A Decade Follow-up of a Thalassemia Major (TM) Cohort Monitored by Cardiac Magnetic Resonance Imaging (CMR): Significant Reduction In Patients with Cardiac Iron and In Total Mortality
Authors: Thomas Alison S , Garbowski Maciej , Ang Ai Leen , Shah Farrukh T , Walker J. Malcolm , Moon James C , Pennell Dudley J , Porter John B 
Published: October 2019

Abstract
Abstract 1011

Background.
CMR was introduced in London to assess myocardial iron loading in 1999 and some of these patients now have 10 years of follow-up, most with contemporary CMR determinations. The impact of long-term monitoring of myocardial iron loading in thalassemia major (TM) on the proportion of patients with increased myocardial iron (cT2* <20ms) and on patterns of mortality has not been previously described in a longitudinal cohort over this duration.

Patients and Methods.
All patients regularly attending two London thalassemia centres, who received their first CMR Jan 1999 - Dec 2000 were analyzed as a cohort. Patients underwent initial CMR at the Royal Brompton Hospital and received CMR follow up (FU) either there or at the Heart Hospital (UCLH). 132 patients were identified as having received a CMR in 1999–2000. A minimum 7 years CMR FU was required for inclusion in the long-term CMR analysis. 109 patients had at least 7 years of CMR follow up (range 7.0–10.6 years, median 9.2). The median age at 1st CMR was 27.9 years (range 7.7 – 49.5 years). At baseline, patients were receiving chelation with deferoxamine (DFO) monotherapy (70%), deferiprone (DFP) monotherapy (21%), or a combination of these agents (9%). At latest FU, patients were receiving DFO (32%), deferasirox (DFX) (28%), DFP (22%), or combined DFP and DFO therapy (18%).

Results: Improvement in cardiac iron:
In 1999–2000, 60% of TM patients had cT2* values ≤20ms and 17% had cT2* values <10ms. By contrast, at long term FU, only 23% now have cT2* ≤20ms, 7% have cT2* values <10ms (p<0.001).

Changes to chelation therapy:
31% of patients stayed on the same chelator; 33% had 1 chelator switch, 26% 2 switches and 11% 3 or more switches. 18 switches in chelation therapy were due to side-effects (12 DFP, 5 DFX, 1 DFO). There were 9 breaks in chelation therapy during pregnancy in 8 different women. The proportions of patients with T2* < 20ms fell significantly for those who remained on DFO or DFP monotherapies throughout, or who changed chelation modalities on only one (p=0.002) or two (p=0.02) occasions. Patients who received had 3 or more switches did not show a improvement in this respect. The latter group was also the only subset that showed significant deterioration in myocardial iron (p<0.001).

Mortality rates:
the overall mortality rate for the initial cohort was 1.65 per 1000 patient years (95% CI 0.71 – 3.24); median age at death 35.6 years (range 27.3–48.4). This is a substantial improvement in the mortality index compared with the UK thalassemia registry data, of 4.3 per 1000 patient years during the period 2000–2003 (Modell et al, JCMR, 2008). The incidence rate ratio is 0.387 (95% CI 0.11–0.961), p<0.05, with patients in our cohort 61% less likely to die than those in the 2000–2003 cohort.

Causes of death:
there were 8 deaths during the FU period: 3 with complications of hepatitis C (all with cT2* > 20ms), 3 with sepsis (2 with cT2* <10ms and impaired ejection fraction, 1 with cT2* of 18ms), 1 with breast cancer, 1 with sudden unexplained death (cT2* > 20ms). Thus in only 2 patients could excessive cardiac iron loading be considered a causal/contributory factor. There was no significant difference in the baseline cT2* between those who died and those currently still alive (p= 0.2), meaning that death as a drop-out cause does not explain iron loading trends over FU. Chelators at death: DFO (4), DFP (2), DFX (1), combination (1).

Conclusions:
Over a decade we have seen an almost 3 fold fall in the proportion of patients with myocardial iron overload. Mortality has become substantially lower and cardiac iron overload is no longer the leading cause of mortality. In addition to CMR, this decade has seen the advent of two new oral iron chelators and many patients switched chelation regimen, sometimes several times, during the follow up period. Whilst the contribution of the individual components of this practice to the improved outcome cannot be concluded without randomized studies, it is clear that this modern management of TM is associated with reduced TM mortality.

Disclosures:
Off Label Use: Deferiprone is off label in the USA but licensed in Europe. Shah:Novartis: Honoraria, Speakers Bureau; Apotex/ Swedish Orphan: Honoraria. Pennell:Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardiovascular Imaging Solutions: Director of CVIS, Equity Ownership. Porter:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.