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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.

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.

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

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.

Lenalidomide has proven efficacy and safety and has been shown to reduce transfusion requirements and reverse cytogenetic abnormalities in lower-risk myelodysplastic syndromes (MDS). However, long-term follow-up data have not yet been reported. Here, we describe 6 patients with International Prognostic Scoring System low- or intermediate-1-risk MDS who began lenalidomide therapy between April 2002 and June 2003 as part of the MDS-001 study and who have maintained long-term therapy. Five of these patients had an ongoing requirement for red blood cell transfusions despite previous treatment with recombinant erythropoietin. One patient began lenalidomide therapy because of progressive and symptomatic anemia. To date, all patients maintained long-term transfusion independence (over 4.5 years) while receiving oral lenalidomide therapy, including 5 patients who remain on therapy. Sustained erythroid response was reported despite persistence of the deletion 5q [del(5q)] abnormality in 3 of the 4 patients with del(5q) at study entry. Side effects were largely predictable and manageable. The favorable outcomes presented here show that lenalidomide can induce durable erythroid responses with sustained transfusion independence that can exceed 6 years in patients with lower-risk MDS.

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.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm frequently complicated by transfusion dependent anemia. Both anemia and transfusion-dependence are associated with a poor outcome, at least in part because of toxic effects of iron overload (IOL). Iron-chelating therapy (ICT) is increasingly used in order to prevent IOL in this setting. Here, we describe the case of a 73-year-old man affected by PMF and severe transfusion-dependent anemia who experienced a dramatic erythroid response after being treated with deferasirox to prevent IOL.

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

Abstract 4968 In our previous paper (Ferrero et al, BJH 2009) we reported the treatment of 63 MDS patients (median age 75, 16 RAEB1, 47 non RAEB) with a combination of human recombinant erythropoietin (alfa or beta epoetin, 30–80000 U/ week, median 65000U/week), 13-cis-retinoic acid (20 mg day) and dihydroxylated vitamin D3 (1 ug day). Eleven of the 16 RAEB1 patients also received intermittent, low dose of 6-thioguanine. In spite of adverse prognostic factors for response to erythropoietin (all patients with Hb At previous evaluation (41 months of follow-up) a survival advantage was evident for non RAEB patients with erythroid response. Now we updated the casistic after 3 years from the previous evaluation. Median follow up for alive patients is now 64 months (5 months - 12 years). Median duration of erythroid response is now increased to 25 (2-88+) months for non RAEB and 6 (2.5-34.5+) months for RAEB1, 32.5% of responses in non RAEB patients have lasted more than 3 years. Twenty-nine/46 non RAEB and 14/16 RAEB1 patients died, with a median survival respectively of 57 and 15 months. Acute myeloid leukemia evolution occurred to 10 patients (5 RAEB1 and 5 non RAEB patients). Although the erythroid response did not correlate with known risk factors such as IPSS score, caryotype and transfusion requirement, it confirmed its positive prognostic role for survival in non RAEB patients (p 0.04, HR 2.06): median survival 71.5 months (range 12–150+) for responders, 30.6 months (range 5–149) for non responders. A trend towards a better survival for responder was also observed among RAEB1 patients (median survival 17 months for responders, 10 months for non responders), however, due to the low numbers of patients in this group, the difference was not statistically significant, even if border line (p 0.052, HR 2.52). In conclusion our long term follow-up confirmed the positive role of our combined treatment for response duration and survival in a group of non RAEB patients, most of them with unfavorable prognostic features.Figure 1.Overall survival of myelodisplastyc patients according to erythroid response: A. Non-RAEB patients:“___” responsive patients, “—” not responsive patients (p 0.04, HR 2.06) B. RAEB patients: “___” responsive patients, “—” not responsive patients (p 0.05, HR 2.52)Figure 1. Overall survival of myelodisplastyc patients according to erythroid response: A. Non-RAEB patients:“___” responsive patients, “—” not responsive patients (p 0.04, HR 2.06) B. RAEB patients: “___” responsive patients, “—” not responsive patients (p 0.05, HR 2.52) Disclosures: Off Label Use: The use of 13-cis retinoic acid and 1; 25(OH)2 vitamin D3 in myelodisplastyc syndrome is off-label. In our study we used that drugs in combination with erythropoietin as differentiative agents.

7094 Background: EPO+G/GM-CSF has been associated with higher ER rates vs EPO alone. Several non-ESAs have also been studied as single agents or in combination without growth factor. This meta-analysis compares ER rates achieved with EPO either as a single agent or in combination with G/GM-CSF or other agents vs non-ESA therapies (including thalidomide, azacytidine, all-trans retinoic acid, As2O3, etc). Methods: Data extraction was performed on studies from PubMed, ASCO/ASH proceedings in MDS pts treated with EPO±G/GM-CSF or other non-ESAs (search cutoff date 9/30/07). To allow cross comparison, only studies using IWG or IWG-like ER criteria and treatment-naive pts were selected. Pooled estimates of ER rates were calculated using random-effect (R- E) meta-analysis methods and results were stratified by: (i)EPO monotherapy (monotx), (ii)EPO+G/GM-CSF, (iii)EPO+non-ESAs, (iv)Non-ESA monotx, and (v)Non-ESA combinations. Results: Of 790 studies identified, 35 were included. Most pts (>59%) had RA/RARS, except ...

7031 Background: LEN promotes erythropoiesis in a subset of lower risk MDS pts who fail EPO treatment (tx) [N Eng J Med 2005;352:549]. We reported that LEN acts to relieve suppression of the EPO-R signal in non-del(5q) MDS progenitors. We hypothesized that erythroid response (HI-E) to LEN is influenced by endogenous EPO level and can be augmented by combined tx (CT) with EPO in pts with low serum EPO (sEPO) concentration. To evaluate the potential benefit of CT, the effect of sEPO level, and the effects of LEN pharmacokinetics (PK) on cytopenias, we performed a two-stage PK and efficacy study. Methods: Eligible pts had transfusion-dependent (TD), Low/Int-1 IPSS MDS who failed prior treatment with EPO. In the 1st stage pts received LEN monotherapy (MT) at 10mg/d [n=25] or 15mg/d [n=15]. Single dose [n=12] and steady state [n=24] PK were evaluated on days -7 and +14 at the 10mg LEN dose. After 16 wks of MT, erythroid non-responders (NR) and minor (MiE) responders (IWG 2000) were offered CT with epoetin alph...

Background: Lenalidomide (LEN) is effective in MDS patients (pts) with or without deletion (del) 5q cytogenetic abnormalities. Common toxicities include neutropenia and thrombocytopenia. Both occurrence of cytopenias and response to LEN is more common in pts with the del 5q abnormality. This study analyzes whether development of treatment-related cytopenias is associated with response to LEN in lower-risk MDS pts. Methods: Transfusion-dependent, low/int-1-risk MDS pts were enrolled in the MDS-003 (del 5q pts) and MDS-002 (non-del 5q pts) studies. Pts were treated with 10 mg LEN (daily or 21/28 days). Baseline thrombocytopenia was defined as a platelet (plt) count Results: Of 147 evaluable pts in MDS-003, 59 (40%) had thrombocytopenia, 59 (40%) neutropenia, and 84 (57%) neutropenia and/or thrombocytopenia according to baseline labs. Of 210 evaluable pts in MDS-002, 69 (33%) had thrombocytopenia and 81 (39%) neutropenia at baseline. For both studies, median age was 71 and 72 years and MDS duration was 2.5 and 2.2 years, respectively. RBC transfusion independence (TI) was achieved by 99 pts (67%) in MDS-003 (List et al. NEJM 2006) and 56 pts (26%) in MDS-002. For pts with del 5q, development of thrombocytopenia correlated with TI, regardless of baseline plt count (p=0.005). Comparing pts who had a ≥50% drop vs those who did not, TI was achieved in 76% vs 47% of pts without baseline thrombocytopenia and in 67% vs 38% of pts with thrombocytopenia, respectively. Similar results held for pts without baseline neutropenia: 82% whose ANC fell ≥75% achieved TI, compared to 56% whose ANC fell Conclusions: In MDS pts with del 5q, treatment-related thrombocytopenia, and neutropenia in those with normal baseline ANCs, correlate with response to LEN, supporting the link between suppression of the del 5q clone and erythroid response. This correlation was not observed in non-del 5q MDS pts, indicating alternate mechanisms of action of LEN.

Background: MDS with del 5q are characterized by profound anemia, which until the recent introduction of lenalidomide (N Engl J Med2005; 352: 549–57, J Clin Oncol2005;16S:5), was considered generally unresponsive to available treatments. In order to reevaluate the outcome of those patients in the pre-lenalidomide era, we analyzed response of anemia in MDS with del 5q treated with EPO ± G-CSF and thalidomide in previous GFM trials. Patients: MDS with del 5q included in 419 MDS treated with EPO or Darbepoetin (DAR) ± G-CSF by GFM centers (including 3 successive GFM trials: Blood2004; 104: 321–7; Blood2005;106 suppl 1: 712a; Br J Haematol2006;133: 513–9 and submitted to ASH 2006), and in 134 MDS treated with thalidomide in two successive GFM trials (Br J Haematol2005; 131: 609–18, and submitted to ASH 2006). Patients received at least 30,000 U/w of EPO or 300 mg/w of DAR and doses ranging from 50 to 800 mg/d of Thalidomide during at least 12 weeks. Results: 48 MDS with del 5q received EPO (or DAR) ± G-CSF, including 30 pts with del 5q alone, 9 with one and 9 with >1 additional cytogenetic abn; 21/48 had marrow blasts ≥5% (7 had >10%). 17 had the “5q- syndrome” according to WHO. Median pre-treatment EPO level was 287 UI/L (range 12–5,665), i.e. significantly more than in non del 5q cases (median 68, p1 additional cytogenetic abn, and marrow blasts ≥5%. Response duration was significantly shorter in MDS with del 5q than in other MDS (mean 12 vs. 24 months, p=0.019) and in pts with 5q- syndrome vs. other MDS with marrow blasts Conclusion: MDS with del 5q with ≤1 additional cytogenetic abn and no excess of marrow blasts may have erythroid response to EPO ± G-CSF but responses are generally very short, while response rates to thalidomide are low. Those results are clearly inferior to results obtained with lenalidomide in MDS with del 5q.

Background: EPO has been used in the treatment of refractory anemia in MDS patients for many years. Recently, with the identification of definitive patient selection criteria (low serum EPO [sEPO] levels and receipt of minimal transfusions) and standardization of ER rate evaluation methods using the IWGc, response to EPO therapy has been shown to be significantly enhanced in low/int-1 risk MDS patients. The present meta-analysis was conducted to compare ER rates (defined as major + minor response) of the two erythropoiesis-stimulating therapies (ESTs) currently available in the US, EPO and DARB, in MDS patients who were selected and evaluated for ER using the aforementioned uniform criteria. Methods: A systematic review and data extraction of studies from PubMed and ASCO/ASH proceedings from 1990–2006 in MDS patients treated with EPO monotherapy and from 2003–2006 in those treated with DARB monotherapy was performed. Pooled estimates of ER rates were calculated in each group using random-effects meta-analysis methods, which incorporated both between- and within-group variations. Multivariate meta-regression analysis was further conducted to control for differences in baseline characteristics between the two groups. Results: Nine EPO studies (N=619 patients, N evaluable for ER rate =589) and 8 DARB studies (N=442, N evaluable for ER rate =389) were identified. Baseline characteristics were comparable between the two groups with respect to age, gender, mean baseline hemoglobin, transfusion dependency rates, and proportion of patients with refractory anemia/refractory anemia with ringed sideroblasts. The mean baseline sEPO levels were significantly higher in the EPO group, compared to the DARB group (376: range 43–418; vs. 133: range 68–303 mU/mL, p=0.0026). The average initial weekly dose in the EPO studies was 47,851 (range: 30,000–80,000) Units, while that in the DARB studies was 176 (range: 100–315) mcg. There was no significant difference in the pooled estimate of the ER rates for either EST (57.6%: 95% CI; 45–70) for the EPO studies vs. (59.4%: 95% CI; 49–70) for the DARB studies, (p=0.8282). Further, as compared to the studies with standard doses of the two ESTs per week (EPO 30,000–40,000 Units; DARB ≤ 150 mcg), those using higher doses of EPO (60,000–80,000 Units) or DARB (>150 mcg) per week showed significantly higher ER rates (EPO- 47.8% vs. 63.3%, p Conclusions: This current meta-analysis demonstrates that, with the use of standardized patient selection and response evaluation methods, the two clinically available ESTs yield comparable ER rates in MDS patients.

Background: EPO continues to be a primary therapeutic choice for the treatment of anemic patients with low to intermediate-1 risk MDS. Initially, without standardized response criteria, ER rates were modest. Recently, a meta-analysis of EPO monotherapy studies in MDS demonstrated a significant improvement in ER rates with the application of standardized International Working Group criteria (IWGc) for response evaluation (Moyo V et al. 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 6572). This meta-analysis was expanded to determine the impact of higher doses of EPO or the addition of granulocyte or granulocyte-macrophage colony stimulating factor (G- or GM-CSF) to EPO on ER rates (defined as major + minor response). Methods: A systematic review and data extraction of studies from PubMed, ASCO and ASH proceedings from 1990–2006 in MDS patients treated with EPO monotherapy or EPO + G-/GM-CSF combination therapy was performed. Pooled estimates of ER rates were calculated in studies defining ER rates without IWGc application (non-IWGc) for EPO monotherapy at Standard (std) dose (30,000–40,000 Units per week) in comparison to studies that defined ER rates using IWGc, where EPO was used at std dose or high dose (60,000–80,000 Units per week) or in combination with G-/GM-CSF. Results: A total of 23 studies were evaluated in this analysis. As shown in the table below the IWGc studies using EPO at std dose or high dose or in combination with G-/GM-CSF demonstrated significantly higher ER rates than the non-IWGc studies (p Conclusions: The findings from this present meta-analysis confirm the impact of IWGc on ER rates for EPO therapy previously observed. Further improvement in ER rates was observed with the use of higher doses of EPO alone or the combination of EPO + G-/GM-CSF. Increasing the EPO dose appeared to have a greater impact on ER than the addition of G-/GM-CSF. Non-IWGc IWGc Study Group EPO Std Dose EPO Std Dose EPO High dose EPO + G-/GM-CSF Starting EPO Dose Units/week 30,000–40,000 30,000–40,000 60,000–80,000 30,000–40,000 No. of Studies 8 5 4 6 No.of Evaluable Patients 262 393 196 152 ER Rates (%)(95% CI) 32.1 (26–38) 47.8 (43–53) 63.3 (57–70) 50.7 (42–59)

6572 Background: Refractory anemia is a clinical hallmark of MDS. The most consistently used therapy for this anemia is EPO. Prior to the introduction of IWGc in 1997, ER rates varied substantially between studies. The present meta-analysis was undertaken to compare ER rates in studies of EPO-treated patients in MDS when defined by either IWGc or non-IWGc. Methods: A systematic review and data extraction of studies published from 1990–2005 in MDS patients treated with EPO was performed and yielded 21 studies evaluating a total of 895 patients. Pooled estimates of ER rates, stratified by IWGc, were calculated using random-effects meta-analysis methods, which incorporated both between- and within-study variations. Univariate meta-regression analyses were conducted to identify study characteristics that were significant determinants of ER rate. Results: Ten studies (604 patients) used the IWGc to define ER (overall, major, minor), while 11 studies (291 patients) used other definitions. Mean age for all patients was 70.6 years; 45% women. Mean baseline (BL) serum erythropoietin level and proportion of patients with refractory anemia or refractory anemia with ringed sideroblasts were comparable between studies; however, the proportion of transfusion-dependent patients at BL was lower in the IWG studies vs the non-IWG studies (36% vs. 84%, respectively, p [Table: see text]

The regulation of iron absorption is only partially understood. A cause and effect relationship between the erythropoietic and the absorption rates has been postulated, but not firmly established. Experiments in polycythemic mice were undertaken in an attempt to separate the effect of hypoxia on iron absorption from that on the erythropoietic activity. The latter parameter was evaluated on the basis of per cent values of peripheral reticulocytes, nucleated red cells in red pulp of spleen, and/or RBC-59Fe incorporation. In the first series of experiments the erythroid response to an 18- or 96-hr period of hypoxia was selectively suppressed by administration of antierythropoietin (anti-Ep) serum. However, the enhancement of iron absorption induced by an equivalent hypoxic stimulus was not significantly modified by anti-Ep. In additional studies, polycythemic mice were subjected to either fractionated Ep administration or hypoxic stimuli, lasting 24, 48, or 72 hr. The stimulatory effect on erythropoiesis induced by Ep was either greater or equivalent to that of hypoxia. However, although these hypoxic stimuli induced a four- to sixfold increase in iron absorption, Ep administration evoked either little or no enhancement of iron absorption. These experiments provide evidence against concepts linking the primary regulation of iron absorption to the erythropoietic rate.

The progression of plasma lactate dehydrogenase and heme biosynthetic activity in the spleen was followed in mice infected with Friend and Rauscher viruses. Plasma lactate dehydrogenase increased progressively in both viral diseases and paralleled the increase in spleen weight. Despite the similarity of the spleen weight responses, Friend virus promoted an earlier and more potent erythroid response as measured by porphobilinogen and porphyrin production than did Rauscher virus. The possible origin of the substantial increases in plasma lactate dehydrogenase is discussed.

The effect of hypoxia on red cell production and stem cells, as measured by CFU, was studied in two strains of mice. One of these strains, the CAF1, has been shown to produce relatively little erythropoietin in response to hypoxia; the other, the CF1, produces substantial amounts of erythropoietin. In the studies reported herein the CAF1 mice had an increase of ∼ 30 per cent in red cell mass after 23 days of exposure to either discontinuous (16 hrs./day) or continuous hypoxia equivalent to 23,000 feet of altitude. The CF1 mouse doubled its red cell mass after similar exposure. The splenic CFU decreased to as low as 17 per cent in the poorly responding CAF1 but remained at or near control levels in the CF1. It is suggested that the dissociation between erythroid response and changes in the CFU reflect a secondary effect of hypoxia not directly related to the erythropoietin-induced increase in red cell production.

Reliable methods have recently been developed to assay murine erythroid precursors in either plasma clot or methylcellulose cultures.1–3 At least two populations of erythroid stem cells have been identified, i.e., the erythroid burst- (BFU-e) and colony-forming unit (CFU-e), which give rise to large or small erythroid colonies respectively, colonies peaking at 8 to 12 days or 36 to 48 hr after Ep addition.3–5 Furthermore, evidence has been presented indicating that in the erythropoietic pathway the BFU-e and the CFU-e represent, respectively, an early and a late erythroid precursor.3–7 Recently, Gregory8 has identified a third population of erythroid stem cells, which is apparently intermediate between BFU-e and CFU-e pools.

Summary. Dibutyryl cyclic AMP (dbc-AMP) was injected into ex-hypoxic polycythaemic mice either alone or with anti-erythropoietin (anti-Ep) serum. Anti-Ep totally abolishes the wave of erythropoiesis evoked by dbc-AMP. These results might indicate either that the action of this agent is totally Ep-dependent, or that a residual amount of endogenous Ep is necessary to allow dbc-AMP to exert a direct effect at the marrow level. The latter mechanism, however, is precluded by experiments indicating that administration of moderate amounts of anti-Ep, although abolishing totally the erythroid response to dbc-AMP, do not induce complete suppression of endogenous Ep activity and erythropoiesis. Furthermore, a significant rise of Ep plasma levels is observed in rats receiving dbc-AMP. Since this agent does not apparently modify the kinetics of endogenous Ep, it is postulated that dbc-AMP induces a rise in Ep production. This phenomenon, although unmodified in ureter-ligated animals, is completely abolished by bilateral nephrectomy. It is therefore concluded that dbc-AMP induces in vivo a stimulatory effect on erythropoiesis via increased production of Ep, via a renal mechanism possibly represented by elevated levels of the renal erythropoietic factor.

A method was introduced to document the progressive changes in the ability of rat skeletal marrow to respond to bleeding over a span of 60 weeks following a single sublethal whole-body x-ray dose. Rats were exposed to a 170-R (200-kVp x-ray) whole-body dose. At intervals of 3, 6, 7, 10, 25, 33, 40, and 60 weeks postirradiation, half of each of the x-irradiated and control groups was bled one-third or two-thirds of the calculated blood volume (cbv) each, and their overall skeletal marrow content of nucleated RBC was determined. The remainder of the x-irradiated and control animals were measured for total marrow content of nucleated RBC without bleeding. The increase in RBC precursors on bleeding in the x-irradiated animal was compared with that found in the control animal on bleeding. This ratio (x-irradiated RBC precursor increase ÷ control RBC precursor increase) constitutes the "erythroid response index" (ERI) and is expressed as a percentage. An ERI value of 100% is taken to mean a lack of residual inj...

The erythroid and stem cell (colony-forming unit) responses were observed in the mouse after transfusion-induced polycythemia. Although there was a 40% decrease in erythroid differentiation 24 hours after transfusion, an increase in splenic CFU was not evident until 48 hours. This reached a level of approximately 200% by the seventh day, a time when maximum suppression of erythropoiesis was observed. With the administration of erythropoietin, a marked increase in splenic erythropoiesis was noted within 24 hours but the number of splenic CFU was not significantly changed from control values. Thereafter splenic CFU increased, following the erythroid response by approximately 24 hours. Bone marrow erythropoiesis gradually returned to the normal levels; however, quantitative estimates indicated at 15-20% decrease in marrow CFU. These responses to erythropoietin are similar to what has been observed in nonpolycythemic animals and suggest stem cell migration from the marrow to the spleen. The delays noted in st...