Response to Interferon Alfa-2b in a Patient with Systemic Mastocytosis

Kluin-Nelemans, Hanneke C.; Jansen, Joop H.; Breukelman, H.; Wolthers, B.G.; Kluin, Philip M.; Kroon, Herman M.; Willemze, R.

doi:10.1056/nejm199202273260907

Cited by 207 publications

(129 citation statements)

References 19 publications

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“…While symptomatic management is recommended to patients with indolent systemic mastocytosis, mast-cell cytoreductive therapy is indicated for the aggressive variants of systemic mastocytosis associated with poorer prognoses. 25 The current options for cytoreductive therapy of mastocytosis include interferon alfa-2b 26 and cladribine. 27 While these drugs can at least temporarily halt the progression of disease and lead to a variable degree of mast-cell cytoreduction, they are not uniformly effective in all patients and their use is fraught with poor tolerability and potentially serious adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Shah

Lee

Luo

et al. 2006

Blood

246

179

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Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KIT D816V ) that results in autophosphorylation of the KIT receptor in a ligandindependent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KIT D816V . Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KIT D816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KIT D816V -harboring human mastocytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KIT D816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT IntroductionSystemic mastocytosis and mast-cell leukemia are relatively rare conditions that are characterized by a pathologic accumulation of mast cells in various tissues. 1 Previous work has demonstrated the clonal nature of the disorder as evidenced by an activating point mutation in the KIT receptor tyrosine kinase. 2,3 This mutation, KIT D816V , occurs near the activation loop of the kinase and can be identified in more than 80% of systemic mastocytosis cases and thus represents an attractive target for this disorder, for which few effective therapeutic options exist. 1 Although a small molecule tyrosine kinase inhibitor of KIT, imatinib mesylate, has been available to patients recently, both preclinical and clinical studies have demonstrated convincingly that the KIT D816V mutation is inherently resistant to imatinib. [4][5][6] The crystal structure of the wild-type KIT kinase domain has been solved in an autoinhibited state, with the activation loop of the kinase in a closed conformation, 7 similar to the cocrystal structure of imatinib bound to the ABL kinase domain. 7,8 These structural studies suggest that substitution of valine for aspartic acid at position 816 in KIT may alter the conformation of the activation loop and thus prevent imatinib from efficiently binding to KIT D816V .Inhibition of KIT D816V has thus become the focus of recent studies aiming to find a curative therapy for mast-cell disease, and several potential drug candidates with an ability to inhibit KIT D816V have been identified. [9][10][11][12][13][14][15] Dasatinib (BMS-354825) is a novel, potent, oral, multitargeted kinase inhibitor that targets ABL, SRC, KIT, PDGFR, ...

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Section: Discussionmentioning

confidence: 99%

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Shah

Lee

Luo

et al. 2006

Blood

246

179

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“…4 Even high-dose bone marrow ablative therapy followed by stem cell transplantation has usually not been successful, with persistence of the mast cell infiltration 4,5 Because of its similarity with myeloproliferative disorders, patients have been treated with interferon-alfa (IFN-alfa). 6 For the first time, this intervention resulted in a decrease of mast cell infiltration with clearing of the skin lesions, decrease of bone marrow infiltration, decrease of hepatosplenomegaly, and accompanying diminishment of mast cell mediator-related symptoms. 6 Several series of patients have been described since, generally with most of the patients responding.…”

Section: Introductionmentioning

confidence: 94%

Cladribine therapy for systemic mastocytosis

Kluin-Nelemans¹,

Oldhoff²,

Doormaal³

et al. 2003

Blood

220

148

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Patients with systemic mastocytosis (SM) can suffer from disabling symptoms related to mast cell mediator release or mast cell infiltration, requiring mast cell eradication. In the present absence of any curative therapy, a recent case report describing the efficacy of cladribine showed promising results. In a pilot study, the efficacy of cladribine (0.10-0.13 mg/kg in a 2-hour infusion, days 1-5; repeated at 4-8 weeks until 6 cycles) was studied. Ten patients with SM with severe symptoms were treated. Four patients were classified as having indolent or smoldering mastocytosis, 3 as having aggressive systemic mastocytosis, and 3 as having SM with an accompanying hematologic malignancy. Nine patients received 6 courses, 1 patient stopped because of toxicodermia. All responded concerning signs, symptoms, and mast cell parameters (serum tryptase and urinary histamine metabolite excretion), although none achieved a complete remission. Prolonged follow-up is required, as response is ongoing in most cases. One patient relapsed within 11 months and showed a second response. Side effects were mainly related to bone marrow suppression. Single-agent cladribine is an effective and relatively safe treatment for severe systemic mastocytosis. The optimal dose and schedule need to be explored.

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“…IFN-a is often considered the first-line cytoreductive therapy in symptomatic SM; since the initial report in 1992 [79], several case reports or small series have shown IFN-a (IFN-a2b in most instances) to improve symptoms of MC degranulation, decrease BM MC infiltration, and ameliorate mastocytosis-related ascites/hepatosplenomegaly, cytopenias, skin findings, and osteoporosis [80][81][82][83][84][85][86][87][88][89][90][91][92]. IFN-a treatment is not uniformly effective [93], and the frequency of major response (i.e., complete resolution of one or more baseline 'C' findings) is 20-30%; the optimal dose and duration of IFN-a therapy for SM remain unclear, however concurrent administration of corticosteroids (prednisone) may improve its efficacy (up to 40% major response rate) and tolerability [87,94].…”

Section: Interferon (Ifn)-amentioning

confidence: 99%

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

Pardanani

2015

American J Hematol

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Disease overview: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extracutaneous organs.Diagnosis: The major criterion is presence of multifocal clusters of morphologically abnormal MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC expression of CD25 and/or CD2, and presence of KITD816V.Risk stratification: The 2008 World Health Organization classification of SM has been shown to be prognostically relevant. Classification of SM patients into indolent SM (ISM), aggressive SM (ASM), SM associated with a clonal non‐MC lineage disease (SM‐AHNMD), and mast cell leukemia (MCL) subgroups is a useful first step in establishing prognosis.Management: SM treatment is generally palliative. ISM patients have a normal life expectancy and receive symptom‐directed therapy; infrequently, cytoreductive therapy may be indicated for refractory symptoms. ASM patients have disease‐related organ dysfunction; interferon‐α (+/−corticosteroids) can control dermatological, hematological, gastrointestinal, skeletal, and mediator‐release symptoms, but is hampered by poor tolerability. Similarly, cladribine has broad therapeutic activity, with particular utility when rapid MC debulking is indicated; the main toxicity is myelosuppression. Imatinib has a therapeutic role in the presence of an imatinib‐sensitive KIT mutation or in KITD816‐unmutated patients. Treatment of SM‐AHNMD is governed primarily by the non‐MC neoplasm; hydroxyurea has modest utility in this setting; there is a role for allogeneic stem cell transplantation in select cases.Investigational Drugs: Recent data confirms midostaurin's significant anti‐MC activity in patients with advanced SM. Am. J. Hematol. 90:251–262, 2015. © 2015 Wiley Periodicals, Inc.

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Response to Interferon Alfa-2b in a Patient with Systemic Mastocytosis

Cited by 207 publications

References 19 publications

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis

Cladribine therapy for systemic mastocytosis

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

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