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The myelodysplastic syndromes are a heterogeneous group of disorders of the hematopoietic stem cell and stem cell niche.[1][1] The revised version of the International Prognostic Scoring System (IPSS-R), which is based on disease-related factors, was recently published.[2][2] In 2010, the MDS

Broséus, J., Lippert, E., Harutyunyan, A.S., Jeromin, S., Zipperer, E., Florensa, L., Milosevic, J.D., Haferlach, T., Germing, U., Luño, E., Schnittger, S., Kralovics, R., Girodon, F.

Patients with myelodysplastic syndromes (MDS) often show elevated serum ferritin levels at diagnosis, probably caused by increased intestinal iron uptake attributable to ineffective erythropoiesis. Many patients also develop transfusional iron overload. Hepcidin, a pivotal regulator of iron homeostasis, controls iron uptake in the duodenum as well as iron release from macrophages and is potentially involved in iron distribution to different organs. We measured serum hepcidin, together with other laboratory parameters related to iron metabolism and hematopoiesis (ferritin, transferrin, transferrin saturation, soluble transferrin receptor, erythropoietin, and hemoglobin), and C-reactive protein as marker of inflammation, in 89 MDS patients. Hepcidin levels were measured with two different competitive ELISAs: (a) EIA-4705 as described by Schwarz et al. (J Gastroenterol 46:648–656; 2011) and (b) Hepcidin 25 bioactive ELISA (EIA-5258), which was develop by DRG Diagnostics, Marburg, in 2012. Median hepcidin levels with EIA-5258 were as follows: entire cohort 17.5 ng/ml (n = 89), RA/RARS 5.9 ng/ml (n = 5), RCMD 17.8 ng/ml (n = 38), RS-RCMD 8.7 ng/ml (n = 7), RAEB I/II 29.1 ng/ml (n = 22), CMML I/II 16.9 ng/ml (n = 10), and MDS with del(5q) 26.3 ng/ml (n = 7). Hepcidin levels of the RA/RARS patients were significantly lower than in the other groups except RS-RCMD. RS-RCMD had significantly lower levels than RAEB and 5q− patients. There was a positive correlation between hepcidin levels and serum ferritin and transferrin saturation, and a negative correlation between hepcidin and hemoglobin and transferrin. Malcovati et al. (Blood 112:2676a, 2008), Santini et al. (PLoS One 6:e23109, 2011), and Ambaglio et al. (Haematologica 98:420–423, 2013), using mass spectrometry, reported similar results. We further assessed transfusional status and could show that patients who had been transfused have significantly higher hepcidin levels (median 33.3 versus 8.8 ng/ml (p

Background Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. Design and Methods We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. Results In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600×109/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia ( P

The incidence of myelodysplastic syndromes increases with age and a high prevalence of co-morbid conditions has been reported in these patients. So far, risk assessment in myelodysplastic syndromes has been mainly based on disease status. We studied the prognostic impact of comorbidity on the natural history of myelodysplastic syndrome with the aim of developing novel tools for risk assessment. The study population included a learning cohort of 840 patients diagnosed with myelodysplastic syndrome in Pavia, Italy, and a validation cohort of 504 patients followed in Duesseldorf, Germany. Information on comorbidity was extracted from detailed review of the patients' medical charts and laboratory values at diagnosis and during the course of the disease. Univariable and multivariable survival analyses with both fixed and time-dependent covariates were performed using Cox's proportional hazards regression models. Comorbidity was present in 54% of patients in the learning cohort. Cardiac disease was the most frequent comorbidity and the main cause of non-leukemic death. In multivariable analysis, comorbidity had a significant impact on both non-leukemic death (P=0.01) and overall survival (P=0.02). Cardiac, liver, renal, pulmonary disease and solid tumors were found to independently affect the risk of non-leukemic death. A time-dependent myelodysplastic syndrome-specific comorbidity index (MDS-CI) was developed for predicting the effect of comorbidity on outcome. This identified three groups of patients which showed significantly different probabilities of non-leukemic death (P

We studied the impact of comorbidities on survival and evaluated the prognostic utility of comorbidity scores in MDS patients, who received best supportive care and were assessable according to the Charlson Comorbidity Index (CCI) and the Hematopoietic Stem Cell Transplantation Comorbidity Index (HCTCI): 171 patients were identified in the Duesseldorf MDS Registry. The HCTCI captured more comorbidities. Both scoring systems had prognostic relevance, but the HCTCI more clearly distinguished between low-, intermediate- and high-risk patients. Median survival times of the different risk groups according to the HCTCI were 68, 34 and 25 months, respectively. The HCTCI showed prognostic impact in the IPSS intermediate- and high-risk group. On multivariate regression analysis, only the HCTCI remained a prognostic factor independent of IPSS. Considering their prognostic impact, comorbidities of MDS patients should receive appropriate attention in clinical trials as well as day-to-day clinical decision making.

We wish to confirm recent reports showing that JAK2 V617F[1][1][⇓][2][⇓][3][⇓][4]–[5][5] is commonly detectable in patients with thrombocytosis who also have ringed sideroblasts in their bone marrow.[6][6][⇓][7][⇓][8]–[9][9] For such patients, the WHO classification provides the

The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow

time of 4.7 months (1-36). Out of 260 pts with at least 2 FISH analyses and a median follow-up time of 12 months (2-36), 50 (19.2%) developed additional aberrations during the course of the disease not provable at study entry. Six further pts showed a KE only by CB, not by FISH. Of these 50 pts, 12 (24%) initially had a normal karyotype, 38 (76%) showed an abnormal karyotype at first diagnosis. Only one step of KE was detected in 36 pts (72%), 2 steps of clonal evolution were detectable in 12 pts (24%), and 2 pts (4%) went through 3 sequential steps of KE detectable from PB. The most common aberrations occurring as KE were in order of frequency: del(7q)/-7 (19%), del(20q) (11.4%), del(17p) (10.1%), del(21q)/-21/+21 (10.1%), +8 (10.1%), -Y (10.1%), followed by del(5q), -X, del(12p), +(1q), del(18q)/+18, +11, +13, +14. AML transformation followed KE in 50% of pts. Conclusions: FISH analysis of circulating CD34+PB cells is a valuable tool for sequential follow-up analyses of MDS pts to decipher genetic background of disease evolution. Especially younger pts eligible for allogeneic stem cell transplantation can benefit from CD34+PB FISHmonitoring to detect KE as an early marker of progressive disease as soon as possible.

Abstract 1964 Introduction: Treatment with azacitidine (Aza) and donor lymphocyte infusions (DLI) can induce sustained remissions in some patients (pts) with AML or MDS relapsing after allogeneic stem cell transplantation (allo-SCT). Meanwhile incidence and severity of GvHD seems to be relatively low when compared to historical data using DLI alone. As a potential mechanism murine models have suggested that Aza upregulates the transcription factor FoxP3 thereby expanding CD4+ regulatory T cells (Tregs). This has also been recently shown in 17 AML pts receiving Aza maintenance therapy following allo-SCT (Goodyear et al., 2012). Patients and Methods: To confirm and expand this knowledge we monitored CD4+CD25+FoxP3+ Tregs and lymphocyte subsets (CD3+; CD3+/CD4+; CD3+/CD8+; CD3−/CD56+; CD20+) by flow cytometry in 46 pts during salvage therapy with Aza (up to 8 cycles either 100 mg/m2/day d1-5 or 75 mg/m2/d d1-7) and DLI (envisaged on day 34/90/146) for relapse following allo-SCT. PB samples were obtained prior treatment (d0), after the 1st (d6), 2nd (d34), 4th (d90) and 6th cycle (d146). To assure a serial measurement only pts who had received at least 4 Aza cycles were eligible. Thereby 13 pts could be included, while 33 pts were excluded as a consequence of early drop-of resulting from progression or death (n=21), or due to missing samples (n=12). Results: Relapse of AML (n=8) or MDS (n=5) occurred in median 446 d (range:19–1688) following allo-SCT in these 13 pts. They received a median of 6 Aza cycles (range: 4–8). DLI were administered in all patients with a median number of 2 DLI per patient (range:1–4) resulting in a median total T cell dose of 5.0×106CD3+ cells/kg per patient (range:1–119). A CR rate of 62% (n=8) was observed in these 13 pts being overestimated in comparison to a CR rate of 33% (n=15) in the whole group due to positive selection of pts. Prior to relapse 6 pts (46%) had suffered from aGvHD (Io 1 pt, IIo 1 pt, IIIo 3 pts, IVo 1 pt) and 2 pts (15%) from cGvHD (limited 1 pt, extensive 1 pt). At the beginning of Aza treatment 3 pts were still on immunosuppresion which could be tapered in all cases without GvHD flare. Following treatment with Aza aGvHD was observed in 5 pts (overall 38%, Io 3 pts, IIIo2 pts) in median 129 d (range: 20 – 253) following the 1st DLI, while cGvHD developed in 6 pts (overall 46%, limited 5 pts, extensive 1 pt). In concordance with this rather mild presentation of GvHD, a 1.5-fold increase of Tregs was observed after 4 Aza cycles (d0: 8.23/μl vs. d90: 13.26/μl, p=0.0479). By grouping the pts on the basis of the median time to relapse (day 446), we observed a 3.2-fold increase of the absolute number (d0: 4.7/μl vs. d90: 14.8/μl, p=0.031) as well as an 1.9-fold increase of the frequency of Tregs (d0: 6.7% vs. d90: 12.9% of CD3+CD4+ cells, p=0.06) during treatment with Aza in the group of patients who relapsed early. On the other hand, in those patients who relapsed late the absolute number of Tregs (d0: 12.2/μl vs. d90: 11.9/μl, n. s.) was already higher and remained together with the Treg frequency (d0: 4.7% vs. d90 3.9%, n. s.) unchanged during treatment. Of interest, in those patients with early relapse only 1 pt developed aGvHD (Io), in contrast to 4 pts with aGvHD in those with late relapse. No significant changes were observed with regard to other lymphocyte subpopulations. Conclusions: We here demonstrate an intra-individual Treg expansion, which might be induced by Aza and may explain the low rate and mild presentation of GvHD observed following the combination of Aza and DLI. In line with the data of Goodyear et al. Aza-induced expansion of Tregs seems to be restricted to patients relapsing early after allo-SCT where the Treg repertoirs is still immature. Disclosures: Schroeder: Celgene: Travel support Other. Platzbecker:Celgene: Honoraria, Research Funding, Speakers Bureau. Bug:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, Travel support Other. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kröger:Celgene: Research Funding. Kobbe:Celgene: Research Funding.

Abstract 1982 Background: Consolidation with 2 cycles of 25 mg lenalidomide and/or maintenance treatment with a dosage of 10–15 mg lenalidomide after high-dose therapy (HDT) and autologous stem cell transplantation (SCT) improves event-free survival (EFS) in patients with multiple myeloma (MM), as has been shown recently by two randomised clinical trials in the US and France with patients up to the age of 70 and 65, respectively. So far data on longer consolidation treatment and different dosages in the maintenance setting is lacking. Methods: In the randomized, open label phase III LenaMain trial (clinical trials gov: NCT00891384) patients up to the age of 75 years are treated with six cycles of lenalidomide consolidation at a full dosage of 25 mg starting three months after first-line treatment with HDT and autologous SCT. After consolidation patients receive maintenance treatment with either lenalidomide 5 mg or 25 mg, both until disease progression. Here we present data of an interim safety analysis of the consolidation phase of the study. The trial is conducted in 4 transplant centers in Germany und plans to enrol 194 patients. Enrolment started in April 2009, and interim safety analysis was conducted in September 2011 with the first 68 patients enrolled and 50 patients finishing the consolidation phase. Myeloma subtype was IgG, IgA, others in 55, 23, 23% of patients, respectively, who had a median age of 64 years (range 37–73) and an ISS stage of I in 50%, II in 27% and III in 23% of cases at the time of diagnosis. All patients were treated with a median of 3 (range: 1–6) cycles of induction treatment followed by cytotoxic stem cell mobilisation with cyclophosphamide (4g/m2) and HDT and autologous SCT. Thirty-seven patients younger than 66 yrs received conditioning with melphalan 200 mg/m2, which was repeated in 7 patients not achieving at least a very good partial response. Tandem-HDT with melphalan 100 mg/m2was used for 32 patients older than 65 yrs. A median of 113 days (range:56–153) after the last HDT, consolidation treatment with lenalidomide 25 mg daily for 21 days of a 28 days cycle was initiated. All patients received aspirin for prevention of deep-vein thrombosis. Results: Response rates at baseline 3 month after HDT for sCR, CR, vgPR, PR, MRSD, PD were 0%, 14%, 53%, 31%, 2% and 0%, respectively. Three patients developed an early relapse during the six cycles of consolidation therapy. After cycle 6 of consolidation treatment response rates for sCR, CR, vgPR, PR, MRSD, PD were 10%, 16%, 41%, 24%, 2% and 7%, respectively. The remission status was improved in one third of patients. After 6 cycles of consolidation treatment 4 patients had discontinued treatment due to AEs, 2 patients withdrew consent and sudden death of unknown cause occurred in one patient during cycle 1. A lenalidomide dosage of 25 mg for 6 cycles could be applied to 53% of patients. Dose reductions were necessary in 47% of patients. Lenalidomide dosage after cycle 6 was 20 mg, 15 mg, 10 mg and 5 mg in 21%, 6%, 15%, and 2% of patients, respectively. The most common hematologic AE was neutropenia (Grade 1–2 in 42%, Grade 3–4 in 39%). Anemia (Grade 1–2: 88 %, Grade 3–4: 3%) and thrombocytopenia (Grade 1–2: 67 %, Grade 3–4: 7 %) occurred less frequently. No bleeding AE was documented. Infectious complications were seen in 59% of patients including 7% with Grade 3–4. Non-hematologic toxicity was low, and Grade 3–4 AEs included pain (2%), skin symptoms (2%), and neurological and constitutional symptoms (7%). There was no statistically significant difference in toxicity and tolerated dosage between patients younger or older than 65 years. Conclusion: Dose-escalation with lenalidomide 25 mg for 6 cycles as consolidation treatment was very well tolerated and the toxicity was consistent with published data with lower lenalidomide exposure. This was also true for patients aged 66–75 who did not experience an increased toxicity. Lenalidomide 25 mg for six cycles appears to be an effective consolidation treatment, with approximately one third of patients improving their response status. Disclosures: Fenk: OrthoBiotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide is not approved for maintenace treament of patients with myeloma. Giagounidis:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kröger:Celgene: Research Funding. Schroeder:Celgene: Travel support Other. Kobbe:OrthoBiotec: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 4113 Introduction: Most of the data related to RARS-T, a rare disorder, involve small cohorts of patients. We aimed to analyze more patients also considering a variety of myelodysplastic or myeloproliferative disorders. Objective: To compare a large cohort of patients with RARS-T to refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts and multilineage dysplasia (RARS-MD) or essential thrombocythemia (ET) at the time of diagnosis and during disease evolution, in terms of survival and complications. Materials: Data of a European multi-center study was used including 199 cases of RARS-T 173 cases of RARS, 102 cases of RARS-MD and 431 cases of ET. Results: At baseline, compared to RARS and RARS-MD patients, RARS-T patients had similar hemoglobin concentration, but a higher white blood count. The JAK2V617F mutation was observed in 43%, 12% and 5% in RARS-T, RARS and RARS-MD patients, respectively. When separated in 2 groups (450,000600,000 × 109/l), RARS-T patients were comparable for sex, age, hemoglobin level and survival. However, patients with platelet count > 600,000 × 109/l had higher WBC (11 ×109/l versus 7.5 ×109/l, p Conclusion: According to our results, the outcome in RARS-T more closely mimics myelodysplastic syndromes rather than myeloproliferative neoplasms. Our results agree with the WHO 2008 classification that considers RARS-T as a separate disorder. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Gattermann:Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Myelodysplastic syndromes (MDS) occur mainly in older persons, who are likely to be affected with extra-hematological comorbidities. Recent findings suggest that proper assessment of comorbidities is useful to predict the outcome of MDS patients receiving allogeneic transplantation. However, the results obtained in this highly selected subset of patients cannot be applied to the whole MDS population. In this study, we evaluated the impact of extra-hematological comorbidities on the natural history of MDS with the aim of developing a specific prognostic index. The patients comprised a “learning cohort”, in which we defined the set of variables to be included in the prognostic model and their weighted scores, and a “validation cohort”, in which we confirmed the prognostic value of the scoring system. The learning cohort included 840 MDS patients diagnosed at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, between 1992 and 2006, while the validation cohort consisted of 504 patients seen at the Heinrich-Heine-University Hospital, Duesseldorf, Germany, between 1982 and 2006. All cases were classified according to the WHO criteria. Patients who underwent allogeneic transplantation or intensive chemotherapy were censored at the time of the procedure. One or more comorbidities were present in 455 (54%) patients in the learning cohort at the time of diagnosis: the older the age, the higher the prevalence. Cardiac disease was the most frequent extra-hematological morbidity (25% of patients) and the main cause (63%) of non-leukemic death (NLD). In a Cox multivariable analysis with time-dependent covariates, the onset of a comorbidity significantly affected the risk of NLD (HR=2.29, P Table 1. MDS-specific comorbidity index (MDS-CI) Comorbidity Score Cardiac disease 2 Moderate-to-severe hepatic disease 1 Severe pulmonary disease 1 Renal disease 1 Solid tumor 1 Risk groups: Low (score 0), Intermediate (score 1–2), High (score >2). MDS-CI allowed us to identify 3 groups of patients with different probability of NLD and OS (P