Impact of Dexrazoxane on Diffuse Myocardial Fibrosis and Quantitative Perfusion in Children who Received Anthracycline Chemotherapy

Background: Anthracyclines are an important class of chemotherapy agents but carry risks of anthracycline-induced cardiotoxicity (AIC) in pediatric cancer survivors. Dexrazoxane is a cardioprotective agent which has been shown to reduce subclinical cardiotoxicity and heart failure in adult patients. There is a lack of pediatric data surrounding its efficacy as measured by CMR functional and parametric markers.

Methods: This is a prospective study of 27 patients with anthracycline exposure, 15 of which received dexrazoxane. Groups were matched as closely as possible at recruitment. Patients underwent adenosine stress perfusion CMR using standardized protocols, including T1and T2 mapping and late gadolinium enhancement (LGE). The study was empowered adequately to detect a meaningful difference in extra-cellular volume (ECV).

Results: Baseline demographics, including total anthracycline dose equivalent did not differ between groups (Table 1). Those who received dexrazoxane had a statistically significant shorter duration between diagnosis and time of CMR (8.24± 2.62 vs 13.19 ± 3.23, p< 0.001). There were no qualitative perfusion deficits noted with adenosine and none of the patients had LGE. Left ventricular ejection fraction, end-diastolic volume indexed, and mass to volume ratio did not significantly differ between the two groups (Table 2). Quantitative perfusion demonstrated no significant difference in myocardial blood flow (MBF) at rest (1.75 ± 0.49 vs 1.98 ± 0.65, p = 0.35), and stress (3.61 ± 0.54 vs 3.34 ± 0.63 p = 0.28). Myocardial perfusion reserve (MPR) was not statistically significantly different between the two groups (dexrazoxane group 2.29 [1.91–3.35] vs non-dexrazoxane 1.80 [1.35–2.45], p=0.15), although was decreased overall compared to accepted normal values. Strain parameters, including global circumferential and longitudinal strain, showed no significant differences (p > 0.29). There were no significant differences in native global T1 (988ms [974.5, 993] vs 918ms [974.5, 990], p=0.68), as well as T2 maps (53.36ms± 3.62 vs 55.34ms ± 3.2, p =0.17), which were all within the normal range. ECV did not statistically differ between the groups (Table 2).

Conclusion: These young adult survivors of childhood cancer that received anthracyclines showed mostly normal functional indices and multiparametric CMR measurements. The effect of dexrazoxane showed no statistically significant differences. However, it may be worth noting that in the non-dexrazoxane group, the mean MPR was less than the accepted cutoff of 2 (dexrazoxane group 2.29 [1.91–3.35] vs non-dexrazoxane 1.80 [1.35–2.45], p=0.15, Figure 1). Dexrazoxane use did not prevent medium-term fibrosis, as measured by ECV, but was associated with a trend toward preserved microvascular function (given by MPR). This finding supports continued use of dexrazoxane pending long-term definitive confirmation.

Table 1: Demographics

Characteristics	Received Dexrazoxane (n=15)	Did Not Receive Dexrazoxane (n=12)	P-value
Age (years)	15.40 ± 3.85	16.83 ± 3.54	0.32
Weight (kg)	64.00 [48.00, 71.00]	68.50 [53.00, 86.25]	0.56
Height (cm)	158.73 ± 13.80	166.17 ± 14.29	0.19
Male n (%)	11 (73)	7 (58)	0.45
BSA (m2)	1.65 ± 0.29	1.83 ± 0.53	0.29
Total Anthracycline dose equivalent (mg/m2)	360.00 [341.00, 375.00]	321.00 [273.75, 432.50]	0.24
Time since diagnosis (years)	8.24 ± 2.62	13.19 ± 3.23	< 0.001

Values listed as mean ± SD or median and interquartile range [Q1, Q3]BSA: Body surface areaTable 2: MRI Parameters by Group

Parameters	Received Dexrazoxane	Did Not Receive Dexrazoxane	P-value
Mean MBF Rest (ml/g/min)	1.75 ± 0.49 (n=14)	1.98 ± 0.65 (n=11)	0.35
Mean MBF Stress (ml/g/min)	3.61 ± 0.54 (n=14)	3.34 ± 0.63 (n=11)	0.28
Mean MPR	2.29 [1.91, 3.00] (n=14)	1.80 [1.35, 2.45] (n=11)	0.15
Peak GCS (%)	-18.33 ± 2.93 (n=15)	-18.02 ± 2.46 (n=12)	0.77
Peak GLS (%)	-16.06 ± 3.20 (n=15)	-15.03 ± 1.64 (n=12)	0.29
LVEF (%)	58.27 ± 7.23 (n=15)	55.00 ± 3.93 (n=12)	0.15
LV EDVi (ml/m2)	78.10 ± 15.38 (n=15)	83.63 ± 11.88 (n=12)	0.30
LV Mass:Volume	0.59 [0.50, 0.63] (n=15)	0.52 [0.50, 0.57] (n=12)	0.17
Native Global T1 (ms)	988.00 [974.50, 993.00] (n=15)	981.50 [974.50, 990.00] (n=12)	0.68
T2 Map (ms)	53.36 ± 3.62 (n=13)	55.34 ± 3.20 (n=11)	0.17
ECV (%)	25.00 [23.00, 29.00] (n=15)	26.50 [26.00, 27.50] (n=12)	0.39

Values listed as mean ± SD or median and interquartile range [Q1, Q3]. MBF: Myocardial blood flow, MPR: Myocardial perfusion reserve,GCS: Global circumferencial strain, GLS: Global longitudinal strainLVEF: Left vetricular ejection fraction, LVEDVi: Left ventricular end-diastolic volume indexed, ECV: ExtracellularMyocardial Perfusion Reserve