The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 83

96. Why are cancer drugs used to treat mast cell disease?

Disclaimer: The following post was written by me in my capacity as a subject matter expert in mast cell disease and author of MastAttack. This is not work product of my position as a Senior Scientist for a large research organization. All below statements are attributable directly to me in my role as author of MastAttack and are in no way attributable to my employer. Information presented here is publicly available and includes no confidential information learned in my capacity as a Senior Scientist for my employer.

  • There are a number of medications used to treat cancers that are also used to treat mast cell disease. Some of those medications are old school chemotherapies, some are newer, targeted chemotherapies, and some help to control the immune system.
  • In mastocytosis, the body makes too many mast cells. If the bone marrow makes way, way too many mast cells, and those mast cells don’t function correctly, the mast cells can act like cancer cells. This can cause the mastocytosis to behave like cancer.
  • Systemic mastocytosis has several subtypes. The least serious forms do not act like cancer.
  • Indolent systemic mastocytosis (ISM) is the least severe form of systemic mastocytosis. ISM has a normal lifespan. While patients with ISM are at risk of dying for anaphylaxis, an important distinction is that patients with ISM do not die because the mast cell disease acts like a cancer. ISM does not act like cancer.
  • Smoldering systemic mastocytosis (SSM) is a moderately serious form of systemic mastocytosis. SSM can shorten lifespan. In SSM, the body is starting to make lots more mast cells than it should. Those mast cells can affect how organs function. SSM acts like an early cancer.
  • SSM requires treatment to stop it from becoming a more serious form of mastocytosis called aggressive systemic mastocytosis (ASM) that acts like a serious cancer. The treatments used to manage SSM are also used in some cancer patients to help fight cancer. These include meds that affect your immune system, like interferon; newer targeted therapies and chemos, like tyrosine kinase inhibitors; and older chemo drugs, like cladribine.
  • Aggressive systemic mastocytosis (ASM) is a serious form of systemic mastocytosis. ASM shortens lifespan significantly. In ASM, the body makes way too many mast cells. The bone marrow churns out so many mast cells into the bloodstream and then the abnormal mast cells get stuffed into various organs. The mast cells cause organ damage and can cause organ failure. ASM is often referred to as being malignant because it behaves just like a cancer. It is also treated like a cancer.
  • As mentioned above, interferon is a therapy that can affect how the immune system works. Interferon is sometimes used for ASM but it is less commonly used in ASM than in SSM. ASM patients need more aggressive treatment. Newer targeted therapies like tyrosine kinase inhibitors and multitarget kinase inhibitors are frequently used in ASM. Some of these newer therapies are FDA approved for treating some ASM patients. Cladribine and hydroxyurea are still common treatments for ASM.
  • Mast cell leukemia (MCL) is the most serious form of systemic mastocytosis. MCL greatly reduces lifespan. MCL causes production of an unbelievable number of mast cells. There are so many mast cells that they cannot all get stuffed into organs like ASM. This means that while there are lots of mast cells in the organs in MCL patients, there are so many mast cells like that there are still tons of them in the bloodstream. This leads to rapid organ failure, leading to death. Mast cell leukemia is cancer. It is treated like cancer with newer therapies like tyrosine kinase inhibitors and multitarget kinase inhibitors, as well as hydroxyurea or cladribine in some cases. As in ASM, some of the newer therapies are FDA approved to treat mast cell leukemia.
  • Sometimes patients with systemic mastocytosis develop a second blood disorder. This is called systemic mastocytosis with associated hematologic disease. Sometimes this second blood disorder is a form of cancer, like chronic myeloid leukemia. In these instances, the other blood disorder would be treated using cancer medications.
  • Mast cell sarcoma (MCS) is a cancerous form of systemic mastocytosis. Patients with MCS rapidly develop MCL and are treated as described above.
  • None of the therapies I mentioned here are indicated for cutaneous mastocytosis. Cutaneous mastocytosis does not behave like a cancer and is not treated like one.
  • In recent years, two other forms of mast cell disease have been described: mast cell activation syndrome and monoclonal mast cell activation syndrome.
  • Monoclonal mast cell activation syndrome (MMAS) is often considered to be a “pre-SM”. It is treated like indolent systemic mastocytosis and does not behave like a cancer.
  • Mast cell activation syndrome (MCAS) is not know to be an early form of SM. Many people live with MCAS for decades without ever developing SM.
  • Despite the fact that mast cell activation syndrome, monoclonal mast cell activation syndrome, and indolent systemic mastocytosis do not behave like cancer, cancer therapies are sometimes used in these patients. They are used when other therapies have failed and their symptoms are still poorly controlled. Generally, they are used when persistent mast cell activation becomes life threatening. In some instances, they may be used when a patient’s symptoms are not life threatening but are very disabling and cause a poor quality of life. In these cases, the patient and their provider make the assessment that they are able to assume the risk of using these medications.
  • There is very little data on the use of chemo and targeted therapies in patients with MCAS, MMAS and ISM, and no cancer therapies are FDA approved for these conditions. However, use of cancer meds for nonmalignant conditions is not that unusual. It is pretty common in autoimmune disease where lower doses of chemotherapy drugs can be effective in controlling the disease. Basically, the idea is that if we know that these therapies help forms of mast cell disease that behave like cancers then it might help those forms that don’t act like cancer.
  • On a number of occasions, I have seen patients discussing the dangers around certain cancer meds that are sometimes used to treat mast cell disease. In particular, I have seen comments that newer targeted therapies “do not kill cells”, “cannot cause organ damage”, and are “harmless.” This is completely untrue. There are thousands of articles on the side effects and complications of all of the meds I have described here. None of them are harmless. Patients need to understand the risks associated with these therapies.
  • I would like to add a note about something sort of related. Xolair is an anti-IgE medication that is used by many mast cell patients. It is a subcutaneous injection and is administered in a healthcare setting. Patients are required to stay in the office for a little while after the shots are given to be sure that they don’t have a bad reaction. Because the patient is monitored in the office after the shot, the provider’s office will bill insurance for the observation period. The old billing code for this often comes up as “chemotherapy observation” because the same code was used for patients who needed monitoring after chemo. This means that patients may see “chemo” on the explanation of benefits from their insurance company. This does not mean that they received chemo. Xolair is NOT chemotherapy. It’s just a quirk of the medical billing. There is now a new code for post injection observation for meds that are not chemo but not everyone has caught up to it. Just figured I would mention this as people ask about it from time to time.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 76

I get asked a lot about how mast cell disease can affect common blood test results. I have broken this question up into several more manageable pieces so I can thoroughly discuss the reasons for this. The next few 107 series posts will cover how mast cell disease can affect red blood cell count; white blood cell count, including the counts of specific types of white blood cells; platelet counts; liver function tests; kidney function tests; electrolytes; clotting tests; and a few miscellaneous tests.

89. How does mast cell disease affect platelet counts?

Before I continue, I want to explain one basic fact. Even though they are often included in the term “blood cells”, platelets are not actually cells. They are actually pieces of an original large cell called a megakaryocyte that lives in the bone marrow. Even though platelets are not really cells, they more or less act like they are.

An unusual thing about platelets is that sometimes a specific trigger can cause platelets to become lower or higher.

There are several ways in which mast cell disease can make platelet counts lower.

  • Swelling of the spleen. This can happen in some forms of systemic mastocytosis, and may also happen in some patients with mast cell activation syndrome, although the reason why it happens in MCAS is not as clear. Swelling of the spleen can damage blood cells and platelets, causing lower platelet counts. If the spleen is very stressed and working much too hard, a condition called hypersplenism, the damage to blood cells and platelets is much more pronounced. This may further lower platelet counts. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Medications. Some medications that are used to manage mast cell disease can cause low red blood cell count. Chemotherapies, including targeted chemotherapies like tyrosine kinase inhibitors, can cause low platelet counts. Non steroidal anti-inflammatory drugs (NSAIDs) are used by some mast cell patients to decrease production of prostaglandins. They can interfere with platelet production in the bone marrow. Proton pump inhibitors, often used by mast cell patients to help with GI symptoms like heart burn, can decrease platelet coun Some H2 antihistamines can also lower platelet production. However, none of these H2 antihistamines are currently used in medicine.
  • Heparin induced thrombocytopenia. Mast cells make and release large amounts of heparin, a powerful blood thinner. When there is an excessive amount of heparin circulating, it can cause your body to incorrectly produce antibodies that cause an immune response to heparin. A side effect of this situation is that platelets are activated incorrectly, which can lead to the formation of blood clots and low platelet counts. Heparin induced thrombocytopenia has only been definitively described in patients who receive medicinal heparin as a blood thinner. However, it is reasonable to assume that this situation can also affect mast cell patients who have higher than normal levels of platelets circulating in the blood.
  • Liver damage. Liver damage is associated with malignant forms of systemic mastocytosis such as aggressive systemic mastocytosis and mast cell leukemia. Liver damage can also occur as the result of IV nutrition, which is sometimes needed by patients with mastocytosis or mast cell activation syndrome. When the liver is damaged enough, it may not make enough of the molecules that tell the bone marrow to make platelets.
  • Excessive production of blood cells. In very aggressive forms of systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia, the bone marrow is making huge amounts of mast cells. As a result, the bone marrow makes fewer platelets and cells of other types.
  • Vitamin and mineral deficiencies. Chronic inflammation can affect the way your body absorbs vitamins and minerals through the GI tract, and the way it uses vitamins and minerals that it does absorb. Deficiency of vitamin B12 or folate can decrease platelet production.
  • Excess fluid in the bloodstream (hypervolemia). In this situation, the body doesn’t actually have too few platelets, it just looks like it. If your body loses a lot of fluid to swelling (third spacing) and that fluid is mostly reabsorbed at once, the extra fluid in the bloodstream can make it look like there are too few platelets if they do a blood test. This can also happen if a patient receives a lot of IV fluids.

There are also reasons why mast cell disease can cause the body to make too many platelets.

  • Anemia of chronic inflammation. This is when chronic inflammation in the body affects the way the body absorbs and uses iron. It can result in iron deficiency. Iron deficiency can increase platelet counts.
  • Hemolytic anemia. In hemolytic anemia, the body destroys red blood cells. This can happen for several reasons that may be present in mast cell patients. Hemolytic anemia can increase platelet counts.
  • Iron deficiency. Iron deficiency for any reason can elevate platelet counts.
  • Excessive bleeding. Mast cell disease can cause excessive bleeding in several ways. Mast cells release lots of heparin, a very potent blood thinner that decreases clotting. This makes it easier for the body to bleed. It is not unusual for mast cell patients to have unusual bruising. Bleeding in the GI tract can also occur. Mast cell disease can cause ulceration, fissures, and hemorrhoids, among other things. Mast cell disease can contribute to dysregulation of the menstrual cycle, causing excessive bleeding in this way. It is not unusual for mast cell patients to have GI bleeding, as well as ulceration, fissures, and hemorrhoids.
  • Sustained GI inflammation. Sustained GI inflammatory disease can cause elevated levels of platelets. Given what we know about mast cell driven GI inflammation, it is reasonable to infer that mast cell GI effects and damage may also elevate platelet levels.
  • Clot formation. If a large clot forms, it can affect the amount of platelets circulating in the blood. Some mast cell patients require central lines for regular use of IV therapies or to preserve IV access in the event of an emergency. Blood clots can form on the outside surface of the line, inside the line, or between the line and the wall of the blood vessel it is in.
  • General inflammation. Platelets are activated by a variety of molecules released when the body is inflamed for any reason. This can translate to increased levels of platelet production.
  • Allergic reactions. Platelets can be directly activated by mast cell degranulation through molecules like platelet activating factor (PAF).
  • Heparin. Heparin can cause platelet levels to increase. As I mentioned above, it can also cause platelet levels to decrease.
  • Removal of the spleen. The spleen can become very stressed and work too hard, a condition called This situation is remedied by removing the spleen. Hypersplenism occurs in aggressive systemic mastocytosis or mast cell leukemia. It is not a feature of other forms of systemic mastocytosis and I am not aware of any cases as a result of mast cell activation syndrome.
  • Glucocorticoids. In particular, prednisone is known to increase platelet counts. Prednisone and other glucocorticoids can be used for several reasons in mast cell patients.
  • Third spacing. If a lot of fluid from the bloodstream becomes trapped in tissues (third spacing), there is less fluid in the bloodstream so it makes it look like there are too many cells. As I mentioned above, this is not really a scenario where you are making too many red blood cells, it just looks like that on a blood test.

For additional reading, please visit the following posts:

Anemia of chronic inflammation

Effect of anemia on mast cells

Mast cell disease and the spleen

MCAS: Anemia and deficiencies

Mast cells, heparin and bradykinin: The effects of mast cells on the kinin-kallikrein system

MCAS: Blood, bone marrow and clotting

Third spacing

Gastrointestinal manifestations of SM: Part 1

Gastrointestinal manifestations of SM: Part 2

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 72

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 73

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 66

80. When is chemotherapy necessary for mast cell disease?

  • For mastocytosis patients, chemotherapy is used for patients with systemic mastocytosis in whom the disease is malignant (aggressive systemic mastocytosis or mast cell leukemia) or seems to be progressing towards a cancerous form of the disease (smoldering systemic mastocytosis). There are very clear cut guidelines for this. Interferon and chemotherapy are used when a patient has smoldering mastocytosis with increasing mast cell counts; aggressive systemic mastocytosis; or mast cell leukemia, in order to kill off mast cells to slow disease progression and extend a patient’s lifespan.
  • A patient who already meets the criteria for systemic mastocytosis, who has two or more B findings, is considered to have smoldering systemic mastocytosis. SSM is a transition state between indolent SM, which has a normal lifespan, and malignant forms of mast cell disease, including ASM and MCL.
  • Having two or more of the following gets you a diagnosis of SSM: mast cell aggregates that take up 30% or more of cells in a bone marrow biopsy, and/or serum tryptase over 200 ng/mL; bone marrow with too many cells in it overall, without evidence of MDS or a myeloproliferative neoplastic disease; or organ swelling that has not yet affected organ function (swelling of the liver without ascites, spleen swelling enough that it can felt by palpation, lymph nodes swollen to 2 cm or larger).
  • Patients with SSM are watched to see if their body is making lots of mast cells quickly, or if their organs are feeling the strain of too many mast cells. One of the way they check this is to see how quickly their tryptase level increases. If their provider feels that their disease is progressing, they receive chemo or interferon to try and knock the disease down enough that they don’t reach the criteria for ASM.
  • Patients are diagnosed with ASM if they meet the criteria for SM and any of the following criteria: the body not making enough blood cells, cytopenia (absolute neutrophil count below 1000/ul, hemoglobin below 10g/dl, or platelets below 100000/ul); swelling of the liver along with free fluid in the abdomen (ascites), elevated liver enzymes, or portal hypertension; swelling of the spleen along with decreased blood cells due to damage in the spleen, excessive production of blood cells by the bone marrow to compensate, and likely resolution if the spleen is removed; malabsorption in the GI tract causing low protein in the blood (albumin) and weight loss; and severe bone dysfunction, causing a series of bone breaks and large osteolytic lesions from mastocytosis.
  • ASM patients are put on chemotherapy or interferon, usually continuously, unless there is evidence that they have killed off enough mast cells to have a less dangerous disease category.
  • Mast cell leukemia patients are on chemotherapy continuously.
  • There is no described use for chemo in cutaneous mastocytosis.
  • There are situations where patients with other disease categories (ISM, MMAS, MCAS) are put on chemo drugs to try and manage symptoms or shock episodes after all other therapies have failed. While this has been mentioned in literature, there have been no studies on it.
  • Chemo drugs should be used as a last resort. They can have significant side effects and complications that cannot always be remedied by stopping the treatment.
  • Please note that while newer, targeted chemos have become more common, they are in fact chemotherapy and carry significant risks despite being more tailored, including the potential for organ damage or failure.

For additional reading, please visit the following posts:

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Natural history of SM-AHD, MCL, MCS 

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The question I get asked the most

Whether or not SM is cancer is, by far, the question I get asked the most.  Because I get asked so often, I have done a lot of digging on this topic in the last few months.  Here’s what I found.

On the surface, from a biological point of view, SM looks like cancer.  It is characterized by excessive, improper cell growth.  It can cause organ infiltration and damage.  Over 90% of patients have a mutation in the CKIT gene, which is a proto-oncogene.  A proto-oncogene is a gene that becomes an oncogene when mutated.  An oncogene is a gene that contributes to cancer.  CKIT mutations can lead to gastrointestinal stromal tumors (GIST), melanoma, acute myeloid leukemia and, of course, mast cell disease.  So if SM has unregulated cell growth and a mutation in a proto-oncogene, that makes it cancer, right?
The World Health Organization (WHO), an organization I generally consider to know what they are doing, says it doesn’t.  To find out exactly why, I talked to a pathologist familiar with mast cell disease.  This is what she said:
“All cancers are neoplasms, but not all neoplastic cells are cancerous.  It is cancerous when the cells grow out of control.  In mastocytosis, even if you do nothing (meaning take no medications designed to kill off the mast cells), most of the time, the prognosis is very good because the cells are not growing that much.  Not like a cancer.  The other thing is when the cells invade other organs and the bloodstream and damage the organs.  When it is widespread and damaging, it is malignant.”
The majority of people with systemic mastocytosis have indolent disease, for which the life expectancy is normal, usually without any kind of therapy to kill off mast cells.  So if we follow the guidelines laid out above, SM is not cancer.   It is a myeloproliferative neoplasm (MPN.)
I know some people with ASM identify as having cancer.  ASM has a lot more features we typically associate with cancer, so I think that’s fine.  And MCL, obviously, is leukemia.
There is some terminology that gets thrown around incorrectly and I think it scares people who don’t understand that the wrong terms are being used.  One of them is chemo.  People with more aggressive types of mast cell disease may need chemo drugs.  People sometimes use the term incorrectly to reference more common treatments.  If you’re a rookie, I can see how you might get scared thinking that lots of people with indolent disease are on chemo.
Another term is compassionate use.  Compassionate use is the use of an experimental drug outside of a clinical trial.  It is generally allowed only when the person has no other treatment options and is gravely ill.  I have seen some people use it when discussing patient assistance programs, in which a pharmaceutical company will distribute a drug to a patient at a significant discount or at no cost.  They are not the same thing.
In the last few months, I have noticed that some people with SM will tell people that they have a “rare kind of leukemia.”  This is not accurate.  With the obvious exception of MCL, mast cell disease is not leukemia.  SM is a blood disorder. 
I think that part of why some people with mast cell disease say they have leukemia is because they want the sort of empathy given to cancer patients.  I understand that.  I wrote a whole post about how I hate when people say, “At least it’s not cancer.”  But it’s important to remember that cancer has two entities: the medical, biological aspect of the disease, and the social construct.  When you have ISM and you tell someone you have leukemia, their first thought is that you could die from it.  Mast cell disease is scary enough with scaring everyone around you extra with misinformation. 
I know that it’s frustrating that people know what cancer is and they probably don’t know what mast cell disease is.  And to be clear, I’m not talking about an offhand comment you make to some stranger asking you why you have a port at the grocery store to get them to go away.  I’m talking about the people who are actually in your life.  (I’m also obviously not referring to the SM-AHNMD people, who may very well have leukemia in addition to SM.)  If our mission is to educate people, stuff like this matters.  The words we use  matter.  A lot.  
I’m aware that this post is probably going to make some people angry, and that’s fine.  You can feel however you want to feel.  But I’m getting enough questions about this from people who are really worried, so I feel it’s important to set the record straight.