Advanced systemic mastocytosis (AdvSM)

Mast cells are immune cells that take part in allergic reactions. They are made in the bone marrow, the soft tissue inside bones where blood is made. In systemic mastocytosis, abnormal mast cells build up in the marrow and can gather in other organs too.

Systemic mastocytosis ranges from milder forms, called indolent and smoldering, in which people generally live a normal or near-normal lifespan, to more serious ones. “Advanced” systemic mastocytosis is the name for three serious types: aggressive systemic mastocytosis, in which the mast cells damage organs; systemic mastocytosis with an associated hematologic neoplasm, in which a second blood cancer is found at the same time; and mast cell leukemia, the rarest and most serious type. The second type is the most common, making up about 6 or 7 in 10 advanced cases.

Two classification systems are in use, so reports can differ. The World Health Organization calls the second type “systemic mastocytosis with an associated hematologic neoplasm” (SM-AHN). The International Consensus Classification calls it systemic mastocytosis “with an associated myeloid neoplasm” (SM-AMN).

In more than 9 in 10 people with systemic mastocytosis, the mast cells carry a change in a gene called KIT, most often one known as KIT D816V. The KIT gene makes a switch that tells mast cells to grow. The change leaves that switch stuck on, so mast cells keep building up.

This change happens in cells during a person’s life. It is generally not inherited from a parent, and it is not an infection that can be caught from anyone.

Most people with advanced disease also have other gene changes in their blood cells, most often in genes called TET2, SRSF2, ASXL1, RUNX1 or JAK2. Some of these, such as changes in ASXL1, RUNX1, SRSF2 or NRAS, are linked to a harder course. They help doctors judge risk and plan treatment.

Mast cells release chemicals that cause allergy-type symptoms. People may have flushing, stomach pain, diarrhea, nausea, tiredness, low blood pressure and lightheadedness. Some have severe allergic reactions (anaphylaxis), and triggers such as temperature changes, insect stings, some pain medicines or stress can set off symptoms.

In advanced disease, mast cells also build up in and harm organs such as the liver, spleen and lymph nodes. This can cause fluid to collect in the belly and, in aggressive systemic mastocytosis, thinning bones that break easily. When a second blood cancer is present, it causes problems of its own, and sometimes that second cancer is acute myeloid leukemia.

Diagnosis usually needs a bone marrow biopsy that shows clusters of mast cells, a blood test for tryptase (a chemical made by mast cells) and a test for the KIT change. Doctors then work out the type and look for other gene changes. Several risk scores can help estimate how the disease may behave.

Treatment aims to lower the number of abnormal mast cells and reverse organ damage. Two pills that block the KIT signal have changed treatment. In the US, midostaurin was approved in 2017 and avapritinib in 2021, both for adults with any of the three advanced types. Avapritinib is not recommended when platelets are very low (under 50,000), and in the European Union it is approved for people who have already had at least one other treatment.

These medicines can work well, and avapritinib has brought deep responses in some people, but neither medicine cures everyone and how long they work varies. Avapritinib often causes swelling, diarrhea, nausea and tiredness and can affect memory and thinking, and in its clinical trials, which also included people with another type of cancer, bleeding in the brain happened in about 3 in 100 people who took it. Midostaurin often causes nausea, vomiting and diarrhea, and in some cases serious lung inflammation. Other options include cladribine, a chemotherapy medicine used to lower mast cells, and, less often now, interferon.

When a second blood cancer is present, treatment is aimed mainly at that cancer, especially if it is acute leukemia. A donor (allogeneic) stem cell transplant is the only treatment that may cure advanced systemic mastocytosis, and European and American expert groups recommend it for people whose disease resists medicines or is otherwise high-risk. But a large registry study published in 2026 found that transplant improved survival only for people whose second cancer was acute myeloid leukemia (AML). For other types, how well the disease responded to a KIT pill mattered more, and the authors suggest those medicines may be preferred.

Living with advanced systemic mastocytosis often means regular blood tests, marrow checks and clinic visits, along with care for allergy-type symptoms. People learn which triggers to avoid, and patient groups offer emergency-room plans and alert cards in case of a severe reaction.

Outlook varies widely by type. Experts writing in 2024 put the average (median) survival at about 1 to 4 years, depending on the type and risk score, and mast cell leukemia is usually the hardest to treat. These are averages across groups of people, and they cannot predict how any one person will do.

Deciding about a transplant is hard. The team looks at the type, how well the disease has responded to medicine, other gene changes and the person’s overall health. In a German registry, people whose disease responded to treatment before transplant lived longer on average. If the disease returns afterward, a KIT pill may be used.

Most people with advanced systemic mastocytosis are treated with medicines and do not have a transplant. In a large European-led registry, about 1 in 9 people with advanced disease had a donor transplant. The transplants reported for this condition use blood-forming cells from a donor, not the person’s own cells.

Donors vary. In a German registry of people transplanted from 1999 to 2021, 6 in 10 of those with known donor details received cells from an unrelated volunteer, fully or partly matched. Most of the rest had a matched relative, and some had a half-matched (haploidentical) family donor.

Joining a registry cannot promise a match for any one person. But for the smaller group who need a transplant and have no matched relative, a volunteer donor can make it possible.