Vol 10, No 3 (2019)
Guidelines / Expert consensus
Published online: 2019-12-20
Advanced systemic mastocytosis — experts’ statement on diagnostic and therapeutic approach
Hematologia 2019;10(3):113-123.
Abstract
Systemic mastocytosis (SM) is characterized by clonal proliferation of abnormal mast cells and their accumulation in skin and/or other organs. The annual incidence of SM is between 5–10 new cases per million population and it usually occurs above 30 years of age. The diagnostic criteria include the detection of aggregates of mast cells in bone marrow, an increased serum tryptase level, the expression of CD25 on the mast cells and the presence of somatic mutation within the KITD816V. An advanced SM encompasses three variants with which hematologists should be familiar with 1) aggressive SM (ASM), 2) SM with an associated hematological neoplasm (SM-AHN) and 3) mast cell leukemia (MCL). Among them MCL has the worst prognosis with median survival of 2 months. The prognostic factors in SM include both clinical, laboratory and molecular parameters, but the latter are of special interest. The adverse prognosis is associated with the mutations within the genes: SRSF2, RUNX1 and ASXL1. The therapeutic approach independently from SM variant, should be aimed at avoidance of known triggers of mast cell activation and anti-mediator therapy as needed. Midostaurin with overall response rate of 60% should be the first-line choice when the symptoms of organ dysfunction occurs. The other treatments comprise cladribine and [peg]interferon alpha. The only curative therapy for SM is allogeneic stem cell transplantation. In this manuscript we present the current views on diagnostic and therapeutic approach for patients with this rare entity.
Keywords: systemic mastocytosistryptasemast cellsKITD816Vmidostaurincladribineallogeneic hematopoietic stem cell transplantationprognosis
References
- Horny HP, Metcalfe DD, Akin C. Mastocytosis. In: Swerdlow SH, Campo E, Harris NL NL. ed. HO Classification of Tumors of Hematopoietic and Lymphoid Tissues. International Agency for Research and Cancer (IARC), Lyon 2017: 62–69.
- Brockow K. Epidemiology, prognosis, and risk factors in mastocytosis. Immunol Allergy Clin North Am. 2014; 34(2): 283–295.
- Valent P, Oude Elberink JNG, Gorska A, et al. Study Group of the European Competence Network on Mastocytosis (ECNM). The Data Registry of the European Competence Network on Mastocytosis (ECNM): set up, projects, and perspectives. J Allergy Clin Immunol Pract. 2019; 7(1): 81–87.
- Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113(23): 5727–5736.
- Valent P, Spanblöchl E, Sperr WR, et al. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood. 1992; 80(9): 2237–2245.
- Soucie E, Hanssens K, Mercher T, et al. In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells. Blood. 2012; 120(24): 4846–4849.
- Tefferi A, Levine RL, Lim KH, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009; 23(5): 900–904.
- Gotlib J, Gerds AT, Bose P, et al. Systemic mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018; 16(12): 1500–1537.
- Horny HP, Valent P. Histopathological and immunohistochemical aspects of mastocytosis. Int Arch Allergy Immunol. 2002; 127(2): 115–117.
- Jordan JH, Walchshofer S, Jurecka W, et al. Immunohistochemical properties of bone marrow mast cells in systemic mastocytosis: evidence for expression of CD2, CD117/Kit, and bcl-x(L). Hum Pathol. 2001; 32(5): 545–552.
- Sotlar K, Horny HP, Simonitsch I, et al. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. Am J Surg Pathol. 2004; 28(10): 1319–1325.
- Sotlar K, Cerny-Reiterer S, Petat-Dutter K, et al. Aberrant expression of CD30 in neoplastic mast cells in high-grade mastocytosis. Mod Pathol. 2011; 24(4): 585–595.
- Hatch EW, Geeze MB, Martin C, et al. Variability of PD-L1 expression in mastocytosis. Blood Adv. 2018; 2(3): 189–199.
- Shomali W, Gotlib J. The new tool "KIT" in advanced systemic mastocytosis. Hematology Am Soc Hematol Educ Program. 2018; 2018(1): 127–136.
- Pardanani A, Kimlinger T, Reeder T, et al. Bone marrow mast cell immunophenotyping in adults with mast cell disease: a prospective study of 33 patients. Leuk Res. 2004; 28(8): 777–783.
- Sotlar K, Fridrich C, Mall A, et al. Detection of c-kit point mutation Asp-816 → Val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res. 2002; 26(11): 979–984.
- Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006; 108(7): 2366–2372.
- Valent P, Spanblöchl E, Sperr WR, et al. Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood. 1992; 80(9): 2237–2245.
- Sotlar K, Colak S, Bache A, et al. Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD). J Pathol. 2010; 220(5): 586–595.
- Schwaab J, Schnittger S, Sotlar K, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood. 2013; 122(14): 2460–2466.
- Sperr WR, El-Samahi A, Kundi M, et al. Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematology. Eur J Clin Invest. 2009; 39(10): 914–923.
- Jawhar M, Schwaab J, Álvarez-Twose I, et al. MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. J Clin Oncol. 2019; 37(31): 2846–2856.
- Pardanani A, Shah S, Mannelli F, et al. Mayo alliance prognostic system for mastocytosis: clinical and hybrid clinical-molecular models. Blood Adv. 2018; 2(21): 2964–2972.
- Pardanani A, Finke C, Abdelrahman RA, et al. Increased circulating IL-2Rα (CD25) predicts poor outcome in both indolent and aggressive forms of mastocytosis: a comprehensive cytokine-phenotype study. Leukemia. 2013; 27(6): 1430–1433.
- Pardanani A. Systemic mastocytosis in adults: 2019 update on diagnosis, risk stratification and management. Am J Hematol. 2019; 94(3): 363–377.
- Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016; 374(26): 2530–2541.
- Jawhar M, Schwaab J, Naumann N, et al. Response and progression on midostaurin in advanced systemic mastocytosis: D816V and other molecular markers. Blood. 2017; 130(2): 137–145.
- Barete S, Lortholary O, Damaj G, et al. Long-term efficacy and safety of cladribine (2-CdA) in adult patients with mastocytosis. Blood. 2015; 126(8): 1009–1016.
- Casassus P, Caillat-Vigneron N, Martin A, et al. Treatment of adult systemic mastocytosis with interferon-alpha: results of a multicentre phase II trial on 20 patients. Br J Haematol. 2002; 119(4): 1090–1097.
- Alvarez-Twose I, Matito A, Morgado JM, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 mutations and review of the literature. Oncotarget. 2017; 8(40): 68950–68963.
- Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood. 2003; 102(9): 3093–3096.
- Ustun C, Arock M, Kluin-Nelemans HC, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014; 32(29): 3264–3274.
- Ustun C, Gotlib J, Popat U, et al. Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis. Biol Blood Marrow Transplant. 2016; 22(8): 1348–1356.
- Deininger MW, Gotlib J, Robinson WA, et al. Avapritinib (BLU-285), a selective KIT inhibitor, is associated with high response rate and tolerable safety profile in advanced systemic mastocytosis (AdvSM): results of a phase 1 study. HemaSphere. 2018; 2. ; 257(Suppl 1): abstract.
- Schneeweiss M, Peter B, Bibi S, et al. The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. Haematologica. 2018; 103(5): 799–809.
- Gotlib J, Baird JH, George TI, et al. A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis. Blood Adv. 2019; 3(15): 2264–2271.
- Gotlib J, Pardanani A, Akin C, et al. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood. 2013; 121(13): 2393–2401.
