Page 1678 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 93

LATE COMPLICATIONS OF HEMATOLOGIC DISEASES

AND THEIR THERAPIES

Wendy Landier and Smita Bhatia

The past three decades have seen a marked improvement in survival CHF. Among childhood cancer survivors, the incidence of CHF is
for patients with hematologic malignancies. The 5-year survival is as less than 5% with cumulative anthracycline exposure of less than
2
2
follows: leukemia, 58%; Hodgkin lymphoma (HL), 87%; non- 250 mg/m , approaches 10% at doses between 250 mg/m and
2
2 28–30
1
Hodgkin lymphoma (NHL), 71%; and multiple myeloma, 43%. As 600 mg/m , and exceeds 30% for doses higher than 600 mg/m .
a consequence, the population of long-term cancer survivors contin- However, cumulative anthracycline exposure as low as 101–150 mg/
2
ues to grow. As of January 1, 2014, there were 316,210 leukemia m may be associated with a 3.9-fold increased risk for cardiomyopa-
survivors living in the United States, 197,850 HL survivors, and thy when compared with those unexposed to anthracyclines. 31
569,820 NHL survivors. 2 Among survivors of adult-onset cancer, the incidence of CHF has
2 32
Attendant with this success is an increasing awareness of the been estimated at 7.5% to 26% with a dosage of 550 mg/m .
occurrence of long-term morbidity and mortality associated with the However, this cumulative anthracycline exposure has considerably
2
very treatments responsible for the improvement in survival. The higher dosages than the 300 mg/m typically used for patients treated
subject of long-term morbidity suffered by cancer survivors has been with six cycles of doxorubicin (Adriamycin), bleomycin, vinblastine,
the topic of numerous reports. 3–12 These reports demonstrate that and dacarbazine (ABVD) or rituximab, cyclophosphamide, doxoru-
survivors are at risk for developing adverse outcomes, including bicin, vincristine, and prednisone (R-CHOP); the cardiac effects of
premature death, subsequent neoplasms, organ dysfunction (e.g., moderate-dose doxorubicin, given as part of ABVD or R-CHOP to
cardiac, pulmonary, gonadal), reduced growth, decreased fertility, young adults, are less clear. Small case series either show no cardiac
impaired intellectual function, difficulties obtaining employment and toxicity 33,34 or significant deterioration in several echocardiographic
35
insurance, and overall reduced quality of life. measures of ventricular function with 6 months of exposure. , In
Hematopoietic cell transplantation (HCT) is the treatment of addition, 5-year cumulative risks of significant cardiac events and
36
choice for patients with hematologic malignancies experiencing CHF were 19% and 10%, respectively. Among survivors older than
disease recurrence after conventional regimens and for those with 65 years of age, the risk of late-onset CHF was 29% higher among
disease characteristics associated with poor prognosis if treated with those exposed to doxorubicin, compared with those not treated with
conventional chemotherapy and radiation regimens. Complications doxorubicin, and an increase in the number of cycles of doxorubicin-
observed after HCT often have a multifactorial origin encompassing containing chemotherapy was significantly associated with increasing
37
issues related to prior cancer therapy, intensity of the preparative risk of CHF. In a clinical trial designed to evaluate cardiac toxicity
regimen, graft-versus-host disease (GVHD), and other posttransplan- after R-CHOP for diffuse large B-cell lymphoma (DLBCL) (median
tation complications. 13–22 age at treatment: 68 years), 6% of the patients developed CHF after
This chapter summarizes select adverse outcomes among individu- six to eight cycles. 38
als treated for hematologic malignancies with conventional therapy Among HCT recipients, the risk of CHF is highest after autolo-
24
alone or with HCT. Recommendations for providing ongoing gous HCT, approaching 10% at 15 years after HCT. Autologous
follow-up care to this population of survivors are also reviewed. HCT survivors are at a nearly fivefold risk of CHF when compared
with age-matched and sex-matched individuals from the general
population. Outcome after post-HCT CHF is poor, with less than
CARDIOVASCULAR DISEASE 50% of patients surviving 5 years after a diagnosis of CHF. The risk
39
of late-occurring CHF is primarily due to pre-HCT exposure to
One of the more serious adverse events encountered in survivors of anthracyclines. 24,39 A recent study found that a doxorubicin dose
2
hematologic malignancies is the development of late-occurring car- ≥300 mg/m and a cardiac radiation therapy (RT) dose greater than
diovascular events, which include coronary artery disease (CAD) 30 Gy were independent risk factors for left ventricular systolic
(myocardial infarction, atherosclerotic heart disease, and angina dysfunction. 40
pectoris) and cardiac disease (cardiomyopathy and congestive heart
failure [CHF], valvular disease, conductive abnormalities, and con-
strictive pericarditis). These complications are more common than Modifying Factors for Cardiac Disease
expected, 23,24 and often occur earlier than would be expected for the
general population. 13,25,26 Young age at exposure is a significant modifier of anthracycline-
related cardiotoxicity. 41,42 Females treated in childhood are at greater
risk of developing doxorubicin-induced ventricular dysfunction than
Cardiac Disease are males. The combined use of doxorubicin and chest radiation
28
has been associated with a greater risk of late cardiac toxicity than
The anthracycline class of drugs is a well-known cause of late-onset either treatment given alone. For men treated for HL at age 40
cardiomyopathy. Anthracyclines are directly toxic to the myocardium years, the estimated 15-year rate of cardiac-related hospitalization
through a variety of mechanisms, including free radical-mediated was 9.8% (standardized incidence ratio [SIR]: 1.92) following
oxidative damage and induction of cellular apoptosis. Compared with mantle RT (median dose: 35 Gy) and 16.5% following combined
the general population, survivors of childhood cancer are at a 15-fold doxorubicin with mediastinal RT (SIR: 2.80). 33,34 Another study
6
increased risk of developing CHF and at a sevenfold increased risk found the addition of anthracyclines to mediastinal RT significantly
27
of premature death due to cardiac causes. There is a strong dose- increased the risk of CHF (relative risk [RR]: 2.81) vs mediastinal
dependent relationship between anthracycline exposure and risk of RT alone. 33
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