | 31 | | Nordic >+1 | 27 | 37 | | Nordic -1 to + 1 | 8 | | * [↵][5]* please note that Nordic scores, WHO classifications and IPSS scores could not be determined in all patients. Table 1. Response rates by Nordic score, IPSS, Transfusion status and ESA ![Figure][6] Legend: 1. Unclassified+5q+RA+RARS+MDS-U+RCUD-A 2. RCMD+RCMD-RS 3. RAEB1+RAEB2+CMML1+CMML2 ![Figure][6] Disclosures: Wells: Alexion: Honoraria, Research Funding; Janssen Ortho: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Buckstein: Celgene: Honoraria, Research Funding. [1]: #T1 [2]: #F1 [3]: #F2 [4]: #fn-1 [5]: #xref-fn-1-1 [6]: pending:yes