January 2015: Post summaries and take home points

Mast cell mutations: JAK2 and myeloproliferative neoplasms

  • JAK2 is a helper protein that helps other molecules send signals to make more cells and to increase inflammation.
  • JAK2 mutation V617F makes some cells more responsive to growth factors, so they grow too much. These cells include red blood cells, platelets and mast cells.
  • Marker associated with other myeloproliferative diseases essential thrombocythemia (too many platelets), polycythemia vera (too many red blood cells), myelofibrosis (fibrosis of bone marrow).
  • About 5% of SM patients have JAK2 V617F mutation. Indicates higher probability of developing another myeloproliferative disease.
  • Doesn’t necessary mean lifespan is shorter.

Heritable mutations in mastocytosis

  • About 75% of MCAD patients have at least one first degree relative with MCAD.
  • The CKIT D816V mutation is not known to be heritable, but other CKIT mutations have been found in multiple family members.

Progression of mast cell diseases (Part 1)

  • Life expectancy with indolent systemic mastocytosis (ISM) is normal.
  • Average age at diagnosis of ISM is 49.
  • Type and severity of symptoms vary and do not correlate with disease type, presence of CKIT D816V mutation or tryptase level.
  • Mediator related symptoms are not indicative of aggressive or progressing disease.
  • Organ swelling is not always indicative of ASM. Organs can be swollen for many years without functional damage or C findings.

Progression of mast cell diseases (Part 2)

  • 5-10 years from diagnosis with ISM, 1.7% of patients progressed to SSM/ASM.
  • 20-25 years from diagnosis with ISM, 8.5% of patients progressed to SSM/ASM.
  • Risk of transformation of ISM to acute leukemia or ASM was less than 1% and 3% respectively.
  • ASM and MCL are associated with accumulation of neoplastic mast cells in organs, impairment of organ function, drug resistance, poor prognosis and organ failure.
  • In most SSM patients, disease stays stable over years or decades.
  • SSM patients have higher incidence of anemia, constitutional symptoms and mast cell mediator levels than ISM patients.
  • SSM is diagnosed later than ISM, around 64 years.
  • ASM can be slow progressing and stable for many years or rapidly progressing.
  • During progression of ASM and MCL, some patients lose the CKIT D816V mutation.
  • Slow progression ASM can be kept under control for several months or even years with interferon and cladribine.
  • In a group of 342 patients, 0.6% ISM patients developed MCL or AML, 6.5% ASM, and 13% SM-AHNMD.
  • It is possible for disease to convert to less severe category.

Progression of mast cell diseases (Part 3)

  • Mast cell accumulation is mostly due to decrease in apoptosis (cell death) rather than excessive proliferation.
  • 20-30% of SM patients have tryptase below 20 ng/ml.
  • If you test negative for CKIT D816V in blood, you may still be positive.
  • Bone marrow test for CKIT D816V is most accurate.
  • Histamine intolerance has been proposed as deficiency of enzymes to metabolize histamine. There is no evidence that this occurs in mast cell disease.
  • 33% of MCAS patients are positive for elevated tryptase, 56% n-methylhistamine, 44% PGD2.
  • 66% of patients with MCAS have major or complete regression in symptoms after one year of treatment.

Progression of mast cell diseases (Part 4)

  • ISM is not life threatening in and of itself. Anaphylaxis, a symptom of ISM, is life threatening.
  • 49% of SM patients experience anaphylaxis in their lifetime. 48% of anaphylaxis episodes in ISM patients were severe.
  • There is no consensus on what is a normal count of mast cells in GI tract. Some healthy patients have more than 20 mast cells/hpf.
  • Most patients with adult onset cutaneous mastocytosis also have systemic mastocytosis.
  • Early studies indicated CM and MCAD were different, but frequency of CKIT mutations the same in patients with CM, SM and MCAS (about 86% in each group in one study). NOTE: The CKIT mutations were not always the D816V mutation.
  • Patients with MMAS (monoclonal mast cell activation syndrome) and MCAS (mast cell activation syndrome) never have CM.
  • ASM and MCL patients frequently lack CM.

Progression of mast cell diseases (Part 5)

  • 55% of pediatric mastocytosis cases occur in the first two years of life.
  • 35% occur between ages of 15 and 18.
  • Cutaneous mastocytosis can result in mediator release symptoms without having systemic mastocytosis.
  • 2/3 of childhood mastocytosis patients had complete resolution of cutaneous disease and symptoms before adulthood. They were not treated with steroids, PUVA or chemo drugs.
  • Bone marrow biopsies of children with CM often show more mast cells than normal. High bone marrow mast cells in these children does not affect resolution.
  • In a study of 50 pediatric CM patients, 86% had a CKIT mutation and36% had the D816V mutation.

Mast cell mutations: TET2 and mutation profiles of aggressive subtypes

  • TET2 is mutated in 20.8-29% of SM patients.
  • Several mutations are seen.
  • TET2 is involved in DNA methylation which affects gene expression.
  • 96% of SM patients with major blood abnormalities had mutations in at least two genes regardless of SM subtype.

Mast cell mutations: SRSF2 in SM-AHNMD

  • SRSF2 is a protein that affects gene expression.
  • An SRSF2 mutation was found in 24-37% of SM patients.
  • Most common mutation in SM after CKIT D816V.
  • Strongly associated with SM-AHNMD.
  • Also found in other cell types besides mast cells. In SM-AHNMD, may cause both mast cell disease and associated blood disorder.

Anticholinergic use and dementia

  • People who took higher amounts of anticholinergics had an increased risk of dementia.
  • Some medications used to treat mast cell disease are strong anticholinergics, like diphenhydramine and doxepin.
  • It is not clear if the medications caused dementia or if the conditions that required those medications caused dementia.