Tyrosine kinase inhibitors for the treatment of indolent systemic mastocytosis: Are we there yet?
2022; Elsevier BV; Volume: 149; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2022.04.020
ISSN1097-6825
AutoresCem Akin, Michel Arock, Peter Valent,
Tópico(s)Autoimmune Bullous Skin Diseases
ResumoIndolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety. Indolent systemic mastocytosis (ISM) is the most prevalent form of systemic mastocytosis. Many patients with ISM suffer from mast cell (MC) mediator-related symptoms. In a small number of patients, hematologic progression is seen in the follow-up. In some patients with ISM, symptoms arising from MC-derived mediators including gastrointestinal symptoms, anaphylaxis, and neuropsychiatric symptoms are kept under control with conventional mediator-targeting drugs or MC-stabilizing agents. However, in a substantial number of patients, the symptoms are refractory to such conventional therapy. For these patients, novel drugs and targeted approaches are considered. One reasonable approach may be to apply tyrosine kinase inhibitors directed against KIT and other key kinase targets expressed in neoplastic MCs in ISM. Because MCs in more than 90% of all patients with typical ISM display the KIT D816V mutant receptor, clinically effective KIT-targeting drugs have to be active against this mutant form of KIT. The 2 such most effective and well-studied agents currently available are midostaurin and avapritinib. Other KIT-targeting drugs, such as imatinib or masitinib, are less effective or even noneffective against KIT D816V and are thus recommended for use only in patients with other KIT mutant forms (noncodon 816 mutations) or with wild-type KIT. In the present article, we review the current state in the treatment of ISM with tyrosine kinase inhibitors, with special emphasis on treatment responses and potential adverse effects. In fact, all of these agents also have unique and common adverse effects, and their use to treat patients with ISM should be balanced against their toxicity and short- and long-term safety. Indolent systemic mastocytosis (ISM) is the most common variant of systemic mastocytosis (SM), accounting for more than 75% of all patients diagnosed with SM.1Valent P. Oude Elberink J.N.G. Gorska A. Lange M. Zanotti R. van Anrooij B. et al.The Data Registry of the European Competence Network on Mastocytosis (ECNM): set up, projects, and perspectives.J Allergy Clin Immunol Pract. 2019; 7: 81-87Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar ISM is diagnosed most often after a bone marrow biopsy, based on meeting World Health Organization criteria, and absence of advanced disease findings, that is, mast cell leukemia, associated non–mast cell lineage hematologic neoplasm, and absence of findings consistent with aggressive SM or smoldering SM (no C finding and <2 B findings).2Valent P. Horny H.P. Escribano L. Longley B.J. Li C.Y. Schwartz L.B. et al.Diagnostic criteria and classification of mastocytosis: a consensus proposal.Leuk Res. 2001; 25: 603-625Crossref PubMed Scopus (934) Google Scholar,3Valent P. Akin C. Metcalfe D.D. Mastocytosis: 2016 updated WHO classification and novel emerging treatment concepts.Blood. 2017; 129: 1420-1427Crossref PubMed Scopus (360) Google Scholar The life expectancy in ISM is generally comparable to that in age-matched general population, with low (<5%) risk of progression to advanced disease and low disease-related mortality.4Trizuljak J. Sperr W.R. Nekvindová L. Elberink H.O. Gleixner K.V. Gorska A. et al.Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.Allergy. 2020; 75: 1927-1938Crossref PubMed Scopus (24) Google Scholar ISM is a chronic disease, and spontaneous remissions are extremely rare.The management of ISM relies on prevention or reduction of mast cell mediator symptoms, using various antimediator drugs, including H1 and H2 histamine receptor blockers, antileukotriene drugs, mast cell stabilizers, omalizumab, and glucocorticoids in selected cases.5Castells M. Butterfield J. Mast cell activation syndrome and mastocytosis: initial treatment options and long-term management.J Allergy Clin Immunol Pract. 2019; 7 (1097-106)Abstract Full Text Full Text PDF Scopus (52) Google Scholar,6Lemal R. Fouquet G. Terriou L. Vaes M. Livideanu C.B. Frenzel L. et al.Omalizumab therapy for mast cell-mediator symptoms in patients with ISM, CM, MMAS, and MCAS.J Allergy Clin Immunol Pract. 2019; 7: 2387-2395.e3Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar However, despite best efforts in symptomatic antimediator management, a substantial percentage of patients continue to experience symptoms leading to a reduced quality of life.7Jennings S. Russell N. Jennings B. Slee V. Sterling L. Castells M. et al.The Mastocytosis Society survey on mast cell disorders: patient experiences and perceptions.J Allergy Clin Immunol Pract. 2014; 2: 70-76Abstract Full Text Full Text PDF PubMed Scopus (89) Google ScholarMost common symptoms in ISM include cutaneous, gastrointestinal, cardiovascular, and neurocognitive domains.8Theoharides T.C. Valent P. Akin C. Mast cells, mastocytosis, and related disorders.N Engl J Med. 2015; 373: 163-172Crossref PubMed Scopus (285) Google Scholar In addition to cosmetic problems posed by maculopapular skin lesions of mastocytosis, symptoms of itching, flushing, abdominal pain, acid reflux, nausea, diarrhea, brain fog, and musculoskeletal pain are commonly reported. Some patients may experience acute symptom flares, which may include anaphylaxis with low blood pressure, tachycardia, and syncopal or presyncopal episodes requiring the use of epinephrine. In several of these cases, a concomitant allergy and a mast cell activation syndrome can be diagnosed.SM-associated osteoporosis is seen in approximately one-third of the patients with ISM.9Greene L.W. Asadipooya K. Corradi P.F. Akin C. Endocrine manifestations of systemic mastocytosis in bone.Rev Endocr Metab Disord. 2016; 17: 419-431Crossref PubMed Scopus (20) Google Scholar In these patients, therapy with bisphosphonates or a receptor activator of nuclear factor kappa-β ligand (RANKL) inhibitor may be effective and may slow down or even stop the process of progressing bone loss.A patient poll conducted by the Mast Cell Disease Society in the United States revealed that more than half of the patient population surveyed experienced daily or occasional symptoms of moderate to severe intensity, and more than 75% stated that the disease had a moderate to severe impact on their quality of life.7Jennings S. Russell N. Jennings B. Slee V. Sterling L. Castells M. et al.The Mastocytosis Society survey on mast cell disorders: patient experiences and perceptions.J Allergy Clin Immunol Pract. 2014; 2: 70-76Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Among the most commonly cited causes of impact on quality of life were unpredictability of the symptoms, fatigue, gastrointestinal complaints, pain, inability to work or participate in social events, anxiety, and anaphylactic episodes.As mentioned before, the symptoms in most but not all of these patients can be kept under control with conventional symptomatic therapies. However, in many other cases, symptoms cannot be controlled and represent a real challenge for the physician. Therefore, cytoreductive therapy is considered in some patients with persistent severe symptoms despite optimized symptomatic management. Traditionally, cytoreductive treatment of mastocytosis is reserved for patients with advanced mastocytosis due to the risk of adverse effects of nonspecific cytoreductive agents such as cladribine, alpha interferon, or polychemotherapy.10Ustun C. Arock M. Kluin-Nelemans H.C. Reiter A. Sperr W.R. George T. et al.Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice.Haematologica. 2016; 101: 1133-1143Crossref PubMed Scopus (43) Google Scholar Recent availability of tyrosine kinase inhibitors (TKIs) however presented an attractive option because these agents have improved tolerability as well as increased efficacy with fewer adverse effects as compared with traditional cytoreductive options.Rationale for KIT TKIs in nonadvanced SMIn more than 90% of all patients with typical ISM, the KIT D816V mutation, which is a somatic gain-of-function mutation, can be detected in neoplastic mast cells.11Arock 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: 1223-1232Crossref PubMed Scopus (172) Google Scholar The mutation induces proliferation, differentiation, and expansion of immature mast cell progenitor cells as well as maturation and reduced apoptosis in mature mast cells. KIT encodes a transmembrane molecule, with the extracellular part binding stem cell factor (SCF) and the intracellular part encoding an intrinsic tyrosine kinase domain. KIT signaling is critical for proliferation and differentiation and potentially contributes to activation of normal mast cells.12Taylor M.L. Metcalfe D.D. Kit signal transduction.Hematol Oncol Clin North Am. 2000; 14: 517-535Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar Under normal physiologic circumstances, dimerization of KIT induced by SCF leads to autophosphorylation of tyrosine residues, which activates downstream signal transduction pathways. D816V mutation in exon 17 of KIT obviates the need for ligand interaction and induces a constitutive autophosphorylation of the molecule (Fig 1).13Akin C. Metcalfe D.D. The biology of Kit in disease and the application of pharmacogenetics.J Allergy Clin Immunol. 2004; 114 (quiz 20): 13-19Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar Therefore, KIT D816V mutation presents an attractive target for cytoreductive therapy of SM. KIT D816V is seen in both indolent and advanced SM. In ISM and in smoldering SM (SSM), KIT D816V may be the primary driver of disease evolution and mast cell expansion. In advanced SM, however, additional hematopoietic mutations are observed14Schwaab J. Schnittger S. Sotlar K. Walz C. Fabarius A. Pfirrmann M. et al.Comprehensive mutational profiling in advanced systemic mastocytosis.Blood. 2013; 122: 2460-2466Crossref PubMed Scopus (176) Google Scholar and the hematopoietic lineage involvement is not restricted to the mast cell lineage.15Garcia-Montero A.C. Jara-Acevedo M. Teodosio C. Sanchez M.L. 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: 2366-2372Crossref PubMed Scopus (392) Google Scholar Given the efficacy of KIT D816V inhibitors in advanced disease, these drugs may be expected to have even a greater impact on mast cell cytoreduction due to the more limited lineage involvement and absence of other mutations in patients with ISM and SSM. Finally, mast cell activation may in part be triggered by SCF in normal and neoplastic mast cells, and although IgE-dependent activation may be the prominent mechanism, blockage of additional SCF-induced KIT activation may also decrease mediator-related symptoms in patients with nonadvanced SM (Fig 1).Clinically relevant KIT TKIs in ISMNon-KIT D816V-targeting TKIsImatinibImatinib was the first small-molecule tyrosine kinase inhibitor developed. It inhibits wild-type (WT) KIT along with ABL, PDGFR tyrosine kinases but not D816V-mutated KIT, and therefore is not an effective option for the great majority of patients with SM.13Akin C. Metcalfe D.D. The biology of Kit in disease and the application of pharmacogenetics.J Allergy Clin Immunol. 2004; 114 (quiz 20): 13-19Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar It has been approved for use in adult patients with aggressive SM without the D816V KIT mutation or with unknown KIT mutational status. Imatinib was the first TKI shown to induce disease remission in a case report of a patient with KIT F522C mutation.16Akin C. Fumo G. Yavuz A.S. Lipsky P.E. Neckers L. Metcalfe D.D. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib.Blood. 2004; 103: 3222-3225Crossref PubMed Scopus (293) Google Scholar This patient was also the first patient to be described with a rare pathologic variant of SM called well-differentiated SM (WDSM). Patients with WDSM generally experience disease onset during childhood but experience persistence of disease into adulthood. Bone marrow pathology in WDSM is unusual in that the classic diagnostic mast cell aberrations such as spindling morphology and CD25 expression are absent, but patients are diagnosed on the basis of clusters of mast cells with round and well-differentiated morphology, increased serum tryptase levels, aberrant expression of CD30, and demonstration of clonality where applicable.17Álvarez-Twose I. Jara-Acevedo M. Morgado J.M. García-Montero A. Sánchez-Muñoz L. Teodósio C. et al.Clinical, immunophenotypic, and molecular characteristics of well-differentiated systemic mastocytosis.J Allergy Clin Immunol. 2016; 137: 168-178.e1Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar WDSM usually does not harbor KIT D816V mutation, and therefore patients with WT or noncodon 816 KIT mutations can respond to imatinib. A phase IV study evaluating 10 adult patients with SM lacking exon 17 KIT mutation included 3 patients with ISM.18Alvarez-Twose I. Matito A. Morgado J.M. 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. 2016; 8: 68950-68963Crossref PubMed Google Scholar All 3 patients with ISM had WDSM morphology. Interestingly, complete remission was observed in 1 patient with K509I KIT mutation, whereas the other 2 patients with WT KIT had no response to therapy. These data suggest that imatinib may be particularly effective in rare patients with noncodon 816 gain-of-function KIT mutations rather than those with WT KIT, although other case reports exist describing successful disease remission in patients with ISM and WT KIT.19Valent P. Cerny-Reiterer S. Hoermann G. Long-lasting complete response to imatinib in a patient with systemic mastocytosis exhibiting wild type KIT.Am J Blood Res. 2014; 4: 93-100PubMed Google Scholar,20Agarwala M.K. George R. Mathews V. Balasubramanian P. Thomas M. Nair S. Role of imatinib in the treatment of pediatric onset indolent systemic mastocytosis: a case report.J Dermatolog Treat. 2013; 24: 481-483Crossref PubMed Scopus (12) Google ScholarImatinib is also very effective in patients with FIP1L1-PDGFRA rearrangement; however, these patients also have concurrent chronic eosinophilic leukemia and therefore have an advanced disease variant and will not be discussed in this review.21Shomali W. Gotlib J. World Health Organization-defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management.Am J Hematol. 2022; 97: 129-148Crossref PubMed Scopus (13) Google ScholarDroogendijk et al22Droogendijk H.J. Kluin-Nelemans H.J. van Doormaal J.J. Oranje A.P. van de Loosdrecht A.A. van Daele P.L. Imatinib mesylate in the treatment of systemic mastocytosis: a phase II trial.Cancer. 2006; 107: 345-351Crossref PubMed Scopus (123) Google Scholar reported treatment of 9 patients with ISM, 7 of whom had a known D816V KIT mutation. Interestingly, modest reductions in bone marrow mast cell burden, tryptase levels, and urinary histamine metabolites were reported in most patients, although the patients also received steroids and oral glucocorticoids in the beginning of therapy, which may have contributed to the initial response. Four patients were also noted to have decreased skin lesions. In contrast, Lim et al23Lim K.H. Pardanani A. Butterfield J.H. Li C.Y. Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine.Am J Hematol. 2009; 84: 790-794Crossref PubMed Scopus (146) Google Scholar reported imatinib treatment of 7 patients with ISM, with only 1 response in reduction of skin lesions. Common adverse effects associated with imatinib therapy include fluid retention, hematologic and gastrointestinal toxicities, and muscle cramps.24Gleevec [package insert]. Novartis Pharmaceuticals Corp., East Hanover, NJ2020Google Scholar In addition, imatinib therapy may be complicated by an increase in liver and/or pancreatic enzymes, sometimes leading to the clinical picture of an overt hepatopathy or pancreatitis. In a few patients under long-term treatment with imatinib, a decrease in the kidney function has been reported. Most of these adverse events are reversible on drug discontinuation. Initially, imatinib was also reported to induce or promote cardiac dysfunction (arrhythmia). However, overall cardiac side effects are rare.MasitinibMasitinib is a WT KIT inhibitor that also targets LYN and FYN. It has been shown to be effective in a patient with mast cell leukemia with a dup501-502 KIT mutation.25Georgin-Lavialle S. Lhermitte L. Suarez F. Yang Y. Letard S. Hanssens K. et al.Mast cell leukemia: identification of a new c-Kit mutation, dup(501-502), and response to masitinib, a c-Kit tyrosine kinase inhibitor.Eur J Haematol. 2012; 89: 47-52Crossref PubMed Scopus (41) Google Scholar The drug is not expected to cause significant mast cell cytoreduction in typical SM because it is not effective against the KIT D816V mutant kinase; however, it may result in symptomatic improvement of mast cell activation symptoms, probably due to its inhibitory effects on LYN and FYN. In a placebo-controlled phase III trial, 135 severely symptomatic patients with ISM not controlled by optimal antimediator therapies received either masitinib (6 mg/kg/d) or placebo and symptomatic improvement was assessed at 24 weeks of treatment.26Lortholary O. Chandesris M.O. BulaiLivideanu C. Paul C. Guillet G. Jassem E. et al.Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study.Lancet. 2017; 389: 612-620Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar The primary end point was 75% improvement in at least 1 of the 4 symptoms: pruritus, flushing, depression, or asthenia. There was a 18.7% cumulative response rate versus 7.4% of placebo, regardless of the KIT mutational status. Interestingly, the study also reported slightly decreased serum tryptase levels and improvement of skin lesions in the masitinib arm. Most frequent adverse events were diarrhea (11%), rash (6%), and asthenia (6%). However, why masitinib is active only in a subset of patients independently of their KIT mutational status is still unclear and deserves further investigation. Another phase III placebo-controlled trial is currently enrolling patients with ISM and SSM.KIT D816V-targeting TKIsImatinib’s lack of efficacy in most D816V KIT+ mastocytosis cases prompted further efforts to evaluate second-generation KIT TKIs with potential inhibitory activity against the mutation. Dasatinib was among the first such drugs to be evaluated for mastocytosis. Dasatinib is an SRC/ABL inhibitor that had activity against imatinib-resistant forms of BCR-ABL, and was shown to exert inhibitory activity in vitro against both WT and D816V-mutated forms of KIT.27Shah N.P. Lee F.Y. Luo R. Jiang Y. Donker M. Akin C. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis.Blood. 2006; 108: 286-291Crossref PubMed Scopus (235) Google Scholar A clinical trial with dasatinib reported treatment of 33 patients with SM, with 33% overall response rate, which included 2 transient complete responses, both of which occurred in patients without D816V KIT mutation.28Verstovsek S. Tefferi A. Cortes J. O’Brien S. Garcia-Manero G. Pardanani A. et al.Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis.Clin Cancer Res. 2008; 14: 3906-3915Crossref PubMed Scopus (151) Google Scholar Most common grade 3 adverse effects included pleural effusions in 10% of patients, as well as hematologic toxicities and headaches. Given the lack of meaningful clinical response in D816V KIT+ patients as well as high rate of adverse events, dasatinib is not a viable option for most patients with SM, especially in view of more effective drugs discussed below.MidostaurinGiven the lack of efficacy of imatinib and masitinib for the most common forms of mastocytosis associated with D816V KIT mutations, other TKIs with activity against this mutation were evaluated. Midostaurin was the next TKI approved for advanced SM. It is a multikinase inhibitor whose targets include WT and D816V KIT. In the initial clinical trial demonstrating efficacy in advanced disease,29Gotlib J. Kluin-Nelemans H.C. George T.I. Akin C. Sotlar K. Hermine O. et al.Efficacy and safety of midostaurin in advanced systemic mastocytosis.N Engl J Med. 2016; 374: 2530-2541Crossref PubMed Scopus (281) Google Scholar improvements in quality of life in both physical and mental domains were noted30Hartmann K. Gotlib J. Akin C. Hermine O. Awan F.T. Hexner E. et al.Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.J Allergy Clin Immunol. 2020; 146: 356-366.e4Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar (Fig 2). Based on encouraging data on symptom reduction, an open-label phase 2 trial was conducted in 20 patients with ISM, all with D816V KIT mutation.31van Anrooij B. Oude Elberink J.N.G. Span L.F.R. de Monchy J.G.R. Rosati S. Mulder A.B. et al.Midostaurin in patients with indolent systemic mastocytosis: an open-label phase 2 trial.J Allergy Clin Immunol. 2018; 142: 1006-1008.e7Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar After 12 weeks of therapy with midostaurin (100 mg orally twice daily), 75% experienced symptom reduction and 80% had improved skin lesions. All responses were associated with serum tryptase reductions, and 50% also had decrease in bone marrow mast cell burden. Nausea and vomiting were the most common adverse events. Another retrospective study of midostaurin in ISM reported similar results in 11 patients with ISM and 2 with SSM, of which 92% had D816V KIT mutation.32Farrukh F. Gangat N. Shah M.V. Litzow M.R. Elliott M.A. Begna K. et al.Midostaurin therapy for indolent and smoldering systemic mastocytosis: retrospective review of Mayo Clinic experience.Am J Hematol. 2022; 97: E138-E140Crossref Scopus (3) Google Scholar Mast cell mediator symptoms and skin lesions improved in 62% and 44% of patients, respectively. Seventy-five percent of patients required dose reductions due to nausea. These results suggest that midostaurin is effective in reducing mast cell mediator-related symptoms and skin lesions in ISM; however, its utility in indolent disease is limited by its high rate of gastrointestinal toxicity.Fig 2Improvements in health-related QOL (according to SF-12 scores) in response to midostaurin in advanced SM. Median changes in SF-12 scores from baseline over the first 6 cycles of treatment in patient-reported health-related QOL measures (SF-12). Median change over baseline in QOL with up to 36 cycles of midostaurin. Reprinted from Hartmann et al,30Hartmann K. Gotlib J. Akin C. Hermine O. Awan F.T. Hexner E. et al.Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.J Allergy Clin Immunol. 2020; 146: 356-366.e4Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar with permission. QOL, Quality of life; SF-12, Short-form health survey.View Large Image Figure ViewerDownload Hi-res image Download (PPT)AvapritinibAvapritinib is a selective inhibitor of KIT D816V mutant receptor, which has recently been approved by the US Food and Drug Administration and European Medicines Agency for advanced SM, based on 2 clinical trials showing superior efficacy in inducing disease remission as compared with midostaurin (75% vs 17%).33DeAngelo D.J. Radia D.H. George T.I. Robinson W.A. Quiery A.T. Drummond M.W. et al.Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.Nat Med. 2021; 27: 2183-2191Crossref PubMed Scopus (22) Google Scholar,34Gotlib J. Reiter A. Radia D.H. Deininger M.W. George T.I. Panse J. et al.Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial.Nat Med. 2021; 27: 2192-2199Crossref PubMed Scopus (27) Google Scholar However, there was a high rate (13%) of intracranial bleeding events observed in patients with thrombocytopenia with platelet counts less than 50,000/μL in the first study.33DeAngelo D.J. Radia D.H. George T.I. Robinson W.A. Quiery A.T. Drummond M.W. et al.Safety and efficacy of avapritinib in advanced systemic mastocytosis: the phase 1 EXPLORER trial.Nat Med. 2021; 27: 2183-2191Crossref PubMed Scopus (22) Google Scholar In the second study, when thrombocytopenic patients were excluded, no intracranial bleeding events were observed in patients with platelet counts of more than 50,000.34Gotlib J. Reiter A. Radia D.H. Deininger M.W. George T.I. Panse J. et al.Efficacy and safety of avapritinib in advanced systemic mastocytosis: interim analysis of the phase 2 PATHFINDER trial.Nat Med. 2021; 27: 2192-2199Crossref PubMed Scopus (27) Google Scholar The drug label states that “in patients with AdvSM who received [avapritinib] at 200 mg daily, intracranial hemorrhage occurred in 2 of 75 patients (2.7%) who had platelet counts ≥50 × 109/L before initiation of therapy.”35Avapritinib [package insert]. Blueprint Medicines, Cambridge, MA2021Google Scholar Neurocognitive adverse events were also observed in 28% of patients with advanced SM, with 3% being greater than grade 3; however, only 2% required discontinuation due to this adverse event. Other common adverse events in these trials on advanced mastocytosis included peripheral and periorbital edema, diarrhea, nausea, and cytopenias.Avapritinib is currently being evaluated in ISM in a double-blind placebo-controlled trial, consisting of 3 parts: First part to find a recommended dose, a second part to test the recommended dose against placebo in a larger sample size, and a third open-label part.36Akin C. Sabato V. Gotlib J. Castells M. Deininger M.W. Elberink H.O. et al.PIONEER: a randomized, double-blind, placebo-controlled, phase 2 study of avapritinib in patients with indolent or smoldering systemic mastocytosis (SM) with symptoms inadequately controlled by standard therapy.J Allergy Clin Immunol. 2020; 145: AB336Abstract Full Text Full Text PDF Google Scholar In the first part of the trial, 3 doses (25, 50, and 100 mg per os [by mouth] once daily) were compared with placebo in 39 patients who had recurrent symptoms despite best supportive care with antimediator drugs. Based on efficacy and tolerability, the 25-mg dose was chosen to move forward as the part 2 dose. At 16 weeks of therapy, patients on all doses experienced an average of 30% symptom reduction (vs 3% in placebo) based on a patient-reported outcome tool developed and validated by the company. The drug was overall well tolerated with no grade 4 or 5 adverse events. Most common adverse events included fluid retention, nausea, diarrhea, and headaches. Intracranial bleeds were not encountered in this ISM trial, which enrolled patients with normal platelet counts and used a lower dose of the drug. There was 1 grade 3 neurocognitive adverse event observed in the 100-mg cohort, which improved with dose reduction to 25 mg. The trial has completed enrollment, and part 2 results are pending analysis.Investigational pipeline of KIT TKIsTwo other trials in ISM recently started enrollment to evaluate D816V selective KIT inhibitors BLU-263 and bezuclastinib (can be accessed a
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