Again in agreement with Beppe and Tim with one thing for certain. I believe that dasatinib must be stopped at any dose. The PAH that is dasatinib associated does not respond well to the typical PAH therapies and the only thing I understand from the literature that may stabilize if not improve the situation is stopping. Otherwise, I think a switch in TKI if she loses is indicated and the suggestions given are very appropriate.


(original case repeated here for reader reference)
I have a 72 year old female patient who was diagnosed with CML in 1988. Treated with Interferon + Ara-C initially with complete cytogenetic remission. Cytogenetic relapse managed with interferon alone and continued IFN until July 2002. Fluctuating CCR-MCR. Started Imatinib 400 mg/d July 2002, achieved undetectable Q-PCR by January 2003. Considered for stopping trial in 2007 but not eligible due to occasional low level transcripts. Changed to Dasatinib 100mg/d July 2012 for cramps and periorbital odema on imatinib. Symptomatically very well apart from mild breathlessness on exertion, e.g. 200 metres uphill. Normal physical examination but echocardiogram shows mild moderate pulmonary hypertension, Pulmonary artery systolic pressure 48 mm/Hg but normal right ventricular size and function.

The BCR-ABL levels have been low but detectable for the past 4 years and that she has remained in an MR4.5 for at least the past 2 years.

Question:

a) Stop TKI therapy and monitor as for treatment cessation studies even though occasional low level +ve Q-PCR results.

OR

b) Continue dasatinib at lower dose 50mg/d considering already has a good response so lowering dose is not a risk if closely monitored and recent OPTIM study suggesting that many patients are effectively treated at lower doses. Check ECHOcardiogram in 2-3 months.

OR

c) Change to nilotinib. Minimal risk factors for cardiovascular disease. Borderline elevation of LDL cholesterol, hypertension controlled on antihypertensive medication, non-smoker, not obese or diabetic.


Any feedback is most welcome.

Regards
Chris Arthur

Hi Chris. I perfectly agree with your suggestions and with the observations of Tim. Try to stop. If the BCR-ABL increases above MMR level, restart with Nilotinib at a low leve,l 200 mg BID or maximum 300mg BID. Yours, Beppe

(original case repeated here for reader reference)
I have a 72 year old female patient who was diagnosed with CML in 1988. Treated with Interferon + Ara-C initially with complete cytogenetic remission. Cytogenetic relapse managed with interferon alone and continued IFN until July 2002. Fluctuating CCR-MCR. Started Imatinib 400 mg/d July 2002, achieved undetectable Q-PCR by January 2003. Considered for stopping trial in 2007 but not eligible due to occasional low level transcripts. Changed to Dasatinib 100mg/d July 2012 for cramps and periorbital odema on imatinib. Symptomatically very well apart from mild breathlessness on exertion, e.g. 200 metres uphill. Normal physical examination but echocardiogram shows mild moderate pulmonary hypertension, Pulmonary artery systolic pressure 48 mm/Hg but normal right ventricular size and function.

The BCR-ABL levels have been low but detectable for the past 4 years and that she has remained in an MR4.5 for at least the past 2 years.

Question:

a) Stop TKI therapy and monitor as for treatment cessation studies even though occasional low level +ve Q-PCR results.

OR

b) Continue dasatinib at lower dose 50mg/d considering already has a good response so lowering dose is not a risk if closely monitored and recent OPTIM study suggesting that many patients are effectively treated at lower doses. Check ECHOcardiogram in 2-3 months.

OR

c) Change to nilotinib. Minimal risk factors for cardiovascular disease. Borderline elevation of LDL cholesterol, hypertension controlled on antihypertensive medication, non-smoker, not obese or diabetic.


Any feedback is most welcome.

Regards
Chris Arthur

I would be nervous about the danger of progressive pulmonary arterial hypertension and would definitely cease dasatinib in this case. Although OPTIM suggested that dose modification in patients with high trough levels of dasatinib might reduce the incidence of pleural effusions I am not aware of any information about the relationship between dose and PAH. Since she has been in MR4.5 or thereabouts for several years it would be reasonable to cease TKI and watch closely (ideally with the patient enrolled in our withdrawal registry) with monthly PCR studies. I presume she has never been beyond chronic phase or developed mutations or acquired resistance. The French studies do suggest that absolute PCR negativity is not necessary for successful cessation. If she loses MMR after stopping I would then start another TKI - but not dasatinib, even at low dose.

Regards

Tim


(original case repeated here for reader reference)
I have a 72 year old female patient who was diagnosed with CML in 1988. Treated with Interferon + Ara-C initially with complete cytogenetic remission. Cytogenetic relapse managed with interferon alone and continued IFN until July 2002. Fluctuating CCR-MCR. Started Imatinib 400 mg/d July 2002, achieved undetectable Q-PCR by January 2003. Considered for stopping trial in 2007 but not eligible due to occasional low level transcripts. Changed to Dasatinib 100mg/d July 2012 for cramps and periorbital odema on imatinib. Symptomatically very well apart from mild breathlessness on exertion, e.g. 200 metres uphill. Normal physical examination but echocardiogram shows mild moderate pulmonary hypertension, Pulmonary artery systolic pressure 48 mm/Hg but normal right ventricular size and function.

The BCR-ABL levels have been low but detectable for the past 4 years and that she has remained in an MR4.5 for at least the past 2 years.

Question:

a) Stop TKI therapy and monitor as for treatment cessation studies even though occasional low level +ve Q-PCR results.

OR

b) Continue dasatinib at lower dose 50mg/d considering already has a good response so lowering dose is not a risk if closely monitored and recent OPTIM study suggesting that many patients are effectively treated at lower doses. Check ECHOcardiogram in 2-3 months.

OR

c) Change to nilotinib. Minimal risk factors for cardiovascular disease. Borderline elevation of LDL cholesterol, hypertension controlled on antihypertensive medication, non-smoker, not obese or diabetic.


Any feedback is most welcome.

Regards
Chris Arthur

I have a 72 year old female patient who was diagnosed with CML in 1988. Treated with Interferon + Ara-C initially with complete cytogenetic remission. Cytogenetic relapse managed with interferon alone and continued IFN until July 2002. Fluctuating CCR-MCR. Started Imatinib 400 mg/d July 2002, achieved undetectable Q-PCR by January 2003. Considered for stopping trial in 2007 but not eligible due to occasional low level transcripts. Changed to Dasatinib 100mg/d July 2012 for cramps and periorbital odema on imatinib. Symptomatically very well apart from mild breathlessness on exertion, e.g. 200 metres uphill. Normal physical examination but echocardiogram shows mild moderate pulmonary hypertension, Pulmonary artery systolic pressure 48 mm/Hg but normal right ventricular size and function.

The BCR-ABL levels have been low but detectable for the past 4 years and that she has remained in an MR4.5 for at least the past 2 years.

Question:

a) Stop TKI therapy and monitor as for treatment cessation studies even though occasional low level +ve Q-PCR results.

OR

b) Continue dasatinib at lower dose 50mg/d considering already has a good response so lowering dose is not a risk if closely monitored and recent OPTIM study suggesting that many patients are effectively treated at lower doses. Check ECHOcardiogram in 2-3 months.

OR

c) Change to nilotinib. Minimal risk factors for cardiovascular disease. Borderline elevation of LDL cholesterol, hypertension controlled on antihypertensive medication, non-smoker, not obese or diabetic.


Any feedback is most welcome.

Regards
Chris Arthur