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Defining Suboptimal Response to BCR-ABL TKI Therapy in CML

Insights From: Javier Pinilla-Ibarz, MD, PhD, Moffitt Cancer Center; Camille N. Abboud, MD, Washington University School of Medicine
Published: Friday, Jan 20, 2017


Transcript:

Javier Pinilla-Ibarz, MD, PhD:
In order to identify suboptimal response to TKI (tyrosine kinase inhibitor) therapies these days, we really follow the NCCN guidelines. There are very specific recommendations about the milestones that patients need to achieve, at certain times, to be able to have very good outcomes at the end. At 3 months, 6 months, and 12 months, patients need to be at specific PCR levels or cytogenetic levels. And, at this point, although there are not many, there is a proportion of patients who still cannot achieve these milestones, for whom we do recommend to switch therapies. Most of the times, we recommend to switch to another TKI, sometimes from a first-generation to a second-generation TKI. But, of course, we have many of them. However, because sometimes patients are resistant to multiple of these TKIs or are even intolerant—more frequent is resistant—we have to try to find known TKI therapies that can solve this problem with these patients.

Camille N. Abboud, MD: There are many patient characteristics that prompt a switch in tyrosine kinase inhibitors, or TKIs, and they are predictable by the choice of the tyrosine kinase inhibitor used. For example, imatinib mesylate, which was the first TKI to be tested in CML, was found to be very effective, but its main side effect was edema and some GI toxicity, which, in rare cases, caused abnormal liver function tests and some diarrhea that led patients to switch.

Later on, nilotinib was tested as a second-generation TKI along with dasatinib, the latter being an Src inhibitor, and their spectrum of complications or intolerance is different. With nilotinib, it’s pancreatitis, liver function abnormalities, and worsening of diabetes. Whereas, with dasatinib, and later on, bosutinib, a more narrow Src inhibitor, the side effects were fluid accumulation, especially pleural effusion. Later observations have also found that there are late complications, such as cardiovascular complications, with certain TKIs, and some of these include arterial thrombosis in the case of nilotinib, and pulmonary hypertension and other events with dasatinib.

The last TKI that I did not mention is ponatinib, which has the greatest amount of side effects on the cardiovascular side. And most TKIs are also associated with hypertension. So, again, you have to individualize each case when you decide to switch. In my experience, patients later tend to switch, also, if they have dark skin and they find lightening of the skin, because the c-KIT inhibitor TKIs—imatinib, bosutinib, and nilotinib—are able to inhibit c-KIT and inhibit melanocyte production in the skin.

Transcript Edited for Clarity
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Transcript:

Javier Pinilla-Ibarz, MD, PhD:
In order to identify suboptimal response to TKI (tyrosine kinase inhibitor) therapies these days, we really follow the NCCN guidelines. There are very specific recommendations about the milestones that patients need to achieve, at certain times, to be able to have very good outcomes at the end. At 3 months, 6 months, and 12 months, patients need to be at specific PCR levels or cytogenetic levels. And, at this point, although there are not many, there is a proportion of patients who still cannot achieve these milestones, for whom we do recommend to switch therapies. Most of the times, we recommend to switch to another TKI, sometimes from a first-generation to a second-generation TKI. But, of course, we have many of them. However, because sometimes patients are resistant to multiple of these TKIs or are even intolerant—more frequent is resistant—we have to try to find known TKI therapies that can solve this problem with these patients.

Camille N. Abboud, MD: There are many patient characteristics that prompt a switch in tyrosine kinase inhibitors, or TKIs, and they are predictable by the choice of the tyrosine kinase inhibitor used. For example, imatinib mesylate, which was the first TKI to be tested in CML, was found to be very effective, but its main side effect was edema and some GI toxicity, which, in rare cases, caused abnormal liver function tests and some diarrhea that led patients to switch.

Later on, nilotinib was tested as a second-generation TKI along with dasatinib, the latter being an Src inhibitor, and their spectrum of complications or intolerance is different. With nilotinib, it’s pancreatitis, liver function abnormalities, and worsening of diabetes. Whereas, with dasatinib, and later on, bosutinib, a more narrow Src inhibitor, the side effects were fluid accumulation, especially pleural effusion. Later observations have also found that there are late complications, such as cardiovascular complications, with certain TKIs, and some of these include arterial thrombosis in the case of nilotinib, and pulmonary hypertension and other events with dasatinib.

The last TKI that I did not mention is ponatinib, which has the greatest amount of side effects on the cardiovascular side. And most TKIs are also associated with hypertension. So, again, you have to individualize each case when you decide to switch. In my experience, patients later tend to switch, also, if they have dark skin and they find lightening of the skin, because the c-KIT inhibitor TKIs—imatinib, bosutinib, and nilotinib—are able to inhibit c-KIT and inhibit melanocyte production in the skin.

Transcript Edited for Clarity
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