relation between chelation and clinical outcomes in lower risk patients with myelodysplastic syndromes registry analysis at 5 years

Richardsd, Nicholas DiBellae, Guillermo Garcia-Manerof a Texas Oncology and US Oncology Research, 4411 Medical Drive, San Antonio, TX 78229, United States b Texas Oncology and US Oncolog

Invited review

Roger M Lyonsa,∗, Billie J Marekb, Carole Paleyc, Jason Espositoc, Katie McNamarac,

Paul D Richardsd, Nicholas DiBellae, Guillermo Garcia-Manerof

a Texas Oncology and US Oncology Research, 4411 Medical Drive, San Antonio, TX 78229, United States

b 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

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

Prospectivedataareneededtoascertaintheimpactofironchelationtherapyinpatientswith myelodys-plasticsyndromes.Thepresent5-yearprospectiveregistryanalysiswasconductedtocompareclinical outcomesbetweenchelatedandnonchelatedpatientswithlower-riskmyelodysplasticsyndromesand transfusionalironoverload.Inaninterimanalysisat24months,wepreviouslyreportedthatchelation therapywasassociatedwithlongermedianoverallsurvivalandatendencytowardlongerleukemia-free survivalandfewercardiacevents.Inthepresentreport,wedetailfindingsfromthefinalanalysisat

5years.Weconfirm,attheconclusionofthis5-year,prospective,non-interventionalstudy,that over-allsurvivalwassignificantlylongerinpatientswhoreceivedironchelationtherapyvsthosewhodid not.Causesofdeathintheoverallpopulationwerepredominantlymyelodysplasticsyndromes/acute myeloidleukemiafollowedbycardiacdisease.Timetoprogressiontoacutemyeloidleukemiawasalso significantlylongerinpatientsreceivingchelationtherapy,andsignificantlyfewerpatientsprogressed

toleukemiavsthosenotreceivingchelationtherapy.Limitationsofthestudyincludeapotentialfor clinicalbias,aspatientswithlongerpredictedsurvivalmayhavebeenchosenforchelationtherapy,the differencespresentinconcomitantconditionsatbaseline,andthepossibilitythatsomehigh-riskpatients werenotidentifiedduetolimitedcytogeneticclassification

©2017TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND

license(http://creativecommons.org/licenses/by-nc-nd/4.0/)

Contents

1 Introduction 89

2 Patientsandmethods 89

3 Results 89

3.1 Baselinecharacteristics 89

3.2 Survival 90

3.3 Progressiontoleukemia 90

3.4 Safety 90

4 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.

Funding 94

Acknowledgments 94

References 94

1 Introduction

withMDSwithIO[7–13,21–23]

2 Patients and methods

3 Results

Table 1

Baseline Demographics and MDS Risk Status.

(n = 329)

Chelated (n = 270)

Chelated ≥6 Months (n = 203)

Overall (n = 599)

Median number of lifetime units

infused (range)

Median serum ferritin, ng/mL (range) 1367

(3–7379)

1500 (33–16422)

1486 (81–16422)

1444 (3–16422) MDS risk status, n (%)

Refractory anemia with ringed

sideroblast

Refractory anemia with multilineage

dysplasia

Refractory anemia with multilineage

dysplasia and ringed sideroblast

Refractory anemia with ringed

sideroblast

MDS risk stratification, n (%) IPSS 160 (48.6) 134 (49.6) 102 (50.2) 294 (49.1)

(Table2).Notably,thenonchelatedgroupcontainedahigher

groups

(Table 4) Therewas a statisticallysignificant differencein the

Table4)

num-Table 2

Baseline Concomitant Conditions.

Parameter, n (%) Nonchelatedc

(n = 329)

Chelated (n = 270)

Chelated ≥6 Months (n = 203)

Overall (n = 599)

Fig 1. 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).

4 Discussion

[1,19].In a recentlypublishedmeta-analysisof 8 observational

Table 3

Overall Survival of Patients With or Without Cardiovascular or Endocrine Concomitant Conditions (Cond) Prior to or During the Study.

Cardiovascular

No Cond (n = 42)

With Cond (n = 287)

No Cond (n = 72)

With Cond (n = 198)

No Cond (n = 60)

With Cond (n = 143)

Endocrine

No Cond (n = 163)

With Cond (n = 166)

No Cond (n = 148)

With Cond (n = 122)

No Cond (n = 115)

With Cond (n = 88)

a P-value for comparison within treatment group of No Cond vs With Cond.

b P-value for comparison of Nonchelated with Chelated and Nonchelated with Chelated ≥6 Months regarding overall survival without cardiovascular condition and with cardiovascular condition.

Fig 2.Summary of Causes of Death for All Enrolled Patients There were 241 (73.1%), 168 (62.2%), and 121 (59.6%) deaths in the nonchelated, chelated, and chelated ≥6 months groups, respectively (P = 0.001 for nonchelated vs chelated ≥6 months) The differences in causes of death between the nonchelated and chelated groups were statistically significant (P = 0.0014), and were primarily driven by the higher rates of death due to MDS/AML, infection, and malignancy in the nonchelated group AML, acute myeloid leukemia; CVA, cerebrovascular accident; GvHD, graft-versus-host disease; MDS, myelodysplastic syndromes.

Table 4

Time From MDS Diagnosis to Progression to Leukemia: Leukemia-Free Survival (All Enrolled Patients).

(n = 329)

Chelated (n = 270)

Chelated ≥6 Months (n = 203)

Overall (n = 599) Patients progressing while on registry, n (%) 241 (73.3) 169 (62.6) 122 (60.1) 410 (68.4)

Fig 3.Progression to Acute Myeloid Leukemia: All Enrolled Patients Time to progression to acute myeloid leukemia was significantly longer in chelated vs nonchelated patients (P < 0.0001) The median time from diagnosis to leukemic progression was 46.7 months in the nonchelated group, 86.3 in the chelated group, and 97.8 in the ≥6 months chelated group.

Fig 4.Serum Ferritin: Change Fom Baseline 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.

respec-tively)

Conflicts of interest

Corpora-tion

Cor-poration

Funding

Acknowledgments

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