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

Natural history of systemic mastocytosis with associated hematologic disease (SM-AHD):

  • SM-AHD is defined by systemic mastocytosis in the presence of another clonal hematologic disease. SM-AHD is thought to comprise 30-40% of all mastocytosis cases[i].
  • In about 90% of cases, the associated blood disorder is a myeloid neoplasm such as myelodysplastic syndrome, myeloid leukemias, or myeloproliferative diseases such as polycythemia vera or essential thrombocythemia[i] . Janus kinase 2 (JAK2) V617F mutation, which has a known association with myeloproliferative neoplastic conditions such as essential thrombocythemia and polycythemia vera, is sometimes present in SM-AHD patients[vii].
  • In this condition, SM and the other blood disorder are treated as separate entities as if they did not co-occur[i]. The conditions are synchronous and the associated hematologic disease does not occur secondarily to SM or treatment thereof. Prognosis in SM-AHD depends almost exclusively upon the associated hematologic concern. In multiple studies, fatalities are reported as result of associated malignancies[ii].
  • Myeloid neoplasms are the most common AHD, including chronic myelomonocytic leukemia or other leukemias, myelodysplastic syndrome, or myeloproliferative diseases[i].
  • In a 138 patient cohort: about 1/3 demonstrated Hgb <100 g/L and platelets<100×109/L; 51% had elevated white cell count; 31% demonstrated frank eosinophilia <1.5×109/L[vii].
  • SM-AHD patients are at increased risk of leukemic transformation relative to other forms of systemic mastocytosis (excluding mast cell leukemia) with a frequency of 14% in a 138 patient cohort[vii].
  • The SM aspect of SM-AHD is diagnosed and staged according to the SM diagnostic algorithm. It is therefore possible for a patient with SM-AHD to have mast cell leukemia or any other subtype of SM[vii].

Natural history of mast cell leukemia (MCL):

Table 1: Diagnostic criteria for mast cell leukemia[iii] 
Meets criteria for systemic mastocytosis Mast cells compromise 20% of all nucleated cells in blood smears

 

Table 2: C findings present in acute MCL[iii] 

 

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)

 

  • Mast cell leukemia is defined by SM where ≥20% nucleated cells in marrow are mast cells. In leukemic variant, >10% of nucleated cells in blood are mast cells; in aleukemic variant, there are <10% mast cells[iii].
  • MCL can occur de novo or from a previous mast cell neoplastic condition such as aggressive systemic mastocytosis or mast cell sarcoma[iii].
  • CKIT D816V mutation is less common in MCL than in other forms of systemic mastocytosis (50-80%). Some patients have mutations elsewhere in the coding regions of CKIT or a non-D816V mutation at CKIT codon 816. An unusual feature of MCL is that when the disease progresses quickly, the patient may lose positivity for the D816V mutation[iv].
  • MCL patients do not typically demonstrate mastocytosis in the skin[iii].
  • In the absence of C findings, some MCL patients have stable disease without markers of progression. This is referred to as chronic MCL[iii] .
  • >90% mature mast cells is a positive prognostic indicator. Presence of mostly immature mast cells is associated with more aggressive disease[iii] .
  • Acute MCL rapidly causes catastrophic organ damage. Median survival in acute cases is six months, though some MCL patients live for years through the use of newer targeted therapies[iv].
  • Hematopoietic stem cell transplant (HSCT) is an experimental option for MCL patients. In one study, overall survival at the three year mark was 17% (2 of 12 patients)[viii].

Natural history of mast cell sarcoma:

  • Mast cell sarcoma is an exceedingly rare tumor with high grade cytology that can present in a variety of tissues[v].
  • Mast cells that comprise the tumor resemble neither morphologically normal mast cells or spindled cells often seen in SM. In mast cell sarcoma, mast cells are often bilobed and multinucleated tumor cells have been reported. Of note, mast cells compromising the sarcoma often express CD30[iv].
  • Mast cell sarcomas often have neither CKIT D816V mutation nor mutations elsewhere in CKIT coding regions[vi].
  • Mast cell sarcomas often induce only local symptoms at the time of diagnosis but systemic involvement rapidly follows. Mast cell sarcoma may progress to mast cell leukemia. Median survival is 12 months[vi].

References:

[i] Gotlib J. (2013). Approach to the diagnosis and management of mastocytosis. The Hematologist, 10(1). Retrieved from: http://www.hematology.org/Thehematologist/Ask/5960.aspx

[ii] Wang SA. (2013). Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): clinical significance and comparison of chromosomal abnormalities in SM and AHNMD components. Am J Hematol, 88(3), 219-224.

[iii] Valent P, et al. (2014). Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal. Ann Oncol, 25(9), 1691-1700.

[iv] Youk J. (2016). A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data. Blood Res, 51(1), 17-22.

[v] Ryan RJH, et al. (2013). Mast cell sarcoma: a rare and potentially underreecognized diagnostic eneity with specific therapeutic implications. Modern Pathology, 26, 533-543.

[vi] Georgin-Lavialle S, et al. (2013). Mast cell sarcoma: a rare and aggressive entity – report of two cases and review of the literature. JCO, 31(6), e50-e57.

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

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