Page 1679 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 93 Late Complications of Hematologic Diseases and Their Therapies 1497

The presence of one or more conventional cardiac risk factors evidence for dexrazoxane as a cardioprotectant. Dexrazoxane decreases
62
(diabetes, dyslipidemia, smoking, and hypertension) has a significant oxygen free radicals through intracellular iron chelation. In two
effect on the incidence of heart disease among both HL survivors and metaanalyses, dexrazoxane was associated with 60% to 80% fewer
older patients with DLBCL. 33,37 The risk of post-HCT anthracycline- clinical and subclinical cardiac events during and after anthracycline-
related cardiotoxicity also increases significantly among individuals based therapy. 63,64 Overall, toxicity and measures of tumor response
with one or more conventional cardiac risk factors. 23,24,43,44 were similar between patients exposed and unexposed to dexrazox-
63
ane. Currently, the Food and Drug Administration approves
dexrazoxane for women with metastatic breast cancer who have
Arterial Disease received 300 mg/m of doxorubicin and who need additional
2
anthracycline-based therapy. The American Society of Clinical
Radiation to the chest produces late-onset intimal thickening of the Oncology also recommends considering dexrazoxane for adults with
2
coronary arteries and microvascular damage that causes reduced any history of cancer who have already received 300 mg/m of
myocardial perfusion. Several cohort studies have shown that patients doxorubicin-based therapy. 65
who received mediastinal irradiation for HL had an increased risk of Intermediate or surrogate endpoints in randomized clinical trials
CAD compared with the respective general populations. 45–51 The risk show that dexrazoxane reduces cardiotoxicity in children exposed to
of radiation-related CAD is generally higher among men and among anthracyclines. 66,67 Among 206 children with acute lymphoblastic
younger patients. A large, retrospective cohort study reported the risk leukemia (ALL), those receiving dexrazoxane had fewer episodes of
of deaths related to myocardial infarction to be 2.5-fold higher among elevated cardiac troponin T (cTnT) concentrations after anthracy-
67
HL patients when compared with an age-matched and sex-matched cline treatment (21% vs. 50%, p < .001) Longer term follow-up
general population. While the RR declined with increasing age of the data demonstrate that various echocardiographic indices of left
HL cohort, the absolute excess risks of death from myocardial infarc- ventricular (LV) structure and function are worse in those not
66
tion increased with older age up to age 65 years at first treatment. receiving dexrazoxane. Girls benefit from dexrazoxane more than
The statistically significantly increased risk of myocardial infarction boys, particularly with respect to changes in the LV end-diastolic
mortality persisted through to 25 years after first treatment. Risks thickness-to-dimension ratio, a marker of pathologic LV remodel-
were increased statistically significantly for patients treated with ing. Dexrazoxane was also found to demonstrate cardioprotection in
68
supradiaphragmatic radiation, anthracyclines, or vincristine. Patients children treated with doxorubicin for T-cell ALL and lymphoma.
treated with the doxorubicin, bleomycin, vinblastine, and dacarbazine A recent report demonstrates no impact on late mortality among
69
regimen were at a 9.5-fold increased risk of mortality due to myocar- HL patients randomized to dexrazoxane. However, comprehensive
dial infarction. Among those exposed to supradiaphragmatic radia- longer term follow-up is required to document that dexrazoxane does
tion and vincristine and followed for 20 or more years after first indeed have a cardioprotective effect while maintaining comparable
treatment, the risk was 14.8-fold that of the general population. 52 event-free survival. 70,71
Arterial disease in the transplant setting is related to an accelerated Previous reports have suggested that doxorubicin-induced cardio-
atherosclerosis, attributed to pre-HCT and conditioning-related toxicity can be prevented by continuous infusion of the drug. 72–74
75
radiotherapy, and is compounded by the development of cardiovas- Lipshultz et al compared cardiac outcomes in children with leuke-
cular risk factors (hypertension, diabetes, and dyslipidemia) in the mia receiving bolus or continuous infusion doxorubicin and reported
early post-HCT period. 43,53 The cumulative incidence of arterial that continuous doxorubicin infusion over 48 hours did not offer a
events such as clinically overt CAD or stroke among allogeneic HCT cardioprotective advantage over bolus infusion. Both regimens were
recipients is 10% at 15 years and the risk exceeds 20% at 20 years. 25,26 associated with progressive subclinical cardiotoxicity. Several other
In this population, the median age at first myocardial infarction is as studies have reported no statistically significant difference in echocar-
low as 53 years (range: 35–66 years), 44,54 which is earlier than would diographic characteristics of children with cancer 5–7 years after
55
be expected for the general population (67 years) or that reported treatment with either continuous infusion (over 6–24 hours) or bolus
for survivors of autologous HCT (61 years). 44,54 infusion of anthracyclines. 76,77
Liposome-encapsulated anthracyclines have been explored for
their propensity to result in a lower incidence of cardiotoxicity. The
Cardiovascular Risk Factors premise behind this theory is as follows: liposome-encapsulated
anthracyclines escape the capillaries with wide endothelial gaps in the
The risk of developing cardiovascular risk factors such as hyperten- tumor, thus reaching high concentrations in the interstitial fluid of
sion, diabetes, and dyslipidemia is especially high in allogeneic HCT the tumor bed, but are less likely to escape the tight capillary junc-
recipients when compared with autologous HCT recipients, as well tions of the heart. Biopsy results have confirmed the relative safety in
as age-matched and sex-matched individuals in the general popula- clinical use. 78,79 Data on the potential cardioprotection associated
tion. 44,56 The 10-year cumulative incidence of hypertension, diabetes, with liposomal formulations of anthracyclines is limited. A phase I
and dyslipidemia in allogeneic HCT recipients was 37.7%, 18.1%, study of liposomal daunorubicin in 48 children reported no
and 46.7%, respectively; the risk for multiple (>2) cardiovascular risk cardioprotection. 80
factors approached 40% (compared with 26% in survivors of autolo- Specific recommendations for monitoring, based on age and
gous HCT). therapeutic exposure, are delineated within the Children’s Oncology
81
Conditioning with total body irradiation (TBI) has been associated Group Long-Term Follow-Up Guidelines (COG LTFU guidelines)
82
with an increased risk of dyslipidemia and diabetes in pediatric 57,58 available at http://www.survivorshipguidelines.org. According to
56
and adult survivors of HCT. Abdominal radiotherapy possibly these guidelines, patients exposed to anthracyclines need ongoing
contributes to insulin resistance and/or metabolic syndrome, sug- monitoring for late-onset cardiomyopathy using serial noninvasive
gesting a role for radiation-induced pancreatic or hepatic injury. 59,60 testing (echocardiogram) and physical examination. The frequency
The increased risk of diabetes and dyslipidemia among HCT sur- of echocardiograms can range from yearly to every 5 years, depending
vivors with prior exposure to TBI could potentially be due to the on cumulative anthracycline dose, age at exposure, and treatment
combined effects of abdominal radiotherapy and post-HCT gonadal with mediastinal radiation. Pregnant women previously treated with
dysfunction. 61 anthracyclines should be closely monitored, because changes in
volume during the third trimester could add significant stress to a
potentially compromised myocardium. In addition to monitoring for
Prevention of Cardiotoxicity cardiomyopathy, survivors who received radiation involving the heart
field also need monitoring for potential early-onset atherosclerosis.
Given the known cardiac complications of cancer therapy, prevention Heart-healthy lifestyles should be encouraged for all survivors,
of cardiotoxicity is a focus of active investigation. There is strong including implementation of a regular exercise program, dietary