24-Month Analysis of the Impact of Chelation on Clinical Outcomes in a 600 Patient Registry of Lower-Risk MDS Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2800-2800 ◽  
Author(s):  
Roger M. Lyons ◽  
Billie J. Marek ◽  
Surabhi Sharma ◽  
Carole Paley ◽  
Jason Esposito ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Lower Risk ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Disease Status ◽  
Cardiac Events ◽  
Leukemic Transformation ◽  
The Impact

Abstract Abstract 2800 Introduction: Many patients with MDS require regular transfusions. Several reviews have documented poorer clinical outcomes and overall survival (OS) in transfusion-dependent MDS patients. A US registry of 600 lower-risk MDS patients prospectively collected data on clinical outcomes in chelated and non-chelated transfused patients. This 24-month interim analysis reports on cardiac events, leukemic transformation and OS. Methods: This is a 5-year, non-interventional registry in MDS patients (aged ≥18 years) with lower-risk MDS (based on WHO, FAB and/or IPSS criteria) from 107 US centers. Patients had to have transfusional iron overload (serum ferritin ≥1000 μg/L and/or ≥20 packed red blood cell units and/or ongoing transfusion requirement of ≥6 units every 12 weeks). Follow-up was every 6 months for up to 60 months or death. Use of chelation therapy was not required. Chelated patients were those who had ever used iron chelation; a sub-analysis was done on patients with ≥6 months chelation. Assessments included demographics, disease status, MDS therapy, comorbidities, and causes of death. Differences between non-chelated and chelated patients are reported. Results: 600 patients enrolled; as of May 26, 2011, 249 continued in the registry. 351 patients discontinued due to: lost to follow-up (n=51, 8.5%); death (n=278, 46.3%); other (n=22, 3.7%). 263/600 patients received chelation therapy, of whom 191 received ≥6 months. Leukemic transformation and cardiac events were more common in non-chelated patients (Table 2). Time to leukemic transformation was significantly shorter in non-chelated versus chelated patients. A greater percentage of deaths occurred in non-chelated patients; time to death was significantly shorter in non-chelated versus chelated patients. The most frequent reasons for death were MDS/AML, cardiac, and infection. At baseline, non-chelated patients had a higher incidence of cardiac disorders than chelated patients (51.3% vs 35%). While on the registry, non-chelated patients had a higher incidence of comorbidities than did chelated patients, predominantly vascular, cardiac and endocrine. Lifetime use of MDS therapies (pre- and on-registry) was lower among non-chelated versus chelated patients (88.4% vs 94.3%). Conclusions: At the 24-month analysis, use of chelation was associated with lower AML transformation, fewer cardiac events, and better OS. The two patients groups had similar age, gender, and risk status breakdown (IPSS); however the non-chelated group had a higher prevalence of cardiac comorbidities. Ongoing follow-up for the 5-year duration of this registry will provide further data on differences in outcomes between chelated and non-chelated patients. Disclosures: Lyons: Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding. Sharma:Novartis: Employment. Paley:Novartis: Employment. Esposito:Novartis: Employment.

Clinical Parameters in 391 Iron-Overloaded Patients with Lower-Risk MDS Enrolled in a Prospective, Non-Interventional Multicenter Registry.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4834-4834
Author(s):  
Guillermo Garcia-Manero ◽  
Billie J. Marek ◽  
Roger M. Lyons ◽  
Noelia Martinez-Lopez ◽  
Carole Paley ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Serum Ferritin ◽  
Lower Risk ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Advisory Committees ◽  
The Impact

Abstract Abstract 4834 Introduction Despite recent improvements in therapies for patients with myelodysplastic syndromes (MDS), 60–80% will require continuing packed red cell blood (pRBC) transfusions for prolonged periods. Complications resulting from the iron burden may, therefore, become clinically significant for many patients during the course of their disease. Patients with lower-risk MDS have a greater chance of developing the long-term toxicity of iron overload because of their prolonged survival, and are more likely to benefit from effective iron chelation therapy. This report describes data from a registry designed to study the impact of iron overload and iron chelation therapy on organ function and survival in patients with lower-risk MDS. Methods This is an ongoing, prospective, non-interventional, multicenter 5-year registry in 107 US centers, enrolling 600 patients (aged ≥18 years) with lower-risk MDS (by WHO, FAB and/or IPSS criteria) and transfusional iron overload (defined as serum ferritin ≥1000 μg/L and/or having received ≤20 cumulative pRBC units and/or an ongoing transfusion requirement ≥6 units every 12 weeks). Follow-up will be performed at least every 6 months for a maximum of 60 months or until death. Recommended assessments include serum ferritin, creatinine, calculated creatinine clearance, echocardiograms, and endocrine and hematological status. Results As of May 31 2009, 391 patients have enrolled in the registry. Demographic data are available from 389 patients. Median age: 74.4 years (range 21–99); male: 218, female: 171; ethnicity: 331 Caucasian (85%), 25 African-American (6%), 24 Hispanic (6%), five Asian (1%), two Native American (0.5%), and two other (0.5%). The median time since diagnosis (n=385) was <3 years in 217 patients (56%); ≥3–<5 years in 72 (19%); ≥5–<7 years in 48 (12%); and ≥7 years in 48 (12%). The MDS classification of the patients by WHO, FAB and IPSS, as well as patients' serum ferritin and transfusion burden, are summarized in the table. The most frequent concomitant conditions classified by organ (n=384 patients) were: 205 (53%) patients with vascular, 160 (42%) endocrine, and 171 (45%) cardiac dysfunction. At registry entry, 249 patients were receiving erythropoietin; 61 granulocyte colony stimulating factor; seven hydroxyurea; 25 thalidomide (Thalomid); 147 5-azacytidine (Vidaza); 95 lenalidomide (Revlimid) and 90 decitabine (Dacogen). 137 of 391 (35%) patients were on iron chelation therapy at study entry: 34 (9%) received deferoxamine for mean and median treatment durations of 803 and 383 (range 1–4386) days, respectively, while 117 (30%) received deferasirox for mean and median durations of 488 and 396 (9–1269) days, respectively. Calculated creatinine clearance was normal (>80 mL/min) in 37 (9%) patients; mildly abnormal (51–80 mL/min) in 30 (8%); and moderately abnormal (30–50 mL/min) in nine (2%) patients. Conclusions These baseline data indicate the demographic distribution as well as the co-morbidities associated with lower-risk MDS patients. In spite of recent guidelines, fewer than 50% of iron-overloaded patients are receiving any iron chelation treatment, despite the presence of cardiac, vascular and endocrine concomitant conditions in 40-54% of patients. Recent retrospective data highlights the impact of chelation on mortality in lower-risk MDS patients. This ongoing registry will prospectively assess the impact of iron chelation on survival and organ function in iron-overloaded patients with lower-risk MDS. Disclosures Lyons: Novartis: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Research Funding. Martinez-Lopez:Novartis Pharmaceuticals: Employment. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Greenberg:Amgen: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Relationship Between Chelation and Clinical Outcomes in 600 Lower-Risk MDS Patients: Registry Analysis At 36 Months

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3800-3800
Author(s):  
Roger M. Lyons ◽  
Billie J. Marek ◽  
Carole Paley ◽  
Jason Esposito ◽  
Lawrence Garbo ◽  
...  
Keyword(s):  
Blood Cell ◽  
Clinical Outcomes ◽  
Red Blood Cell ◽  
Lower Risk ◽  
Research Funding ◽  
Causes Of Death ◽  
Disease Status ◽  
Red Blood Cell Transfusion ◽  
Cardiac Events ◽  
Risk Status

Abstract Abstract 3800 Introduction: Treatment of anemia in pts with myelodysplastic syndromes (MDS) may require packed red blood cell transfusion. Transfusion dependence in MDS is associated with poorer clinical outcomes and reduced overall survival (OS). This US registry prospectively collected data on clinical outcomes in chelated and non-chelated, transfused, lower-risk MDS pts. OS, leukemic transformation, and clinical events are reported for non-chelated and chelated pts at 36 mos on study. Methods: This 5-year, non-interventional registry enrolled 600 pts from 107 US centers. Pts were ≥18 years old with lower-risk MDS (WHO, FAB, and/or IPSS) and transfusional iron overload (serum ferritin ≥1000 μg/L and/or ≥20 packed red blood cell units and/or ≥6 units every 12 weeks). The chelated group included all pts who had ever used iron chelation; sub-analysis was performed on pts with ≥6 mos chelation. Assessments were every 6 mos for 5 years or until death and included demographics, survival, disease status, comorbidities, causes of death, and MDS therapy. Results: Baseline demographics and IPSS risk status were similar between groups, although transfusion burden trended higher in chelated pts (Table 1). As of April 30, 2012, 169 pts continued on registry, and 431 discontinued (345 died, 57.5%; 61 lost to follow-up, 10.2%; and 25 other, 4.2%). In all, 264 (44%) pts received chelation therapy; 200 had ≥6 mos chelation. OS and time to acute myeloid leukemia (AML) transformation were significantly longer, and percentage of deaths was significantly lower in chelated ≥6 mos vs. non-chelated pts (P<0.0001, P=0.011 [median not reached in either group], P=0.0002, respectively; Table 2). AML transformations were also lower in chelated ≥6 mos pts (not significant [NS]). Cardiac (non-chelated, 51.5%; ≥6 mos chelation, 30.5%) and vascular disorders (non-chelated, 59.2%; ≥6 mos chelation, 45.5%) were more prevalent in non-chelated pts at baseline; this trend continued on study: cardiac (non-chelated, 49.7%; ≥6 mos chelation, 42.5%); vascular (non-chelated, 55.7%; ≥6 mos chelation, 48.5%; NS, all comparisons). Most frequent causes of death were MDS/AML, cardiac events, and infection. The percentage of pts who had ever received MDS therapy was lower among non-chelated pts (non-chelated, 88.4%; ≥6 mos chelation, 93.5%; NS). Conclusions: At 36 mos, chelated pts had significantly longer OS and time to AML transformation, as well as significantly fewer deaths. Trends toward fewer AML transformations and cardiac disorders were observed in chelated pts. Baseline characteristics and IPSS risk status were similar between groups, with the exception of more prevalent cardiac and vascular comorbidities in non-chelated pts. Additional assessments over the 5-year duration of this registry will provide further information on the association between chelation and clinical outcomes. Disclosures: Lyons: Novartis: Research Funding; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Telik: Research Funding. Paley:Novartis: Employment. Esposito:Novartis: Employment. Garcia-Manero:Novartis: Research Funding.

Improved Survival with Iron Chelation Therapy for Lower IPSS Risk MDS Appears to Have a Stronger Association in Patients with a Non-RARS Diagnosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1732-1732
Author(s):  
Heather A Leitch ◽  
Christopher Chan ◽  
Chantal S Leger ◽  
Lynda M Foltz ◽  
Khaled M Ramadan ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Advisory Committees

Abstract Abstract 1732 Background: Several retrospective analyses suggest that transfusional iron overload portends inferior survival in lower risk MDS and that iron chelation therapy (ICT) is associated with improved survival in this group of patients. However an analysis of 126 patients with RARS from the Mayo Clinic showed no association between elevated ferritin level at diagnosis or transfusion burden on overall survival (OS). We performed a retrospective analysis of 268 MDS patients seen at our center to determine whether an association between transfusional iron overload or receiving iron chelation therapy (ICT) and survival differed between RARS and other lower risk MDS. Methods: Patients were identified from the clinical database of the hematology practice. Patients with a diagnosis (dx) of MDS confirmed by bone marrow biopsy (bmbx) were included. Clinical and laboratory data were collected by retrospective chart review. Survival analyses were performed using SPSS version 19. Results: 268 patients with a bmbx confirmed diagnosis of MDS by WHO or FAB criteria were identified. The following patients were excluded: uncertain IPSS score, n=35; intermediate-2 risk, n=33; high risk, n=16; RAEB-t, n=3; concomitant diagnosis of advanced stage non-Hodgkin lymphoma of uncertain type, n=1. The remaining 182 patients had the following characteristics: median age 69.5 (range 30–94) years and 109 (69.9%) were male. Specific MDS dx were: RA, n=27; RARS, n=53; RCMD, n=34; RAEB, n=15; MDS-U, n=22; hypocellular MDS, n=6; 5Q- syndrome, n=6; CMML, n=21. IPSS scores for all patients were: intermediate-1, n=101; low, n=74; uncertain (but IPSS score not >1.0), n=7. The marrow blast count was 6–9 x109/L in 4 patients and <5 x109/L in all others. Specific MDS treatment (rx) was: supportive care, n=82; erythropoiesis stimulating agents (ESA), n=22; immunosuppressive therapy (IST), n=10; lenalidomide, n=7; and chemotherapy, n=6. 137 patients received RBC transfusions and 38 received ICT: deferasirox (DFX), n=19; deferoxamine (DFO), n=9; DFO followed by DFX, n=9; and DFX followed by DFO, n=1. The median duration of ICT was 10.5 (range 0.5–64) months. Clinical features significantly associated with OS in univariate analyses of all 182 patients included: specific MDS dx; IPSS score; total number of red blood cell (RBC) units transfused over the course of follow-up; receiving ICT; specific MDS rx received; requirement for hospitalization; experiencing at least one episode of infection; and AML transformation (P</=0.01 for all); serum ferritin level >1000ng/mL was not significant in this analysis (P=not significant [NS]). In a multivariate analysis (MVA), the following factors remained significant for OS: specific MDS dx; IPSS score; receiving ICT; specific MDS rx; and AML transformation (P</=0.01 for all). In an MVA stratified for RARS, significant were: specific MDS dx (P<0.0001); IPSS score (P=0.005); specific MDS rx (P=0.038) and receiving ICT (P=0.039). At a median follow-up of 28 (0.1–245.9) months, 121 patients were alive (non-RARS, n=83 [64.3%]; RARS, n=38 [71.6%]) and the projected median OS for all patient was 99 months. The projected median OS for non-RARS patients without ICT and with ICT was 44 months and not reached (NR), respectively, and for RARS without and with ICT was 99 and 134.4 months (P<0.0001). The 5 year OS in these four groups was 39.2% and 91.7% (P=0.04); and 72.4% and 76.3%, respectively (P=NS). However, when RARS ICT patients were compared to only RBC transfusion dependent RARS patients not receiving ICT, the median OS was 73.8 vs 134.4 months, respectively, and 5 year OS was 59.9% and 76.3%, respectively (P=0.025). Conclusions: These results suggest an association between receiving iron chelation therapy and survival in lower IPSS risk MDS, in keeping with prior analyses. However, the association between ICT and OS in non-RARS MDS appeared to be stronger than in RARS, in keeping with data from Mayo suggesting transfusional iron overload may not have a major association with outcome in RARS. The median follow-up in the current study was just over 2 years, and median duration of ICT only 10.5 months; longer follow-up may be needed in RARS to determine whether ICT is potentially beneficial in this subgroup of patients with a relatively long expected survival. As with all retrospective analyses, these results must be considered hypothesis generating, and prospective trials are needed for firm conclusions to be drawn. Disclosures: Leitch: Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Iron chelation agents for the treatment of transfusional iron overload in MDS. Vickars:Novartis Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Impact of Iron Chelation Therapy on Overall Survival and AML Transformation in Lower Risk MDS Patients Treated At the Moffitt Cancer Center

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2776-2776 ◽  
Author(s):  
Rami S. Komrokji ◽  
Najla H Al Ali ◽  
Eric Padron ◽  
Jeffrey E. Lancet ◽  
Alan F. List
Keyword(s):  
Overall Survival ◽  
Serum Ferritin ◽  
Lower Risk ◽  
Chelation Therapy ◽  
Ferritin Level ◽  
Elevated Serum ◽  
Iron Chelation ◽  
Cancer Center ◽  
Baseline Characteristics ◽  
The Impact

Abstract Abstract 2776 Background: Elevated serum ferritin levels and red blood cell transfusion dependence are associated with poor outcome in patients with lower risk myelodysplastic syndromes (MDS). Few retrospective and observational studies suggest that iron chelation therapy (ICT) may favorably impact outcome in lower risk MDS. The vast majority of patients in those studies were treated with deferoxamine (Desferal). Two studies reported that oral deferasirox (Exjade) significantly decreases ferritin level over time in MDS. An ongoing randomized placebo-controlled trial (TELESTO) is designed to address the impact of deferasirox on overall survival (OS) in lower risk MDS. We examined the impact of ICT predominantly deferasirox in lower risk MDS patients treated at the Moffitt Cancer Center (MCC). Methods: Patients were retrospectively identified from the MCC database and individual patients' records reviewed. Inclusion criteria included lower risk MDS patients defined as low or intermediate-1 (int-1) risk disease by the international prognostic scoring system (IPSS) and serum ferritin level ≥ 1000 ng/ml. Patients were divided into two comparator groups: ICT vs. no ICT. Baseline characteristics were compared between the two groups; chi square test was used for categorical variables and t-test for continuous variables. The primary endpoint was overall survival compared between the two groups using Kaplan-Meier estimates. Cox regression was used for multivariate analysis. All analyses were conducted using SPSS version 19.0 statistical software. Results: Between July 2001 and July 2009, 97 patients with lower risk MDS and serum ferritin ≥ 1000 ng/ml were identified. Forty five (46.4%) received ICT and 52 did not. The ICT included deferasirox in 35 patients and deferoxamine in 10 patients. The baseline characteristics between the two groups (ICT and no ICT) are summarized in (table-1). No statistically significant difference in baseline characteristics was observed except more patients in the ICT group were transfusion dependent. The median duration of follow up was 85.7 month from time of diagnosis. The median OS was 59 months (95%CI 22–48) for patients who received ICT compared to 33.7 months (95%CI 38–80) for patients who did not receive ICT (P= 0.013). After adjustment for age and cytogenetics in Cox multivariable analysis, ICT was associated with better OS (HR 0.52, 95%CI 0.31–0.87, P= 0.013). The rate of AML transformation was 21.2% in patients who did not receive ICT compared to 15.6% in those who had ICT. (p=0.33). Conclusion: ICT in lower risk MDS patients with elevated serum ferritin ≥ 1000 ng/ml was associated with improved overall survival and a trend to lower AML transformation. Results of ongoing randomized clinical study with deferasirox are needed to confirm the retrospective data. Disclosures: Komrokji: Novartis: Honoraria, Research Funding.

Prognostic Impact of Transfusions Intensity on Survival and Development of Thrombocytopenia in Newly Diagnosed Lower-Risk MDS Patients Participating in the European Leukemianet EU-MDS Registry

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1677-1677
Author(s):  
Louise De Swart ◽  
Tom Johnston ◽  
Alexandra Smith ◽  
Pierre Fenaux ◽  
Argiris Symeonidis ◽  
...  
Keyword(s):  
Lower Risk ◽  
Research Funding ◽  
Control Group ◽  
Rapid Decline ◽  
Prognostic Impact ◽  
Platelet Counts ◽  
Risk Of Death ◽  
Increased Risk ◽  
The Impact

Abstract Background The outcome of lower-risk MDS patients with red blood cell transfusions (RBCT) dependency is inferior to that of RBCT independent patients, but whether the intensity of RBCT is important for prognosis is unknown. The EUMDS Registry is a non-interventional, observational longitudinal study enrolling patients with lower-risk MDS from 142 sites in 17 countries as described elsewhere (1). The EUMDS registry has accrued 1,902 patients as of July 21, 2015. We hypothesized that RBCT intensity is an independent prognostic factor for survival. Methods We first assessed the impact of RBCT intensity in the first year post-diagnosis (1yrPD) on progression-free survival among the 1034 patients who survived at least 1yrPD and had potential for a further year of follow-up. Secondly, we developed a longitudinal model of platelet counts throughout follow-up for 1660 patients in the registry with potential for at least one year follow-up. Results Among the 1034 patients, 323 patients had died: 67 after progression to higher-risk MDS/AML and 256 without progression. A further 41 surviving patients had progressed to AML. The overall 5-year survival was 52%. In a proportional hazards regression model (Table), the risk of death or progression increased in a non-linear fashion with age at diagnosis (p<0.001). The risk of death was increased in the intermediate IPSS-R risk group compared to low risk. Patients with RARS and 5q- syndrome had a better outcome compared to RCMD. Increased RBCT intensity in 1yrPD (Table, Figure) was strongly associated with an increased risk of death (p<0.001). In the 1660 patients no significant decline in platelet counts was observed (0.16x109 platelets/l average monthly decline, p=0.16) among patients who were not RBC transfused at any time during follow-up. However platelet counts of patients receiving RBCT declined more quickly (p<0.0001) at an average rate of 1.14x109 platelets/l/month. Among the 920 RBCT dependent patients, lower platelet counts were associated with receiving more RBCT units in the preceding six months. 185 Patients had at least 2 observations both before and after becoming RBCT dependent, defined as 1st RBCT. 50% of these patients had a decreasing trend of platelets prior to their 1st RBCT and 67% had a decreasing slope of platelets after their 1st RBCT. In the control group of RBC untransfused patients, decreasing slopes of platelets occurred in around 50% of the patients throughout the whole observation period of 4 visits. Logistic regression of the risk of having a post-1st RBCT decreasing trend in platelets showed that transfused patients were at a greater risk (OR=1.7, 95% CI: 1.1-2.7) of having a post-1st RBCT decreasing trend in platelets than untransfused patients. Conclusion These multivariate regression models including age, sex, country, IPSS and WHO classification showed that more intensive RBCT treatment is associated with poor prognosis and a more rapid decline of platelets. This indicates that the intensity of RBCT should be incorporated in the regular prognostic scoring systems and the choice of therapeutic interventions. (1): De Swart L et al. Br J Haematol 2015; 170: 372-83. Disclosures Fenaux: NOVARTIS: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding. Hellström-Lindberg:Celgene Corporation: Research Funding. Sanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Mittelman:Roche: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Amgen: Research Funding. Almeida:Bristol Meyer Squibb: Speakers Bureau; Shire: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Park:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Itzykson:Oncoethix: Research Funding. de Witte:Novartis: Research Funding.

48-Month Update On Survival and AML Transformation In a 600-Patient Registry Of Lower-Risk MDS Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2775-2775 ◽  
Author(s):  
Roger M. Lyons ◽  
Billie J. Marek ◽  
Carole S. Paley ◽  
Jason Esposito ◽  
Katie McNamara ◽  
...  
Keyword(s):  
Blood Cell ◽  
Clinical Outcomes ◽  
Red Blood Cell ◽  
Lower Risk ◽  
Research Funding ◽  
Causes Of Death ◽  
Pharmaceutical Research ◽  
Comorbid Conditions ◽  
Leukemic Transformation ◽  
Risk Status

Abstract Introduction Packed red blood cell transfusion is often required for the treatment of anemia in patients (pts) with myelodysplastic syndromes (MDS). Transfusion requirement is associated with poorer clinical outcomes and reduced overall survival (OS) in MDS. We prospectively collected data on clinical outcomes in chelated and non-chelated, transfused, lower-risk MDS pts. OS, leukemic transformation, and clinical events are reported for these groups at 48 mos on study. Methods This 5-year, non-interventional registry enrolled 599 pts from 107 US centers. Pts were ≥18 years old with lower-risk MDS (WHO, FAB classification, and/or IPSS) and transfusional iron overload (serum ferritin ≥1000 μg/L and/or ≥20 packed red blood cell units and/or ≥6 units every 12 weeks). The chelated group included all pts who had ever used iron chelation; sub-analysis was performed on pts with ≥6 mos chelation. Assessments were every 6 mos for 5 years or until death and included demographics, survival, disease status, comorbidities, causes of death, and MDS therapy. Results We present results for non-chelated pts and those chelated ≥6 mos. Baseline demographics and IPSS risk status were similar between groups, although transfusion burden appeared higher in chelated pts (Table 1). At 48 mos, 120 pts continued on registry and 479 had discontinued (379 died [63.3%]; 64 lost to follow-up [10.7%]; 25 other [4.2%]; and 11 completed the study [1.8%]). In all, 269 pts (44.9%) received chelation therapy; 202 had ≥6 mos lifetime chelation. The percentage of pts who had ever received MDS therapy was lower among non-chelated (88.2%) vs chelated ≥6 mos pts (93.6%; P=0.0425). At enrollment, cardiac and vascular comorbid conditions were higher and endocrine conditions trended higher in non-chelated vs chelated ≥6 mos pts (52.1% vs 30.7% [P<0.0001], 59.4% vs 45.0% [P=0.0013], and 43.9% vs 35.6% [P=0.0588], respectively). While on registry, cardiac, vascular, and endocrine comorbid conditions all trended higher in non-chelated vs chelated ≥6 mos pts (50.9% vs 44.1%, 56.4% vs 49.0%, and 40.3% vs 38.6%, respectively; P>0.05 all comparisons). Presence of cardiovascular comorbidities was associated with a significantly shorter mean (SE) OS (89.1 [5.83] mos vs 85.2 [4.43] mos; P<0.01); however this association was not seen with endocrine comorbidities. Median OS was longer in chelated ≥6 mos vs non-chelated pts (P<0.0001; Table 2). Most frequent causes of death were MDS/acute myeloid leukemia (AML), cardiac events, and infection. Time from diagnosis to leukemic transformation was longer in chelated ≥6 mos vs non-chelated pts (P<0.0001). Conclusions At 48 mos, chelated pts had significantly longer OS and time to AML transformation. At baseline, fewer chelated ≥6 mos vs non-chelated pts had cardiac and vascular comorbidities. Baseline characteristics and IPSS risk status were similar between groups. Additional assessments over the 5-year duration of this registry will provide further information on the association between chelation and clinical outcomes. Disclosures: Lyons: Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis Pharmaceutical: Research Funding; Telik: Research Funding. Paley:Novartis Pharmaceuticals: Employment. Esposito:Novartis Pharmaceuticals: Employment. McNamara:Novartis Pharmaceutical: Employment. Garcia-Manero:Novartis Pharmaceutical: Research Funding.

scholarly journals Early CMV Infection Detected By Quantitative Nucleic Acid Testing (QNAT) Is Associated with Lower Risk of Relapse after Reduced Intensity, but Not Myeloablative, Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1913-1913
Author(s):  
Mehrdad Hefazi Torghabeh ◽  
Moussab Damlaj ◽  
Hassan B Alkhateeb ◽  
Raymund Razonable ◽  
Aref Al-Kali ◽  
...  
Keyword(s):  
Lower Risk ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Multivariable Analysis ◽  
Disease Status ◽  
Cmv Infection ◽  
The Impact ◽  
Reduced Intensity ◽  
Risk Of Relapse

Abstract Background The impact of cytomegalovirus (CMV) infection on the risk of relapse after Hematopoietic Cell Transplantation (HCT) remains controversial, with some studies demonstrating lower risk (Green et al, Blood 2013), while others demonstrating no impact (Schmidt-Hieber et al, Blood 2013), or lower relapse risk only in myeloablative (MA) (Manjappa et al, BBMT, 2014) or in reduced intensity conditioning (RIC) (Cichocki et al, ASH 2014) HCT. Furthermore, the majority of studies have used antigenemia for CMV monitoring, while there is limited data with the use of Quantitative Nucleic Acid Testing (QNAT). Aim To determine the impact of CMV infection, as detected by QNAT, on transplant-related outcomes for patients with acute myeloid leukemia (AML), stratified by MA or RIC HCT. Methods After IRB approval, consecutive adults with AML who underwent allogenic HCT from HLA-matched peripheral blood (PB) grafts at our institution between 2006 and 2014 were retrospectively reviewed. All grafts were T-cell replete. Early CMV infection was defined as any positive CMV result by PCR assay during the first 100 days post HCT. Relapse incidence (RI), non-relapse mortality (NRM), disease-free survival (DFS), and overall survival (OS) were compared between patients with and without CMV infection, and stratified according to MA or RIC. DFS and OS were estimated using the Kaplan-Meier method, and compared with log-rank test. Cumulative incidence of relapse and NRM were analyzed as competing events, using Gray's test. Multivariable analyses adjusting for patient's age, disease status at transplant, cytogenetic risk, and ABO incompatibility were performed using Cox's proportional hazards regression, and the Fine and Gray approach. Results A total of 190 consecutive patients, including 94 (49%) MA and 96 (51%) RIC HCT were analyzed. Patients, disease, and transplant characteristics are shown in table 1. Of the 94 MA HCT (median age 45 y, 50% male), 66 (70%) received total body irradiation. After a median follow up of 18 m, 36 (38%) CMV infection, 16 (17%) relapses, 22 (23%) NRM and 35 (37%) deaths occurred in the MA group. Median time to CMV infection and to relapse in this group was 38 (range 8-241) and 140 (29-1690) days, respectively. Among the recipients of MA HCT, patients with early CMV infection showed no difference in the RI (figure 1), but had a significant trend towards higher NRM and significantly lower DFS and OS in both univariate and multivariable analysis (figure 2) (P values shown in table 2). Among 96 RIC HCT (median age 59 y, 56% male), fludarabine plus melphalan was used in 62 (65%) and fludarabine plus busulfan in 34 (35%) patients. In this group, early CMV infection occurred in 33 (34%), relapse in 25 (26%), NRM in 25 (26%), and deaths in 46 (48%) patients after a median follow up of 21 m (1-91 m). Among the recipients of RIC HCT, median time to CMV infection and to relapse was 40 (17-175) and 291 (19-1971) days, respectively. In the RIC group, early CMV infection was associated with a significant trend towards lower RI (figure 1) and higher NRM in both univariable and multivariable analysis, but no difference in DFS and OS (figure 2). Conclusion Our study of a large homogenous group of AML patients who underwent a uniform HLA-matched PB HCT demonstrates a significantly lower risk of relapse associated with early CMV infection detected by QNAT following RIC, but not MA HCT. Early CMV infection in MA HCT is associated with higher NRM and therefore inferior survival, whereas in the RIC HCT, there is no impact on survival as the benefit of lower relapse is offset by the higher NRM. Table 1. Patients, disease and transplant characteristics according to CMV infection All Patients Patients with CMV Viremia Patients without CMV Viremia P value Patients, no (%) 190 (100) 69 (36) 121 (64) - Median age, y (range) 54 (18-72) 54 (26-70) 54 (18-72) 0.75 Male Patients, no (%) 104 (55) 30 (43) 74 (61) 0.02 D/R CMV Serostatus, no (%) <0.0001 -/- 29 (15) 1 (1) 28 (23) +/+ 64 (34) 35 (51) 29 (24) +/- 13 (7) 1 (1) 12 (10) -/+ 84 (44) 32 (47) 52 (43) Conditioning 0.65 MA 96 (51) 33 (48) 63 (52) RIC 94 (49) 36 (52) 58 (48) Disease status at Transplant 0.96 CR1 129 (68) 46 (67) 83 (69) CR2 34 (18) 13 (19) 21 (17) Other 27 (14) 10 (14) 17 (14) Cytogenetic 0.65 Favorable 8 (4) 2 (3) 6 (5) Intermediate 130 (68) 46 (67) 84 (69) Unfavorable 52 (28) 21 (30) 31 (26) Disclosures Al-Kali: Novartis: Research Funding.

scholarly journals Relationship Between Chelation and Clinical Outcomes in Lower-Risk Patients with Myelodysplastic Syndrome (MDS): Registry Analysis at 5 Years

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1350-1350 ◽  
Author(s):  
Roger M. Lyons ◽  
Billie J. Marek ◽  
Carole Paley ◽  
Jason Esposito ◽  
Katie McNamara ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Cause Of Death ◽  
Lower Risk ◽  
Multiorgan Failure ◽  
Clinical Status ◽  
Iron Chelation ◽  
Cardiovascular Comorbidity ◽  
Time To Death ◽  
Risk Patients

Abstract Introduction: We prospectively collected data from lower-risk patients (pts) with MDS in an ongoing US registry in order to assess the association between chelation and clinical outcomes. In addition, we evaluated the association between chelation and overall survival (OS). Here we report outcomes at 5 years. Methods: The registry enrolled 600 pts from 107 US centers. Pts were ≥18 years old with lower-risk MDS (WHO, FAB, and/or IPSS criteria) and transfusional iron overload (serum ferritin ≥1000 µg/L and/or ≥20 packed red blood cell units and/or ≥6 units every 12 weeks). Pts were analyzed by iron chelation status; ie, had never been chelated or had ever used iron chelation, and a subgroup of the latter group—pts with ≥6 mo of chelation. Pts were evaluated every 6 mo for 5 years or until death with respect to characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy. Results: 600 pts (median age, 76 years [range, 21-99], 346 [57.8%] male, 519 [86.6%] Caucasian) were evaluated. IPSS status was similar across chelation groups. Chelated pts (n=271) had a greater median number of lifetime units transfused at the time of enrollment vs nonchelated pts (n=328): 38.5 vs 20.0. At baseline, cardiac and vascular comorbidities (CVC) were significantly higher in nonchelated vs chelated pts (52.4% vs 34.3% [P<0.0001], 59.8% vs 48.0% [P=0.0039], respectively). Endocrine comorbidities (EC) were numerically higher in nonchelated vs ≥6 mo chelated pts (44.2% vs 35.6%). As of May 1, 2014, 61 pts continue in the registry; 538 discontinued (400 died, 66 lost to follow-up, 46 completed study, and 26 discontinued for other reasons). Of the 271 chelated pts, 187 (69.0%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, 32 (11.8%) with deferoxamine, and 1 (0.4%) with an unknown chelator; in 11 (4.1%), the chelator name was not provided. Cumulative duration of chelation was 18.9 mo in pts who had ever used iron chelation and 27.0 mo in pts with ≥6 mo of iron chelation. OS from diagnosis of MDS and time to acute myeloid leukemia (AML) were significantly greater in the chelated vs nonchelated pts (P<0.0001 for both). In pts with CVC, median OS was also significantly greater in chelated vs nonchelated pts (67.66 vs 43.40 mo; P<0.0001). In pts with EC, median OS was also greater in chelated pts (74.98 vs 44.63 mo; P<0.0001) (Table). Patients with ≥6 mo of chelation had numerically fewer deaths in the registry, numerically greater OS, time to death, and time to AML transformation vs pts who had any chelation (Table). Conclusions: Limitations of these analyses include variation in time from diagnosis, duration of chelation, impact of pt clinical status on decision to chelate, and optional conduct of clinical assessments. Nonetheless, the results after 5 years of follow-up of lower-risk pts with MDS suggest iron chelation therapy is associated with improved OS and longer time to AML transformation. Causation has not been established. Abstract 1350. TABLE. Characteristics of Patients Nonchelated, Chelated, and Chelated ≥6 Months Nonchelated n=328 Chelated n=271 Chelated ≥6 Months n=202 Time to death, median (min/max) mo 47.8 (43.4, 53.1) 88.0 (78.4, 103.0) *P<0.0001 100.0 (83.4, 118.2) *P<0.0001 Deaths (n), % 239 (72.9) 161 (59.4) *P=0.0005 115 (56.9) *P=0.0002 Median OS (mo): No CVCMedian OS (mo): With CVC 34.0 (n=42) 43.4 (n=286) 69.3 (n=72) 67.7 (n=199) *P<0.0001 79.3 (n=60) 72.6 (n=142) *P<0.0001 Median OS (mo): No ECMedian OS (mo): With EC 38.5 (n=162) 44.6 (n=166) 67.1 (n=149) 75.0 (n=122) *P<0.0001 69.6 (n=114) 81.8 (n=88) *P<0.0001 Time to AML transformation from diagnosis, median (min, max) mo 46.4 (6.9, 82.5) 72.1 (16.4, 176.6) *P<0.0001 78.8 (16.4, 176.6) *P<0.0001 AML transformation, n (%) 34 (10.4) 17 (6.3) 14 (6.9) Cause of death, n (%) MDS/AML 103 (31.4) 73 (26.9) 53 (26.2) Cardiac 36 (11.0) 21 (7.7) 15 (7.4) Infection 27 (8.2) 14 (5.2) 14 (6.9) Other 16 (4.9) 16 (5.9) 10 (5.0) Unknown 29 (8.8) 18 (6.6) 12 (5.9) Malignancy 14 (4.3) 2 (0.7) 0 (0.0) Respiratory 7 (2.1) 7 (2.6) 4 (2.0) Multiorgan failure 3 (0.9) 3 (1.1) 3 (1.5) CVA 1 (0.3) 5 (1.8) 3 (1.5) GvHD/transplant 3 (0.9) 2 (0.7) 1 (0.5) CVC, cardiovascular comorbidity; EC, endocrine comorbidity; CVA, cerebrovascular accident; GvHD, graft-vs-host disease *Versus nonchelated. Disclosures Paley: Novartis Pharma: Employment. Esposito:Novartis Pharma: Employment. McNamara:Novartis Pharmaceuticals Corporation: Employment. Garcia-Manero:Novartis Pharma: Research Funding.

scholarly journals Elevated Labile Plasma Iron (LPI) Levels in Patients with Lower-Risk Myelodysplastic Syndromes (MDS) Are Associated with Decreased Quality of Life and Reduced Survival

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4392-4392
Author(s):  
Marlijn Hoeks ◽  
Tim Bagguley ◽  
Rian Roelofs ◽  
Louise De Swart ◽  
David Bowen ◽  
...  
Keyword(s):  
Lower Risk ◽  
Research Funding ◽  
Iron Chelation ◽  
Index Score ◽  
Ineffective Erythropoiesis ◽  
Iron Species ◽  
Plasma Iron ◽  
Eq5d Index

Abstract Background: Patients with lower-risk MDS (LR-MDS) are prone to iron toxicity due to long-term iron accumulation either caused by RBC transfusions or ineffective erythropoiesis. Nontransferrin bound iron (NTBI), including labile plasma iron (LPI), are toxic iron species that may mediate cellular damage via oxidative stress. The EUMDS registry collects prospective observational data on newly diagnosed LR-MDS patients from 145 centers in 17 countries since 2008. Methods: We analyzed serum from 247 LR-MDS patients collected at six-month intervals for ferritin, transferrin saturation (TSAT), hepcidin-25, soluble transferin receptor (sTfR) and toxic iron species (NTBI and LPI) in order to evaluate temporal changes in iron metabolism, the presence of potentially toxic forms of iron and their impact on survival, and quality of life. In addition, we measured the impact of iron chelation on the iron species levels and its impact on the outcome parameters. Results: The median age was 73 years (range: 37 to 95 years) and 66% were males. WHO2001 MDS-subtypes were RCMD (45%), RARS (22%), RA (18%), RAEB-1 (7%), 5q-syndrome (4%) and RCMD-RS (4%). The IPSS-R categories were: (very) low risk: 66%; intermediate risk: 11%; (very) high risk: 2% and unknown: 20%. The median EQ5D index score was 0.80 (p10 to p90: 0.52 to 1.00). The table shows iron parameters at registration, 1 and 2 years follow-up both in transfusion-dependent (TD) and transfusion-independent (TI) patients and according to: MDS-RS (RARS/RCMD-RS) or MDS Other (RA/RCMD/RAEB/5q-syndrome). Mean serum ferritin levels were increased in TD patients, compared to TI patients (Table). Increase of ferritin levels over time was high in both TD groups, but the increase was more pronounced in the RS subgroup. Elevated CRP levels (> 10mg/L) were observed in TD nonRS patients, especially during the first year after diagnosis. Markedly increased mean TSAT levels (>75%) occurred in the subgroup of TD-RS patients throughout the observation period. Hepcidin levels were most markedly elevated in TD nonRS patients at registration and remained elevated during follow-up (Table). Hepcidin levels were low in MDS-RS TI patients at all time points compared to nonRS MDS patients and decreased over time as a result of an increased (ineffective) erythropoiesis (Table). This is supported by the highest levels of STfR also noted in this patient category (data not shown). The highest NTBI and LPI levels were observed in TD-RS patients compared to the other 3 subgroups (Table). Both NTBI and LPI levels had a strong correlation (p <0.001) with TSAT. Elevated LPI levels in combination with high TSAT levels (>80%) occurred almost exclusively in patients with MDS-RS and/or previous transfusions. Both the EQ5D index score and EQ-VAS showed a negative correlation (r) with LPI levels with r = -0.09 (p = 0.028) and r = -0.07 (p=0.046) respectively. This negative effect of elevated LPI levels was most pronounced in the TD RS subgroup with a negative correlation of -0.17 for the EQ5D index score and -0.2 for the VAS score. In total 16 patients received iron chelation during the sample collection period (11 patients deferasirox, 4 patients desferioxamine and 1 patient unknown). LPI levels were normal in 14 out of the 17 samples collected during deferasirox treatment and in 2 out of 5 samples collected during desferoxamine treatment. The Kaplan-Meier curves (Figure) demonstrate the prognostic impact of elevated LPI levels by transfusion status as a time dependent variable; once a subject had an elevated LPI level, they remained in this group. Patients were censored at time of starting iron chelation (16 patients). In a multivariate analysis comparing elevated LPI levels and transfusion dependency to the control group with undetectable LPI and no transfusion showed a significantly decreased survival in all 3 risk groups after adjustment for age at diagnosis, baseline IPSS-R category and ESA treatment status; for details, see supplementary table. Conclusion: This study illustrates labile plasma iron species as a clinically relevant assay for identification of the toxic fraction of overt iron overload and its negative impact on HRQoL and overall survival in transfusion dependent and transfusion independent patients. Table. Table. Disclosures Culligan: Merck Sharp & Dohme (MSD): Honoraria; Abbvie: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Pfizer: Honoraria; Celgene: Other: Support to attend conferences; JAZZ: Honoraria; Daiichi-Sankyo: Other: Support to attend conferences. Garelius:novartis: Honoraria. de Witte:Celgene: Honoraria, Research Funding; Novartis: Research Funding; Amgen: Consultancy, Research Funding.

Combination Therapy of Deferasirox and Deferoxamine As Paregoric Treatment of Severe Iron Overload in Patients with Thalassemia Major

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5181-5181
Author(s):  
Vassilis Ladis ◽  
Dimitra Kyriacopoulou ◽  
Konstantinos Stokidis ◽  
Aggeliki Moira ◽  
Antonios Kattamis
Keyword(s):  
Combination Therapy ◽  
Iron Overload ◽  
Research Funding ◽  
Chelation Therapy ◽  
Combined Treatment ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Duration Of Treatment ◽  
Considerable Problem

Abstract Abstract 5181 Background: Despite the recent availability of multiple therapeutic options for chelation therapy, severe iron overload remains a significant cause of morbidity and mortality in a small group of patients with thalassemia major (TM). Every effort to induce negative iron balance for these patients is warranted. In this context, combination of deferasirox (DFX) and deferoxamine (DFO) may be of significant value. In this report, we present the paregoric use of DFX and DFO in severely iron overloaded thalassemic patients. Patients and Methods: Five patients (3 Males, 2 females) have been treated with DFX and DFO as a last rescue measure. In these patients previous combined treatment with DFO and DFP had failed. Informed consent and approval for the use of this schema as paregoric therapy was obtained by patients and hospital. The main inclusion criteria for this treatment were: LIC>30 mg/gr d. w. and T2* cardiac <10 msec. Treatment consisted of daily DFX at 30–40 mg/kg/day and DFO at 40–50 mg/kg/day for 3–6 days/week. Results: Patients' characteristics, results and toxicity are shown in table 1 and 2. Improvement in iron load status ranged widely during a follow-up from 1 to 3 yrs. LIC reduced in 4/5 patients, cardiac T2* increased in 3/5 patients, while LVEF showed no significant changes. Ferritin levels improved in 2/5 patients. Deterioration of safety parameters necessitated not to discontinue treatment. Conclusions: These data in the use of combination therapy of DFX and DFO suggest a potential modality of chelation therapy in severely iron overloaded patients. Response was variable and seemed not to be always related to compliance or the duration of treatment. Increase of serum creatinin and AST in all patients is a considerable problem in patients with persistent significant iron overload and already impaired hepatic and renal function, despite having been treated with different schema of iron chelation. Longer and cautious follow-up is needed to come to reliable conclusions. Disclosures: Ladis: Novartis: Consultancy, Honoraria, Research Funding; Apopharma: Consultancy, Honoraria, Research Funding. Kattamis:Apopharma: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

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