Leukemia Research 56 (2017) 88–95 Contents lists available at ScienceDirect Leukemia Research journal homepage: www.elsevier.com/locate/leukres Invited review Relation between chelation and clinical outcomes in lower-risk patients with myelodysplastic syndromes: Registry analysis at years Roger M Lyons a,∗ , Billie J Marek b , Carole Paley c , Jason Esposito c , Katie McNamara c , Paul D Richards d , Nicholas DiBella e , Guillermo Garcia-Manero f a Texas Oncology and US Oncology Research, 4411 Medical Drive, San Antonio, TX 78229, United States Texas Oncology and US Oncology Research, 1901 South 2nd Street, McAllen, TX, 78503, United States c Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, United States d Blue Ridge Cancer Care and US Oncology Research, 900 Electric Road, Salem, VA 24153, United States e Rocky Mountain Cancer Centers and US Oncology Research, 1700 South Potomac Street, Aurora, CO 80012, United States f The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, United States b a r t i c l e i n f o Article history: Received 23 September 2016 Received in revised form 23 January 2017 Accepted 30 January 2017 Available online 31 January 2017 Keywords: Iron chelation Iron overload Myelodysplastic syndromes a b s t r a c t Prospective data are needed to ascertain the impact of iron chelation therapy in patients with myelodysplastic syndromes The present 5-year prospective registry analysis was conducted to compare clinical outcomes between chelated and nonchelated patients with lower-risk myelodysplastic syndromes and transfusional iron overload In an interim analysis at 24 months, we previously reported that chelation therapy was associated with longer median overall survival and a tendency toward longer leukemia-free survival and fewer cardiac events In the present report, we detail findings from the final analysis at years We confirm, at the conclusion of this 5-year, prospective, non-interventional study, that overall survival was significantly longer in patients who received iron chelation therapy vs those who did not Causes of death in the overall population were predominantly myelodysplastic syndromes/acute myeloid leukemia followed by cardiac disease Time to progression to acute myeloid leukemia was also significantly longer in patients receiving chelation therapy, and significantly fewer patients progressed to leukemia vs those not receiving chelation therapy Limitations of the study include a potential for clinical bias, as patients with longer predicted survival may have been chosen for chelation therapy, the differences present in concomitant conditions at baseline, and the possibility that some high-risk patients were not identified due to limited cytogenetic classification © 2017 The Authors Published by Elsevier Ltd This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Contents Introduction 89 Patients and methods 89 Results 89 3.1 Baseline characteristics 89 3.2 Survival 90 3.3 Progression to leukemia 90 3.4 Safety 90 Discussion 91 Abbreviations: AML, acute myeloid leukemia; ECOG, Eastern Cooperative Oncology Group; FAB, French-American-British; HR, hazard ratio; ICT, iron chelation therapy; IO, iron overload; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; RA, refractory anemia; RARS, refractory anemia with ring sideroblasts; RBC, red blood cell; WHO, World Health Organization ∗ Corresponding author E-mail addresses: roger.lyons@usoncology.com (R.M Lyons), billie.marek@usoncology.com (B.J Marek), carole.paley@novartis.com (C Paley), jason.esposito@novartis.com (J Esposito), katie.mcnamara@novartis.com (K McNamara), paul.richards@usoncology.com (P.D Richards), nick.dibella@usoncology.com (N DiBella), ggarciam@mdanderson.org (G Garcia-Manero) http://dx.doi.org/10.1016/j.leukres.2017.01.033 0145-2126/© 2017 The Authors Published by Elsevier Ltd This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4 0/) R.M Lyons et al / Leukemia Research 56 (2017) 88–95 89 Conflicts of interest 94 Funding 94 Acknowledgments 94 References 94 Introduction Patients with myelodysplastic syndromes (MDS) have deficiencies in hematopoiesis and are at increased risk for progression to acute myeloid leukemia (AML) [1–3] As many as 80% of patients with MDS will develop anemia, and transfusion dependency is common throughout the course of disease [2,3] Each unit of red blood cells (RBCs) is estimated to contain 200–250 mg of iron, and since there is no physiologic mechanism for iron excretion, chronic transfusion of patients with MDS is associated with risk for iron overload (IO) [2–4] In retrospective studies, transfusiondependent patients with MDS had significantly shorter survival than those who were not transfusion dependent (hazard ratio [HR] = 2.16; P < 0.001); leukemia-free survival was also shorter in the transfusion-dependent group (HR = 2.02; P < 0.001) [5] Development of secondary IO (defined in the study as serum ferritin >1000 ng/mL) resulted in an adverse impact on survival, which was also demonstrated in the transfusion-dependent patients: For each 500-ng/mL increase above the defined threshold, a 1.3-fold increase in the risk for death was observed (P = 0.003) [5] Similar findings were reported by Cermak et al., who found a significant impact of transfusion dependency on survival in a subset of patients with early MDS [4] Complications of transfusional IO include cardiac, hepatic, and endocrine organ damage In particular, cardiac complications have been reported as a frequent cause of death in patients with MDS with a high transfusional burden [2–4,6] Therefore, the use of iron chelation therapy (ICT) has been considered a treatment to reduce IO and its associated complications in transfusion-dependent patients with MDS The results of several retrospective and observational studies in MDS populations have suggested that ICT is associated with improved survival in patients with MDS with IO [7–13,21–23] Oral therapies such as deferasirox are available for ICT and have been investigated in patients with MDS and evidence of IO Results of these studies have generally shown substantive reductions in total iron burden, as assessed by serum ferritin, despite continued transfusional requirements, although they have not been designed nor sufficiently powered to determine the impact on IO-related morbidity or mortality [14–16] A prospective, placebo-controlled study (TELESTO) is examining the use of ICT with deferasirox in patients with MDS with low and intermediate-1 risk MDS and transfusional IO [17] Results of the TELESTO study are anticipated in late 2017, but prospective data on the relation of ICT to morbidity and mortality in this population are presently lacking Previously, we reported data from a 5-year registry of 599 lower-risk patients with MDS in the United States The goal of the registry study was to provide prospective data on clinical and safety parameters in chelated and nonchelated transfusion-dependent patients with MDS with IO [18] At the 24-month interim analysis, we found that chelated patients had significantly longer median survival compared with nonchelated patients (99.3 vs 52.2 months; P < 0.0001) There was also a trend toward less progression to AML, and fewer newly diagnosed or progressive cardiac conditions after study entry in chelated patients relative to nonchelated patients [18] Here, we present the final 5-year analysis of clinical outcomes in this population of patients with lower-risk MDS with transfusional IO Data on hematologic parameters, overall survival, and the time to AML transformation are presented This work was presented in part at the 56th American Society of Hematology Annual Meeting and Exposition, December 6–9, 2014, San Francisco, CA Patients and methods This prospective, 5-year, non-interventional study enrolled 599 patients from 118 centers across the United States The primary objective of the study was to evaluate the impact of chelation on overall survival (up to years) in iron overloaded patients with lower-risk MDS The study was limited to patients aged ≥18 years with lower-risk MDS as determined by of MDS classification systems: World Health Organization (WHO), French-American-British (FAB), or International Prognostic Scoring System (IPSS) Eligible patients had transfusion-dependent IO, defined as ≥20 units of packed RBCs or an ongoing transfusion requirement of ≥6 units every 12 weeks, and/or a serum ferritin level >1000 ng/mL, and had lower-risk MDS Patients classified as IPSS intermediate-1 risk were also eligible for enrollment in this study Approved and experimental MDS therapies were permitted, and investigators in the study used institutional standard practices for MDS care and ICT Analysis of patient outcomes was conducted as previously described, with patients defined as nonchelated, chelated (having received ICT at any point), or chelated for ≥6 months cumulatively Subanalyses of patients who had received ≥6 months of ICT were preplanned in the study [18] Follow up was performed at 6-month intervals and patients were observed for a maximum of 60 months, or until death Demographics, survival, cause of death, leukemic transformation, serum ferritin, concomitant illnesses, transfusion requirements, and safety were included among the assessments [18] Descriptive summaries were provided for demographic parameters (age, sex, race) and Eastern Cooperative Oncology Group (ECOG) performance status, as well as patient study completion status, time on study, concomitant conditions while in the study, MDS treatment, MDS status, cumulative duration of ICT, and RBC transfusions The study protocol and all amendments were reviewed by the Independent Ethics Committee or Institutional Review Board for each center The study was conducted according to the ethical principles of the Declaration of Helsinki and all patients gave written informed consent prior to enrollment Results 3.1 Baseline characteristics The demographics and MDS risk status for all enrolled patients in the groups (nonchelated, n = 329; chelated, n = 270; ≥6 months chelation, n = 203) are shown in Table Patient demographics were typical of an MDS population and were mostly balanced across treatment groups The median age was 76 years (range 21–99) across all study groups Of the 599 enrolled patients, the majority were male (57.8%) The majority of patients in the study population were Caucasian (86.6%), 6.2% were Hispanic, 5.5% were African American, and 1.0% were Asian Overall, 25.5% had an ECOG performance status of zero, 52.4% had ECOG performance status of 1, and 18.9% had ECOG performance status of Overall median time from MDS diagnosis to study enrollment was 24.5 months (range 0–429.9): 18.6 months for the nonchelated group, 33.9 months for the chelated group, and 41.1 months for the ≥6 months chelated group At diagnosis, 43.6% of patients were classified under the 90 R.M Lyons et al / Leukemia Research 56 (2017) 88–95 Table Baseline Demographics and MDS Risk Status Parameter Nonchelated (n = 329) Chelated (n = 270) Chelated ≥6 Months (n = 203) Overall (n = 599) Median age, y (range) Male, n (%) Median number of lifetime units infused (range) Median serum ferritin, ng/mL (range) 77 (47–99) 193 (58.7) 20 (0–250) 75 (21–94) 153 (56.7) 40 (2–620) 74 (21–94) 106 (52.2) 44 (2–620) 76 (21–99) 346 (57.8) 28 (0–620) 1367 (3–7379) 1500 (33–16422) 1486 (81–16422) 1444 (3–16422) 114 (34.7) 41 (36.0) 33 (28.9) 77 (28.5) 10 (13.0) 42 (54.5) 62 (30.5) (12.9) 34 (54.8) 191 (31.9) 51 (26.7) 75 (39.3) 20 (17.5) 12 (15.6) 10 (16.1) 32 (16.8) (6.1) (10.4) (9.7) 15 (7.9) 13 (11.4) (6.5) (6.5) 18 (9.4) French-American-British Refractory anemia Refractory anemia with ringed sideroblast Refractory anemia with excess blasts 55 (16.7) 21 (38.2) 15 (27.3) 59 (21.9) 22 (37.3) 29 (49.2) 39 (19.2) 13 (33.3) 20 (51.3) 114 (19.0) 43 (37.7) 44 (38.6) 19 (34.5) (13.6) (15.4) 27 (23.7) MDS risk stratification, n (%) IPSS IPSS risk group – low IPSS risk group – INT-1 160 (48.6) 54 (33.8) 106 (66.3) 134 (49.6) 59 (44.0) 75 (56.0) 102 (50.2) 41 (40.2) 61 (59.8) 294 (49.1) 113 (38.4) 181 (61.6) MDS risk status, n (%) World Health Organization Refractory anemia Refractory anemia with ringed sideroblast Refractory anemia with multilineage dysplasia Refractory anemia with multilineage dysplasia and ringed sideroblast MDS associated with isolated del(5q) WHO system, of which 36.4% had refractory anemia with ring sideroblasts (RARS) and 21.8% had (RA) 21.5% of patients were classified under the FAB system, of which 41.9% had RA and 38.0% had RARS; and 34.2% of patients were risk stratified under the IPSS, of which 52.7% were in the intermediate-1 risk group and 45.4% were in the low-risk group Overall, 326 (54.4%) patients had vascular conditions, the majority of whom had hypertension (304 patients; 50.8%); 265 (44.2%) patients had cardiac conditions, the majority of whom had coronary artery disease (151 patients; 25.2%); 246 (41.1%) patients had endocrine conditions, the majority of whom had diabetes mellitus (147 patients; 24.5%) and thyroid disorders (126 patients; 21%) (Table 2) Notably, the nonchelated group contained a higher proportion of patients with cardiac, vascular, endocrine, respiratory, musculoskeletal, and ophthalmologic conditions than the chelated groups 3.2 Survival Overall, 409 (68.3%) of the 599 enrolled patients died during follow up: 241 (73.3%) of 329 patients in the nonchelated group, 168 (62.2%) of 270 patients in the chelated group, and 121 (59.6%) of 203 patients in the ≥6 months chelated group There was a higher rate of death in the nonchelated group compared with the chelated group (P = 0.0039) and the ≥6 months chelated group (P = 0.001) Patients who received ICT during the study had greater survival than patients who were nonchelated, and patients receiving ≥6 months of chelation had the greatest survival among the groups (Fig 1) Overall survival for patients receiving ICT (overall, and in those with ≥6 months ICT) was significantly longer than that observed for patients who received no ICT, inclusive of those with cardiovascular or endocrine concomitant conditions (Table 3; for both chelated and chelated ≥6 months groups, P < 0.0001) The most common cause of death in the overall population was MDS/AML (181 patients; 30.2%), followed by cardiac causes (57 patients; 9.5%); the differences in causes of death between the nonchelated and chelated groups were statistically significant (P = 0.0014) (Fig 2) This difference was primarily driven by the higher rates of death due to MDS/AML, infection, and malignancy in the nonchelated group There were no statistically significant differences between the groups with regard to the relation between transfusion status, serum ferritin levels, and overall survival (P-value of 0.1663 and 0.8199, respectively) The most common cause of death among patients with ≥6 months of chelation was MDS/AML (57 patients, 47%), followed by cardiac causes (15 patients, 12%) and infection (14 patients, 11%) 3.3 Progression to leukemia While on study, 410 (68.4%) of 599 enrolled patients progressed to leukemia: 241 (73.3%) of 329 patients in the nonchelated group, 169 (62.6%) of 270 patients in the chelated group, and 122 (60.1%) of 203 patients in the ≥6 months chelated group (Table 4) There was a statistically significant difference in the number/percentage of patients who progressed to leukemia in the nonchelated group compared with the chelated group (P = 0.0052) and the ≥6 months chelated group (P = 0.0015) Patients who received ICT had longer leukemia-free survival than patients who were nonchelated (P < 0.0001), and patients receiving ≥6 months of chelation numerically had the greatest leukemia-free survival (P < 0.0001 vs nonchelated) The median time from diagnosis to leukemic progression was 62.6 months in the overall population, 46.7 months in the nonchelated group, 86.3 months in the chelated group, and 97.8 months in the ≥6 months chelated group (Fig and Table 4) 3.4 Safety The time on study was comparable among the groups For each time period, the majority of patients were considered to be stable (MDS status did not improve or progress), with a greater percentage of stable patients in the chelated and ≥6 months chelated groups (37.4% and 39.9%, respectively, at the end of study) compared with the nonchelated group (26.7% at the end of study); more patients in the nonchelated group progressed to leukemia compared with the chelated and ≥6 months chelated group A greater proportion of chelated patients received blood transfusions compared with nonchelated patients at each time period; however, the mean num- R.M Lyons et al / Leukemia Research 56 (2017) 88–95 91 Table Baseline Concomitant Conditions Parameter, n (%) Nonchelatedc (n = 329) Chelated (n = 270) Chelated ≥6 Months (n = 203) Overall (n = 599) Cardiac Vascular Endocrine Gastrointestinal Musculoskeletal Neoplasms Respiratory Neurologic/psychiatric Ophthalmologic Audiologic Infectious disease Hepatobiliary Renal 172 (52.3) 199 (60.5) 145 (44.1) 122 (37.1) 113 (34.3) 41 (12.5) 43 (13.1) 34 (10.3) 56 (17.0) 31 (9.4) 22 (6.7) (2.7) (2.1) 93 (34.4) 127 (47.0) 101 (37.4) 97 (35.9) 71 (26.3) 32 (11.9) 43 (13.1) 40 (14.8) 24 (8.9) 26 (9.6) 19 (7.0) 11 (4.1) (1.1) 62 (30.5) 92 (45.3) 72 (35.5) 69 (34.0) 50 (24.6) 24 (11.8) 43 (13.1) 30 (14.8) 18 (8.9) 18 (8.9) 14 (6.9) (4.4) (0.5) 265 (44.2) 326 (54.4) 246 (41.1) 219 (36.6) 184 (30.7) 73 (12.2) 69 (11.5) 74 (12.4) 80 (13.4) 57 (9.5) 41 (6.8) 20 (3.3) 10 (1.7) Fig Overall Survival: All Enrolled Patients Patients who received iron chelation therapy had longer overall survival compared with nonchelated patients Kaplan-Meier curves for overall survival show median time to death from myelodysplastic syndrome diagnosis in the nonchelated, chelated, and chelated ≥6 months groups as 47.8, 86.3, and 98.7 months, respectively (P < 0.0001 for nonchelated vs both chelated groups) bers of units per week, units since last visit, and transfusions since last visit were comparable among the groups The median duration of ICT for patients in the chelated group was 18.8 months and the median duration of ICT for patients in the ≥6 months chelated group was 27.1 months The ICT received by most patients during the study was deferasirox (76.7% of chelated patients), followed by deferoxamine (19.3% of chelated patients) The most common concomitant conditions during the study were vascular conditions (the majority of which was hypertension) Changes from baseline for hematologic variables, clinical chemistry variables, and weight at each time period were generally comparable between the nonchelated and chelated groups and between the nonchelated and ≥6 months chelated groups (data not shown) Fig shows the change from baseline in serum ferritin At all time points, the change from baseline in serum ferritin levels was not statistically significant in the chelated and ≥6 months chelated groups compared with the nonchelated group Discussion Based largely on retrospective and observational data, guidelines from the National Comprehensive Cancer Network have suggested that ICT may be considered for patients with MDS who have received between 20 and 30 units of RBC transfusions, particularly for patients in the lower-risk group (low/intermediate1 by IPSS criteria), and for those with serum ferritin levels of >2500 ng/mL The treatment goal is to reduce levels to