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 MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 59

73. Can mast cell disease cause organ damage?

  • Yes.
  • The term organ damage is tricky because people use it to mean a lot of things while providers and researchers often use it to mean one very specific thing. For providers and researchers, the term “organ damage” usually means a change in the organ that affects its structure, like it becomes misshapen or deformed in some way. Structural changes like this are often irreversible. This damage to the organ’s shape and structure usually affects how the organ works, called organ function.
  • When patients and laypeople talk about organ damage, they usually mean a change in the way the organ functions, even if the structure is not changed at all. This is different in a very important way: changes in an organ that do not affect its permanent structure can sometimes be reversible.
  • Both cutaneous and systemic mastocytosis cause organ damage in a way that damages the organ’s structure. When too many mast cells burrow into the tissue of an organ, it has to push other things out of the way. When you have mastocytosis, the mast cells like to stick together and form a big clump in the tissue. This punches holes in the tissue, affecting the organ’s structure and shape. This is called dense infiltration. It is one of the criteria for systemic mastocytosis and also happens in cutaneous mastocytosis.
  • In patients with mastocytosis, those mast cells clumping together cause a lot of the organ damage. This means that people who have the most mast cells usually have the worst organ damage. Patients with malignant forms of mast cell disease, like mast cell leukemia or aggressive systemic mastocytosis, often have organs that are riddled with TONS of mast cells.
  • Mast cells don’t live in the blood so when your body makes way too many mast cells, those mast cells will dive into whatever organ they can to get out of the bloodstream. This causes damage to the structure that you can see with scans or in biopsies.  People with mast cell leukemia and aggressive systemic mastocytosis suffer so much damage to the shape and function of their organs that the organs can totally stop working, called organ failure.
  • One of the key differences researchers and providers see between mastocytosis and mast cell activation syndrome is that mast cells don’t cause THIS TYPE of structural damage in mast cell activation syndrome patients.
  • We know this because in biopsies, they do not have mast cells clumped together to punch holes in the tissue. Sometimes they have lots of mast cells, but it is much less damaging to the tissue if they aren’t clumped together. Think of it like poking something with finger versus punching with your fist.
  • In MCAS, mast cells do not cause structural damage to organs IN THIS WAY. However, many people with MCAS do have structural damage to their organs. Many of them also have organs that do not function correctly even if the organs look normal.
  • Even if you don’t have mast cells punching holes in all your organs, they can still do a lot of damage. This is because mast cells cause lots of inflammation, which can stress out your organs. Over time, your organs can be damaged by the mast cells releasing too many mediators. While this is not always dangerous, it is certainly painful and frustrating.
  • Many MCAS and mastocytosis patients have a lot of damage to their GI tracts from years of vomiting, obstructions, diarrhea or constipation. Hives and mastocytosis spots can damage your skin, causing discoloration, scarring or sensitivity. Muscles can become weaker over time because of mast cell inflammation. Swelling can stretch out your skin and connective tissues. Nerves can be damaged significantly, affecting organ function. Bones can become brittle and break, or can become too dense because the body is making new bone when it shouldn’t.
  • All of these effects on organ function can be caused by mast cells. Major changes in organ function can also cause secondary conditions to arise.
  • Mast cell patients are also at an increased risk for anaphylaxis which can cause changes in organ function or organ damage.
  • Patients who have trouble breathing or low blood pressure may not be getting enough oxygen to their whole body. That can cause lasting damage if it goes on long enough.

For more detailed reading, please visit the following posts:

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 48

59. Is systemic mastocytosis a form of cancer? Why do some papers say the life expectancy for systemic mastocytosis patients is much shorter?

Systemic mastocytosis is a term that different people use in different ways, often without defining them for the audience. This can lead to some confusion.

In its broadest sense, systemic mastocytosis is actually a disease category rather than one specific diagnosis. The subtypes of systemic mastocytosis are indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), systemic mastocytosis with associated hematologic disease (SM-AHD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL).

When patients talk about systemic mastocytosis without specifying which diagnosis, they almost always mean indolent systemic mastocytosis (ISM), the most common form of SM. ISM is benign and has a normal life expectancy. But when providers and researchers talk about systemic mastocytosis, they usually mean the disease category that includes all of these diagnoses.

I just recently explained in another post what a neoplasm is. It is essentially when the body grows something that doesn’t belong there, like extra cells or a tumor. Cancers are neoplasms but not all neoplasms are cancerous. Indolent systemic mastocytosis is not cancerous. Even without taking drugs to kill off lots of mast cells, the prognosis is excellent with a normal life span. However, aggressive systemic mastocytosis and mast cell leukemia are considered cancerous. Without taking drugs to kill off mast cells, the body would be unable to cope with the huge number of mast cells and the damage they cause. Smoldering systemic mastocytosis is sort of a bridge between ISM, which is benign, and ASM, which is not.

If you are not aware that research papers usually use the term systemic mastocytosis to mean all forms of systemic mastocytosis and not just indolent systemic mastocytosis (ISM), it is easy to get confused and misunderstand what is being said. There was a paper published in 2009 that discussed expected survival for the various forms of systemic mastocytosis. It provides a very jarring statistic for patients who may not understand the context. This study found that many patients with systemic mastocytosis died 3-5 years after diagnosis.

Let’s pull this apart. We know there are five forms of SM: indolent SM, the most common form, which usually has a normal life span; smoldering SM, which usually has a shortened life span; aggressive SM, which can have a very shortened life span; mast cell leukemia, which has a very shortened life span; and SM with an associated hematologic disorder, which may have a shortened life span. When you average the life expectancies for a mixed group of patients with these various diagnoses, it shows that overall, SM patients are more likely to die 3-5 years after diagnosis when compared to healthy people of the same age.

Additionally, a lot of the patients in this study group were older and died of causes unrelated to systemic mastocytosis. However, because they were part of the study, their deaths of unrelated causes were still included in this data.

Let’s recap: in a research paper, the term systemic mastocytosis includes forms of SM that are malignant and can really shorten your life expectancy as well as forms that are benign and do not shorten your life expectancy. When you average the life expectancies of all of these forms together, it looks like patients are more likely to die 3-5 years after diagnosis. A bunch of other papers then used the data from this study in 2009 without explaining the details behind it. However, most patients with SM have normal life spans.

For more detailed information, please visit these 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 and MCS

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 45

54. How does mast cell disease affect clotting?

Heparin is a very potent blood thinner and inhibits the body’s ability to form clots.  Mast cells are full of heparin. Mast cells stores chemicals like heparin in little pouches inside them called granules. In the granules, histamine is stuck to heparin. This means that when mast cells open their granules and release histamine, heparin comes out with it. This can contribute to things like bruising or bleeding more than expected.

Mast cells release other chemicals that can affect clotting. Platelet activation factor and thromboxane A2 both encourage the body to make clots. Some chemicals that help to regulate when to make a clot can activate mast cells, like complement C3a and C5a.

55. How many people have mast cell disease?

It is hard to know exactly how many people have a rare disease because they are not reported if they are recognized and correctly diagnosed. As recognition and diagnosis improves, rare diseases are often found to be more prevalent than previously thought. The numbers below are current estimates.

Systemic mastocytosis is thought to affect around 0.3-13/100000 people. In one large study, indolent systemic mastocytosis (ISM) makes up 47% of cases. Aggressive systemic mastocytosis (ASM) has been described in various places as comprising 3-10%. Systemic mastocytosis with associated hematologic disease could count for as many of 40% of cases of SM. Mast cell leukemia is extremely rare and accounts for less than 1% of SM cases.

Systemic mastocytosis accounts for about 10% of total mastocytosis cases. This means that total mastocytosis cases come in at around 3-130/100000 people. The remaining 90% of mastocytosis cases are cutaneous with incidence roughly around 2.7-117/100000 people.

We do not have yet have a great grasp upon how many people have mast cell activation syndrome (MCAS) but from where I am sitting, it’s a lot and that number is likely to grow. We know that genetic studies have found mutations that might be linked to MCAS in up to 9% of the people in some groups. However, having a mutation is not the same thing as having a disease. As we learn more about MCAS, we will gain some clarity around how many people have it.

For more detailed reading, please visit the following posts:

Progression of mast cell diseases: Part 2

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

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

The Provider Primer Series: Cutaneous mastocytosis/Mastocytosis in the skin

 

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 37

44. What is a myeloproliferative neoplasm? Is that what mast cell disease is?

First, let’s pull this term apart.

“Myelo” means marrow, like bone marrow. In this context, it refers to a specific group of blood cells that are made in the bone marrow. These cells are called myeloid or myelogenous cells. These cells all start as one kind of cell called a myeloid progenitor cell. Mast cells and eosinophils are myeloid cells. There are other myeloid cells, too.

“Proliferative” means making lots of cells quickly. In this case, it means making many cells too quickly. When too many cells are made too quickly, the cells are often not made correctly so they don’t work right.

“Myeloproliferative” means making too many myeloid cells very quickly, producing cells that often don’t work right.

“Neo” means new.

“Plasm” means the substance that makes up something living, like what makes up a cell or a tissue. “Plasm” is part of many words used in biology.

“Neoplasm” means the body growing new things, things that don’t belong there. For example, cancers are neoplasms. (Although not all neoplasms are cancers).

Myeloproliferative neoplasm means your body making too many myeloid cells that don’t work correctly.

Speaking generally, any condition where the body makes too many of these myeloid cells when they shouldn’t is a myeloproliferative neoplasm. This means all form of mastocytosis and mast cell tumors (mast cell sarcoma and mastocytoma) are myeloproliferative neoplasms.

However, when people ask if mast cell diseases are myeloproliferative neoplasms, they are usually asking about the WHO (World Health Organization) classification of mast cell disease, which is a little different.

The WHO puts out an exhaustive list of diseases for reference. They group similar diseases together under one category. This list is also revised periodically as new data becomes available or experts request it.

Under the 2008 WHO guidelines, mast cell diseases were classified as myeloproliferative neoplasms along with several other diseases. The other diseases also included in this category make too many myeloid cells too quickly, like essential thrombocythemia, in which the body makes too many platelets.

The mast cell diseases classified as myeloproliferative neoplasms were cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated hematologic disease (SM-AHD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); and mast cell sarcoma. Smoldering systemic mastocytosis (SSM) was mentioned as a provisional category rather than a formal category, meaning that the WHO did not agree that this diagnosis was different enough from ISM to warrant its own category. Neither monoclonal mast cell activation syndrome (MMAS) or mast cell activation syndrome (MCAS) were classified anywhere in the 2008 WHO Guidelines as they were not yet recognized by the WHO as diseases.

Last year, the WHO revised the classification of myeloproliferative neoplasms. It removed all forms of mast cell disease from the myeloproliferative neoplasm category and made a different category for mast cell diseases. This was done because the WHO recognized that mast cell diseases differed from the other myeloproliferative neoplasms in specific ways. They also recognized that mast cell activation syndrome has a ton in common with other mast cell diseases even though it’s not a neoplastic disease. (Mast cell activation syndrome is not from the body making too many mast cells).

So all mast cell diseases were put together. In the new category, the following mast cell diseases were included: cutaneous mastocytosis: maculopapular cutaneous mastocytosis (MPCM), diffuse cutaneous mastocytosis (DCM), and solitary mastocytoma of the skin; systemic mastocytosis: indolent systemic mastocytosis (ISM), systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD), aggressive systemic mastocytosis (ASM), and mast cell leukemia (MCL); mast cell sarcoma; monoclonal mast cell activation syndrome (MMAS); and mast cell activation syndrome (MCAS).

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 26

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

34. What are the differences between the forms of systemic mastocytosis?

Indolent systemic mastocytosis

  • A form of SM in which the amount of mast cells produced in the bone marrow is excessive but not inherently dangerous to organ function.
  • Mast cells produced in the bone marrow are damaged.
  • These mast cells are released into the blood. While there are more mast cells than usual, there are not enough to overwhelm the blood.
  • There are fewer mast cells than in mast cell leukemia. There are often fewer mast cells than aggressive systemic mastocytosis or smoldering systemic mastocytosis.
  • The mast cells leave the blood and may enter organs inappropriately. Some patients do not have signs of too many mast cells being in an organ other than bone marrow.
  • The presence of mast cells in organ tissue can cause symptoms and medical signs but is not inherently dangerous to organ function.
  • It is not unusual for ISM patients to have typical mast cell symptoms and complications like anaphylaxis.
  • The lifespan for ISM is normal.
  • In indolent systemic mastocytosis, patients die from progressing to a more aggressive form of SM, such as MCL, ASM or SM-AHD.
  • Fatal anaphylaxis is always a risk with mast cell disease.

Smoldering systemic mastocytosis

  • A form of SM in which the amount of mast cells produced in the bone marrow is increasing to the point at which it might cause organ damage.
  • Mast cells produced in the bone marrow are damaged.
  • These mast cells are released into the blood. There are fewer mast cells than in mast cell leukemia. There are often fewer mast cells than aggressive systemic mastocytosis.
  • Mast cells leave the blood and enter organs in larger numbers than is normal. The presence of mast cells in these organs can cause symptoms and medical signs, like swelling of the liver.
  • Organ dysfunction can sometimes be corrected with surgery or certain medications.
  • It is not unusual for SSM patients to have typical mast cell symptoms and complications like anaphylaxis.
  • The lifespan for SSM is widely variable. One well known paper published survival of around ten years. However, many of the patients in this study were over 60 and age may have affected the average survival found in this group.
  • Patients with smoldering systemic mastocytosis are monitored to look for signs of significant organ dysfunction.
  • People with this diagnosis are considered to be possibly transitioning to a more serious form of systemic mastocytosis.
  • Smoldering systemic mastocytosis is the diagnosis that occurs between aggressive systemic mastocytosis and indolent systemic mastocytosis. It is thought of as the stage crossed when a patient with indolent systemic mastocytosis progresses to having aggressive systemic mastocytosis or mast cell leukemia.
  • In smoldering systemic mastocytosis, patients die from progressing to a more aggressive form of SM, such as MCL, ASM or SM-AHD.
  • Fatal anaphylaxis is always a risk with mast cell disease.

Aggressive systemic mastocytosis

  • A dangerous form of SM in which your bone marrow makes way too many damaged mast cells.
  • These mast cells are released into the blood. There are fewer mast cells than in the blood than in mast cell leukemia.
  • The mast cells leave the blood and go into various organs.
  • The presence and activation of the mast cells in the organs can affect organ function.
  • Over time, the presence and activation of mast cells in the organs can cause organ failure. This can sometimes be corrected with surgery or certain medications.
  • Typical mast cell mediator symptoms and complications like anaphylaxis are less common than in less serious types of SM.
  • The lifespan for ASM is much shorter than normal but is dependent upon response to treatment and which organs are involved. Older papers reference an average of 41 month survival but this has changed with more recent treatment options.
  • Generally, people with ASM live longer than those with MCL.
  • In aggressive systemic mastocytosis, patients die from the organ damage that has accrued over time by the presence and activation of mast cells in places they don’t belong.
  • Fatal anaphylaxis is always a risk with mast cell disease.

Mast cell leukemia

  • A very dangerous form of SM in which your bone marrow makes massive amounts of damaged mast cells.
  • These mast cells are released into the blood in overwhelming numbers.
  • The mast cells leave the blood and end up in various organs.
  • Specifically because of how many mast cells are present, mast cells invading the organs break up the organ tissue and cause severe organ damage.
  • The organ damage leads to organ failure, which leads to death.
  • Typical mast cell mediator symptoms and complications like anaphylaxis are less common than in less serious types of SM.
  • The lifespan for MCL is much shorter than normal.
  • Lifespan for MCL is usually quoted as being in the range of 6-18 months. However, there are more recent reports of some patients living 4+ years.
  • In mast cell leukemia, patients die from the organ damage caused by large amounts of mast cells entering and breaking up organ tissue.
  • Fatal anaphylaxis is always a risk with mast cell disease.
  • Of note, there is a newly described chronic form of mast cell leukemia. In this form, patients have stable mast cell disease despite having an overwhelming amount of mast cells in their bodies. The reason for this is unclear and long term survival is not yet known.

Systemic mastocytosis with associated hematologic disease

  • A form of SM in which the patient also has a separate blood disorder that produces too many cells of a different kind.
  • A patient with systemic mastocytosis with associated hematologic disease has too many mast cells and too many blood cells of a different kind. 
  • Previously called SM-AHNMD, systemic mastocytosis with associated clonal hematologic non mast cell lineage disease.
  • The two blood disorders, SM and the other disorder, are treated separately the same way they would be if the patient only had one or the other.
  • The lifespan for SM-AHD is wildly variable as it depends both on which type of SM the patient has as well as the type and severity of the other blood disorder.
  • An important thing to remember is if a patient has SM and another blood disorder that produces too many cells, they are classified as SM-AHD regardless of the type of SM they have. For example, if a patient who has ISM (normal lifespan) also has chronic myelogenous leukemia, they have SM-AHD. However, if the patient has ASM (shortened lifespan) and chronicle myelogenous leukemia, they still have SM-AHD even though the prognosis changes considerably.
  • In SM-AHD, patients die from having an aggressive form of SM, such as MCL or ASM, or as a result of their other blood disorder.
  • Fatal anaphylaxis is always a risk with mast cell disease.

For more detailed reading, please visit these posts:
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 15

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.
23. Is mast cell disease progressive?
No, mast cell disease is not inherently progressive. Many patients live their entire lives with the same diagnosis.
“Progressive” is not the same thing as “changing.” The way mast cell disease can change over time and often does.
• “Progressive” has a very specific meaning in this context. It means movement from one diagnostic category to another, essentially changing your diagnosis to a more serious form of mast cell disease.
We do not have studies yet on whether or not MCAS “becomes” SM. However, we know that many people live with MCAS for decades without evidence of SM.
• There are several subtypes of systemic mastocytosis. In order of increasing severity, they are: indolent systemic mastocytosis; smoldering systemic mastocytosis; systemic mastocytosis with associated hematologic disease; aggressive systemic mastocytosis; and mast cell leukemia.
• The relative danger of systemic mastocytosis with associated hematologic disease (SM-AHD) when compared with other forms of systemic mastocytosis varies wildly. SM-AHD is when you have SM and another blood disorder where your body makes way too many cells. The other blood disorder is an important factor in life expectancy and risk of organ damage so it is difficult to compare it to other forms of mastocytosis.
• For patients with indolent systemic mastocytosis, in the 5-10 years following diagnosis, about 1.7% of patients progressed to smoldering mastocytosis, aggressive systemic mastocytosis, or mast cell leukemia.
• For patients with indolent systemic mastocytosis, in the 20-25 years following diagnosis, about 8.4% of patients progressed to smoldering mastocytosis, aggressive systemic mastocytosis, or mast cell leukemia.
• For patients with indolent systemic mastocytosis, one study found that roughly 8% of patients progressed to smoldering systemic mastocytosis.
• For patients with indolent systemic mastocytosis, two studies found that roughly 3% and 4% of patients progressed to aggressive systemic mastocytosis.
• For patients with indolent systemic mastocytosis, about 0.6% of patients progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia)..
• For patients with smoldering systemic mastocytosis, about 18% of them progressed to aggressive systemic mastocytosis or mast cell leukemia.
• For patients with aggressive systemic mastocytosis, about 6.5% of them progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia).
• For patients with systemic mastocytosis with associated hematologic disease, about 13% of them progressed to acute leukemia (mast cell leukemia or acute myelogenous leukemia).

For more detailed reading, please visit these posts:

Progression of mast cell diseases: Part 2

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

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 2

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

3. What causes mast cell disease?

  • The cause of mast cell disease is not yet definitively known.
  • As mentioned yesterday, when the body makes too many copies of a broken cell, those cells are called ‘clonal’ cells. In clonal forms of mast cell disease, the bone marrow makes too many mast cells. Those mast cells also don’t work correctly. Examples of clonal mast cell diseases are systemic mastocytosis and cutaneous mastocytosis.
  • Patients with systemic mastocytosis often have a specific genetic mutation called the CKIT D816V mutation. About 80-90% of systemic mastocytosis patients have this mutation. This mutation is in mast cells and it tells the mast cells to stay alive WAY longer than they should. And mast cells already live for months or years, a very long time for cells to live in the body. So patients with this mutation can end up with way too many broken mast cells.
  • Despite the fact that we know that many patients have this mutation, we do not say that this mutation CAUSES the disease. The reason for this is that sometimes, mast cell patients don’t have the mutation when they get sick but they develop it later. Sometimes, mast cell patients have the mutation and then lose it later. So we are still looking for something that causes the disease.
  • Patients with non-clonal mast cell disease do not have a single major mutation like the CKIT D816V mutation. This makes it harder to diagnose. Researchers have found that many times, patients with MCAS DO have mutations similar to the ones systemic mastocytosis patients do. But the MCAS patients often have different mutations from each other. That’s why it’s not helpful yet for diagnosis.
  • Despite the fact that the mutations described here are not considered to be heritable, there is more and more evidence that mast cell disease can happen to many people in the same family. See the next question for more details.

4. Is mast cell disease heritable?

  • Mast cell disease often affects multiple members of the same family. Importantly, patients often have a different type of mast cell disease than their relatives. This implies that mast cell disease is more of a spectrum rather than several different diseases.
  • A survey found that 74% of mast cell patients interviewed reported at least one first degree relative that had mast cell disease. This same study found that 46% of those patients had mast cell disease that affected more than just their skin. This is called systemic disease.
  • The CKIT D816V mutation is the mutation most strongly associated with clonal mast cell disease. The CKIT D816V mutation is NOT heritable.
  • There are very rare instances of other heritable mutations in families that have mast cell disease. The significance of this is not clear.

5. Can mast cell disease be cured?

  • Generally speaking, there is no cure for mast cell disease.
  • Children who present with cutaneous mastocytosis sometimes grow out of their disease. Their lesions disappear. Their mast cell symptoms affecting the rest of the body may disappear. We do not know why this happens. It has been heavily researched with long term follow up of children with childhood mastocytosis (at least one paper followed them for 20 years).
  • Children with true systemic mastocytosis do not grow out of their disease.
  • There is not yet data on children with MCAS. Anecdotally, they do not seem to grow out of their disease like kids with cutaneous mastocytosis can. Importantly, this is just what it looks like to me. Again, there is no data.
  • People with adult onset mast cell disease have lifelong disease.
  • There is one notable exception to this scenario. There are reports of curing mast cell disease following hematopoietic stem cell transplant/bone marrow transplant.
  • Transplantation is EXTREMELY dangerous. The transplant is MUCH, MUCH more dangerous than mast cell disease. Many people do not survive the protocol necessary to prepare for transplant. Many die from complications, or from a disease they acquired after their transplant.
  • Rarely, people may have malignant forms of mast cell disease, aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL). A few patients with these diseases have tried transplants after everything else failed. While some did see improvement after transplant, no one has survived more than a few years.
  • Conversely, sometimes people with mast cell disease have these transplants for other reasons, like having another blood cancer or bone marrow disease that requires transplant. In this group of people, some see drastic improvement of their mast cell disease. Some see a full remission of mast cell disease. Some do not get any improvement. These findings are pretty recent so it’s hard to be more specific.

For more detailed reading, please visit these posts:

The Provider Primer Series: Introduction to Mast Cells

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

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

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

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

Mast cell disease in families

Heritable mutations in mastocytosis

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

Systemic mastocytosis (SM) is a primary hematologic disorder marked by the excessive proliferation of mast cells.

Neoplastic nature of mastocytosis:

  • Mast cells produced in this disease are neoplastic and may have some or all of the following markers: presence of somatic gain-of-function mutation at codon 816 of CKIT (KIT), usually, but not always, the D816V mutation; expression of CD2 or CD25 on mast cell surface; atypical spindled morphology of mast cells[i].
  • Mastocytosis is a neoplastic condition that is not described exclusively by excessive population of mast cells. Mast cell hyperplasia can occur in response to a number of conditions including chronic urticaria[ii], irritable bowel syndrome[iii], and other hematologic neoplasia, including chronic lymphocytic leukemia, non-Hodgkin lymphoma, and myeloproliferative conditions[iv].
  • To meet criteria for SM, mast cell infiltration must be dense with at least 15 mast cells per cluster. In many instances, there is not a validated range of mast cells/hpf in healthy controls[iv].
Table 1: Diagnostic criteria for systemic mastocytosis[v]

1 major and 1 minor criterion; or 3 minor criteria

Major Multifocal dense infiltrates of mast cells (15 or more in aggregate) detected in sections of bone marrow and/or extracutaneous organ
Minor In biopsy sections, more than 25% of mast cells in infiltrated space are spindle-shaped or otherwise morphologically abnormal; or, of all mast cells in bone marrow aspirate smears, more than 25% mast cells are immature or abnormal. Detection of CKIT mutation at codon 816 in bone marrow, blood or extracutaneous organ Mast cells in bone marrow, blood or other extracutaneous organ that co-expresses CD-117 with CD2 and/or CD25 Baseline serum tryptase of 20 ng/ml or higher.

 

Presence of dense infiltrates:

  • The hallmark sign of systemic mastocytosis is multifocal dense infiltration of an organ that is not the skin. Despite this fact, it is possible to biopsy negative while still having SM. A 2004 study reported the pathological findings of bilateral bone marrow biopsies for 23 patients. 83% of patients demonstrated positive biopsy for SM bilaterally while 17% of patients had only one positive biopsy[vi].
  • One study found that 20% of ISM patients did not have dense infiltration of mast cells in bone marrow[vii].

Tryptase level in systemic mastocytosis:

  • Tryptase ≥20 ng/mL is a minor criterion for SM. In order to meet this criterion, tryptase must be ≥20 ng/mL at baseline, not during or following a reactive or anaphylactic event. Per Phadia, producer of ImmunoCAP® Tryptase test, it can take up to fourteen days for tryptase to return to baseline[viii]. However, other sources recommend shorter time to baseline, as low as “24 hours after clinical signs and symptoms have completely subsided”[ix].
  • 20-30% of SM patients do not meet the minor criterion of tryptase level ≥20 ng/mL[xiii].

Detection of CKIT D816V mutation:

  • The CKIT D816V mutation may not be detected in peripheral blood in a positive patient. Bone marrow aspirate is the preferred sample type for reliable testing for this mutation[xii].
  • One study reported as few as 78% of ISM patients were positive for the CKIT D816V mutation in bone marrow[xiii].

Natural history of indolent systemic mastocytosis:

  • Indolent systemic mastocytosis (ISM) is SM that does not meet criteria for smoldering systemic mastocytosis, aggressive systemic mastocytosis or mast cell leukemia.
  • ISM is largely described by mediator release symptoms and increased risk of anaphylaxis. Mast cell infiltration does not cause appreciable organ dysfunction in this variant[x].
  • Progression from ISM to SSM occurred in about 8% of patients in a cohort of 74. In this same cohort, 4% ISM patients progressed to ASM[xi]. The risk of leukemic transformation from ISM was 0.6% in a cohort of 159[xii].
  • Organomegaly can present without loss of function at any level of hematologic disease in SM. Organ swelling may be stable over long periods of time without progression to aggressive systemic mastocytosis (ASM)[x].
  • Lifespan for indolent systemic mastocytosis is normal[x].
Table 2: Diagnostic criteria for smoldering systemic mastocytosis

 (2 or 3 B findings in addition to meeting criteria for systemic mastocytosis)[i]

B findings Increased mast cell burden (>30% mast cell aggregates on bone marrow biopsy and/or serum tryptase >200 ng/mL) Hypercellular marrow, signs of myelodysplasia or myeloproliferation in absence of MDS or MPN Organ swelling without deficit of organ function (hepatomegaly without ascites, palpable splenomegaly, lymphadenopathy >2 cm)

 

Natural history of smoldering systemic mastocytosis:

  • Smoldering systemic mastocytosis (SSM) is defined by increased systemic mast cell burden, presence of markers associated with progression toward ASM (B findings), and potential need for cytoreduction[xiii].
  • SSM can remain stable for many years, even decadesix. In a cohort of 22 patients with SSM, 1 transformed to acute leukemia and 3 progressed to ASM[xiv].
  • Lifespan may be shortened in SSM. A widely reported study found an average lifespan of 10 years but reported that death was often unrelated to mastocytosis and in some cases was of natural old age[xiii].
Table 3: Diagnostic criteria for aggressive systemic mastocytosis

(1 or more C finding in addition to meeting criteria for systemic mastocytosis)[i]

C findings One or more cytopenias (absolute neutrophil count <1000/µl; Hemoglobin <10g/dl; platelets <100000/µl) Hepatomegaly with ascites, elevated liver enzymes with or without portal hypertension Splenomegaly with hypersplenism Malabsorption evidenced by low albumin and weight loss Large osteolysis and/or severe osteoporosis and pathologic fractures (2 or more fractures as direct result of mast cell activity)

 

Natural history of aggressive systemic mastocytosis:

  • Aggressive systemic mastocytosis (ASM) is defined by significant organ damage and failure as a direct result of mast cell infiltrationxv. Lifespan is often significantly shortened and can be as short as three years[ix] .
  • ASM generally follows one of two paths: a slow progressing form that resembles SSM but has C findings; or a rapidly progressing form that resembles mast cell leukemia. In rapidly progressing ASM, the patient may lose the CKIT D816V mutation[ix] .
  • ASM is managed with cytoreduction but patient response is often short lived. Tyrosine kinase inhibitors and other kinase inhibitors are also used in this population[ix] .
  • In treatment resistant cases, hematopoietic stem cell transplant offers an experimental option. One study on HSCT in advanced systemic mastocytosis included seven ASM patients. 3 (43%) achieved complete remission; 3 (43%) demonstrated progression free survival at the three year mark[xv].

References:

[i] Arber DA, et al. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391-2405.

[ii] Minnei F, et al. (2006). Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch, 448(3), 262-268.

[iii] Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut, 56, 203-209.

[iv] Hamilton MJ, et al. (2011). Mast cell activation syndrome a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol, 128, 147-152.

[v] Molderings GJ, et al. (2011). Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 10.1186/1756-8722-4-10

[vi] Butterfield JH, Li, CY. (2004). Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient? Hematopathology, Am J Clin Pathol, 121: 264-267.

[vii] Sanchez-Munoz L, et al. (2011). Evaluation of the WHO criteria for the classification of patients with mastocytosis. Mod Pathol, 24(9), 1157-1168.

[viii] Phadia AB. ImmunoCAP® Tryptase: Clinical utility of Total Tryptase. Retrieved from: http://www.phadia.com/Global/Market%20Companies/Sweden/Best%C3%A4ll%20information/Filer%20(pdf)/ImmunoCAP_Tryptase_Clin_Util.pdf

[ix] Schwartz LB. (2006). Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunology and Allergy Clinics of North America, 26(3), 451-463.

[x] Valent P, et al. (2010). How I treat patients with advanced systemic mastocytosis. Blood, 116(26), 5812-5817.

[xi] Matito A, et al. (2013). Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. PLoS One, 8(10), e76116.

[xii] Lim KH, et al. (2009). Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood, 113(23), 5727-5736.

[xiii] Pardanini A. (2013). How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). Blood, 121, 3085-3094.

[xiv] Pardanini A. (2010). WHO subvariants of indolent mastocytosis: clinical details and prognostic evaluation in 159 consecutive adults. Blood, 115, 150-151.

[xv] Ustun C, et al. (2014). Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol, 32(29), 3264-3274.

[xvi] Pardanini A. (2013). Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. American Journal of Hematology, 88(7, 612-624).

[xvii] Valent P, et al. (2003). Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. Leuk Res, 27(7), 635-641.

Bone involvement in ISM, SSM, SM-AHNMD and ASM: More literature review (part 3)

A 2009 paper looked at prognosis of 157 ISM patients (Escribano 2009). 27% had bone involvement, with 18% patients having osteoporosis, 6% having diffuse bone sclerosis, 4% having patchy bone sclerosis 2% having small osteolysis and 3% having pathological fracture.

A 2012 paper (van der Veer 2012) assessed the frequency of osteoporosis and osteoporotic fractures in a group of 157 ISM patients. They found 28% had osteoporosis, with 27% having osteoporosis of the lumbar spine and 1% having osteoporosis of the hip. 4% had evidence of osteosclerosis.

43% of patients under 50 years old had had at least one fracture (osteoporotic or not) and 61% of patients over 50 years old had had at least one fracture. 27% of patients had one or more vertebral fractures and 21% had non-vertebral, osteoporotic fractures. 23% of male patients under 50 had osteoporosis as well as 38% over 50. 12% of women under 50 had osteoporosis as well as 33% over 50. In total, 37% had osteoporotic fractures. In the group with comorbidities that might cause osteoporosis or fractures, 49% had osteoporotic fractures and 37% had osteoporosis. 59% ISM patients without UP had osteoporotic fractures compared to 28% with UP.

A 2013 paper (Matito 2013) looked at the association of baseline serum tryptase with disease features, including progression to SSM or ASM. 74 patients with ISM were included in the study and were followed for at least 48 months. None of them received cytoreductive therapy. Patients with an increased serum baseline tryptase slope and those without significant tryptase increase had similar prevalence of osteoporosis, patchy bone sclerosis and diffuse bone sclerosis at both presentation and end of study. However, the group with increased serum baseline tryptase was more likely to develop diffuse bone sclerosis in the time span between the beginning of the study and the end of the study (13% vs 2% without significant tryptase increase).

Among the group with low serum baseline tryptase increase, 9% had osteoporosis at the start, and 14% at the end; 5% had patchy osteosclerosis at the end; 2% had diffuse bone sclerosis at the end. None in this group progressed to SSM or ASM.

Among the group with high serum baseline tryptase increase, 10% had osteoporosis at the start, and 16% at the end; 6% had patchy osteosclerosis at the end; 13% had diffuse bone sclerosis at the end. 13% progressed to SSM and 6% to ASM.

Four patients in this study progressed to SSM after the start of the study, in a time ranging from 8-85 months. All had serum baseline tryptase of at least 200 ng/ml and had increased serum baseline tryptase slope. They also had D816V CKIT mutation in cells other than mast cells. Two of these patients progressed to ASM. Both of these patients had diffuse bone sclerosis and swelling of both the liver and spleen. The authors of this paper recommend special attention to the development of hepatomegaly and splenomegaly and diffuse bone sclerosis.

 

References:

Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans & J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.

Matito A, Morgado JM, Álvarez-Twose I, Laura Sánchez-Muñoz, Pedreira CE, et al. (2013) Serum Tryptase Monitoring in Indolent Systemic Mastocytosis: Association with Disease Features and Patient Outcome. PLoS ONE 8(10): e76116. doi:10.1371/journal.pone.0076116

Escribano L, A lvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish network on mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514–521.