Combining and Sequencing BCR-ABL TKIs with Omacetaxine in CML

Transcript:Javier Pinilla-Ibarz, MD, PhD: The use of omacetaxine in combination with tyrosine kinase inhibitors early in the disease is not a common practice. It’s because most of the tyrosine kinase inhibitors are really effective in the frontline or even in the second line. However, in more advanced phases of the disease, such as an accelerated phase or even after multiple TKI failures, there are not really specific data about that. But, in an anecdotal way, it’s been described in the literature, and I have my own experience, to combine these 2 drugs. However, once again, there is not really a very common form of therapy, nor is there really a clinical trial to support this management.

There is no specific rationale to combine a tyrosine kinase inhibitor with omacetaxine. However, there are anecdotal data published in the literature in the form of a case report, and even my own experience within certain instances, where there is no other alternative for therapy, or the TKIs are not really good enough to control the disease. Combination of these 2 forms of therapies, tyrosine kinase and omacetaxine, show some benefit for patients. Once again, there is no formal clinical trial conducted, but there is anecdotal experience in the literature and in my own practice.

Camille N. Abboud, MD: The combination of omacetaxine with a TKI earlier in the phase of treatment is an interesting question. I’ve not personally used that, but I’m aware of reports where the combination of a second-generation TKI, such as nilotinib, led to more effective hematologic response and eventually disappearance of the BCR-ABL transcript. In that particular case report, the investigator noted that the patient had the T35I mutation, which disappeared fairly promptly after omacetaxine induction therapy, suggesting that, in this case, the omacetaxine was very effective at deleting or removing this very-hard-to-treat mutation. And later on, because the patients failed to attain a hematologic response, the nilotinib was added to the continued omacetaxine treatment, and the combination of both led to a complete hematologic remission, as well as disappearance of the T35I clone.

The rationale for combining omacetaxine with a second-generation tyrosine kinase inhibitor, especially in patients who are resistant to imatinib, is a very interesting one because it’s well known that those patients who failed to respond to first-generation imatinib mesylate can have the potential of having reduced survival and higher incidence of blast crisis transformation. It’s also well known that the combination leads to more efficacy of the RNA inhibitor because the TKI—in this case, nilotinib or even the imatinib before it—opens up the RNA and allows the omacetaxine to be more effective. So, you’re getting a synergy from the standpoint of inhibiting translation. Even if the second-generation TKI is not totally active by itself in these patients who have failed to respond to imatinib mesylate, the combination still remains a more powerful tool, and obviously is an area that should be studied further.

Javier Pinilla-Ibarz, MD, PhD: The use of omacetaxine to deepen the molecular response of patients on a TKI is a subject of investigation. However, it’s a very tough area of investigation because most of these patients really have not reached very deep levels of response. They’re really tolerating the drugs and they’re doing relatively well. The introduction of a subcutaneous therapy in this way—chemotherapy in the subcutaneous administration—is a really hard decision for patients and doctors to make. So, it still is a research question that has not been validated in any clinical trial.

Camille N. Abboud, MD: The question is aimed at identifying whether re-challenging the second-generation TKI is a useful action after treatment with omacetaxine in patients who have the T35I mutation. I would quickly point out that most practitioners would use ponatinib, which is FDA approved for this mutation, and it’s quite active. In the case of the patient that we discussed earlier, that patient had developed endocarditis, which was related to his accelerated phase CML, and had arterial thrombi. So, I was very hesitant to use ponatinib, which has severe cardiovascular and thrombotic side effects. In that case, the use of omacetaxine with imatinib mesylate or another TKI becomes a very rational endeavor and a more effective one. Whether or not this will lead to complete molecular remission and durable responses is unknown at this time.

Transcript Edited for Clarity