Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase

[Guest guest]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010822/?tool=pubmed

A good summary of the paper by my GIST friend, Marina Symcox.

" " Most adverse effects occur within the first 2 years of starting therapy;

however, late effects, many being unique, are now being recognized. " "

" " The general consensus is that the majority of patients who develop

cardiotoxicity, heart failure, and/or myocardial infarction are older

(>65 years old) and have pre-existing cardiac risk factors or existing

cardiac disease. While overt clinical heart failure may well be of rare

incidence in patients taking IM, studies to access early signs of heart

failure have been undertaken " "

" " The longer term effects of IM therapy on bone remodelling have also been

studied. ....The authors observed an increase in total bone volume along

with a significant decrease in serum phosphate and calcium concentrations

after extended IM therapy. They speculated that IM restrains bone resorption

(by inhibiting c-Fms on osteoclasts) and stimulates bone formation (by

inhibiting PDGF-R on osteoblasts), thus sequestrating both calcium and

phosphate in bone. This can result in secondary hyperparathyroidism, which

decreases renal phosphate absorption, leading to hypophosphatemia. " "

" " ...prudent to advise female patients to avoid conception while on IM. The

management of women who do conceive while on IM is enigmatic, with some

specialists advocating a fine balance of the risks to both the mother and

the fetus versus the potential for a loss of response on discontinuing IM.

Parenthetically, it should be noted that since IM is secreted in breast

milk, breastfeeding is not recommended while on IM. " "

" " In the majority of patients studied, IM was associated with a decrease in

the production of testicular hormones, and in 7 patients gynecomastia was

noted " "

" " At present it appears reasonable to monitor TSH levels more frequently in

IM-treated patients on thyroid replacement. Moreover, based on the findings

of overt hypothyroidism secondary to the use of other TKIs, it would also be

prudent to monitor thyroid function in patients who exhibit symptoms of

hypothyroidism. " "

" " it has been speculated that these drugs will probably have an impact on

the immune responses of patients. Recently, investigators have reported a

range of effects, from hypogammaglobulinemia to a suppressive effect on T-

and NK-cell activation and cytotoxicity in vitro. " "

" " IM has also been speculated to reverse the inhibition of immune responses

to IM-resistant CML cells by Tregs. " "

" " Cutaneous reactions are probably TKI-class related and often seen in

patients with CML on IM. The precise incidence of rashes appears to be

around 35%, with most associated with pruritus " "

" " patients noted progressive repigmentation of scalp gray hair. " "

" " data from 27 patients who appeared to have developed interstitial lung

disease (ILD) while on IM therapy.61 The majority of these patients (23 of

27) either improved or had complete resolution of ILD with the

discontinuation of IM and the addition of low doses of short-term steroids.

" "

" " there was much speculation of the possible increase in the risk of

urothelial malignancies in a small cohort of patients subjected to

imatinib.61 Importantly, however, a much larger study of 9,000 patients

failed to confirm this suspicion. " "

" " About 5% of all patients with CML appear to develop mild (grade 1/2)

hepatotoxicity characterized by an abnormal bilirubin and transaminases

within the first 2 years of receiving IM. Serious hepatotoxicity (grade 3/4)

is, however, extremely rare. In all cases, the hepatic dysfunction appears

to be fully reversible with dose interruption/dose reduction " "

[Guest guest]

Very interesting. Not surprising that scientists are discovering additional side

effects from long term drug use. I am pretty sure that this is the case, even

with the most innocuous drugs.

It will be interesting to see the differences in long term side effects between

the different TKI's and whether we can modify the side effects by switching

drugs periodically (I know -scary, but so are some of the side effects from

long-term use)

Leah

>

> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010822/?tool=pubmed

>

>

>

> A good summary of the paper by my GIST friend, Marina Symcox.

>

>

>

> " " Most adverse effects occur within the first 2 years of starting therapy;

> however, late effects, many being unique, are now being recognized. " "

>

>

>

> " " The general consensus is that the majority of patients who develop

> cardiotoxicity, heart failure, and/or myocardial infarction are older

>

> (>65 years old) and have pre-existing cardiac risk factors or existing

> cardiac disease. While overt clinical heart failure may well be of rare

> incidence in patients taking IM, studies to access early signs of heart

> failure have been undertaken " "

>

>

>

> " " The longer term effects of IM therapy on bone remodelling have also been

> studied. ....The authors observed an increase in total bone volume along

> with a significant decrease in serum phosphate and calcium concentrations

> after extended IM therapy. They speculated that IM restrains bone resorption

> (by inhibiting c-Fms on osteoclasts) and stimulates bone formation (by

> inhibiting PDGF-R on osteoblasts), thus sequestrating both calcium and

> phosphate in bone. This can result in secondary hyperparathyroidism, which

> decreases renal phosphate absorption, leading to hypophosphatemia. " "

>

>

>

> " " ...prudent to advise female patients to avoid conception while on IM. The

> management of women who do conceive while on IM is enigmatic, with some

> specialists advocating a fine balance of the risks to both the mother and

> the fetus versus the potential for a loss of response on discontinuing IM.

> Parenthetically, it should be noted that since IM is secreted in breast

> milk, breastfeeding is not recommended while on IM. " "

>

>

>

> " " In the majority of patients studied, IM was associated with a decrease in

> the production of testicular hormones, and in 7 patients gynecomastia was

> noted " "

>

>

>

> " " At present it appears reasonable to monitor TSH levels more frequently in

> IM-treated patients on thyroid replacement. Moreover, based on the findings

> of overt hypothyroidism secondary to the use of other TKIs, it would also be

> prudent to monitor thyroid function in patients who exhibit symptoms of

> hypothyroidism. " "

>

>

>

> " " it has been speculated that these drugs will probably have an impact on

> the immune responses of patients. Recently, investigators have reported a

> range of effects, from hypogammaglobulinemia to a suppressive effect on T-

> and NK-cell activation and cytotoxicity in vitro. " "

>

>

>

> " " IM has also been speculated to reverse the inhibition of immune responses

> to IM-resistant CML cells by Tregs. " "

>

>

>

> " " Cutaneous reactions are probably TKI-class related and often seen in

> patients with CML on IM. The precise incidence of rashes appears to be

> around 35%, with most associated with pruritus " "

>

>

>

> " " patients noted progressive repigmentation of scalp gray hair. " "

>

>

>

> " " data from 27 patients who appeared to have developed interstitial lung

> disease (ILD) while on IM therapy.61 The majority of these patients (23 of

> 27) either improved or had complete resolution of ILD with the

> discontinuation of IM and the addition of low doses of short-term steroids.

> " "

>

>

>

> " " there was much speculation of the possible increase in the risk of

> urothelial malignancies in a small cohort of patients subjected to

>

> imatinib.61 Importantly, however, a much larger study of 9,000 patients

> failed to confirm this suspicion. " "

>

>

>

> " " About 5% of all patients with CML appear to develop mild (grade 1/2)

> hepatotoxicity characterized by an abnormal bilirubin and transaminases

> within the first 2 years of receiving IM. Serious hepatotoxicity (grade 3/4)

> is, however, extremely rare. In all cases, the hepatic dysfunction appears

> to be fully reversible with dose interruption/dose reduction " "

>

>

>

>

>

>