Prognostic Factors Of Response and Survival To Azacitidine (AZA) +/- EPO In RBC Transfusion Dependent (TD) IPSS Low and Int-1 (LR) MDS Resistant To EPO, With Particular Emphasis Of Genetic Lesions: A Study By The GFM

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 658-658 ◽  
Author(s):  
Sylvain Thepot ◽  
Raouf Ben Abdelali ◽  
Sylvie Chevret ◽  
Aline Renneville ◽  
Odile Beyne Rauzy ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Genetic Markers ◽  
Research Funding ◽  
Prognostic Value ◽  
Response Rate ◽  
Univariate Analysis ◽  
Snp Array ◽  
Erythroid Response ◽  
Rbc Transfusion

Abstract Background Although anemia of LR MDS initially responds to erythroid stimulating agents (ESA) in 40-50% of patients, response is generally transient. AZA may lead to RBC transfusion independence (RBC-TI) in 30-40% of LR-MDS patients but it has not been studied prospectively in those resistant to ESA. While prognostic factors of response and survival to AZA have been largely analysed in high risk MDS, including by our group (Itzykson, Blood, 2011), they remain uncertain in LR-MDS, especially regarding new genetic factors. We previously reported (J Clin Oncol 30, 2012 # 6523) in a randomized phase II trial comparing AZA and AZA+EPO in 93 LR-MDS that were RBC-TD and resistant to ESA, a similar erythroid response rate in the 2 treatment arms (NCT01015352). Here, we report prognostic factors of response and overall survival in this trial, including genetic markers (SNP array-based karyotype and somatic mutations). Methods Patients included in the trial received AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) or with added EPO 60000U/week (AZA+EPO arm). Erythroid response was evaluated after 4 and 6 cycles of AZA, according to the IWG 2000 criteria. Responders were then eligible for 12 AZA+/-EPO maintenance cycles. Affymetrix SNP array 6.0 (SNPa) analysis was performed at baseline on marrow mononuclear cells, and mutations of SF3B1, TET2, DNMT3A, ASXL1, JAK2 and 19 other genes were screened by next generation sequencing and validated by Sanger sequencing. The following factors were analysed for their prognostic value on erythroid response (IWG 2000) and survival: age, gender, IPSS, IPSS cytogenetics, WHO diagnosis, time since MDS diagnosis, SNPa karyotype, SF3B1, TET2, DNMT3A, ASXL1 and JAK2 mutations. Results In the 93 patients, M/F was 65/28; median age 72 y (IQR: 65-78); WHO diagnosis: RA 5.3%, RARS 40.9%, RCMD 15.1%, RCMD-RS 17.2%, RAEB-1 12.9%, CMML 7.5%, MDS-U 1%. Median MDS duration prior to inclusion was 37.2 months. IPSS was low in 35 and int-1 in 57 patients (NA in 1). IPSS cytogenetics was fav in 65, int in 9, defav in 2 patients, and failed or not done at study entry in 17 (but cytogenetics at MDS diagnosis was available in 16 of them). An abnormal SNPa karyotype was present in 33/79 patients analysed, including 9 with normal conventional cytogenetics. SF3B1, TET2, DNMT3A, ASXL1 and JAK2 mutations were detected in 59/86, 29/87, 12/87, 5/89 and 3/87 patients. Of the 19 other genes analysed, 12 showed no mutation and 7 (UA2F1, CBL, EZH2, RUNX1, ETV6, KIT, IDH2) were mutated in ≤3 patients and were not further considered in this analysis. In ITT analysis (N=93), erythroid response was 34% after 4 courses (37.5 % vs. 31% in the AZA and AZA+EPO arms, respectively, p=0.82) and 30% after 6 courses (35% vs. 24%, p=1.00). In univariate analysis, none of the factors listed above, including genetic markers, significantly predicted treatment response after 4 or 6 courses, while a trend was observed for a higher response rate after 6 cycles for SF3B1 mutated versus wt. patients (35.6 vs. 14.8 % respectively, P=0.07). Median follow-up of the 93 patients was 30 months (IQR: 23-34). Five patients developed AML (1 in AZA arm and 4 in AZA+EPO arm, P=0.19), all 5 in non-responders after 6 cycles. Median OS was 42.2 months and 2.5 years-OS 79.2% (95%CI: 71.2-88.1), with no difference between randomization arms (P=0.69). In univariate analysis, a shorter time since MDS diagnosis (HR=0.97, 95%CI: 0.95-0.99,P=0.011), IPSS int-1 (HR=2.83, 95%CI: 1.05-7.63, P=0.04), an abnormal SNPa karyotype (HR=3.01, 95%CI: 1.26-7.22, P=0.013) and presence of ASXL1 mutation (HR=5.08, 95%CI: 1.48-17.48, P=0.010) were associated with worse survival. In multivariate analysis, however, only time since MDS diagnosis (HR=0.97, 95%CI: 0.95-0.99) and abnormal SNPa karyotype (HR=2.92, 95%CI: 1.07-8.01) remained of prognostic value. Conclusions In this prospective AZA trial in LR-MDS resistant to ESA, no significant prognostic factor for response to AZA+/- EPO was identified, but a trend for better response (p=0.07) was seen in SF3B1 mutated patients, i.e 2/3 of patients. Among mutations analysed, only ASXL1 mutation predicted survival in univariate analysis, while abnormal SNPa karyotype predicted survival both in univariate and multivariate analysis (together with MDS duration). Thus, SNP array-based karyotyping and ASXL1 gene mutation analysis may become important tools to predict the long-term outcome of ESA resistant LR-MDS treated by AZA Disclosures: Guerci-Bresler: Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Fenaux:Celgene, Inc: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gardin:Celgene, inc: Research Funding.

The Revised IPSS (IPSS-R) Predicts Response To Erythropoietic Stimulating agents (ESA) In Pts With Classical IPSS Low Or Intermediate-1 (int 1)- MDS: A Joint Retrospective Study Of The GFM, Düsseldorf Registry and Fism

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2761-2761
Author(s):  
Valeria Santini ◽  
Jennifer Schemenau ◽  
Alessandro Levis ◽  
Enrico Balleari ◽  
Rosa Sapena ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Prognostic Value ◽  
Transfusion Requirement ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Univariate Analysis ◽  
High Risk Group ◽  
Continuous Variables ◽  
Erythroid Response ◽  
Rbc Transfusion

Abstract Introduction The “classical” IPSS, based on cytogenetics, marrow blast percentage, and number of cytopenias, has played a major role in prognosis assessment in MDS. The recently published revised IPSS (IPSS-R), refines the original IPSS prognostic value (Greenberg et al, Blood 2012). However, its prognostic value for response to ESA has not been assessed. We analyzed it retrospectively in 456 IPSS Low-/Int-1-risk MDS patients (pts) treated with ESA in France, Germany and Italy. Results Those 456 pts had serum EPO < 500mU/ml and Hb≤10g/dl, and had received ESA (EPO alfa or beta 40000-60000 IU/week, or darbepoietin 150 - 300µg/week) for at least 12 weeks. In addition to IPSS-R parameters, age, sex, serum EPO level, serum ferritin (SF), and RBC transfusion requirement before ESA onset were assessed for response to ESA (based on IWG 2006 criteria), and overall survival (OS) from ESA onset. Characteristics of the 456 pts at ESA onset are listed in Table 1. 71% of the pts had never received RBC transfusions, with a median Hb level of 9.3g/dl (range 7.0-10) , and 29% pts had received at least 4 RBC concentrates/8wks before ESA onset (with a maximum of 12). Median SF was 357ng/ml and serum EPO 60mU/ml (range 6-483). IPSS was low in 55% and intermediate-1 in 45% pts. IPSS-R was very low in 15%, low in 61%, intermediate in 19% and high in 4% of the pts. 303 (61%) pts had an erythroid response (ER), including 72% and 52% of low and int-1 risk pts respectively (p=0.001). Using IPSS-R, 85%, 68%, 48% and 31% of pts had ER in the very low, low, intermediate and high risk group respectively (p<0.0001). Other prognostic factors of ER, in univariate analysis, included individual IPSS-R parameters analyzed according to IPSS-R thresholds (Hb level, platelet count, ANC, marrow blast %, cytogenetics) serum EPO level, SF (variables tested as continuous variables) and previous RBC-transfusions. In multivariate analysis, IPSS-R, serum EPO, and SF remained significantly associated with ER (p<0.0001, p=0.002 and p<0.0001 respectively). Applying 1 point to each of the following unfavorable variables of ER: serum EPO >200mU/ml (=1), SF >350 ng/ml (=1), IPSS-R (very low=0, low=1, intermediate=2 and high=3), yielded a score ranging from 0 to 4, with ER rates of 85%, 80%, 64%, 40% and 20% respectively. As expected, IPSS-R also had strong prognostic value for OS (not shown). Conclusion In this patient cohort with overall favorable prognostic factors of response to ESA according to the Nordic score (ie serum EPO <500 mU/ml and no or limited transfusion dependence, Hellstrom-Lindberg et al BJH 2003), IPSS-R alone, and even better, a score >=3 (using IPSS-R, serum EPO and SF) proved useful to identify pts with low response to ESA, who also have worse OS and may require alternative treatments (Kelaidi et al, Leukemia 2013). Disclosures: No relevant conflicts of interest to declare.

Prognostic Factors of Response to Erythropoiesis Stimulating Agents (ESA) Treatment in Non RBC Transfusion Dependent Lower Risk MDS. Preliminary Results of a French and Italian Study (on behalf of the GFM and FISM).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2814-2814 ◽  
Author(s):  
Sophie Park ◽  
Gina Zini ◽  
Valérie Andrieu ◽  
Alessandro Levis ◽  
Daniela Gioia ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Lower Risk ◽  
Prognostic Value ◽  
Response Rate ◽  
Baseline Serum ◽  
Lower Response ◽  
Lower Response Rate ◽  
Rbc Transfusion ◽  
Who 2008

Abstract Abstract 2814 Purpose: ESA are generally the first line treatment of anemia of IPSS low and int1 (lower) risk MDS. While endogenous EPO level and RBC transfusion requirement are well defined prognostic factors of response to ESA (Hellstrom, BJH 2003), many patients (pts) are treated before they require RBC transfusions and, in a GFM large cohort of lower risk MDS with anemia, baseline EPO level was below 500U/l in 88% of the cases (Kelaidi, Haematologica 2010). In non transfusion dependent (non TD) lower risk MDS, it is therefore important to find additional simple prognostic factors of response to ESA. In a joint study of the French (GFM) and Italian (FISM) MDS groups, we retrospectively assessed prognostic factors of response to ESA in non TD lower risk MDS. Particular emphasis was put on the prognostic value of marrow dysplastic features on ESA response, suggested in a previous work (Howe, Blood, 2004). Methods: We are performing a cooperative (GFM and FISM) retrospective study in IPSS low and int 1 (lower risk) MDS diagnosed between 1994 and 2010. The present analysis focused on lower risk MDS with Hb level <10g/dl, non TD, and with baseline serum EPO <500, treated with ESA in France (from the GFM registry and from a previous cohort: Park, Blood 2008) and in Italy (Italian FISM registry). Pts received ESA 30,000 to 60,000IU/l /week(for EPO) or 150 to 300ug/week for Darbepoetin (DAR) during at least 12 weeks, with or without G-CSF. Response to ESA was evaluated after 12 weeks of treatment, using IWG 2006 criteria (responses before 2006 were reassessed). Pts receiving ESA combined with other drugs than G-CSF or after other drug treatment were excluded. The following baseline parameters were analyzed for their prognostic value on response to ESA: Hb, MCV, ANC and platelet count, serum ferritin (SF), serum EPO, WHO 2008 classification (earlier diagnoses were reclassified), IPSS, and precise quantification of marrow blasts, ring cells and dysplastic features on marrow aspirates (harmonized between 6 GFM and Italian morphologists for each pt according to WHO 2008 criteria). Results: For this work, 503 pts with adequate data have been identified. Results are presented in 228 completely reviewed cases. For morphology, there was an inter observer agreement in 85% of cases, discrepancies being resolved by taking mean values. Median values at onset of ESA in those pts were: age 75 (range 21–96), Hb 9.1g/dl (range 4,9–10), MCV 98u3 (85–127), ANC <1.8G/l in 33% pts, <0.8G/l in 8% pts, platelets <100G/l in 20% pts, SF 201ng/ml (range 20–1670), sEPO 29.5 IU/l (range 2–458), marrow blasts 1% (range 0–9). Dysplasia in > 10% marrow cells was present: for dyserythropoiesis (DE) in 188 (82%), dysgranulopoiesis (DG) in 129 (57%) for dysmegacaryopoiesis (DM) in 96 (43%) pts. WHO 2008 classification was: RA 36%/ RARS 12%/ RAEB-1 9%/ RCMD 36%/ RCUD (other than RA) 1%/ MDS 5q-5%/ unclassifiable 1%. IPSS was low in 49%, int-1 in 44%, NA in 7% pts. IWG 2006 response rate was 60,6%. In univariate analysis, Hb<9g/dl (p=0.002), DG (52% vs 71%, p=0.007), WHO (RA 70%, RCMD 58%, RARS 68%, RAEB-1 30%, MDS 5q– 30%, overall p=0.03), serum EPO >150 U/l (p=0.001) were significantly associated with lower response rate. Response was 61% and 58% in pts with and without DE (p=0.8), and 55% and 65% in pts with and without DM (p=0.1), and 58% in RCMD versus 69% in RA, RARS (p=0.08). DG was inversely correlated with ANC (p=0.003), was seen in 45% IPSS low and 69% int 1 (P=0.003), was correlated with WHO (RA 35%, RARS 48%, RAEB-1 60%, RCMD 85%, MDS 5q– 33%, p<0.0001), was more frequent in pts with DM (73% vs 44%, p<0.0001) but was independent of Hb level and serum EPO. In multivariate analysis absence of DG, Hb>9g/dl and EPO <150UI/l, were the only 3 factors associated with better response to ESA (p=0.01, p=0.006, p=0.004, respectively). Conclusion: In this population of lower risk MDS with non transfusion dependent anemia, significant dysgranulopoiesis (DG) was, in addition to Hb<9g/dl, and EPO>150 UI/l, associated with lower response rate to ESA in multivariate analysis. DG was a stronger predictive factor of non response to ESA than the WHO classification and, contrary to the findings of Howe (Blood 2004), multilineage dysplasia had only borderline prognostic value for response to ESA. We are analyzing more patients in this retrospective cooperative study, also studying other potential prognostic parameters of response to ESA including somatic gene mutations. Disclosures: No relevant conflicts of interest to declare.

Prognostic value of hemoglobin in natural killer cell lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17557-17557
Author(s):  
J. Xiao ◽  
T. Lin ◽  
Y. Cao ◽  
X. Fu ◽  
C. Guo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Natural Killer ◽  
Prognostic Value ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Southern China ◽  
Univariate Analysis ◽  
Stage I

17557 Background: Natural Killer (NK) cell lymphoma is a group of increasingly recognized but poorly defined disease entities. This study investigated its clinical features and prognostic factors for southern China population. Methods: Patients with pathologically confirmed NK cell lymphoma in one center since 1999 to 2004 were included. Central histological and immunohistochemical review was undertaken to every case. The major study endpoint was overall survival. Survival curves were estimated by the Kaplan-Meier method. Detailed clinical, pathological and laboratory data were included in univariate analysis and statistically significant factors in univariate analysis were then included in multivariate analysis. Results: Totally 64 eligible patients were identified. Of these, 59 patients were extranodal NK cell lymphoma nasal type, 3 patients were aggressive NK cell lymphoma and 2 patients were blastic NK cell lymphoma. From the basic analysis, 47% of the patients had stage I disease, 42% were stage II, 11% were stage III or IV. B-symptoms were present in 39%. 73% of these patients had International Prognostic Index (IPI) 0 or 1. Before treatment, 25% complicated with anemia. As to the therapy, 38% received chemotherapy alone, 3% received radiotherapy alone and 59% received a multidisciplinary therapy. After initial therapy, 59% achieved CR, 22% achieved PR and 19% were refractory disease. With a median follow-up duration of 20 months, the median overall survival was 28 months (95% CI: 10, 45). Hb lower than 110 g/l before treatment was statistically significant in multivariate analysis (p = 0.031). Presenting B-symptoms and ECOG PS score higher than 1 were also independent prognostic factors (P = 0.001 and 0.006 respectively). Conclusions: The outcome of patients with NK cell lymphoma was poor even for Stage I or II cases. Our data suggested Hemoglobin < 110 g/l had more prognostic value than IPI and Ann Arbor staging system for NK cell lymphoma in southern China, but it needs further confirmation. No significant financial relationships to disclose.

Varying Importance of Prognostic Factors in Subgroups of Myelodysplastic Syndromes Defined by Blast Count, Cytogenetic Risk Group, or WHO Classification.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2776-2776
Author(s):  
Andrea Kuendgen ◽  
Corinna Strupp ◽  
Kathrin Nachtkamp ◽  
Barbara Hildebrandt ◽  
Rainer Haas ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Univariate Analysis ◽  
Risk Groups ◽  
High Risk Group ◽  
Intermediate Risk ◽  
Blast Count

Abstract Abstract 2776 Poster Board II-752 Introduction: We wondered whether prognostic factors have similar relevance in different subpopulations of MDS patients. Methods: Our analysis was based on patients with primary, untreated MDS, including 181 RA, 169 RARS, 649 RCMD, 322 RSCMD, 79 5q-syndromes, 290 RAEB I, 324 RAEB II, 266 CMML I, 64 CMML II, and 209 RAEB-T. The impact of prognostic variables in univariate analysis was compared in subpopulations of patients defined by medullary blast count, namely <5%, ≥5% (table), ≥10%, and ≥20% (not shown), as well as 3 subpopulations defined by the cytogenetic risk groups according to IPSS (table). Multivariate analysis of prognostic factors was performed for cytogenetically defined subgroups and WHO-subtypes. Results: Strong prognostic factors in all blast-defined subgroups were hemoglobin, transfusion dependency, increased WBC, age, and LDH. However, all variables became less important in patients with ≥20% blasts (RAEB-T) and increased WBC was rare. Platelet count and cytogenetic risk groups were relevant in patients with <5%, ≥5%, and ≥10% marrow blasts, but not in RAEB-T. Marrow fibrosis was important in patients with <5% or ≥5% blasts, but not ≥10%. Gender and ANC <1000/μl were significant only in patients with a normal blast count. Furthermore, we looked for the effect of the karyotypes, relevant for IPSS scoring (-Y, del5q, del20q, others, del7q/-7, complex), and found a comparable influence on survival, irrespective whether patients had < or ≥5% marrow blasts. In subpopulations defined by cytogenetic risk groups, several prognostic factors were highly significant in univariate analysis, if patients had a good risk karyotype. These included hemoglobin, sex, age, LDH, increased WBC, transfusion need, and blast count (cut-offs 5%, 10%, and 20%). In the intermediate risk group only LDH, platelets, WBC, and blasts were significant prognostic factors, while in the high risk group only platelets and blast count remained significant. Multivariate analysis was performed for the cytogenetic risk groups and for subgroups defined by WHO subtypes. The analysis considered blast count (</≥5%), hemoglobin, platelets, ANC, cytogenetic risk group, transfusion need, sex, and age. In the subgroup including RA, RARS, and 5q-syndrome, LDH, transfusion, and age in descending order were independent prognostic parameters. In the RCMD+RSCMD group, karyotype, age, transfusion, and platelets were relevant factors. In the RAEB I+II subgroup, the order was hemoglobin, karyotype, age, and platelets, while in CMML I+II only hemoglobin had independent influence. In RAEB-T none of the factors examined was of independent significance. Looking at cytogenetic risk groups, in the favorable group, several variables independently influenced survival, namely transfusion, blasts, age, sex, and LDH (in this order). Interestingly, in the intermediate and high risk group, only blast count and platelets retained a significant impact. Conclusion: Univariate analysis showed prognostic factors (except ANC) included in IPSS and WPSS are relevant in most subgroups defined by marrow blast percentage. However, they all lose their impact if the blast count exceeds 20%. Regarding cytogenetic risk groups, several prognostic factors lose their influence already in the intermediate risk group. This underscores the prognostic importance of MDS cytogenetics. Multivariate analysis showed MDS subpopulations defined by WHO types also differ with regard to prognostic factors. In particular, CMML and RAEB-T stand out against the other MDS types. Disclosures: Kuendgen: Celgene: Honoraria. Hildebrandt:Celgene: Research Funding. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Germing:Novartis, Celgene: Honoraria, Research Funding.

Early Treatment of Anemia of Lower Risk MDS by Erythropoiesis-Stimulating Agents (ESAs): A Report On 112 Cases.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1765-1765
Author(s):  
Sophie Park ◽  
C. Kelaidi ◽  
Rosa Sapena ◽  
D. Vassilieff ◽  
Odile Beyne-Rauzy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Lower Risk ◽  
Research Funding ◽  
Response Rate ◽  
Transfusion Requirement ◽  
Median Response ◽  
Disease Evolution ◽  
Response Versus ◽  
Rbc Transfusion

Abstract Abstract 1765 Poster Board I-791 Background ESAs are frequently effective in anemia of lower risk MDS, and at least 2 groups have shown that ESAs did not increase the risk of AML progression while possibly improving overall survival (OS) in those patients (pts) (Blood 2008:111: 574-582, JCO 2008, 26: 3607-13). Although responses to ESAs are generally transient and most pts ultimately require RBC transfusions, ESAs are increasingly used before RBC transfusion requirement, and we evaluated this attitude in our GFM experience. Patients : In a cohort of 403 MDS patients (pts) treated with ESAs either in GFM clinical trials or according to GFM therapeutic guidelines (www.gfmgroup.org)(Blood 2008:111: 574-582), 112 pts had de novo low or int-1 IPSS MDS with Hb<10g/dl, serum EPO<500UI/l, no del 5q and had never been transfused. Results Median age of the 112 pts was 75y (range 47-91), including 21 RA, 22 RAEB-1, 34 RARS, 19 RCMD, and 16 RCMD-RS. Karyotype was favorable (n=80), intermediate (n=15), missing (n=17, but those pts had isolated anemia and no excess of blasts), IPSS was low (n=39), int-1 (n=56). Median Hb level at onset of ESA was 9.2g/dl (range 8.0-10). Median endogenous EPO level was 51UI/l (10-397 UI/l). Pts received: epoietin alfa 16%, epoietin beta 27%, darbepoeitin 31%, GCSF was added in 16% pts. 70 (63%) pts had erythroid response at 12 weeks (IWG 2006 criteria). After a median follow-up of 29 months, 36 (51%) of them were still responders while 34 (49%) had relapsed after a median duration of response of 28.2 months (range 3-74). In univariate analysis (IWG 2006 criteria), EPO level =<100 U/l (72% response versus 30% with EPO> 100 U/l, p=0.0003) and interval from diagnosis to onset of ESA < 6 months (76% response, versus 46% if the interval was >=6 months, p=0.0005), were associated with higher response rate. In multivariate analysis, interval from diagnosis to onset of ESA <6 months (p=0.01), Hb level >=9g/dl (p=0.04) and serum EPO =<100UI/l (p=0.02), predicted better response to ESA. Allocating one point to each of those 3 parameters resulted in a score where pts could be dichotomized as follows: serum EPO =<100 UI/l: 1 point/ serum EPO>100 UI/l: 0 point; / interval diagnosis- onset of ESA<6 months: 1 point/ >=6 months: 0 point/ Hb level >=9g/dl: 1 point/ <9 g/dl: 0 point. By summing up each category points, a score of 0, 1, 2, or 3 was obtained with a corresponding response rate of 0%, 30, 67% and 89% respectively. Onset of ESA within 6 months of diagnosis was associated with a median response duration of 30 months, vs 20 months in pts who started ESA>= 6 months after diagnosis (p=0.07) In multivariate analysis, shorter time between diagnosis and onset of ESA (p=0.009), lower serum EPO level (p=0.04) and RCMD-RS (compared to other WHO subtypes) (p=0.03) were associated with longer response to ESA. Median interval from diagnosis to first RBC transfusion requirement was 80 months in pts with onset of ESA within 6 months of diagnosis and 35 months in patients who started ESA later (p =0.007), a somewhat unexpected finding because more rapidly evolving anemia may be for many physicians an incentive for earlier onset of ESA. Freedom from AML-progression (FFP) at 5 years was significantly higher in responders (90%) than in non-responders (61%) (p=0.006). Median overall survival (OS) from onset of ESA was 73.5 months in responders and 42.7 months in non-responders (p=0.14). FFP and OS did not differ according to onset of ESA within 6 months or >=6 months from diagnosis. Conclusion ESA onset within 6 months of diagnosis, in lower risk MDS with Hb<10g/dl not requiring RBC transfusions and with serum EPO level <500U/l, was associated with higher response rates and a trend for more prolonged responses, supporting a benefit of early onset of ESA to avoid the consequences of anemia. Our study could also suggest that early introduction of ESA can delay the need for RBC transfusions during disease evolution, hypothetically by slowing the disease course, but randomized studies are required to document this point. Disclosures Rose: Novartis: Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Higher Versus Standard Doses of Recombinant Erythropoietin for the Treatment of Anemia in Patients with Myelodysplastic Syndromes: Results of a Retrospective Survey from the Italian Registry of Myelodisplastic Syndromes (FISM)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4342-4342
Author(s):  
Enrico Balleari ◽  
Rosa Filiberti ◽  
Chiara Salvetti ◽  
Bernardino Allione ◽  
Emanuele Angelucci ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Response Rate ◽  
Response Rates ◽  
Advisory Board ◽  
Recombinant Erythropoietin ◽  
Erythroid Response ◽  
Transfusion Dependency ◽  
Higher Doses

Abstract Introduction: Erythropoietic stimulating agents (ESAs) have not yet received FDA nor EMA approval to treat anemia of myelodysplastic syndromes (MDS), but ESAs are in use in this clinical setting since more than 25 years. Early studies, using various but usually "standard" doses of recombinant EPO (rEPO) (30-40.000 IU weekly), showed a disappointing overall response-rate of no more than 15-25%. In recent years most studies reported a response rate of more than 50%, provided MDS patients were selected according to favorable clinical variables determined during the years ( ie low transfusion requirement, absence of blasts, endogenous EPO levels < 500). Higher response rates with respect to early studies are probably due to higher, not weight-adjusted doses of rEPO (60-80.000 UI weekly). Nevertheless, a direct comparison between the two different schedules of rEPO treatment is still lacking, and the superiority of the so called higher doses of rEPO to standards regimens is inferred only by results of meta-analysis comparing studies performed at different times with various schedules and heterogenous cohorts of MDS patients. Objectives: We aimed at clarifying whether the erythroid response rate differed in patients exposed to higher doses versus standard doses of rEPO. Methods: Within the framework of the Italian Network of regional MDS registries established by Fondazione Italiana Sindromi Mielodisplastiche (FISM) a cohort of 103 MDS patients (pts) with anemia treated with higher doses of rEPO (40.000 IU twice a week, H) for at least 3 months within 6 months from diagnosis were identified; a second cohort of 206 pts, similar for clinical parameters known to influence response to rEPO (i.e. Hb concentrations at the time of starting treatment, IPSS score, transfusion-dependency, endogenous Epo levels at diagnosis and time of treatment from diagnosis) and treated with standard doses (40.000 IU weekly, S) were compared to the first cohort. Univariate and multivariate analysis were performed as appropriate in order to identify factors influencing clinical response to treatment. Results : Characteristics of subjects were: median Hb pre-treatment 8.9 g/dL in H cohort and 9.1 g/dL in S cohort, IPSS score Intermediate-2/high in 5% of H cohort and 8% of S cohort, transfusion-dependency in 25% of H cohort and 26% of S cohort, median EPO at diagnosis 79 IU in H cohort and 69 IU in S cohort. According to IWG 2006 criteria, after 3 months of rEPO treatment the overall erythroid response-rate among all the pts in the two cohorts was 53% (163 out of 309 pts). No difference in erythroid response-rate was found between MDS pts treated with higher doses (49 (48%) responders out of 103 cases) when compared to cases treated with standard doses (114 (55%) responders out of 206 pts, p= 0.23). As expected, IPSS score, transfusion-dependency and EPO serum levels at diagnosis were statistically associated with response. In particular, at multivariate analysis, significantly lower response-rates to rEPO were associated with transfusion-dependency (yes vs no, OR= 0.59 (95%CI: 0.44-0.79, p<0.001), higher endogenous serum EPO levels at diagnosis (>500 vs <=500, OR= 0.36 (95%CI: 0.19-0.68, p=0.002) and higher IPSS score (intermediate 2/ high vs, intermediate 1 / low, OR=0.42 (95%CI: 0.24-0.74, p=0.003). Conclusions : Our data, although derived by a retrospective analysis, seem to indicate that standard doses of rEPO are at least as effective as higher-doses for correcting anemia in MDS patients; in this clinical scenario, a standard-doses rEPO treatment allows for a consistent reduction of costs without precluding to achieve a durable erythroid response to rEPO. Prospective, randomized studies addressing this point are necessary to definitely address this topic. Disclosures Angelucci: Novartis oncology, celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Finelli:Celgene: Research Funding; Celgene: Other: Speaker fees; Novartis: Other: Speaker fees. Oliva:Celgene: Consultancy, Honoraria, Speakers Bureau. Santini:Janssen: Consultancy, Honoraria; Onconova: Other: advisory board; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Other: advisory board; Astex: Other: advisory board; Novartis: Consultancy, Honoraria.

scholarly journals Racial Disparity in Patients with Multiple Myeloma Are Blunted in the Era Novel Therapies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2525-2525
Author(s):  
Leon Bernal-Mizrachi ◽  
Ajay K Nooka ◽  
Chandra Pooja ◽  
Monica S Chatwal ◽  
Sungjin Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Research Funding ◽  
Response Rate ◽  
Univariate Analysis ◽  
Novel Agents ◽  
Factors Associated ◽  
Indolent Disease ◽  
The Impact ◽  
White Patients

Abstract Background: Multiple myeloma is the most common hematological malignancy among african americans (AA). Prior studies have shown conflicting results for outcomes based upon ethnicity following autologous stem cell transplantation (ASCT). However, much of this data is older, and predates the use of novel agents such as bortezomib (V), lenalidomide (R) and thalidomide (T). Methodology: We performed a retrospective analysis of 292 patients (147 AA and 145 Caucasian) treated with novel agents (proteasome inhibitors or immune modulators) and ASCT from 2006 to 2012 at the Winship Cancer Institute of Emory University to evaluate the impact of ethnicity on outcomes. Results: Baseline characteristics such as stage (International Staging System, ISS), presence of lytic lesions or plasmacytomas, immunoglobulin subtype, and cytogenetic risk category at presentation, were comparable between AA and white patients. Among AA, 112 (76.19%) patients received bortezomib containing regimens (VRD: 34.8%, VTD: 22.3%, VDTPACE:11%, VDD:10%, VD:19% and others bortezomib regimens 8%), 54 (36.7%) patients received lenalidomide (VRD: 34.8% or RD: 11.6%) and 72 (49%) patients received thalidomide (VTD: 22.3% or TD: 11.6%). In white patients 113 (77.93%) received bortezomib containing regimens (VRD: 33.1%, VTD: 17.2%, VDTPACE:9.6%, VDD: 1.4% and VD:11.7% and other bortezomib regimens 1.3%), 69 (47.6%) patients received lenalidomide containing regimens (VRD:33.1% and RD:11%) and 62 (42.8%) patients received thalidomide containing regimens (VTD: 17.2% or TD: 15%). A higher percentage of patients in the white cohort carried the antecedent diagnosis of monoclonal gammopathy in white patients (AA:0 vs white: 4.8%, p=0.007), and as expected, AA patients presented at a younger age when compared with whites (mean age of 55 vs 59 years, respectively, p<0.001). The overall response rate (ORR) of induction in the entire population was 86%, with an >VGPR of 58.8%. No difference was identified in pre-transplant ORR and >VGPR between AA (87.9% and 25.9%, respectively) and white patients (81.54% and 22.4%, respectively, p>0.1). Similarly, the ORR and >VGPR 100 days after transplantation was comparable between both ethnic groups (AA: OR:90.74% and >VGPR:74.07% vs white OR:90.65% and >VGPR: 77.57%, p>0.1). The depth of response after ASCT improved similarly in both groups (AA: 57.3% vs white: 67.7%, p=0.1). When the overall survival and progression free survival where evaluated, we found no significant differences between both cohorts. Factors associated with longer PFS in the population studied include AA race and the introduction of lenalidomide in the induction regimen. In AA patients univariate analysis identified early stage at presentation, indolent disease (prolong time from diagnosis to transplant), optimal pre-transplant response, and pre-transplant use of lenalidomide (HR:0.38 (0.18-0.8), p=0.01) as factors that potentially prolong PFS. Multivariate analysis identified the use of lenalidomide, as part of the pretransplant regimen, to reduce the risk of relapse (HR:0.38 (0.18-0.8), p=0.01) compared to bortezomib use (HR: 5.3 (2.11-11.98), p<0.001). In white patients, univariate and multivariate analysis identified that IgG and kappa light chain MM and indolent disease were factors associated with longer PFS, while history of plasma cell leukemia was related to shorter PFS. In conclusion, our results showed that novel agents have improved the response rate of both ethnic populations. From our preliminary analysis, it appears the PFS is longer among AA patients, suggesting a potential difference in MM biology of this patient population. Disclosures Lonial: Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

scholarly journals Retrospective Analysis of Prognostic Factors for Waldenström Macroglobulinemia: A Multicenter Cooperative Study in Japan

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5028-5028
Author(s):  
Akio Saito ◽  
Atsushi Isoda ◽  
Akihiko Yokohama ◽  
Hiroshi Handa ◽  
Norifumi Tsukamoto ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Pleural Effusion ◽  
Initial Treatment ◽  
Response Rate ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Japanese Patients ◽  
Western Countries ◽  
Significant Difference

Abstract Background: Analysis of prognostic factors and clinical trials of novel agents for Waldenstrӧm macroglobulinemia (WM) are ongoing in Western countries, but few studies of WM have been performed in Japan. As a step toward future investigations, we retrospectively analyzed clinical features and prognostic factors in Japanese patients with WM. Methods: We retrospectively analyzed clinical and laboratory characteristics, treatment and outcomes of 110 patients with WM, IgM-MGUS or lymphoplasmacytic lymphoma (LPL) diagnosed from January 2001 to March 2013 at 12 institutes. Overall survival (OS) was analyzed using Kaplan-Meier methods and survival was compared using log-rank testing. Several clinical characteristics at diagnosis were assessed by Cox regression for uni- and multivariate analysis for OS. Results: Median age at diagnosis was 69 (range, 41-96) years, 73.6% were male, 12.0% had an ECOG performance status 2-4 and 6.4% presented with B-symptoms. Hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia and cold agglutinin disease were shown in 9.1%, 4.5%, 1.8%, 4.5% and 2.7%, respectively. In 94 patients with available CT findings at diagnosis, lymphadenopathy, hepatosplenomegaly, pleural effusion, lung involvement, bone involvement and skin involvement were shown in 41.5%, 14.9%, 8.5%, 4.3%, 4.3% and 6.4%, respectively. Median serum monoclonal protein level was 2.62 g/dl (range, 0.70-9.35 g/dl). Symptomatic WM was present in 76 patients, asymptomatic WM in 23 and IgM-MGUS in 2 according to criteria of the Second International Workshop on WM. Seven patients showed IgG- or IgA-secreting LPL and 2 showed LPL without bone marrow infiltration. In patients with symptomatic WM, international prognostic scoring system for WM (ISSWM) was low in 9.2%, intermediate in 34.2%, high in 39.5% and unknown in 17.1%. Among patients with asymptomatic and symptomatic WM, watchful waiting was performed in 91.3% and 40.0%, respectively, with 61.9% and 36.7% remaining untreated, respectively. Median time to treatment from diagnosis of asymptomatic or symptomatic WM was 240 days (range, 3-1238 days) and 31 days (range, 0-2011 days), respectively. Oral alkylating agents were administered to 34.7% of patients with WM, 19.4% were treated with CHOP or CHOP-like regimen with or without rituximab, 8.2% received fludarabine mono- or combination therapy and 6.1% received rituximab monotherapy. Rituximab-containing therapy was administered as the initial treatment in 33.8% of patients who received treatment. Overall response rate (ORR) (complete + partial response rate) was 48.6%, and patients treated with rituximab-containing therapy displayed higher ORR (64.0%) compared to those with non-rituximab therapy (40.8%). Plasmapheresis was performed in 3.7% of patients. Three patients (2.7%) showed transformation to diffuse large B-cell lymphoma, and 7 (6.4%) developed second primary malignancies. Median follow-up was 38 months, 5-year OS rate for all patients was 74.9% (95% confidence interval (CI) 62.5-83.7) and rates for those with symptomatic WM, asymptomatic WM and other LPL were 66.0% (95%CI 50.6-77.6), 100% and 88.9% (95%CI 43.3-98.4), respectively. Significant differences in survival between risk groups of ISSWM in patients with symptomatic WM were not seen (5-year OS: high, 62.4%; intermediate, 64.3%; low, 75.0%; p=0.86). Although no significant difference in OS was observed compared to initial treatment (p=0.265), patients treated with rituximab during the observation period showed significantly prolonged OS compared to those treated without rituximab (5-year OS rates: 78.9% vs. 45.6%, p=0.036). In univariate analysis, age, pleural effusion, serum albumin, C-reactive protein and serum IgM levels were poor prognostic factors for OS. In multivariate analysis, age >65 years (hazard ratio (HR)=3.294; 95%CI 1.097-9.888, p=0.0336) and pleural effusion (HR=4.55; 95%CI 1.602-12.930, p=0.0045) were identified as significant prognostic factors for OS. Conclusion: Prognostic factors for WM in Western countries may not be applicable to Japanese patients. This study suggested presence of pleural effusion at diagnosis is associated with poor clinical outcomes. Further investigations including histopathological examinations and molecular analyses are required to elucidate prognostic factors in Japan. Disclosures No relevant conflicts of interest to declare.

Correlation Between serum ferritin Level at diagnosis and Survival In Lower Risk, Non-Transfusion Dependent, MDS Patients.A Report by the Groupe Francophone Des Myelodysplasies (GFM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2916-2916
Author(s):  
Sophie Park ◽  
Rosa Sapena ◽  
Dominique Vassilieff ◽  
Charikleia Kelaidi ◽  
Dominique Bordessoule ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Serum Ferritin ◽  
Lower Risk ◽  
Research Funding ◽  
Prognostic Value ◽  
Ferritin Level ◽  
Univariate Analysis ◽  
Baseline Serum ◽  
Baseline Characteristics

Abstract 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 level<10g/dl (P=0.0013), MCV >100μm3 (P=0.02), erythroblasts >30% in bone marrow (P=0.008), serum (s) EPO level>100IU/l (P=0.04), RARS (P<0.0001) were significantly associated with increased SF level (ie. >300ng/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 <10g/dl, and sEPO level>100 were associated with SF >1000 ng/ml in univariate analysis, while only Hb level<10g/dl still showed a correlation in multivariate analysis. 5-year OS was 77% and 85% in pts with baseline SF<300 and >300ng/ml resp. (p=0.7) and 81% vs 92% for SF<1000 and >1000ng/ml, resp. (p=0.11) and 5-year cumulative incidence of AML transformation was 2.2% and 3.3% for pts with SF<300ng/ml and >300ng/ml resp (P=0.69), and 3% and 0% for pts with SF<1000ng/ml and >1000ng/ml resp (P=0.86). Conclusions: Increased baseline SF level in non transfusion-dependent lower risk MDS is correlated with a few baseline characteristics including more severe anemia, a diagnosis of RARS and higher baseline serum EPO level, but is not significantly correlated with outcome. Disclosures: Fenaux: CELGENE: Honoraria, Research Funding; JANSSEN CILAG: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; GSK: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; MERCK: Honoraria, Research Funding; CEPHALON: Honoraria, Research Funding.

Prognostic Factors Associated with Progression of Myelodysplastic Syndromes (MDS) to Acute Myeloid Leukemia (AML) In Patients (pts) Treated with Decitabine

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4956-4956
Author(s):  
Amber Fullmer ◽  
Guillermo Garcia-Manero ◽  
Gautam Borthakur ◽  
Tapan Kadia ◽  
Hagop Kantarjian ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Research Funding ◽  
Proportional Hazards ◽  
De Novo ◽  
Treatment Time ◽  
Univariate Analysis ◽  
Cox Proportional Hazards ◽  
Dosing Schedule ◽  
Combined Analysis

Abstract Abstract 4956 Background: About 50% of pts with MDS ultimately progress to AML with no clear pattern in underlying parameters leading to progression. This analysis sought to identify predictive factors in pts with MDS that are associated with progression to AML after treatment with decitabine. Methods: In a combined analysis of MDS pts treated with either a 3- or 5-day dosing schedule of decitabine, pts were stratified on the basis of those who progressed to AML (P) versus those who did not (NP). CR rates by IWG2006 criteria for each of the baseline factors were compared by using the chi-square test. Factors that were significant in the univariate analysis (p<0.05) were included in a multivariate analysis. Logistic regression analysis was conducted for progression to AML. The following variables were identified as predictors of progression: study effect; age; secondary or de novo MDS; prior MDS treatment, including growth factor use only and prior chemotherapy; del 5Q or 7; time to diagnosis; baseline ANC (< 500, 500 – 1000, or >1000 U/L); baseline HGB, plt and BM blast count ≤20; FAB classification; ECOG status; and IPSS (low, int-1, int-2). A Cox proportional-hazards analysis was conducted for survival. Results: A combined analysis of prognostic factors for MDS was completed in 163 pts with a complete response to decitabine; 37 (22.6%) had progressed to AML and 126 (77.3%) had not. Baseline characteristics in pts that progressed had significantly less time since diagnosis (<3mos), more RAEB, RAEB-t and IPSS classification of Int-2 and high-risk, lower baseline HGB levels and fewer prior treatments. From the multivariate analysis, the following factors were selected as predictors of progression: No history of prior treatment, time from diagnosis of MDS <3 months, hemoglobin levels under 10 g/dL, and a 3-day schedule of decitabine (p=0.005, 95% CI 1.4, 6.8). Survival estimates were determined for Del 5q or 7, baseline HGB <10, plt <50 and the 3-day dosing schedule approached but did not achieve a significant effect (p=0.08). Conclusions: MDS pts with a deep anemia (HGB <10), thrombocytopenia (plts <50), and a cytogenetic risk profile that includes a del5 and/or 7 anomaly are at a statistically higher risk of transformation into AML and should be considered for additional treatment options. Disclosures: Borthakur: Eisai Inc.: Research Funding. Kantarjian: Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour: Eisai Inc.: Editorial and statistical support, Honoraria.

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