I would be very grateful if you could give some advice on management of a man, aged 50 yo. With 10 years of evolution of CML in chronic phase. Treated with Gleevec 400 mg / day, which remained in molecular response around 0.0005% for 3 years and then slowly begins to lose the response coming in two years to 0.9%. The patient denies abandoning or irregular compliance with Gleevec, he does not receive other drugs, we find no resistance mutations.
We increased the Gleevec at 800 mg / day and he presented an anaphylactic shock to lidocaine used for cytogenetic study. It was a mild kidney failure. Gleevec was restarted a month and he presented a severe pericardial effusion and bilateral pleural effusion. The pericardial biopsy showed inflammatory changes with no evidence of malignancy. The remaining studies showed no other pathology. Mutational study remains negative and current molecular response is 0.7%.

The question is how to continue the treatment. We maintain Gleevec, we switched by Nilotinib? Dasatinib does not seem good option for the effusions. We only have these three ITK in our country.

Thank you very much for your suggestions.
Dr. Ana-Inés Prado. Uruguay.

Dear Ana-Ines,
At the moment it is difficult to understand the reason for the MMR loss in this patient who had an optimal response for s many years. Although the BCR-ABL level for the moment does not suggest a CCyR loss, due also to the concomitant observations of AEs whose relationship with the imatinib assumption is unclear, but possible, I would switch this patient to nilotinib at the dosage of 300 BID and I would monitor closely both the response and the clinical behaviour.

(original case repeated here for reader reference)...I would be very grateful if you could give some advice on management of a man, aged 50 yo. With 10 years of evolution of CML in chronic phase. Treated with Gleevec 400 mg / day, which remained in molecular response around 0.0005% for 3 years and then slowly begins to lose the response coming in two years to 0.9%. The patient denies abandoning or irregular compliance with Gleevec, he does not receive other drugs, we find no resistance mutations.
We increased the Gleevec at 800 mg / day and he presented an anaphylactic shock to lidocaine used for cytogenetic study. It was a mild kidney failure. Gleevec was restarted a month and he presented a severe pericardial effusion and bilateral pleural effusion. The pericardial biopsy showed inflammatory changes with no evidence of malignancy. The remaining studies showed no other pathology. Mutational study remains negative and current molecular response is 0.7%.

The question is how to continue the treatment. We maintain Gleevec, we switched by Nilotinib? Dasatinib does not seem good option for the effusions. We only have these three ITK in our country.

Thank you very much for your suggestions.
Dr. Ana-Inés Prado. Uruguay.



Comments:
Dear Ana-Ines,

This is a very interesting case. The patient has done very well till now, the basis for the loss of molecular remission is difficult to explain, especially in the absence of any mutant clones. Out of curiosity, you may check the plasma levels of imatinib if available. Nilotinib is worth trying as suggested .

Kind regards.

Muheez Durosinmi

This is a very unusual case and is difficult to understand. As you point out, compliance is a big issue and is probably the most common cause for this profoundly rare event. To the best of your ability, you have ruled this out. Other causes are drug interactions which you have ruled out. Other things to consider include whether the patient has changed his medication without or with his knowledge. Is he actually taking Gleevec or is there a chance that a less than active generic has been used? I do not understand the late development of the effusions or the cause. Has he developed another disease that may be impacting on things like drug absorption? Can you check levels of imatinib? Effusions have been reported rarely for imatinib even with the original studies, but there must have been a trigger here. Has heart failure been rule out?
Have you looked for other reasons for resistance beyond mutations. Specifically has a bone marrow been done with repeat cytogenetics to rule out very rare clonal progression?
Regardless of the cause, your choices are limited. I would hold therapy and try to get rid of the effusions with diuretic +/- steroid. When this settles down in a few weeks, then I would choose nilotinib as you suggest. The effusions make the use of dasatinib less appropriate. If however, the patient has heart failure, this will need to be controlled as any of the TKIs to which you have access, can worsen this.
Good luck and please keep us updated on your outcomes.



(original case repeated here for reader reference)...I would be very grateful if you could give some advice on management of a man, aged 50 yo. With 10 years of evolution of CML in chronic phase. Treated with Gleevec 400 mg / day, which remained in molecular response around 0.0005% for 3 years and then slowly begins to lose the response coming in two years to 0.9%. The patient denies abandoning or irregular compliance with Gleevec, he does not receive other drugs, we find no resistance mutations.
We increased the Gleevec at 800 mg / day and he presented an anaphylactic shock to lidocaine used for cytogenetic study. It was a mild kidney failure. Gleevec was restarted a month and he presented a severe pericardial effusion and bilateral pleural effusion. The pericardial biopsy showed inflammatory changes with no evidence of malignancy. The remaining studies showed no other pathology. Mutational study remains negative and current molecular response is 0.7%.

The question is how to continue the treatment. We maintain Gleevec, we switched by Nilotinib? Dasatinib does not seem good option for the effusions. We only have these three ITK in our country.

Thank you very much for your suggestions.
Dr. Ana-Inés Prado. Uruguay.

Thank you very much everyone for your opinions.
Regarding your questions: we do not have blood Imatinib dosage.
The patient always received the original Gleevec.
We all agree that we can not establish a link between Imatinib and effusions. We discarded neoplasms, heart failure, concomitant infections.
The patient receives only Imatinib. He did not consume illegal drugs or herbal medicines.

Kind regards.
Dr. Ana-Inés Prado

(original case repeated here for reader reference)...I would be very grateful if you could give some advice on management of a man, aged 50 yo. With 10 years of evolution of CML in chronic phase. Treated with Gleevec 400 mg / day, which remained in molecular response around 0.0005% for 3 years and then slowly begins to lose the response coming in two years to 0.9%. The patient denies abandoning or irregular compliance with Gleevec, he does not receive other drugs, we find no resistance mutations.
We increased the Gleevec at 800 mg / day and he presented an anaphylactic shock to lidocaine used for cytogenetic study. It was a mild kidney failure. Gleevec was restarted a month and he presented a severe pericardial effusion and bilateral pleural effusion. The pericardial biopsy showed inflammatory changes with no evidence of malignancy. The remaining studies showed no other pathology. Mutational study remains negative and current molecular response is 0.7%.

The question is how to continue the treatment. We maintain Gleevec, we switched by Nilotinib? Dasatinib does not seem good option for the effusions. We only have these three ITK in our country.

Thank you very much for your suggestions.
Dr. Ana-Inés Prado. Uruguay.