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Alternative Mechanism for Treatment of Resistant CML

Insights From: Javier Pinilla-Ibarz, MD, PhD, Moffitt Cancer Center; Camille N. Abboud, MD, Washington University School of Medicine
Published: Monday, Jan 23, 2017


Transcript:

Javier Pinilla-Ibarz, MD, PhD:
When we treat patients with TKIs, tyrosine kinase inhibitors, sometimes these drugs don’t work. These are a relatively small percentage of patients, but sometimes after 1, 2, 3, or even 4 TKIs, we encounter the clinical situation where TKIs are not working anymore. These are the times that we really try to look for non-TKI alternatives, in this case, some other drugs that can have a completely different mechanism of action of the classical tyrosine kinase inhibition.

After switching to multiple tyrosine kinase inhibitors—in most of the cases for intolerance or even for resistance—there are certain situations where we need to discuss, with our patients, the possibility to switch the mechanism of action completely. In this case, the only alternative available for the treatment of chronic myeloid leukemia after treatment or intolerance of 2 TKIs is a drug called omacetaxine. It’s a chemotherapy drug that is being administered to our patients in a subcutaneous way and is able, in some cases of course, of controlling the disease in our patients.

Camille N. Abboud, MD: The mechanism of action of omacetaxine is unique in that this drug, which is approved for patients who are resistant to 2 or more TKIs, does not rely on binding to the BCR-ABL pocket to inhibit CML cells. But, omacetaxine is a protein translation inhibitor and it works by decreasing survival proteins that are essential for leukemic cells, such as MCL1 and certainly, the BCR-ABL1 protein. So, omacetaxine is ideal in patients who have developed mutations that affect the binding of the TKI to the action pocket of the BCR-ABL kinase, and therefore bypass that resistance.

More specifically, although not approved due to the lack of approval of a PCR test for T35I mutation, one of the most difficult mutations to treat in CML is T315I. And the only drug that’s FDA approved for that indication is ponatinib. That said, we do know from previous studies done with omacetaxine that it also can target these cells, and patients placed on omacetaxine over time can have a diminution in the T35I-positive cells. This occurs later in the course of disease and may be affected by multiple switches, which may be relying on either patient intolerance or patient’s lack of adherence to taking the TKI. This then opens the door for resistance mechanisms to become important and, in this case, the presence of a mutant clone, which is the T35I clone.

Omacetaxine is basically approved for any stage of CML: chronic phase, accelerated phase, and blast phase. The only requirement is that the patients have demonstrated resistance to 2 or more tyrosine kinase inhibitors. Omacetaxine is administered to patients subcutaneously, twice a day. These are prefilled syringes at the dose of 125 mg/m2. And, recently, it has been approved to be administered in the home. Patients learn to administer this drug twice a day. The scheduling is predicated on the activity of the omacetaxine inhibiting RNA synthesis. And, usually, the induction phase of the treatment is 2 injections a day for 2 weeks. Subsequently, the maintenance phase is usually twice a day for 7 days. Obviously, this drug has several side effects which, for the worst part, include pancytopenia. Monitoring of their hematologic parameters is very important to replace platelets or red cells and/or adjust the treatment if the white blood cell count drops to a low level.

Transcript Edited for Clarity
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Transcript:

Javier Pinilla-Ibarz, MD, PhD:
When we treat patients with TKIs, tyrosine kinase inhibitors, sometimes these drugs don’t work. These are a relatively small percentage of patients, but sometimes after 1, 2, 3, or even 4 TKIs, we encounter the clinical situation where TKIs are not working anymore. These are the times that we really try to look for non-TKI alternatives, in this case, some other drugs that can have a completely different mechanism of action of the classical tyrosine kinase inhibition.

After switching to multiple tyrosine kinase inhibitors—in most of the cases for intolerance or even for resistance—there are certain situations where we need to discuss, with our patients, the possibility to switch the mechanism of action completely. In this case, the only alternative available for the treatment of chronic myeloid leukemia after treatment or intolerance of 2 TKIs is a drug called omacetaxine. It’s a chemotherapy drug that is being administered to our patients in a subcutaneous way and is able, in some cases of course, of controlling the disease in our patients.

Camille N. Abboud, MD: The mechanism of action of omacetaxine is unique in that this drug, which is approved for patients who are resistant to 2 or more TKIs, does not rely on binding to the BCR-ABL pocket to inhibit CML cells. But, omacetaxine is a protein translation inhibitor and it works by decreasing survival proteins that are essential for leukemic cells, such as MCL1 and certainly, the BCR-ABL1 protein. So, omacetaxine is ideal in patients who have developed mutations that affect the binding of the TKI to the action pocket of the BCR-ABL kinase, and therefore bypass that resistance.

More specifically, although not approved due to the lack of approval of a PCR test for T35I mutation, one of the most difficult mutations to treat in CML is T315I. And the only drug that’s FDA approved for that indication is ponatinib. That said, we do know from previous studies done with omacetaxine that it also can target these cells, and patients placed on omacetaxine over time can have a diminution in the T35I-positive cells. This occurs later in the course of disease and may be affected by multiple switches, which may be relying on either patient intolerance or patient’s lack of adherence to taking the TKI. This then opens the door for resistance mechanisms to become important and, in this case, the presence of a mutant clone, which is the T35I clone.

Omacetaxine is basically approved for any stage of CML: chronic phase, accelerated phase, and blast phase. The only requirement is that the patients have demonstrated resistance to 2 or more tyrosine kinase inhibitors. Omacetaxine is administered to patients subcutaneously, twice a day. These are prefilled syringes at the dose of 125 mg/m2. And, recently, it has been approved to be administered in the home. Patients learn to administer this drug twice a day. The scheduling is predicated on the activity of the omacetaxine inhibiting RNA synthesis. And, usually, the induction phase of the treatment is 2 injections a day for 2 weeks. Subsequently, the maintenance phase is usually twice a day for 7 days. Obviously, this drug has several side effects which, for the worst part, include pancytopenia. Monitoring of their hematologic parameters is very important to replace platelets or red cells and/or adjust the treatment if the white blood cell count drops to a low level.

Transcript Edited for Clarity
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