Tyrosine kinase inhibitors in the treatment of mast cell diseases

Author’s note: The following post is my personal opinion and is based upon publicly available information and not upon any confidential information I have obtained as a result of my job. The ideas described below are directly attributable to me and not to my employer. I am not a medical doctor and this is not medical advice. This information should be used only to better inform yourself prior to speaking with your provider.

Tyrosine kinase inhibitors have been described in literature for over thirty years. The first tyrosine kinase inhibitor, imatinib, was approved by the FDA in 2001. Because it was the first effective therapy known for a fatal disease, chronic myelogenous leukemia, it was fast tracked through the FDA approval process and approved in two and a half months. In the years that followed, newer tyrosine kinase inhibitors were developed by various pharma organizations. The indications for these therapies expanded from CML to include several other diseases, including certain forms of systemic mastocytosis.

Tyrosine kinase inhibitors were developed with the intention of reducing the toxicity seen in older chemotherapy medications. They do this by targeting specific structures on diseased cells. For example, patients with chronic myelogenous leukemia have a genetic abnormality called the Philadelphia chromosome. This is the result of pieces of DNA getting switched around so that genes that aren’t normally next to each other end up stuck together. This forms a gene called BCRABL that tells cells to continually make new cells even when they aren’t needed. Imatinib targets BCRABL. The idea is that only the cancer cells have BCRABL so healthy cells wouldn’t be damaged.

In reality, it’s a lot more complicated than that. The biggest reason for this is that even though healthy cells don’t have BCRABL, they have other things that look like BCRABL. This is actually why imatinib can treat some cases of systemic mastocytosis: CKIT looks like BCRABL. And there are plenty of other proteins on plenty of other cells, some healthy cells, some diseased cells, that look like BCRABL or CKIT. This means that while tyrosine kinase inhibitors are much more targeted than older forms of chemotherapy, they aren’t so targeted that healthy cells don’t incur any damage at all. Sometimes that damage is serious. Sometimes it is irreversible.

In the mast cell sphere, imatinib was originally used for cases of aggressive systemic mastocytosis that did not have the CKIT D816V mutation. Over time, it was also used for other forms of systemic mastocytosis, including mast cell leukemia, systemic mastocytosis with associated hematologic neoplasm, and smoldering systemic mastocytosis. While imatinib was approved for use in people without the CKIT D816V mutation, there were trials on SM patients who did have the mutation. Published reports found it was less effective but did give benefit to some patients with the mutation. To be clear, the published data strongly points to imatinib being more effective in people without the CKIT mutation than in those that do. But there is some evidence that imatinib might have benefit even if you have the mutation.

I sometimes see people telling other patients that it is dangerous to use imatinib if you have the CKIT mutation. The danger for these people is that it might not work well for them. There’s no special risk beyond that. In fact, the current FDA licensing for imatinib is for patients without the CKIT D816V mutation OR patients in whom CKIT status is unknown. This means that sometimes people are put on it without genetic testing so it’s possible that some of the patients have the mutation.

I want to be so, so super clear about the next thing I say because it is so important that people know this. Imatinib, and other tyrosine kinase inhibitors, are chemotherapies. They are licensed as antineoplastic therapies, also known as chemotherapies. When it’s shipped to your house, it arrives there with the label “contains chemotherapy drugs” on the package. Patients taking it are supposed to be consented for chemotherapy so that they fully understand the risks. TKIs are, for sure, kinder, gentler, more targeted chemo drugs. But they are chemo. And they carry a lot of risks associated with chemotherapy.

I have seen patients describe these drugs as “extremely safe”, “harmless”, “unable to damage other cells”, or even “unable to kill cells.” Those ideas are patently false. These medications are not benign. They are serious. They can cause organ damage, especially liver damage. They can suppress bone marrow, resulting in low blood cell counts. They can cause clotting issues. They most certainly can damage other cells and kill cells, targeted and otherwise. There are hundreds of references describing the ways TKIs can do this, mostly by inducing apoptosis, making a cell kill itself. All of this information is publicly available.

The very fact that TKIs are chemo agents and can cause many of the associated issues is the reason why use of TKIs is controversial in the mast cell community. A lot of people believe that use of TKIs is only warranted in the aggressive forms of systemic mastocytosis that can cause organ damage and death. But there is another school of thought that posits that TKIs are appropriate for indolent SM and MCAS, specifically for cases where anaphylaxis is frequent and severe. They argue that these cases present enough risk to life that the benefits outweigh the risks. Still another group feels that TKIs are safe enough to use for control of non life threatening symptoms in patients with indolent SM and MCAS.

It is my personal opinion that there is benefit to trialing TKIs in patients with indolent SM and MCAS for whom disability or risk to life is significant. I think that you have a right to try unproven therapies when your life is at stake. But I also think that because of the risks, they should only be used when more conservative therapies have failed. The sole fact that they are chemo drugs shouldn’t preclude TKIs from consideration for severe cases of MCAS and ISM. Chemo drugs are prescribed in low doses to treat dozens of conditions, especially immune mediated disorders like autoimmune diseases. But I do think they should be a last resort. I do not personally feel that TKIs are appropriate for general symptom management in non life threatening cases.

My opinion can be summed up pretty cleanly as this: these drugs are serious and they should be reserved for serious cases until such time as we have actual data on how TKIs affect these patients. We need studies, not a handful of case reports, to really understand the risks for MCAS and ISM patients using these therapies. But when other treatments fail and there is risk to life, I think it is appropriate to consider TKIs in these populations.