Somebodies

I’ve been trying to get this post out for a few days. I feel like it’s not finished and sharp in the wrong places but I feel like this needs to be said so I’m saying it now.

When I was first diagnosed with mast cell disease, I was pretty relieved. I had been sick a long time and was so tired of being abused by doctors and called a liar. I could have been diagnosed with anything. I could have been diagnosed with weekly limb falling off disease where every week one of my limbs fell off until I had no limbs left. I needed something to hold onto and a diagnosis had that. (I am grateful to announce that I do not have limb falling off disease.)

I do, however, have mast cell disease. It was a few months before it occurred to me that having mast cell disease might be scary. There wasn’t a lot of information available on it and I didn’t have great journal access then, so I wasn’t able to validate those fears. But I was still afraid. Just a little, at first. And then another several months past and I started having major organ involvement. And I started being afraid for real. This time, my fears were validated.

One of the more common questions I get is whether or not people can die from mast cell disease. I get it a lot from people who are newly diagnosed but I get it from people who have been diagnosed a while. I realized recently that people who have been diagnosed a while only ever ask me this question in private message or email. I’ve been thinking about why that is.

The answer is simple: people are afraid to ask if they can die from mast cell disease in a public forum because, overwhelmingly, the responses are not kind. I am guilty of this, too. Those of us who have been in this community a long time have learned to stratify mast cell patients by level of hematologic malignancy – that is, to separate mast cell patients into those who have malignant forms of mast cell disease (aggressive systemic mastocytosis, mast cell leukemia, and mast cell sarcoma) and those who don’t. Because typically the people who lose their lives to mast cell disease are those with those malignant forms, and those who don’t have them don’t die from mast cell disease. The medical institution views malignant mast cell disease as dangerous and the other forms as not dangerous. Specifically, the establishment touts to everyone who will listen that you don’t die from mast cell disease if it’s not malignant.

But the truth is that’s not really the case, if you think about disease and what it does to a person and all the ways it kills them. It’s true that a person with ASM is not likely to die in the same way as an MCAS patient. A patient with ASM will die from mast cell disease if the thousands of extra mast cells burrow into their organ tissue and destroy that tissue so much that the organ stops working. That’s not what happens in a patient with MCAS. But a patient with MCAS can die in other ways. They can die from anaphylaxis and complications of huge steroid doses and side effects from chemo and sepsis and not being able to afford their health care costs and not having insurance and not being able to face one more minute of the humiliation and desperation that is begging for care from people who don’t want to provide it. All of those things can kill a person, too.

Defining death from mast cell disease along by delineating along the lines of organ failure is disrespectful, unfair and missing the point. All of us who have spent years living inside the data of this disease have done it, including me, and we should be sorry. I am. It has never been my intention to characterize MCAS as less serious than other forms of mast cell disease but I think I did anyway, and whether or not I wanted to do it doesn’t change that. I am sorry for doing this. It is not okay. I am committed to doing better in the future.

Fall is a difficult time for mast cell patients. It’s a lot of change at once. It’s new routines and major environmental upheaval. It’s triggers on crack. Season changes are always hard for us but autumn is harder, I’m not sure exactly why. But in the same way that I associate September with ports, I associate fall with mast cell patients crashing and dying. This year has been no different.

In the last several weeks, we have lost a number of mast cell patients across a variety of diagnoses, to the tune of six in six weeks. It’s painful to even type that. One of them was my friend, an SM patient who died of complications of anaphylaxis. Another was a touchstone in the MCAS community, a young woman who did a great deal to comfort others, and who undoubtedly died of complications of MCAS. Still another died of suicide. These last few weeks have been so, so crushing.

There is a very, VERY good chance that you will live a full life with a normal lifespan as a mast cell patient. But it’s not enough to say that people don’t die from non-malignant forms of mast cell disease because “almost nobody does.” Those “almost nobodies” are somebodies, and they are people with lives and dreams and futures they don’t get to experience. They do not deserve to be lost in the data, digits rounded down to zero.

We owe it to them to remember that they were real and that they were here and that they mattered.

I owe it to them. So let’s do that.

Additional posts on prognosis and disease progression:

Progression of mast cell diseases (Part One)

Progression of mast cell diseases (Part Two)

Progression of mast cell diseases (Part Three)

Progression of mast cell diseases (Part Four)

Progression of mast cell diseases (Part Five)

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

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

On prognosis and dying from mast cell disease

I am not there. I do not sleep.

 

 

 

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

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.

On prognosis and dying from mast cell disease


There isn’t a lot of data on death from mast cell disease.  Not real data, with statistics and numbers.  People with SM and MCAS are frequently reassured that they will live a normal life span.  People with SM-AHNMD are quoted an average survival of about 8.5 years; ASM, 3.5 years; MCL, under a year. 
Of those groups, only the survival time for mast cell leukemia is convincing to me.  This is because mast cell leukemia has a pretty homogenous presentation, meaning that it affects most people in the same way.  When a disease is as rare as MCL, it is important that you remove as many variables as possible in order for the data to be sound.  And that’s the problem with the rest of the survival data, to my eyes – there’s just too much variability.  Throw in a patient population as small as ours and you’ve got a lot of uncertainty.
The effects of mast cell disease are highly individualized.  There are several B and C findings, meaning that combinations of symptoms and manifestations are very variable.  The SM-AHNMD group is a good example of this.  This category lumps together many different combinations of diseases, not to mention the stages of those diseases.  Someone with ASM-AML is going to have a very different prognosis than someone with SM-CEL.  Simply averaging the lifespans of these people and quoting this as a life expectancy does the mast cell community a disservice.  It is important to remember this when you are typing “mast cell disease death” in the middle of the night. 
Even though we know that most people with SM die from something else, or that for many people, it is a very manageable disease, there is always the possibility that it will be different for you.  It’s hard not to imagine that you will be in the unlucky percentage of people that have progressive disease, that develop ASM, that have leukemic transformation.  Admonishing people who bring up this concern as “negative” or “paranoid” doesn’t make it less terrifying.  It just makes people more afraid to talk about the fact that sometimes people die from mast cell disease and often they aren’t sure how best to minimize their chances of becoming one of them.
Due to the differences in presentation, it has been difficult to identify markers that definitively indicate prognosis.  A lot of effort was put into looking at various CKIT mutations, not just D816V, to see if this could be predictive.  There has not been statistically significant data that this is the case.
The closest things we have to prognostic markers don’t get a lot of play in the general mast cell consciousness.  We talk a lot about CKIT because it affects treatment, and symptoms because it affects diagnosis.  But beyond the initial workup, we don’t often hear much about the CD2 and CD25 markers.  However, a paper published in 2009, established a link between “immunophenotype,” in this case which markers the cells present, and prognosis. 
This study looked at bone marrow samples from 123 patients with different types of SM, including MCL.  Importantly, they also had a large control group of people who did not have SM.  A solid control group is key to determining that a finding is real.  They defined the patients as either good-prognosis (SM, well differentiated SM, and cMAD, clonal mast cell activation disorder (what we now call monoclonal mast cell activation syndrome, MMAS)), or poor-prognosis (ASM and MCL.) 
They determined that for patients whose mast cells expressed BOTH CD25 and CD2 (ISM/MMAS) or NEITHER CD25 and CD2 (WDSM), prognosis was good.  However, mixed expression (typically CD25+ and CD2-) indicated a poorer prognosis.  They compared it to current markers, like the D816V mutation and serum tryptase, as well as clinical findings, like swollen spleen, swollen liver, skin lesions and white blood cell count.  The expression of markers was found to be a sounder method for estimating life expectancy than any of these.
It’s okay to be scared.  We all know people who have died from mast cell disease.  It is scary to think that we could be next.  It is scary to live under the looming threat of anaphylaxis.  But the good news is that science is trying to catch up.  More people are being diagnosed with mast cell disease, and science is getting better at identifying the ways that we are alike and different.  There is every reason to think we will have comforting data in the future.  We just have to get there. 


Reference:
Teodosio, Cristina, et al.  2009.  Mast cells from different molecular and prognostic subtypes of systemic mastocytosis display distinct immunophenotypes.  Journal of Allergy and Clinical Immunology, 125: (3), 719-726.