Knowledge on rare diseases and orphan drugs

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is suggested to represent between 10-40% of all cases of SM, for which the prevalence in Europe is estimated between 1/7,700 and 1/10,400.

The disease typically affects adults and the elderly. Although the SM compartment is predominantly of the indolent type (ISM), in rare cases it is aggressive SM (ASM) or mast cell leukemia (MCL). The associated hematologic neoplasms (AHN) most commonly encountered are myeloid neoplasms and are rarely lymphoid neoplasms.When the SM compartment is indolent, the biological and clinical signs, and the prognosis, are dominated by the AHN. In contrast, when the SM compartment is an ASM or MCL, it is difficult to quantify the relative contribution of mastocytosis to typical B- (reflecting a high mast cell burden) and C- (reflecting organ(s) dysfunction(s)) findings. Of note, the SM compartment is often involved in MC mediator-related symptoms such as recurrent syncope, headache, flushing, gastro-intestinal tract symptoms and, in severe cases, life-threatening anaphylactic shock. Skin involvement, mainly with urticaria pigmentosa (UP) is frequently observed.

In the vast majority of cases, an acquired and activating mutation in KIT, mostly KITD816V, can be found in the abnormal MCs of the SM compartment as well as in the malignant cells of certain AHN types. However, SM-AHN is often a complex, multi-mutated disease; reported mutations for SM-CMML or SM-MDS include, TET2, ASXL1, and SRSF2 among others.

It is critical to determine the type of the two malignancies (SM and AHN). Diagnosis of the SM compartment is with the WHO consensus criteria. The SM is then categorized as ISM, ASM or MCL, although this may be difficult. Further testing (phenotyping, cytogenetics, molecular biology) are mandatory to characterize the nature of the AHN.

In the case where the AHN component is of myeloid nature, the two major differential diagnoses are myelomastocytic leukemias and myeloid neoplasms with expression of mast cell lineage antigens or related gene defects. Waldenström macroglobulinemia may be considered in certain circumstances. These diseases do not fulfill the SM criteria.

The disease is due to somatic mutations, genetic counseling is not required.

Each component is treated as per the guidelines for SM and AHN, irrespective of the presence of the other component. Since it is difficult to clearly delineate which component is responsible for the clinical issues/organ damage, all patients with SM-AHN should be treated as having high-risk disease. Midostaurin is approved for treatment in Europe and the USA, and whilst it is promising with partial remission of the SM-compartment, complete remission has not been reported. Patients who achieve a complete remission of their AHN, or exhibit a significant response after treatment, should be considered for allogeneic stem cell transplantation (allo-SCT) to consolidate their response. However, use of allo-SCT is often limited by age, poor performance, or other factors. For these patients, palliative therapy with hydroxyurea is required. MC mediator-related symptoms often requires supportive therapy, including H1 and H2-receptor antagonists.

Currently the overall median survival of 24 months is reported. However, the prognosis of SM-AHN depends both on the nature (aggressiveness) of the SM and the AHN component, with longer median survival reported in SM-MPN patients (31 months) and shorter survival in SM‐CMML (15 months), SM‐MDS (13 months), and SM‐AML (11 months). In addition, multi-mutated disease can negatively impact disease prognosis.

Last update: August 2019 - Expert reviewer(s): Pr Michel AROCK