Clinical Validation of KIT Inhibition in Advanced Systemic Mastocytosis
- 343 Downloads
Purpose of Review
We discuss recent developments in the treatment of advanced systemic mastocytosis (advSM) with inhibitors of the KIT receptor tyrosine kinase.
advSM is a heterogeneous group of neoplasms of poor prognosis characterized by the accumulation of neoplastic mast cells. The canonical KIT D816V mutation is present in approximately 90% of SM patients, and its detection is critical for both diagnosis and therapeutic decision-making. The multikinase/KIT inhibitor midostaurin was recently approved for advSM. This agent can reverse SM-related organ damage and disease symptoms, and decrease the bone marrow mast cell burden and splenomegaly. However, complete remissions are rare and durability of responses is variable. Potent and selective KIT D816V inhibitors including avapritinib (BLU-285) and DCC-2618 have entered clinical trials, and rational combination strategies are under development.
The clinical efficacy of KIT inhibitors validate KIT as a key oncogenic driver in mast cell neoplasms. An improved understanding of the genetic heterogeneity beyond KIT will help inform the dynamics of response and relapse.
KeywordsSystemic mastocytosis KIT D816V Midostaurin Avapritinib Imatinib
Compliance with Ethical Standards
Conflict of Interest
Dr. Gotlib has, or will be serving, as Study Steering Committee Chairman or Co-Chairman of trials involving midostaurin, avapritinib, and DCC-2618 in advanced systemic mastocytosis (AdvSM). His institution received funding for conduct of these clinical trials, as well as brentuximab vedotin, for which he was principal investigator. Dr. Gotlib has also served on advisory boards, received honoraria, and reimbursement for travel expenses from Novartis, Blueprint Medicines, and Deciphera, Inc.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.•• Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405. Revised 2016 World Health Organization classification for mastocytosis, identifying clinical and pathologic diagnostic criteria for disease subtypes CrossRefGoogle Scholar
- 2.Horny H-P, Akin C, Arber DA, Peterson LA, Tefferi A, Metcalfe DD. Mastocytosis. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. World Health Organization (WHO) classification of tumours pathology & genetics tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2017. p. 61–69.Google Scholar
- 9.•• Arock M, Sotlar K, Akin C, Broesby-Olsen S, Hoermann G, Escribano L, et al. KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis. Leukemia. 2015;29:1223–32. Consensus guidelines on diagnostic testing and therapeutic monitoring of KIT D816 mutant allele burden CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A, 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;108:2366–72.CrossRefPubMedGoogle Scholar
- 18.Damaj G, Joris M, Chandesris O, Hanssens K, Soucie E, Canioni D, et al. ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. PLoS One. 2014;9:e85362.CrossRefPubMedPubMedCentralGoogle Scholar
- 21.• Jawhar M, Schwaab J, Schnittger S, Meggendorfer M, Pfirrmann M, Sotlar K, et al. Additional mutations in SRSF2, ASXL1 and/or RUNX1 identify a high-risk group of patients with KIT D816V(+) advanced systemic mastocytosis. Leukemia. 2016;30:136–43. First reported NGS data in advSM patients identifying S/A/R pos phenotype as adverse prognostic risk factor. CrossRefPubMedGoogle Scholar
- 24.• Jawhar M, Schwaab J, Hausmann D, Clemens J, Naumann N, Henzler T, et al. Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis. Leukemia. 2016;30:2342–50. Identification of splenomegaly, elevated alkaline phosphatase, and S/A/R gene panel as independent variables predicting OS for SM patients. CrossRefPubMedGoogle Scholar
- 25.• Pardanani A, Lasho T, Elala Y, Wassie E, Finke C, Reichard KK, et al. Next-generation sequencing in systemic mastocytosis: derivation of a mutation-augmented clinical prognostic model for survival. Am J Hematol. 2016;91:888–93. Identification of clinical-molecular MAPSS prognostic scoring system for SM to predict high-risk groups by OS. CrossRefPubMedGoogle Scholar
- 28.Kristensen T, Broesby-Olsen S, Vestergaard H, Bindslev-Jensen C, Møller MB, Mastocytosis Centre Odense University Hospital (MastOUH). Circulating KIT D816V mutation-positive non-mast cells in peripheral blood are characteristic of indolent systemic mastocytosis. Eur J Haematol. 2012;89:42–6.CrossRefPubMedGoogle Scholar
- 43.Huang L, Wang SA, Konoplev S, Bueso-Ramos CE, Thakral B, Miranda RN, et al. Well-differentiated systemic mastocytosis showed excellent clinical response to imatinib in the absence of known molecular genetic abnormalities. Medicine (Baltimore) [Internet]. 2016 [cited 2018 Feb 12];95. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5072932/.
- 44.Alvarez-Twose I, Matito A, Morgado JM, Sánchez-Muñoz L, Jara-Acevedo M, García-Montero A, et al. Imatinib in systemic mastocytosis: a phase IV clinical trial in patients lacking exon 17 KIT mutations and review of the literature. Oncotarget. 2017;8:68950–63.Google Scholar
- 50.• DeAngelo DJ, George TI, Linder A, Langford C, Perkins C, Ma J, et al. Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia. 2017; Long-term follow-up of midostaurin-treated advSM patients demonstrating the potential for long-term responses and continued drug safety profile Google Scholar
- 51.•• Gotlib J, Kluin-Nelemans HC, George TI, Akin C, Sotlar K, Hermine O, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374:2530–41. Registration study of the multikinase/KIT inhibitor midostaurin in advSM demonstrating high rates of reversion of organ damage, reduction in serum tryptase and BM MC burden, splenomegaly, and improvement in symptom burden/quality of life. CrossRefPubMedGoogle Scholar
- 53.Gotlib J, Pardanani A, Akin C, Reiter A, George T, Hermine O, 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;121:2393–401.CrossRefPubMedPubMedCentralGoogle Scholar
- 54.FDA. Rydapt (midostaurin) capsules [package insert] [Internet]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017 Apr. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/207997s000lbl.pdf.
- 56.•• Jawhar M, Schwaab J, Naumann N, Horny H-P, Sotlar K, Haferlach T, et al. Response and progression on midostaurin in advanced systemic mastocytosis: KIT D816V and other molecular markers. Blood. 2017;130:137–45. First reported NGS data for midostaurin-treated advSM patients describing molecular patterns of response and relapse. CrossRefPubMedGoogle Scholar
- 57.Reiter A, Kluin-Nelemans HC, George TI, Akin C, DeAngelo DJ, Hermine O, et al. Pooled survival analysis of midostaurin clinical study data (D2201 + A2213) in patients with advanced systemic mastocytosis (AdvSM) compared with historical controls. Haematologica. 2017;102:S788.Google Scholar
- 59.Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, et al. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med. 2017;9:eaao1690.Google Scholar
- 60.•• DJ DA, Quiery AT, Radia D, Drummond MW, Gotlib J, Robinson WA, et al. Clinical activity in a phase 1 study of Blu-285, a potent, highly-selective inhibitor of KIT D816V in advanced systemic mastocytosis (AdvSM). Blood. 2017;130:2. Phase I dose-escalation study of the KIT D816V-specific inhibitor avapritinib (BLU-285) in advSM demonstrating high rates of clinical responses and reduction in bone marrow mast cell and KIT D816V allele burden, as well as description of safety/tolerability and recommended phase II dose. CrossRefGoogle Scholar
- 61.Schneeweiss MA, Peter B, Blatt K, Berger D, Stefanzl G, Hadzijusufovic E, et al. The multi-kinase inhibitor DCC-2618 inhibits proliferation and survival of neoplastic mast cells and other cell types involved in systemic mastocytosis. Blood. 2016;128:1965–5.Google Scholar
- 64.Spiegel JY, McNamara C, Kennedy JA, Panzarella T, Arruda A, Stockley T, et al. Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy. Blood Adv. 2017;1:1729–38.Google Scholar
- 65.Gleixner KV, Mayerhofer M, Aichberger KJ, Derdak S, Sonneck K, Böhm A, et al. PKC412 inhibits in vitro growth of neoplastic human mast cells expressing the D816V-mutated variant of KIT: comparison with AMN107, imatinib, and cladribine (2CdA) and evaluation of cooperative drug effects. Blood. 2006;107:752–9.CrossRefPubMedGoogle Scholar
- 67.Baird JH, Verstovsek S, George TI, Reyes I, Abuel J, Perkins C, et al. Phase 2 study of brentuximab vedotin in patients with advanced systemic mastocytosis. Blood. 2017;130:2909–9.Google Scholar
- 70.Vaes M, Benghiat FS, Hermine O. Targeted treatment options in mastocytosis. Front Med (Lausanne) [Internet]. 2017 [cited 2018 Jan 2];4. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517467/.
- 72.• Ustun C, Gotlib J, Popat U, Artz A, Litzow M, Reiter A, et al. Consensus opinion on allogeneic hematopoietic cell transplantation in advanced systemic mastocytosis. Biol Blood Marrow Transplant. 2016;22:1348–56. Consensus recommendations on the role of allogeneic HSCT in the treatment of advSM. CrossRefPubMedGoogle Scholar