Dear colleagues,

I have a question about an interesting patient:

Patient is a male, born April 3, 1959 who is diagnosed with a Ph-chromosome positive CML-CP1, Sokal score 1,4 (group C) in January 2005.
He was treated with imatinib but after one year he had a minor cytogenetic response.
In February 2006, he started with dasatinib (2 x 50 mg in a study) and developed pleural effusions from July 2010 onwards and for this reason dasatinib was stopped on Jan 13, 2013.
On February 2013 EKG was normal (including QT and QTc times) and patient started with nilotinib 2 x 300 mg daily. On February 27, 2013 his EKG was without abnormalities.
However, on June 7, 2013 patient suffered from an out of hospital cardiac arrest (ventricular fibrillation) and was successfully resuscitated by his wife and a neighbour. Nilotinib was stopped. Coronary angiography (CAG), echocardiography and MRI did not show significant abnormalities. QTc time was only once above 500 msec on June 10, 2013.
On June 20 an patient was given an implantable cardioverter defibrillator and was dismissed from the hospital in a very good clinical condition.
On July 10, 2013 he restarted with nilotinib (EKG was without abnormalities) and patient visited the outpatients clinic on July 12. He had some discomfort on his chest and the EKG was normal. However, patient was sent to the cardiologist and the first EKG he made was normal but patient developed ST elevations and CAG showed a total spasm of the left coronary artery without other abnormalities. There was no cardial damage.

My question is: how do I treat this patient? He visited my outpatient clinic today and was in perfect condition. PCR-Bcr/Abl was negative.
I think that he is not longer a candidate for TKI’s.

With many thanks and greetings,

Anton Schattenberg

This is a complicated clinical setting. I would not use nilotinib any longer on this patient. If the PCR is negative with adequate sensitivity (at least 4.5 logs) and has been so sustained for 2 years, considerations of permanent treatment discontinuation are appropriate with close monitoring particularly during the first 6 months. If not, I would consider using bosutinig that appears to have the least cardiac toxicity, with minimal to no QTc effect.

This case is truly challenging. I agree that Bosutinib is a good option. However, considering that we are running out of options for conservative management, the moment he starts Bosutinib, I would immediately begin the work-up for allo-SCT; counseling, patient and donor screening and HLA typing, etc.

This is a complex case for several reasons.
The cardiac issues you describe are probably a class effect and whether they will be seen with other medications such as BOS is uncertain. Although there is a black box warning with NIL, this can occur with all TKIs in theory. Similarly the pleural effusions seen with DAS could recur on BOS.
The patient will require very close observation. I would be sure that they are not taking any prescription or non-prescription meds, supplements, foods etc that may impact on the QTc. Depending what drugs are available to this patient, I would even raise the possibility of restarting DAS at a lower dose such as 50 od. The 034 study definitely did show that the frequency of pleural effusions was lower with once daily dosing, hence the 100 od choice.

This is definitely one of those confusing and difficult cases where it is hard to sort out what may be related and what may be another problem that this patient that is totally unrelated to either his CML or the therapy. I would start by asking a couple of basic questions. You say that he is pcr negative. For how long has this been and what is the sensitivity and reliability of the lab to which you send your samples? If he has been negative now for a couple of years and you have a solid lab with an assay sensitivity of at least 4.5 log (0.0032%IS), then there is a possibility that he may be able to come off therapy completely. I would only contemplate this option if you can repeat his pcr measurements monthly for at least the first year, etc using the monitoring standards established by the Mahon group in France. The questions becomes then, what if your measurement standards cannot meet the above or he recurs with his disease while off therapy, then what do you do? Your comments on no longer being a TKI candidate may be correct. QTc delays are likely a class effect, although only nilotinib received the black box warning requirement. The ischemic changes that you describe in the last event are vasospastic in nature and do not appear to have any connection to the vascular occlusive events described with nilotinib or more recently ponatinib therapy. Are they due to a TKI? I have little or no information to associate the coronary artery vasospasm with any TKI, let alone one in particular. Given two cardiac events however, my feeling would be to avoid nilotinib even if we cannot prove a cause and effect. Let me get back to the dasatinib experience. What was the best response here and did you ever try lowering the dose? If he did respond well and you never tried to persist at a low dose, he may be a candidate for reinitiating therapy at 50mg once daily, a dose that can still induce or in this case possibly sustain a response. The other alternative might be bosutinib if available, although again it is a TKI and its properties are somewhat akin to dasatinib in some ways. Pleural effusion incidence is not zero, but significantly lower. Use of dasatinib or bosutinib again, would obviously depend on your patient’s and your comfort in considering a TKI. If you deem a TKI to be out completely, then I think you have two options in the case of disease recurrence. I do not believe that interferon should be considered, as there have been reports of vasospastic disease, albeit not necessarily cardiac, in its use. This would leave either omacetaxine on a maintence schedule as he has in effect had induction. The other possibility is a stem cell allograft, problably using a reduced intensity regimen. He is still a young man and I do not think the cardiac issues are relevant. I hope this provides some food for thought and allows you to examine or re-examine for that matter, his options.

Thank you very much for your answer. Indeed, we have a solid lab with an assay sensitivity of at least 4.5 log (0.0032%IS). However, our patient has a low but not a longlasting “negative” signal.
Indeed, we have lowered the dasatinib dose to 40 mg daily and ultimately stopped dasatinib because pleural effusion remained (and disappeared after we stopped dasatinib).
We started bosutinib and until now, patient had a normal QTc time and no vasospasms.
Again, many thanks for your comment,
Sincerely yours,
Anton Schattenberg