ALBERT

Description: Abstract 2786 Background: LEN is currently the reference treatment of low/int 1 (lower) risk MDS with del 5q, yielding RBC transfusion independence (TI) in two thirds of the cases, with a median RBC-TI duration of 2.2 years. (MDS 003 trial, List, NEJM, 2006). In case of primary or secondary failure of LEN, however combined analysis of MDS 003 and MDS 004 trial showed prognosis to be unfavorable and treatment approaches uncertain. We report results of treatment with AZA in 13 lower risk MDS with del 5q with primary or secondary failure of LEN. Methods: The 13 cases were treated between November 2005 and June 2011 in 10 centers of the Groupe Francophone des Myelodysplasies (GFM). At onset of LEN, median age was 71 years, M/F 0.43, 7 patients (pts) had RAEB 1 and 6 RA, 11 had isolated del 5q and 2 had 1 additional chromosomal abnormality. IPSS was low in 6 and int 1 in 7 patients. The LEN dose was 5mg/d, 10mg/d 3 weeks/4weeks, 10mg/d in 8, 3 and 2 patients, respectively. 11 (85%) patients had achieved RBC-TI, for a median duration of 26.3m (range 5.8–57.3)(secondary failures), while 2 patients had not achieved RBC-TI (primary failures). At onset of AZA, 11 patients had progressed with a change in WHO category (RA to RAEB1, or RAEB 1 to RAEB2) in 8 patients, and/or acquisition of additional chromosomal abnormalities in 9 patients, 5 eventually having complex karyotype, of whom 2 had chromosome 17 abnormality leading to TP53 gene deletion (TP53 mutation analysis is in progress); IPSS was low (n=0), int 1 (n= 3), int 2 (n=2), high (n=8). Prior to onset of AZA, attempts had been made to increase the LEN dose from 5 to 10 mg/d in 2 patients, without success. Results: AZA was administered at the FDA/EMEA approved schedule (75mg/m2/dx7) in 12 pts, and reduced (5 day schedule) in 1 pt. The median number of cycles administered was 6 (range 1–23). Five patients (46%) achieved a response according to IWG 2006 criteria, including CR, PR, HI in 1, 0 and 4 pts respectively. All 5 responders achieved RBC –TI. 4 patients received less than 4 cycles of AZA: 2 stopped AZA after 1 cycle for hematological toxicity, 1 stopped after 3 cycles for progression, 1 pt died from septic shock after 3 cycles. Response duration was 2.9+, 4.4+, 6.2+, 13.8, and 24.6 months, respectively. No responder was allografted, but the age of responders was 68, 70, 78, 78 and 86 years, respectively. Median survival from onset of AZA was 8.8 m (range 0.8–24.9). The 5 responders were still alive 3+, 4.4+, 6.2+, 13.9+ and 24.8+ m after onset of AZA, while median survival in non-responders was 8.7 months. Among the 5 patients who responded to AZA, 4 had at onset of AZA a high IPSS, 3 had complex karyotype and 2 one additional chromosomal abn, while 4/5 had previously achieved RBC-TI with LEN (with a median duration of 26.1 months). Neither of the 2 patients with TP53 deletion responded to AZA. Finally, among the 2 primary failures to Lenalidomide, one achieved HI with AZA (of 4.4+ months duration) and the other died within 2 months. Conclusion: In this relatively small series almost 40% of the patients with lower risk MDS and del 5q who progressed under LEN could be salvaged by AZA, and might expect survival prolongation. The appearance of novel chromosomal abnormalities or complex karyotype at progression did not predict poor response to AZA, while we are currently analyzing the prognostic value of TP 53 mutations, which occur frequently at th at disease stage (Jadersten, JCO 2011), on response to AZA. Disclosures: Fenaux: Celgene: Honoraria, Research Funding.

Description: Abstract 442 Background. ESAs are usually the first line tx of anemia in non del 5q lower risk MDS. However, not all pts respond to ESAs and median response duration is only about 2 years (Park, Blood 2008;111:574). Long-term outcome of pts who do not respond to or relapse after response to ESAs is incompletely known. We analyzed this outcome by updating a previously reported lower-risk MDS cohort of 403 pts treated with ESA in centers of the GFM (Blood 2008;111:574). Methods. We analyzed in that cohort low and int-1 (lower risk) IPSS pts with Hb75 was associated with shorter survival (median OS 31 mo vs. not reached for age 65 (P=0.03). 83 pts relapsed after an initial response (IWG 2000 major and minor in 60.2% and 39.8% pts, resp) of 16.5 mo median duration (range 3–74 mo). At tx onset, M/F was 1.35, median age 74.3, WHO classification RA, RCMD, RARS, RAEB-1 in 14%, 38%, 32%, 16% of cases, resp, karyotype fav, int in 92% and 8% pts, resp, IPSS low, int-1 in 51% and 49% of pts. Median serum ferritin was 695 ng/mL and median sEPO 64 IU/L. 45% of the pts were TD (median 2 RBC units/mo). Median OS and 3-y CI of AML after relapse were 53 mo and 9.7%, resp. Median OS after relapse was 26 mo in RAEB-1 and not reached in other WHO subtypes (P=0.06) and was not influenced by the presence of multilineage dysplasia. Pts who relapsed after 24 mo had a 4.1% 3-y CI of AML vs 12.8% in pts who relapsed before 24 mo (P=0.40). Median OS was not reached in pts who relapsed after 24 mo vs 53 mo in those relapsing before 24 mo (P=0.90). No pre-tx characteristic was predictive of relapse before or after 24 mo. 16% of the 83 pts were aged 65 (P=0.17), and their 3- CI of AML after relapse was 0% vs 12% in pts aged 〉65 (P=0.31). In the overall pt population (ie pts with primary resistance, pts with relapse and pts with sustained response), univariate competing risk modeling found CI of death from cardiovascular causes to be correlated with TD and older age at tx onset but not with response status, while only age remained significant in multivariate analysis (HR=1.12 [1.014-1.24], P=0.02). Both older age and early failure (ie primary failure or relapse

Description: Abstract 2916 Background: Increased serum ferritin (SF) level has been associated with worse overall survival (OS) in lower risk MDS, presumably though iron overload in vital organs including the heart and liver (Cazzola, NEJM 2005, Malcovati, JCO 2005, Garcia-Manero G et al. Leukemia 2008). However, those high levels are generally associated with RBC transfusion requirement (Malcovati, JCO 2007, Sanz, Blood (ASH 2008 : Abstract 640). High SF level has also been reported in non transfused lower risk MDS, and attributed mainly to ineffective erythropoiesis, but its prognostic value in this context is unclear. We evaluated the prognostic value of SF level at diagnosis in lower risk non transfusion dependent (TD) MDS patients included in the GFM registry of MDS. Methods: We selected in the GFM Registry (1900 pts included between mid 2003 and 2010), 485 newly diagnosed IPSS low and int 1 (lower) risk MDS patients (pts), not transfused during the first 6 months of follow-up, who had a baseline SF level (normal values 20–300 ng/ml), and no other cause of increased SF, including infection and liver disease (due in particular to alcohol abuse). Pts with SF 〈 20ng/mL were excluded. The prognostic value of SF for AML progression and OS was analyzed. Results: Median age of the 485 pts was 77 years (range 29–103), with 53.8% males. WHO classification was RA 21.5%, RCMD 23.5%, RARS 23%, RCMD-RS 0.5%, RAEB-1 22% and 5q- syndrome 5%. Karyotype according to IPSS was fav (61%), int (10%), unfav (2%), not available (17%). IPSS was 0 (44%), 0.5 (31%), 1 (8%), ND (17%). The median level of SF was 276ng/ml (range 20–5558) with 225 (46%), 145 (30%) and 47(10%) pts having SF〉300ng/ml, 〉500ng/ml and 〉1000ng/ml respectively (resp.). In univariate analysis, male gender (P=0.0005), Hb level100μm3 (P=0.02), erythroblasts 〉30% in bone marrow (P=0.008), serum (s) EPO level〉100IU/l (P=0.04), RARS (P300ng/ml) while karyotype, IPSS, % marrow blasts, reticulocytes, platelets showed no correlation. In multivariate analysis, sEPO level〉100IU/l and RARS were significantly associated with higher SF level. As the SF threshold of 1000ng/mL is often proposed to start chelation therapy, prognostic analyses were also made for that level. Hb level 100 were associated with SF 〉1000 ng/ml in univariate analysis, while only Hb level

Description: 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

Description: Introduction: The WHO defined overlapping MDS/MPN group includes two rare entities: BCR-ABL negative aCML and MDS/MPN-U, defined by at least 3 months persistent WBC 〉13G/l or platelets 〉450G/l with at least 1 cytopenia, significant dysplasia (〉10%) in at least 1 lineage, no circulating monocytosis (

Description: Introduction:Long-term outcome of patients with IPSS low or int 1 (LR) MDS treated by IST with horse or rabbit (hATG or rATG) +/-CsA is not well described and patient selection criteria for such a therapy remain ill-defined in daily practice, including after resistance to erythropoiesis stimulating agents (ESA). Methods: We report the outcome of 15 consecutive LR-MDS patients treated in our institution between 2005 and 2013, with h or rATG (15 mg/kg/d for 5 days and 3.5 mg/kg/d for 5 days, respectively), +/- CsA 2 mg/kg BID for 6 months (m). The use of h or rATG formulation was based on institutional practice and availability. Patients with altered renal function or vascular contra-indication to CsA (mostly due to age) only received ATG. Bone marrow (BM) blasts were counted over 500 cells in cases of very low BM cellularity and over 1,000 cells otherwise. FISH analysis of chromosomes 5 and 7 was performed in case of cytogenetic failure. IST response probability score (ISTRPS) was calculated according to Saunthararajah, Blood 2003. Overall response rate (ORR), including complete response (CR), assessed at 12 m, and progressive disease (PD) were defined according to IWG 2006 criteria. Transfusion independence (TI) was defined as independence from RBC transfusion for at least 8 weeks. Results: Median age was 60 years (y) (range 46-77). Median follow-up was 8.1 y. All patients were RBC-transfusion dependent (RCTD). Median RCTD duration was 4.9 m (0-42). Platelet counts were 6 m, P=0.02). There was a trend for a higher TI rate with lower platelet counts (P=0.13) and high ISTRPS (P=0.14). By contrast age, using a 60y cut-off, and presence of a DRB15 allele were not predictive of TI (P=0.58 and 0.31) in this cohort. Two relapsed patients were retreated with hATG +CsA and achieved a second durable response (1 CR (45m+) and 1 TI (9m+)). One non-responding patient, who subsequently developed full-blown PNH, responded to CsA and eculizumab. 5-y cumulative incidence of PD and AML were 42% and 6% respectively and median OS was 5.6 y. Median OS was not reached in responders versus 22 m in non-responders (P=0.004 by log-rank test). A single toxic death from a hemorrhagic stroke occurred very early in a patient heavily pretreated for MDS-associated vasculitis. PNH clone expansion and cytogenetic evolution occurred in 2 (both responders) and 3 patients (2 responders). Conclusion: Lower-risk MDS patients responding to IST have a good long-term outcome. After relapse, durable responses to a second course of IST can be achieved. In addition to RCTD ≤6 m, BM blasts ≤2% emerged as an IPSS-R component strongly predicting response to IST. Age 〉60 y was not associated with worse response. Therefore, IST should be considered as a treatment option for selected lower-risk MDS patients with very low blast counts, irrespective of age. Disclosures Off Label Use: ATG and cyclosporin A are not approved for the treatment of MDS..

Description: Solitary plasmacytoma (SP) is a rare plasma cell dyscrasia characterized by the presence of bone or extramedullary tumors consisting of monoclonal plasma cells, without evidence of systematic multiple myeloma (MM). The treatment of choice is local radiotherapy (RT) with or without surgical excision (SE). Our aim was to describe the clinical features, the outcome and prognosis of SP patients. Thus, we studied 97 consecutive patients, 65 with solitary bone plasmacytoma (SBP) and 32 with solitary extramedullary plasmacytoma (SEP), (M/F: 66/31, median age: 61 years, range 17-85 years) who were diagnosed and treated in 12 Greek Myeloma Centers; treatment was given according to each center’s local policy. Patients with SBP and SEP did not differ in age, gender, performance status (PS), Hb, CRP, LDH, calcium, beta2-microglobulin, renal function or impairment of humoral immunity (immunoparesis). Patients with SEP presented more often with serum or urinary monoclonal component (p

Description: Abstract 976 Background: Lenalidomide (LEN) is particularly effective on anemia of lower risk MDS with del 5q (List et al, NEJM, 2006). A compassionate program (ATU) of LEN in RBC transfusion dependent (TD) low and int 1 (lower) risk MDS with del 5q was opened by the French health agency between Jan and Sept 2007. The concern raised by EMEA that LEN may trigger progression to AML in some MDS with del 5q lead us to compare the outcome of our cohort to that of RBC transfusion dependent lower risk MDS with del 5q that never received LEN. Methods: 95 RBC -TD lower risk MDS pts with del 5q, diagnosed between 1988 and 2007 in GFM centers, received 10 mg of LEN/day, 3 weeks on, 1 week off. Median age was 70.4 years, median interval from diagnosis to LEN was 29 months. IPSS was low in 31% and intermediate-1 in 69% patients. Del 5q was isolated, with 1 additional and 〉 1 additional abn in 79%, 14%, and 6% patients, respectively. 60 (63%) pts achieved transfusion independence (TI). We compared the risk of progression to AML and survival from diagnosis of this cohort and of a historical cohort of 99 similar RBC TD lower risk MDS with del 5q deletion diagnosed between 1985 en 2005 in GFM centers and treated before LEN was available in France (part of those pts have been reported in Kelaidi,Leuk Res 2008). For this non randomized comparison, we used the propensity score method. This method can estimate unbiased treatment effects from observational studies based on a propensity score, ie re-create the exchangeability between two treatments groups. We determined a propensity score defined as a subject's probability of receiving LEN conditionally on his observed covariates. For this purpose, we modeled through multivariate logistic regression, in pts with RBC transfusion dependent lower risk MDS with del 5q the probability of receiving LEN conditionally on a set of baseline characteristics (including age, gender, WHO diagnosis, IPSS score, cytogenetics). The estimated propensity was then used to match 1:1 patients with similar propensity to receive LEN. Results: In the LEN cohort, with a median follow up of 18.5 months from onset of LEN, 6 (6.3%) pts had progressed to AML, after 30 to 67 weeks (median 45 weeks), including 2 pts who had achieved TI. At onset of LEN, 4 of them had an IPSS of 1, and 2 of 0.5. Two had isolated del 5q and 4 had one additional cytogenetic abn. Baseline characteristics of the LEN cohort and the historical cohort treated without LEN were similar, except for age (median 73 years in the latter, vs 70.4, p= 0.03), and % of RARS (14% vs. 4%, p= 0.05). The propensity score was derived from a multivariate logistic model incorporating pt age at diagnosis, gender, WHO, IPSS and cytogenetics. Then, a matched-dataset was constituted between pts who received or not LEN. Seventy-one pts in each group could be matched, erasing differences in covariates between the two treatment groups. In those 71 matched pairs, the 4 year-cumulative incidence of AML from diagnosis was 8.9% in the 71 matched pts treated with LEN and 15.8% in the 71 matched pts who received no LEN (HR= 0.46, 95%CI: 0.16–1.35; p=0.14) (figure 1). Median overall survival was 150 months in the 71 pts treated with LEN vs 72.8 months in the 71 pts treated without LEN (HR= 0.54, 95%CI: 0.26–1.11; p= 0.10). Conclusion: Using a propensity score methodology, we found the incidence of progression to AML from diagnosis, in the present cohort treated with LEN, not to be greater than that of a comparable historical cohort of RBC transfusion dependent lower risk MDS with del 5q treated without LEN. Likewise, no significant survival difference was found between the 2 groups. Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Description: Rational The immunomodulatory drug, Lenalidomide (LEN) has proven to be impressively effective for patients (pts) with myelodysplastic syndromes (MDS) harboring deletion 5q and is currently evaluated for registration for pts without del5q. However, we know from prior studies that response rate is limited to 60% of del5q and 25% of non-del5q pts. Moreover, response duration is limited to 24 to 36 months (m) in del5q and 12 to 18m in non-del5q pts. There is no standard option after failure of LEN and so defining the outcome is important in order to define the impact and efficacy of current and future strategies. Methods This is an international retrospective study from US, French, German and Italian academic centers. Adult pts were included if they were diagnosed with MDS and received at least one cycle of LEN. Patients were excluded from this analysis if LEN was combined with chemotherapy, hypomethylating agents (HMA), or given preemptively after allotransplant. Median overall survival after LEN failure was the primary endpoint. Results 425 pts were included and analyzed separately between del5q and non-del 5q patients. In the del5q cohort (n= 203), median age was 70 years with a female predominance (n=133). 86 pts has del5q syndrome, 43 RARS/RCMD, and 74 pts RAEB-1/2. 34% of pts were previously treated with ESA and 79% were RBC transfusion dependent (TD) at the onset of LEN. Median duration of LEN treatment was 8 months and 115 pts (57%) were responders. Reasons for stopping LEN were loss of HI 55%, no response and SD 27%, no response and PD 11%, intolerance 7%. Median overall survival after LEN failure was 31 months. In pts with lower risk IPSS, ESA resistance, and RBC-TD (n=43), median OS was 43 months. After failure, 64 pts were treated with best supportive care (BSC), 26 were allotransplanted, 69 received HMA, 18 received growth factors, 13 received conventional chemotherapy for progression, and 9 pts received other treatments. There was a significant survival benefit for treated pts vs BSC (39 vs 14m, p=0.01) and for pts treated with HMA post LEN as compared to BSC (31 vs 14m, p=0.003). Advanced age, complex cytogenetics, exposure to HMA prior to LEN, and RAEB negatively impacted outcome in multivariate analysis. Primary vs secondary failure did not influenced outcome but patients with PD without prior HI (11%) had a shorter survival. In the non-del5q lower risk MDS cohort (n= 222), median age was 70 years with a male predominance (n=153). 62 pts had RARS, 104 RCMD, 28 RA/MDS-U, and 28 pts RAEB-1. 62% of pts had received ESA, 30% had received HMA, and 95 % of the pts were RBC-TD at the onset of LEN. Median duration of LEN treatment was 4 months and 55 pts (24%) were responders. Reasons for stopping LEN were loss of HI 24%, no response and SD 65%, no response and PD 10%, intolerance 1%. Median OS after LEN failure was 40m. In pts with lower risk IPSS, ESA resistance, and RBC-TD (n=68), median OS was 37 m. After LEN failure, 43 pts were treated with BSC, 21 pts were allotransplanted, 85 pts received HMA, 15 pts received growth factors, 15 pts received conventional chemotherapy for progression, 40 pts received other treatments. There was a survival benefit for treated pts vs BSC (42 vs 29m) but this was not statistically significant (p=0.26). None of the therapeutic options including transplantation were able to demonstrate a significant survival benefit as compared to BSC. Based on multivariate model, RAEB and prior HMA exposure negatively impacted outcome after LEN failure. Response to LEN did not favorably influence OS (31m for responders vs 43m in non responders, p=0.12, and 48m vs 47m respectively, p=NS, when survival is calculated from LEN onset), suggesting the absence of disease modifying effect in non del5q MDS Conclusions This is the first large study analyzing the outcome of MDS pts after lenalidomide failure Survival without treatment remains relatively poor in both groups and there is only a limited impact of conventional approaches. HMA may represent an interesting option for del5q pts. This study stresses the unmet need for new strategies and gives the basis for the design of future clinical trials. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Prebet: CELGENE: Research Funding. Off Label Use: lenalidomide. Park:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Platzbecker:Amgen, Inc.: Honoraria; Celgene: Honoraria; Novartis: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Vey:Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Komrokji:Pharmacylics: Speakers Bureau; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Incyte: Consultancy.

Description: Background : Most non-del 5q lower risk MDS patients (pts) are first treated with ESA, with about 50% (generally transient) responses, and second line treatments (TX) including hypomethylating agent (HMA), Lenalidomide (LEN) and investigational drugs are then often proposed, but their effect on overall survival (OS) is unknown. In a previous work on 253 such pts, we found worse OS with early failure to ESA, i.e. primary resistance (RES) or relapse (REL) 〈 6 months after ESA onset (Kelaidi, Leukemia, 2013), but only few pts had received, after ESA failure, TX other than RBC transfusions. In the present study, we gathered non-del 5q lower risk MDS treated with ESA from several EU MDS cooperative groups, and analyzed their outcome after ESA failure, and the effect of second line TX on survival. Methods : 1611 IPSS low and int-1 (lower risk) non del 5q MDS pts included in the French (GFM), Italian (FISM), Spanish (GESMD), Greek, Düsseldorf and Munich registries between 1997 and 2014, and treated by ESA were studied. Survival was assessed from failure of ESA (i.e. from primary failure evaluated after 12 to 24 weeks of ESA treatment, or from relapse after a response). Progression at ESA failure was defined upon progression to a higher IPSS-R class at ESA failure as compared with ESA onset. Results : At ESA onset, the 1611 pts were reclassified by IPSS-R in 16% very low, 54% low, 13% int, 6% high, 1% very high and 10% ND. HI-E (using IWG 2006 criteria) to ESA treatment was 66.9%, and the median duration of response was 15 months. The cohort of 1038 pts with ESA failure included 521 RES and 517 REL. Median OS was 4.2 years in REL and 3.7 years in RES pts (p=0.56), and no significant difference was seen, even after restricting the analysis to very low and low IPSS-R pts (p=0.81), or when analyzing "early" vs "late" failures, with cut-off points at 6 or 12 months, as we previously reported (Kelaidi, Leukemia, 2013). 336 (32%) pts received second line treatment (TX2) other than RBC transfusions, including HMA in 88 pts, LEN in 169 pts, and other TX (OT) in 79 pts (including 11 chemotherapy, 17 thalidomide, 11 immunosuppressors (ATG, cyclosporine), or investigational drugs), with response rates of 46%, 39% and 33% respectively (p=0.4). 87 pts had a third line TX (mostly a new drug, but also 7 pts who received HMA after LEN, and 33 pts LEN after HMA). Pts treated with LEN as TX2 were younger (median age 70 vs 75 for BSC, and 70 for HMA p