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 28

36. Is MCAS less serious than SM?

No.

There is a lot of literature presenting data on SM. There is a lot less on MCAS. This is largely because of how recently it has described and the fact that different sets of criteria make it impossible to do large scale studies as have been done with SM. So it’s hard to objectively compare the data because the same volume just doesn’t exist yet.

Many providers and researchers think of MCAS as a form of “preclinical SM”. This term was tossed around in the early 2000s by SM researchers who found patients that seemed to have SM but didn’t meet the criteria for it. There were a few presentations in which an image was shown of a line with the different types of SM shown.

From left to right, the line read:
Preclinical SM/Indolent SM/Smoldering SM/Aggressive SM/Mast cell leukemia

Based upon this figure, and the fact that we are trained to look at lines like this as continuum that either increases or decreases in order, many people latched onto “preclinical SM” (like MCAS) as being the least dangerous. Importantly, the figure refers to the increasing danger of permanent organ damage by mast cells ending up in organ tissues. It does NOT refer to the danger of anaphylaxis.

Indolent systemic mastocytosis (ISM) is the least dangerous form of SM and by far the most common. When people ask if MCAS is less dangerous than SM, they usually mean is MCAS less dangerous than ISM. A couple of small study groups have found that prevalence of anaphylaxis in MCAS is less frequent than in ISM. However, this comparison is flawed. Many people have known they have SM for 20+ years. MCAS hasn’t even been a viable diagnosis for 10 years. MCAS is also less likely to be diagnosed due to decreased exposure on the part of many providers. Many MCAS patients are diagnosed with idiopathic anaphylaxis instead so you’re not really looking at a robust population of MCAS patients in these studies.

ISM has a normal lifespan. It is treated the same way as MCAS and the two conditions have remarkably few differences beyond very specific markers that show the body making too many sloppy mast cells.

Some MCAS patients have protracted anaphylaxis and a normal baseline of very serious daily symptoms. It is my personal opinion that the anaphylaxis episodes I have observed in many MCAS patients can be a lot worse than you see in ISM. MCAS patients also have a harder time finding treatment. While ISM patients certainly run into unknowledgeable providers, it is my experience that having an ISM diagnosis is more helpful for facilitating treatment than an MCAS diagnosis.

We need time in order for larger studies and more unifying MCAS criteria to emerge but I am certain that these will follow. MCAS is at least as dangerous as ISM, if not more. Both MCAS and ISM are less dangerous than SSM, ASM and MCL.

For more detailed reading, please visit these posts:
The Provider Primer Series: Mast cell activation syndrome (MCAS)
The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

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 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.

Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Literature review (part 2)

There have been several publications on bone involvement in SM. Importantly, not all of these papers define SM the same way. Some define it as ISM, while others define it as ISM, SSM, SM-AHNMD and ASM. (I personally am sloppy about not specifying when I mean ISM versus when I mean any all the systemic proliferative groups. So if it’s not clear, please ask.) Another thing to be aware of is that the terminology for osteosclerosis is not consistent. It is sometimes referred to as osteocondensation (this is primarily a term used by French researchers). I have done some digging recently on this and cannot find any indication that these two terms do not represent the same phenomenon (increased deposition of bone), so if anyone knows of any papers or sources that say they are different, please let me know.

A 2010 paper (Barete 2010) defines SM as ISM, SSM, SM-AHNMD and ASM. They divided the study into two groups: Variant 1 (non-aggressive), ISM and SSM; and Variant 2 (aggressive), SM-AHNMD and ASM.

Overall (ISM, SSM, SM-AHNMD and ASM), 49% of patients had some form of bone involvement. Osteoporosis was most common, occurring in 31% of patients. 17% had a vertebral fracture. 8% had osteosclerosis. 4% had a mixed pattern, so more than one type of bone involvement. 5% had osteopenia with a previous fracture (this could be unrelated to mast cell disease, like an arm broken in a fall). Only one patient had a focal area of osteolysis with spontaneous fracture.

56% of variant 2 (aggressive) group had osteoporosis, compared to 23% of variant 1. However, when they excluded people who were classified as variant 2 based upon bone involvement, the association dropped to 17% variant 2 with osteoporosis and 23% of variant 1. Osteoporosis associated with vertebral fracture affected 48% variant 1 and 8% variant 2. Osteoporosis was also found to be associated with fewer GI symptoms, with 39% variant 1 having GI issues while 65% variant 2 did.

A total of six patients (out of a total group of 75) had osteosclerosis. One ISM, one SSM, three ASM and one SM-AHNMD patient had osteosclerosis. This translates to two in the variant 1 group and four in the variant 2 group, so twice as many in the aggressive group (ASM, SM-AHNMD) as in the non-aggressive group. 66% of patients in variant 2 with osteosclerosis had a blood count abnormality (anemia, thrombocytopenia, eosinophilia) vs 12% in variant 1. 83% of patients in variant 2 with osteosclerosis had received cytoreductive therapy vs 33% in variant 1, and higher tryptase level was associated with osteosclerosis. Overall, this means that osteosclerosis was associated with a more severe disease presentation (a patient with ISM and osteosclerosis may have a blood count abnormality), but this study does not provide any insight as to whether osteosclerosis is a marker associated with progression toward ASM or SM-AHNMD.

A 2011 paper (Guillaume 2011) assessed bone involvement in a group of CM and SM patients. In this study, SM included ISM, ASM and SM-AHNMD. 45 patients were included.  They found one patient with osteolysis, eight with osteocondensation (a form of osteosclerosis), four with a mixed pattern and three with fractures. They found no association between the presence of radiologic lesions (lesions detected by imaging techniques) and severity (here classified as non-aggressive: ISM and CM, and advanced: ASM and SM-AHNMD).

This study also looked at chemical markers used for bone remodeling. They found that markers associated with both bone resorption and bone formation were higher in mastocytosis patients than in the general population. The higher levels were thought to represent increased number of osteoblasts and osteoclasts due to the increase in mast cells. Osteoprotegerin was also higher in mastocytosis patients. This is a protein released by osteoblasts that regulates the activity of osteoclasts. Levels of C-telopeptide were significantly higher in patients with SM-AHNMD or ASM than in patients with ISM or CM.

A 2011 paper (Rossini 2011) investigated the relationship between tryptase and bone turnover markers (bone specific alkaline phosphatase, C-telopeptide, osteocalcin) in ISM patients. A total of 82 patients were enrolled in the study. 36% had bone involvement. 20% had osteoporosis, with 18.7% found in the spine and 2.5% at the hip. Five patients had a history of bone breaks outside of the spine. 27 patients had vertebral fractures. Two patients had osteosclerotic features and also had particularly high tryptase levels. Another study previously reported that high tryptase can be associated with increased bone density (Kushnir-Sukhov 2006).

This study had a large amount of ISM patients without skin lesions (55%). A very important finding of this particular study was that ISM patients without skin lesions are at the same risk for osteoporosis. As lesions are often one of the more identifiable markers of mastocytosis, the author raises the very valid point that osteoporosis may in some people be the only sign of latent ISM.

This paper reported that “diffuse osteosclerosis associated with SM is not a[n] “osteopetrosis-like osteopathy”, as previously reported, but a skeletal disease characterized by increased bone turnover.” This is important, as they have previously been equated for lack of distinction. The author further notes that the “pathophysiology of SM-related osteosclerosis remains obscure, although it is known that MCs can exert a direct stimulatory effect on osteoblast proliferation, recruitment, and activity.”

This study found that bone mineral density and serum tryptase did not correlate with the serum markers of bone turnover. However, it did find that ISM patients with osteosclerosis had higher tryptase and bone turnover markers (bone specific alkaline phosphatase and C-telopeptides of type I collagen) than ISM patients with other types of bone involvement.

(Literature review continued tomorrow)

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.

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.

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.

Progression of mast cell diseases: Part 1

Among mast cell patients, we generally assume that a designation of SM means indolent systemic mastocytosis (ISM.) However, in research papers, this term can mean ISM, SSM, ASM or MCL. Advanced SM usually means ASM or MCL. These terms generate a lot of confusion in the patient population. When reading a paper, abbreviations are usually defined on the first page or within the introduction. It is important to check on what the researchers are using the term SM for.

As an example, let’s look at this really alarming quote to someone who thinks SM means ISM:

“The life expectancy of SM patients was shorter relative to age- and sex-matched controls. As initially observed by Travis et al, survival decreased rapidly after diagnosis: to 60% at 3 years, with a subsequent slower decline to 50% at 5 years. Beyond 5 years, the slope of the survival curve was similar to that of the control population. This observation confirms that the deaths in SM patients within the first 3 (and up to 5) years after diagnosis.” (Lim 2009)

In this paper, SM meant ISM, SM-AHNMD, SSM, ASM and MCL. When you average those survival rates together, you get a sharp decline in survival for the first five years. After that, it returns to normal, because most of the ASM and MCL patients in that study died by that time.

 

I get asked A LOT about whether or not ISM is progressive. I see a lot of people describe it as progressive. In medicine, progression usually means moving from one diagnostic category to a more serious one (like ISM to SSM.) However, a lot of patients use this term to mean a worsening of symptoms or disability while staying in the same diagnostic category (like ISM with mild daily symptoms to ISM with severe daily symptoms). Those are two different things. I’m going to answer both.

 

What is the life expectancy with ISM?

It’s normal.

“Patients with ISM have a favorable prognosis. These patients may suffer from mediator-release symptoms, but do not suffer from significant organopathy caused by MC infiltration.” (Valent, 2003)

In a study of 159 patients, 2.2% ± 1.3% died within five years of diagnosis, and 11% ± 5.9% died within twenty five years of diagnosis. “The majority of deaths in this ISM cohort were unrelated to mastocytosis.” (Pardanini 2013)

In a study of 342 patients, ISM was the largest subgroup with 159 patients.  They were significantly younger at presentation (median age 49 years.) “Overall median survival was not significantly different than that of the age and gender matched control population. Advanced age was the primary determinant of inferior survival.” (Pardanini 2013)

 

Will my ISM symptoms get worse with time?

There is really no way to know. In some people, they are stable, while in others, they fluctuate. However, mediator release symptoms (degranulation symptoms) are known to be more common in ISM than ASM and MCL.

“ISM patients can be highly symptomatic; in one study, 70% reported at least some degree of functional limitation, of which 17% reported severe limitation.” (Pardanini 2013)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)

 

If my ISM symptoms get worse, does that mean I am progressing to a more severe category, like SSM, ASM or MCL?

No.

“One important aspect in this regard is that mediator-related symptoms per se are not indicative of aggressive mastocytosis unless accompanied by C-findings.” (Valent 2003)

“Moreover, organomegaly per se is not necessarily indicative of aggressive SM.” (Valent 2003)

“In fact, in a group of patients with SM, organomegaly is recorded over many years without impairment of organ function or development of C-findings.” (Valent 2003)

“The type and severity of symptoms were independent of disease classification (CM vs SM), KITD816V status, and serum tryptase level.” (Pardanini 2013)

 

References:

Pardanini, Animesh. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) 2013; Blood: 121 (16).

Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).

Pardanini, Animesh. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. 2009; Blood: 114 (18).

Lim, Ken-Hong, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. 2009; Blood: 113 (23).

Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).

Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.

Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. 2012; Expert Review of Hematology: 5 (3): 261-274.

Valent, Peter, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. 2003; Leuk Res 27 (7): 635-41.

Hauswirth, Alexander, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. 2004; Leuk Res 28 (3): 249-257.