Received: May 5, 2014
Accepted: May 6, 2014
Meditterr J Hematol Infect Dis 2014, 6(1): e2014037, DOI 10.4084/MJHID.2014.037
This article is available on PDF format at:
Lodovico Balducci and Dawn Dolan
H.
Lee Moffitt Cancer Center and Research Institute. 12902 Magnolia Dr,
Tampa, Florida 33612.
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Introduction
Approximately
50 % of CML patients are 66 and older.[1]
In earlier studies age appeared a poor prognostic factor for survival
and was included as such in all staging models.[2]
It is not clear whether this age effect was due to poorer disease
biology, or to other age –related factors, including competitive causes
of death, increased risk of treatment-related complications, or
contraindications to curative bone marrow transplant. The introduction
of tyrosine kinase inhibitors (TKI) that are better tolerated than
previous treatments and that prolong the survival of the majority of
responding patients indefinitely, allow a fresh look to the
interactions of advanced age and CML. The issue is timely as one expect
that the median age of CML and the prevalence of the disease in older
individuals will progressively increase with the aging of the
population.[3]
After reviewing the definition of age in physiologic terms, this
editorial explores the biology of CML, the effectiveness and tolerance
of TKI in older people and the age adjusted survival of CML patients
since the introduction of TKI.
Physiologic and Chronologic Age
Aging is associated with a progressive reduction in life-expectancy and
functional reserve, and with increased polymorbidity. The ability of
independent living of the older person may be impaired by loss of
memory and judgment and by inadequate sight and hearing. The ability of
independent living and stress tolerance may be determined by the
availability of adequate social support.[4]
Though
these changes are universal they occur at different rate in different
individuals, so that chronologic age reflects chronologic age poorly.
Individualized treatment of cancer in the older aged person implies an
estimate of life expectancy and of the risk of treatment related
complications. A number of laboratory tests have been proposed to
determine physiologic age including the inflammatory index4, the length
of leukocyte telomers,[5] and the
expression of the gatekeeper gene PINK4a,[6]
in normal tissues. None of these tests has been validated in patients
with neoplastic diseases, however. It was repeatedly demonstrated that
a Comprehensive Geriatric Assessment (CGA) may estimate both mortality
risk and tolerance of antineoplastic treatment.[3]
The
CGA involves evaluation of function, comorbidity, polypharmacy,
cognition, depression, social support, and economic issues. It is
recommended that some form of CGA be performed in all individuals aged
70 and older.[7] The assessment of
physiologic age may
provide the answer to important questions related to the management of
CML in the elderly and in particular whether the cancer independent
life-expectancy is long enough to justify the initiation of any
treatment, whether the patients may tolerate treatment and whether the
patients pharmacopeia needs adjustment to prevent dangerous drug
interactions. In countries without a national health care system the
CGA may also reveal whether the patient may afford treatment.
Biology of CML and Aging
Though a number of early studies summarized in reference 2 demonstrated
that the advanced age was an independent prognostic factor for poor
survival, none of them demonstrated a more advanced disease stage at
presentation, or a higher prevalence of multiple cytogenetic
abnormalities in older individuals. Likewise, more recent studies
failed to demonstrate an association of age with BCR/abl mutations
purporting TKI resistance.[8] While
it is still
possible that age-associated immune dysfunctions or age-related changes
in hematopoietic stroma may lead to a more aggressive disease, at
present there is no conclusive evidence that the biology of CML changes
with age. As older patients appear to benefit from TKI to the same
extent as the young[1,9-10] one may conclude that age-related
biological differences do not seem to impact the prognosis of CML in
the elderly.
Age and Survival of CML Patients in the Imatinib Era
Two large population studies[1,9]
have examined the changes in CML survival among patients of all ages,
since the advent of imatinib. The Surveillance, Epidemiology, and End
Results (SEER) study showed that the survival of patients in all age
groups had improved to the same extent.[1]
A Swedish
study encompassing all patients treated in the country since 1958 (when
the national tumor registry was established) until 2008 showed that the
survival of all patients had improved except for those aged 79+. The
causes of this age-related discrepancy could not be analyzed based on
the registry data. It is not farfetched to assume that competitive
causes of death and inadequate treatment might have played a major
role. An Italian study involving 31 medical centers[10]
showed that patients aged 75+ seemed to benefit from imatinib treatment
to the same extent as younger people. It is not clear to what degree
these patients have been selected however.
Age and Pharmacology of TKI
Most of the information available concerns imatinib. In clinical
studies the risk8 of imatinib related side effects and in particular of
fluid retention increased after age 65. Also the combination of
imatinib with p450 inhibitors should be used with caution and the
combinations of these agents with desatinib and nilotinib should be
avoided. P450 inhibitors decrease the metabolism of TKI and may enhance
their complications. The Italian study[10]
demonstrated that the achievement of complete cytogenetic response was
similar in individuals 75 and older and younger individuals. However a
major molecular response was rarer. Also the AUC of imatinib was
increased and the elimination decreased in the elderly. These
individuals required more frequent dose reductions or treatment
interruptions than the young ones.
Conclusions
Current evidence suggests that the biology of CML is not affected by
patient’s age and that older individuals may benefit from TKI treatment
to the same extent as the younger ones. Older individuals may require
more frequent dose reductions, as well as pharmacologic adjustments, to
avoid drug interactions. The assessment of physiologic age through a
CGA may reveal the patients more likely to benefit from treatment. The
cost of these agents may represent a treatment barrier for older
individuals living in countries without universal health care.
References
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