Azacitidine is now considered one of the standard-of-care agents for patients with high-risk myelodysplastic syndromes who are not candidates for high-dose chemotherapy. Considering the mechanism of action of the agent, it is critical to maintain adequate dose intensities for prolonged periods of time in order for treatment to be effective. Therefore, aggressive prevention as well as treatment of side effects is critical. The drug mainly causes hematological toxicity that is managed with growth factor support, blood transfusions, and dose and schedule adjustment. Nonhematological side effects are mainly gastrointestinal and cutaneous in nature, and can be easily managed with symptomatic treatment and correct administration techniques.
Myelodysplastic syndrome with 5q- (MDS 5q-) is the only cytogenetically defined MDS category recognized by the world Health Organization (WHO) in 2001 and 2008 and is defined as a MDS with isolated deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow (BM). It is well known that for patients with MDS 5q- and transfusion dependence (TD), Lenalidomide is the first choice treatment. However, as far as we know there are no data regarding factors that may impact on the development of TD in these patients or the disease evolution in patients diagnosed without TD. In the present study a retrospective multicenter analysis on patients with low-int 1 MDS 5q- without TD at diagnosis has been performed in order to answer these questions. Patients and methods Data from eighty-four low-Int 1 risk MDS 5q- patients diagnosed between 1980 and 2012 were retrospectively analyzed. Ninety percent of patients had a single 5q deletion and according to IPSS-R 99% were in low and very low risk. Statistical analysis The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (Lenalidomide or ESA). Patients follow up was updated on March 30, 2013, and all follow up data were censored at that point. Transfusion free survival (TFS), Overall survival (OS) and AML were analyzed using the Kaplan – Meier method. TFS, OS, and Leukemia free survival (LFS) were measured from diagnosis to TD or to last follow up if transfusion free (TFS), death from any cause or last follow up (OS) and evolution to AML or last follow up (LFS). Multivariate analysis was performed using Cox’s proportional hazards regression model. Incidence of progression to AML was analyzed with cumulative incidence competing risk method. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05 statistical analysis was performed using SPSS 15.0 and NCSS V.8, 2010. Results During the study 61 (73%) became TD at a median of 1.7 years from diagnosis. The unique factor associated with poorer TFS was Hb level <9 g/dl (p=0.007) and this impact retained statistical significance in the multivariate analysis (table.1) Among the 61 TD patients, 49 received treatment: 19 lenalidomide, 24 ESA and 6 other treatments. Fifteen patients were treated (7 with lenalidomide and 8 with ESA) previous to TD development. In order to know the evolution of this very good prognostic subgroup of patients, OS and LFS analysis were performed. Median follow up was 48 months, 46% of patients are alive at the time of the last follow up and 31% developed secondary AML (sAML). Estimated OS at 2 and 5 y was 92% and 50% respectively. Regarding Univariate analysis, platelet <100.000 x109/L, and IPSS-R intermediate risk group were associated with poorer OS (p=0.001 and 0.019 respectively). On the contrary, patients who had received treatment showed better OS. This benefit is more evident among patients receiving Lenalidomide (p=0.015). In the multivariate analysis platelets <100.000 x109/L and Lenalidomide treatment retained the statistical significant impact on OS (table1). When LFS was analyzed the cumulative incidence of progression into AML was 4,4% after 2 y. and 12,7% after 5 y from diagnosis with median time to sAML of 8.16 years (CI 95%: 6.05-10.27). LFS at 2 and 5 y was 86% and 73% respectively. When univariate analysis was performed variables with impact on sAML were platelet <100.000 x109/L (p=<0,001), and to have received treatment (p=0,02). In the multivariate analysis only thrombocytopenia retained statistical significance (table1).In summary, the present analysis shows that Hb is the only parameter that conditions the TD development in MDS-5q- patients. In this very good prognostic subgroup beginning treatment with lenalidomide improves survival. Disclosures: Díez-Campelo: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen-Cilag: Research Funding. Off Label Use: In the present study we describe Lenalidomide treatment among patients with MDS and del(5q-) receiving this drug, not approval for this use in Europe, patients with anemia and transfusional requirements. Solé:Celgene: Consultancy, Honoraria; Celgene: Consultancy. Consuelo:Celgene Jansen-Cilag Arry Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.
Background There is scarce information about the efficacy of ESA in CMML although their use is common in clinical practice. The objective of this study was to analyze the response and OS in a series of 99 pts with CMML treated with ESA and to evaluate the feasibility of the predictive model of response to ESA used in MDS (Hellström-Lindberg, et al. Br J Haematol. 1997; 99: 344-51). Method Between January 1997 and March 2013 99 pts with CMML from the Spanish Registry of MDS and the Düsseldorf-MDS registry were studied. Clinical characteristics, response and OS were analyzed. Predictive model of response to ESA (0 good, 1 intermediate, and 2 poor) based on erythropoetin (EPO) level (< or ≥ 500 U/L) and red blood cell (RBC) transfusion need (< 2 or ≥ 2 RBC/month) was applied. Results 66 (67%) pts were males. Median age (range) was 75 (52-93) years. CMML subtype: myelodysplastic 58 (59%), myeloproliferative 41 (41%), CMML-I 84/98 (86%), CMML-II 14/98 (14%). CPSS score: Low/Int-1 65/90 (72%), Int-2/High 25/90 (28%). Transfusion dependence on initiation of ESA 24/86 (28%). Score based on predicted model of response to ESA: 0 43/62 (69%), 1 15/62 (24%), 2 4/62 (7%). ESA type: EPO alfa 22/94 (24%), EPO beta 16/94 (17%), EPO theta 3/94 (3%) darbepoetin 53/94 (56%). Concomitant medication: hydroxyurea 19 (39%), iron 18 (37%), steroids 4 (8%), azacitidine 3 (6%), etoposide 2 (4%), G-CSF 1 (2%), romiplostim 1 (2%) and oral chelation 1 (2%). Four pts were excluded for response analysis because they received azacitidine (3) and oral chelation (1). Response: Erythroid response (ER) 55/86 (64%), transfusion independence 5/22 (23%). ER according to CPSS (Low/Int-1 vs. Int-2/High): 71% vs. 43%, p=0,032. Median (min,max) time of ER was 4 months (0,88). Pts with 0 score according to predictive model of response to ESA presented significantly higher ER than pts with 1-2 score (77% vs. 24%, p<0.001) (Table 1). Median (range) follow-up was 2.1 years (0.1-10.5) years and median OS was 3.3 years (95%CI 2.7-4). OS of pts of Low/Int-1 risk group with ER (n= 40) was significantly higher than that of non-responding pts (n=16) (median in years (4.4, 95%CI (0.4-8.3) vs. 2.3, 95%CI (1.5-3), p<0.001). Conclusions A high frequency of ER was observed in this series of pts with CMML, the majority belonging to Low-risk CPSS. Predictive model of response to ESA from MDS was feasible, with a similar ER than that of MDS pts. Pts with low-risk CPSS with ER to ESA had a better OS than non-ER patients Supported by RD12/0036/0029 from RTICC-Instituto Carlos III, Spain Disclosures: Germing: Celgene: Honoraria, Research Funding; Jansen-Cilag: Honoraria; Novartis: Research Funding; GSK: Research Funding; Amgen: Research Funding.
INTRODUCTION Anemia is the most frequent cytopenia in lower-risk MDS. Erythropoietic-stimulating agents (ESAs) are commonly used in these patients. The use of ÒclassicalÓ parameters (EPO and ferritin levels) and the revised IPSS (IPSS-R) has been proposed1 (SantiniÕs score) to predict response to ESAs and overall survival (OS) among patients with lower risk MDS by IPSS and a favorable Nordic group score2. OBJECTIVES The main objective of the study was to evaluate overall response rate (ORR) to ESAs and OS according to the proposed SantiniÕs score in an independent and large cohort of anemic lower risk MDS patients receiving treatment with ESAs. METHODS Data from 530 anemic patients with low/int1 risk IPSS de novo MDS (according to FAB and WHO criteria) and sufficient follow-up data available were recorded in Spresas3 (SPanish Registry of Erythropoietic Stimulating Agents Study from GESMD). Two hundred and twenty six patients (42.6% of the patients) were selected according to specific criteria regarding the published SantiniÕs score1: Hb level </=10 g/dL, serum erythropoietin (EPO) <500 mU/mL and ESA (EPO alfa or B 40000-60000IU/week, or darbepoetin 150-300 ug/week). Applying 1 point to each of the following unfavorable variables for response to ESA, EPO>200mU/mL(=1), serum ferritin (SF) >350 ng/mL(=1) and IPSS-R very low=0, low=1, intermediate=2 and high=3) yielded a score ranging from 0 to 5. ESAs response rate and overall survival were analysed according to these score. Response to treatment was evaluated according to IWG 2006 response criteria and a multivariate logistic regression analysis was used to identify independent predictors of erythroid response (ER). OS were defined as the time between diagnosis and the corresponding event or last follow up (Feb 2015) and were analyzed using univariable and multivariable Cox proportional hazards regression methods. RESULTS Median age was 77 years (interquartile range [IQR] 25%-75%: 71-83 y), median Hb level at start of treatment was 10 g/dL (IQR25-75: 9-10), median EPO level was 90 (IQR25-75: 27,25-108) and median ferritin level was 338,5 (IQR25-75: 146,5-568,75). Among 139 patients with this data available, 85 patients (61,1%) were RBC transfusion dependent before ESAs treatment. Median time from diagnosis to ESAs treatment was 82 (IQR25-75: 27-353) days. According to the IPSS, 68.6% (N=155) and 31.4% (N=71) were in low and Int-1 risk groups, respectively. Regarding IPSS-R, 23% (N=52), 66.8% (N=151), 9.7% (N=22) and 0.4% (N=1) were in very low, low, intermediate and high risk, respectively. ORR to ESA treatment was 71.2% (N=161), with a median duration of response of 2.06 years. Prognosis factors of ER showed a trend toward to a higher ER among patients in the lower IPSS-R (P>0.05), low IPSS (p=0.039) and lower EPO levels (p<0.0001) while in multivariate analysis EPO level was confirmed as most significant variable associated to ER (p<0.001). According to SantiniÕs score, 11.5%(N=26), 42.9%(N=97), 25.8%(N=81), 8%(N=18) and 1.8%(N=4) of the patients were in the 0, 1, 2 3 and 4 score. Erythroid response was better for patients in the lower scores, with response rates of 73.1%, 82.5%, 65.4%, 50% and 0%, for patients in 0, 1, 2, 3 and 4 score, respectively (p<0.001, figure 1). After a median follow up of 3.1 years, median OS from diagnosis was 4.99 years. Interestingly, median OS from diagnosis was clearly related to SantiniÕs score (10.7 years, 6.7y, 4.9y, 3.7y and 6.7y for patients with 0, 1, 2, 3, and 4 points, respectively, p=0.041, Figure 2) whereas median OS from start of ESAs showed also some trend (p=0.26). CONCLUSIONS The present study confirms that SantiniÕs score is useful to identify patients with a higher probability of response to ESAs and better OS among lower risk MDS patients with an expected favorable response to ESA according to Nordic group score. Spresas study was partly supported by Janssen 1.-Santini et al, Blood 122(13), 2013. 2.-Hellstršm-Lindberg, Br J Haematol 120(6), 2003. 3.-D'ez Campelo, EHA 2015 meeting, P244. Disclosures Díez Campelo: Novartis: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau. Off Label Use: Use of erythropoietic stimulating agents for anemia in patients with myelodysplastic syndromes. Ramos:JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Falantes:Celgene: Honoraria. Garcia:Celgene: Research Funding. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau.
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