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Systemic Mastocytosis: A Concise Clinical and Laboratory Review

May 18, 2007

By Patnaik, Mrinal M; Rindos, Michelle; Kouides, Peter A; Tefferi, Ayalew; Pardanani, Animesh

Context.-Systemic mastocytosis is characterized by abnormal growth and accumulation of neoplastic mast cells in various organs. The clinical presentation is varied and may include skin rash, symptoms related to release of mast cell mediators, and/or organopathy from involvement of bone, liver, spleen, bowel, or bone marrow.

Objective.-To concisely review pathogenesis, disease classification, clinical features, diagnosis, and treatment of mast cell disorders.

Data Sources.-Pertinent literature emerging during the last 20 years in the field of mast cell disorders.

Conclusions.-The cornerstone of diagnosis is careful bone marrow histologic examination with appropriate immunohistochemical studies. Ancillary tests such as mast cell immunophenotyping, cytogenetic/ molecular studies, and serum tryptase levels assist in confirming the diagnosis. Patients with cutaneous disease or with low systemic mast cell burden are generally managed symptomatically. In the patients requiring mast cell cytoreductive therapy, treatment decisions are increasingly being guided by results of molecular studies. Most patients carry the kit D816V mutation and are predicted to be resistant to imatinib mesylate (Gleevec) therapy. In contrast, patients carrying the FIP1L1-PDGFRA mutation achieve complete responses with low-dose imatinib therapy. Other therapeutic options include use of interferon-α, chemotherapy (2- chlorodeoxyadenosine), or novel small molecule tyrosine kinase inhibitors currently in clinical trials.

(Arch Pathol Lab Med. 2007;131:784-791)

The discovery of mast cells (MCs) in 1878 is credited to Paul Ehrlich, who first described cells that stained with metachromatic dyes such as toluidine blue, which he termed MCs. Since then, extensive work has been done on the physiology, pathology, and genetics of normal MCs and their pathologic counterparts in mast cell disease (MCD). It is now known that MCs are myeloid lineage cells that arise from bone marrow (BM) precursors, more specifically from CD34^sup +^ and Kit^sup +^ hematopoietic progenitors and not from monocytes or basophils as previously thought.1-5 The cytokine stem cell factor (also known as Kit ligand) plays a key role in inducing differentiation of MCs from their progenitors, in concert with other cytokines including interleukin 3.6-8 Normal MCs are round or oval cells, with a round, centrally located, nonlobated nucleus, and have abundant, uniformly distributed cytoplasmic granules. Immunophenotypic characterization of normal MCs typically reveals the presence of 2 characteristic surface markers, the CD117 antigen (c-Kit; the receptor for stem cell factor) and the high affinity receptor for immunoglobulin (Ig) E (FcεRI), neither of which, however, are MC specific.9,10 The typical profile of MCs in normal BM has been described as CD117^sup ++^/CD34^sup -^/CD38^sup – ^/CD138^sup -^/CD45^sup +^/FcεRI^sup +^. Mast cells play an integral role in type I hypersensitivity reactions implicated in bronchial asthma, urticaria, anaphylaxis, and other allergic conditions. Here, engagement of FcεRI receptors promotes MC degranulation and release of histamine and other mediators including proteases, heparin, prostaglandins, leukotrienes, cytokines, and chemokines that mediate many of the clinical features of MCD (reviewed by Castells11).

MAST CELL DISORDERS

Mastocytosis is characterized by the abnormal growth and accumulation of morphologically and immunophenotypically abnormal MCs in 1 or more organs. Neoplastic MCs, in contrast to normal MCs, are more variable in appearance, ranging from round to fusiform variants with long, polar cytoplasmic processes, and may display cytoplasmic hypogranularity with uneven distribution of fine granules and atypical nuclei with monocytoid appearance. 12-14 Immunophenotypic interrogation of MCs has revealed aberrant expression of several markers in patients of virtually all adult systemic mastocytosis (SM) categories. 15-17 Of these, MC expression of CD25 and/or CD2, as determined by either flow cytometry or immunohistochemistry, are the most relevant from the clinical standpoint and serve as a minor criterion for making the diagnosis of SM per World Health Organization (WHO) guidelines.18-20

Mast cells retain surface Kit expression at high levels on maturation, and the interaction between Kit and stem cell factor has been shown to promote the proliferation, maturation, adhesion, chemotaxis, and survival of MCs.8 Consequently, gain-of-function mutations in kit, particularly the D816V mutation, have been found to occur frequently in SM patients.21 The issue as to whether additional genetic “hits” are necessary for neoplastic transformation of MCs and for full expression of aggressive SM subtypes remains unsettled based on currently available data (reviewed by Pardanani et al22).

Furitsu et al23 first demonstrated constitutive phosphorylation of Kit receptor expressed on HMC-1 cells, an immature MC line derived from a patient with mast cell leukemia (MCL), and described the presence of 2 mutations in the kit gene (V560G and D816V) in this cell line. Soon after this report, Nagata et al24 published the first report of the kit D816V mutation in human SM. Since then, other kit mutations, either replacement of D816 with a nonvaline residue (eg, D816Y,25 D816F,25 D816H,26 and D820G27) or mutations in other domains (extracellular,28 transmembrane, 29,30 or juxtamembrane31,32) have also been identified in MCD. The latter mutations include F522C, A533D, K509I, del419, and V559A, many of which are representative of rare alleles detected in germline DNA in several cohorts of familial mastocytosis (reviewed by Akin33). Interestingly, several kindreds with combined familial gastrointestinal stromal tumors and mastocytosis, both of which are associated with gain-of-function kit mutations, have also now been described.28

The classification of mast cell neoplasms has evolved with time. The current WHO classification classifies MCD into 7 variants (Table 1)20,34: cutaneous mastocytosis (CM), indolent SM, SM with an associated clonal hematologic non-mast cell disorder, aggressive SM, MCL, and MC sarcoma. In addition, 2 provisional and relatively rare variants of SM with characteristic clinical and/or pathologic features have also been described-well-differentiated systemic mastocytosis (WDSM)30 and systemic mastocytosis without skin involvement associated with recurrent anaphylaxis.21

The WHO classification of SM mandates a number of staging investigations to define the exact subtype of disease. 20 Identification of “B” findings alone such as more than 30% BM MC burden or serum tryptase more than 200 ng/mL are indicative of a high systemic MC burden (ie, smoldering SM), whereas the additional presence of “C” findings (Table 2) such as cytopenias, pathologic fractures, hypersplenism, and so forth indicate impaired organ function directly attributable to MC infiltration and are diagnostic for presence of “aggressive” disease (ie, aggressive SM).

Non-MCD-related conditions including benign disorders associated with MC activation such as allergic (bronchial asthma) and atopic disorders, chronic urticaria, anaphylaxis, and other systemic disorders mimicking MCD (eg, VIPoma, adrenal tumors, gastrointestinal inflammatory disorders) must be excluded by appropriate testing prior to reaching a diagnosis of MCD.

CLINICAL FEATURES OF MAST CELL DISORDERS

Mast cell disease presents with varied clinical features that can be broadly grouped as follows:

Cutaneous Disease

There are 3 major forms of CM recognized by the WHO.20 The most common is urticaria pigmentosa (also referred to as maculopapular cutaneous mastocytosis), the others being diffuse CM and solitary mastocytoma of the skin. The skin lesions are typically yellow tan to reddish brown macules and may less frequently present as nodules or plaques. The lesions generally involve the extremities, trunk, and abdomen but spare the palms, soles, and scalp. The lesions commonly exhibit an urticarial response to mechanical stimulation such as stroking or scratching (Darier sign or dermographic urticaria).35,36 Biopsies of urticaria pigmentosa/maculopapular cutaneous mastocytosis lesions demonstrate multifocal MC aggregates mainly around blood vessels and around skin appendages in the papillary dermis.36,37 Children account for nearly two thirds of all reported cases of CM, with nearly 80% of these arising in infancy.38- 40 In contrast, most adult MCD patients with urticaria pigmentosa/ maculopapular cutaneous mastocytosis have systemic disease (often indolent) at presentation, which is most commonly revealed by a BM biopsy done as part of the diagnostic workup.41

MC-Mediator Release Symptoms With or Without Cutaneous Manifestations

Most adult patients with MC-mediator release symptoms have a low systemic MC burden, commonly exhibit CM lesions, and generally have indolent disease. Presenting symptoms include pruritus, urticaria, angioedema, flushing, bronchoconstriction, neuropsychiatric manifestations, and hypotension.42 Gastrointestinal features such as nausea, vomiting, abdominal pain, diarrhea, and malabsorption may be prominent in some patients. Histamine receptor stimulation increases gastric acid production, which may cause peptic ulcer diseasewith potential morbidity from a bleeding peptic ulcer and/or perforation.43,44 Presyncope, episodic vascular collapse, and sudden death represent the more dramatic clinical presentations of MCmediator release.45

Musculoskeletal Symptoms

Patients may have indolent or aggressive disease and present with poorly localized bone pain, diffuse osteoporosis or osteopenia, myalgias, arthralgias, pathologic fractures, skeletal deformities, and/or compression radiculopathies. In the absence of typical cutaneous lesions (urticaria pigmentosa/maculopapular cutaneous mastocytosis) or MC-mediator release symptoms, the diagnosis of SM may prove challenging and diagnosis is frequently delayed in this setting. Systemic mastocytosis, in this setting, must be distinguished from other disorders including osteoporosis, metastatic cancer, Paget disease, and multiple myeloma.

Systemic Disease

Systemic mastocytosis patients with systemic disease are generally older, are without CM lesions, frequently exhibit organomegaly and MC atypia (ie, high-grade morphology), and commonly have aggressive disease.13,46,47 Organ infiltration by neoplastic MCs may present as hepatomegaly (with or without liver dysfunction and ascites), splenomegaly (with or without hypersplenism), lymphadenopathy, large osteolyses with or without pathologic fractures, and malabsorption with hypoalbuminemia and weight loss. Extensive marrow involvement may result in anemia and eventually pancytopenia.

DIAGNOSIS OF MAST CELL DISORDERS

The diagnosis of SM is based on identification of neoplastic MCs by morphologic, immunophenotypic, and/or genetic (molecular) criteria in various organs. Per the WHO criteria for MCD classification, the diagnosis of SM requires fulfillment of 1 major and 1 minor criterion or, alternatively, of 3 minor criteria (Table 3).20 The diagnosis of SM is most commonly established by thorough histologic and immunohistochemical examination of a BM specimen (aspirate and biopsy). This is because the BM is almost universally involved in adult MCD, and histologic diagnostic criteria for non- BM organ involvement in SM have not been established and/or widely accepted as of yet.

BM Examination

Bone marrow examination is almost always necessary for the diagnosis of adult SM and helps establish whether an associated clonal non-MC lineage hematologic disorder is present. The pathognomonic lesion, which satisfies the WHO major diagnostic criterion, is the presence of multifocal, dense MC aggregates, frequently in perivascular and/or paratrabecular locations (Figure, A). These aggregates may be relatively monomorphic, composed mainly of fusiform MC, or may be polymorphic withMC admixed with lymphocytes, eosinophils, neutrophils, histiocytes, endothelial cells, and fibroblasts.12 Eosinophils are most commonly found distributed at the periphery of MC aggregates (often focally), but increased eosinophils may also be seen in noninfiltrated areas.13 Although irregular trabecular thickening is commonly noted, particularly when MC aggregates abut the trabeculae, other cases may be characterized by a marked thinning of BM trabeculae and osteopenia. Mast cell infiltrates are commonly associated with a dense network of reticulin fibers. In cases with diffuse BM infiltration by monomorphous, spindled MCs resembling fibroblasts, a diagnosis of idiopathic myelofibrosis may be erroneously made, especially when accompanied with a decrease in normal hematopoietic elements.

Three distinct histologic patterns of BM involvement in SM have been described.12,13 The commonest, type I, is frequently associated with urticaria pigmentosa and exhibits focal MC infiltration with normal distribution of fat cells and hematopoietic elements in the uninvolved marrow space. In contrast, type II pattern reveals significantly increased granulopoiesis in the marrow space not involved by MCs, and type III pattern is characterized by a diffuse marrow infiltration with morphologically atypical MCs, commonly with circulating MCs. The histologic pattern of BM MC involvement appears to be prognostically important, and this feature is reflected in the list of “B” findings in the WHO classification, which helps distinguish between various SM subtypes.13,20 Although MC cytologic atypia (large, irregularly shaped nuclei, increased mitotic activity, decreased numbers of metachromatic granules, etc) has been historically proposed by some authors as a criterion for “aggressive” MCD,47-50 such proposals have not been either broadly accepted or implemented in routine practice.

In general, MCs may not be readily recognized by standard dyes such as Giemsa, toluidine blue, or naphthol ASD chloroacetate esterase (Leder stain), particularly when associated with significant hypogranulation or with abnormal nuclear morphology, and may be confused with a variety of other cells that include fibroblasts, histiocytes, hairy cells, and monocytes.12,51 Furthermore, the metachromatic staining properties of MCs may be significantly diminished or lost with conventional tissue processing, particularly decalcification with acidic solutions that is necessary for sectioning of paraffin-embedded BM tissue.51 Among the immunohistochemical markers, staining for tryptase is considered the most sensitive, being able to detect even small-sized MC infiltrates (Figure, B).52,53 Given that virtually all MCs, irrespective of their stage of maturation, activation status, or tissue of localization, express tryptase, staining for this marker detects even those infiltrates that are primarily comprised of immature, nongranulated MCs.19 Tryptase immunostaining is particularly useful for the diffuse pattern of MC infiltration, in which a loose MC distribution, in lieu of the discrete MC aggregates, may be seen.52 It must be emphasized that neither tryptase nor other immunohistochemical markers such as chymase, c- Kit/CD117 (Figure, C), or CD68 can distinguish between normal and neoplastic MCs.18 In addition, abnormal basophils seen in some cases of acute and chronic basophilic leukemia and in chronic myeloid leukemia and blasts in some acute myeloid leukemia cases may be tryptase positive and may prove difficult to distinguish from MCs.54 In contrast, immunohistochemical detection of aberrant CD25 expression on BM MCs appears to be a reliable diagnostic tool in SM, given its ability to detect abnormal MCs in all SM subtypes, including the rare cases with a loosely scattered, interstitial pattern of MC involvement. 19 Finally, it should be pointed out that the MC burden in normal BM is very low (

MC Immunophenotyping

As mentioned previously, the qualitative and semiquantitative profiling of cell surface antigens by multiparametric flow cytometry can be extremely useful in distinguishing normal BM MCs from their pathologic counterparts in SM (reviewed by Escribano et al56). Normal MCs typically express c-Kit/CD117 and FcεRI, and the typical profile of normal MCs is CD117^sup ++^/FcεRI^sup +^/ CD34-/CD38-/CD33^sup +^/CD45^sup +^/CD11c^sup +^/CD71^sup +^. These cells do not express certain myeloid markers (CD14 and CD15) or lymphoid lineage markers except CD22.57 Neoplastic MCs in most SM subtypes usually express CD25 and/or CD2, and the abnormal expression of at least 1 of these 2 antigens counts as a minor criterion toward the diagnosis of SM per the WHO system.20 In general, the detection of CD25 on MCs, by either flow cytometry or immunohistochemistry, appears to be the more reliable marker (relative to CD2), although some authors have noted significant variation in the percentage of CD2^sup +^ cases by flow cytometry depending on the specific antibody-fluorochrome conjugate used.56 Consistent with flow cytometry data,17 it has been reported that screening for CD2 expression by immunohistochemistry may have relatively low diagnostic value because a significant proportion of cases stain negative, and CD2 expression on BM MCs is generally weak in the cases that are positive.18,19,53 Interval monitoring of CD25 expression on BM MCs may represent one approach for assessing presence of residual disease in patients undergoing MC cytoreductive therapy, generally for aggressive SM disease subtypes.17,58,59 Other aberrant immunophenotypic features of neoplastic MCs include abnormally high expression of complement-related markers such as CD11c,60 CD35,61 CD59,61 and CD88,61 as well as increased expression of the CD69 early-activation antigen,62 and the CD63 lysosomal- associated protein.63

Serum Tryptase Measurement

Measurement of tryptase (an MC enzyme with trypsinlike enzymatic activity) levels in biologic fluids (serum) has proven to be a useful disease-related marker in SM and is included as a minor criterion for the diagnosis of SM per WHO guidelines, provided that certain conditions are satisfied.20,64 There are 2 major forms of MC tryptase-alpha (subtypes alpha 1 and 2) and beta (subtypes beta 1, 2, and 3) (reviewed by Schwartz65). Mature beta 2 tryptase is stored in MC secretory granules and released only during granule exocytosis, thereby reflecting MC activation. In contrast, the precursor forms of both alpha and beta tryptase are constitutively secreted by MCs,66 and the combined “total” serum levels (including precursor and mature tryptase forms) are thought to reflect the total systemic MC burden.67 The commercially available fluoroimmunoenzymatic assay (Pharmacia, Uppsala, Sweden) measures total tryptase levels. In healthy individuals, levels range from 1 to 15 ng/mL, whereas in most patients with SM, total serum tryptase levels exceed 20 ng/mL. In cases of suspected SM, it is important that serum tryptase levels be \interpreted in the appropriate context. Elevated levels of serum tryptase have been documented in patients with non-SM myeloid malignancies, including acute myeloid leukemia,68,69 myelodysplastic syndrome,70 and chronic myeloid leukemia,71 which mandates exclusion of such non-SM myeloid disorders before reaching a diagnosis of SM. Furthermore, levels of total serum tryptase may also be transiently elevated during anaphylaxis or a severe allergic reaction.64

Molecular Studies

In SM patients, molecular studies are important from the diagnostic standpoint and, increasingly, from the therapeutic standpoint as well.

Recent studies underscore the high prevalence of the kit D816V gain-of-function mutation in SM patients, with high correlation between mutation detection and the proportion of lesional cells in the sample, as well as the sensitivity of the screening method used (reviewed by Akin33). Accordingly, the likelihood of mutation detection in peripheral blood mononuclear cells in a case of indolent systemic mastocytosis (with low probability of circulating clonal cells), using a low-sensitivity screening test (eg, direct DNA sequencing), is exceedingly low. Sensitivity of detection may be enhanced by enriching lesional MCs or other clonal cell populations (eg, neutrophils or eosinophils) by laser capture microdissection or magnetic beador fluorescence-activated cell sorter (FACS)-based cell sorting, respectively.72-74 Furthermore, use of higher sensitivity methods including allele-specific polymerase chain reaction,75 or polymerase chain reaction with peptide nucleic acid probes to “clamp” the wild-type allele combined with mutant allele detection with hybridization probes, dramatically enhance the probability of mutation detection in bulk cells (sensitivity, 10-3).21,76 Using the latter method, the D816V mutation was detected in virtually all patients with indolent systemic mastocytosis or aggressive systemic mastocytosis (93%) but less frequently in patients with WDSM (29%) in a recent study.21 Here, kit mutations (I817V and VI815-816) other than D816V were rarely detected (

Well-differentiated systemic mastocytosis may represent a distinct, albeit genetically heterogenous, subtype of SM.21 A subset of WDSM cases carry the F522C germline mutation, which is located in the kit transmembrane domain. 30 In contrast to other SM subtypes, MCs in WDSM do not express either CD2 or CD25 antigens and are mature in appearance.

Eosinophilia (BM and/or peripheral blood) commonly accompanies SM (in 20%-40% of cases-termed SMeos) 77-80 and is demonstrably clonal in a proportion of such cases.73 Up to one half of SM-eos patients carry the FIP1L1-PDGFRA fusion oncogene,81 which results from an ~800-kb interstitial deletion of chromosome 4q12, thereby generating a constitutively active PDGFRA tyrosine kinase. 82 These patients have a multilineage disorder with demonstrable presence of the FIP1L1-PDGFRA gene within cells of multiple hematopoietic lineages including MCs.83 These patients also exhibit clinical and histologic features of myeloproliferation and generally have an elevated serum tryptase level but may lack pathognomonic clusters of atypical MCs in the BM on routine staining. 81,84-86 FIP1L1-PDGFRA^sup +^ cases have been variably classified as a unique subtype of SM81,87 or a “myeloproliferative variant” of hypereosinophilic syndrome84,85 or as chronic eosinophilic leukemia88 or a myelomastocytic overlap syndrome89 in the literature. Given the sensitivity of this lesion to imatinib therapy (discussed later), it is currently recommended that all suspected SM-eos cases be screened for the FIP1L1-PDGFRA fusion by either fluorescence in situ hybridization or reverse transcriptase polymerase chain reaction.90,91

TREATMENT OF MAST CELL DISORDERS

Treatment of MCD patients is highly individualized. The abbreviated treatment guidelines provided below are for general reference only, and readers are referred to specialized hematology texts and literature sources for details.

Cutaneous Mastocytosis

Spontaneous regression is observed in the majority of pediatric- onset CM.40,92 In contrast, most patients with adult-onset CM have persistent disease, with a proportion exhibiting progression to SM. Treatment is symptomatic, and treatment considerations include use of psoralen ultraviolet A therapy and corticosteroids for severe cases.

Treatment of MC-Mediator Release Symptoms

The cornerstone of therapy in indolent cases is avoidance of identifiable triggers for MC degranulation such as animal venoms, extremes of temperature, mechanical irritation, alcohol, certain dyes, or medications (eg, aspirin, radiocontrast agents, certain anesthetic agents). Therapy is supportive, with use of histamine 1 and histamine 2 receptor blockers (pruritus, peptic symptoms) and cromolyn sodium (gastrointestinal symptoms).93 Corticosteroids are reserved for patients with recurrent or refractory symptoms related to MC-mediator release. It is recommended that patients with a history of vascular collapse or anaphylaxis carry an Epi-Pen for epinephrine self-adminstration.94

Management of Aggressive Systemic Mastocytosis (Organopathy Present)

In general, patients with aggressive systemic mastocytosis require effective MC cytoreductive therapy. Potential therapeutic options are interferon-, 2-chlorodeoxyadenosine, polychemotherapy, and molecularly targeted therapy.

Interferon-α. Interferon-α is frequently combined with prednisone and is commonly used as first-line cytoreductive therapy for SM.95 It ameliorates SM-related organopathy in a proportion of cases but is associated with considerable toxicity (flulike symptoms, myelosuppression, depression, hypothyroidism, etc), which may limit its use in SM (reviewed by Butterfield).96

2-Chlorodeoxyadenosine. 2-Chlorodeoxyadenosine is generally reserved for treatment of patients with aggressive systemic mastocytosis, who are either refractory or intolerant to interferon- α.97-99 Potential toxicities of 2-chlorodeoxyadenosine include significant and potentially prolonged myelosuppression and lymphopenia with increased risk of opportunistic infections. Despite its efficacy in the SM treatment, the precise indications and the optimal dose and schedule for this group of patients remains to be ascertained.

Polychemotherapy.-Polychemotherapy including intensive induction regimens of the kind used in treating acute myeloid leukemia, as well as high-dose therapy with stem cell rescue, represent investigational approaches restricted to rare SM patients, such as select patients with MCL.

Molecularly Targeted Therapy.-Molecularly targeted therapy for SM has recently been reviewed by Gotlib.100

Imatinib Mesylate (Gleevec).-Imatinib is an orally bioavailable, small molecule inhibitor of Kit, ABL, ARG, and PDGFR tyrosine kinases. The identification of gain-offunction mutations involving kit and PDGFRA genes (known imatinib targets) in the pathogenesis of SM has obvious therapeutic implications in this regard. Consistent with predictions from in vitro data,101,102 the limited clinical experience to date suggests that the majority of SM patients (kit D816V+) are likely to be refractory to imatinib therapy.103,104 In contrast, clinically meaningful responses have been observed for the rare patients with kit juxtamembrane mutations (eg, F522C, K509I), suggesting that this subgroup of patients has imatinib-responsive disease. 30,32 For SM patients with eosinophilia (SM-eos) who carry the FIPILI-PDGFRA mutation, complete clinical responses are virtually uniformly obtained with low-dose imatinib therapy, in the absence of mutations that confer imatinib resistance (eg, PDGFRA T764I), which may be seen with clonal evolution (reviewed by Pardanani). 81,82,87,105 Lastly, imatinib is predicted to be effective in SM with specific mutations such as V560G106 and del419,28 but this has not yet been clinically demonstrated.

Dasatinib (BMS-354825).-Dasatinib is an orally available, dual SRC/ABL inhibitor that has been shown to have activity against the imatinib resistant kit D816V mutation in preclinical studies and is currently in clinical trials for treatment of SM.107,108

PKC412.-PKC412 is a multitargeted kinase inhibitor with activity against FLT3, Kit, VEGFR2, PDGFR, and FGFR kinases.109-111 Cools et al112 demonstrated that PKC412 effectively inhibits myeloproliferation induced by the imatinib-resistant FIP1L1-PDGFRA T674I mutation in a murine model. Subsequently, after PK412 was shown to inhibit kit D816V in vitro at nanomolar concentrations, Gotlib et al were able to show a significant clinical and histologic response to PKC412 in a single patient with D186V^sup +^ MCL.112,113 This agent is currently under study for SM treatment in phase II trials.

Other Agents.-Other agents such as the ATP-based inhibitors AP23464 and AP23848,114 the quinazoline-based inhibitor MLN518,115 the indolinone compounds SU11652, SU11654, and SU11655,116 the aminopyrimidine-based inhibitor AMN107 (Nilotinib),117 and the thiophene-based inhibitor OSI-930118,119 have activity against at least some of the SM-associated kit mutants and may have a future role in the treatment of this disease.

Accepted for publication October 24, 2006.

From the Department of Medicine, University of Minnesota, Minneapolis (Dr Patnaik); the Departments of Pathology, University of Rochester School of Medicine (Dr Rindos) and Hematology, Rochester General Hospital (Dr Kouides), Rochester, NY; and the Division of Hematology, Mayo Clinic, Rochester, Minn (Drs Tefferi and Pardanani).

The authors have no relevant financial interest in the products or companies described in this article.

Table 1. World Health Organization Variants of Mastocytosis*

Cutaneous mastocytosis (CM)

Maculopapular \CM

Diffuse CM

Mastocytoma of skin

Indolent systemic mastocytosis (SM)

Smoldering SM

Isolated bone marrow mastocytosis

Systemic mastocytosis with an associated clonal hematologic non- mast cell lineage disease (MCD-AHNMD)

Aggressive systemic mastocytosis

With eosinophilia

Mast cell leukemia (MCL)

Aleukemic MCL

Mast cell sarcoma

Extracutaneous mastocytoma

* From Valent et al.20

Table 2. “C” Findings*

Cytopenia(s): absolute neutrophil count

Hepatomegaly with ascites and impaired liver function

Palpable splenomegaly with hypersplenism

Malabsorption with hypoalbuminemia and weight loss

Skeletal lesions: large-sized osteolysis or severe osteoporosis causing pathologic fractures

Life-threatening organopathy in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic mast cells

* “C” findings are an indication of impaired organ function resulting from mast cell infiltration. From Valent et al.20

Table 3. World Health Organization Criteria for Diagnosis of Systemic Mast Cell Disease*

Major

Multifocal dense infiltrates of mast cells in bone marrow or other extracutaneous organs (>15 mast cells aggregating)

Minor

Mast cells in bone marrow or other extracutaneous organs show an abnormal (spindling) morphology (>25%)

Codon 816 c-kit mutation D816V in extracutaneous organs

Mast cells in the bone marrow express CD2, CD25, or both

Serum tryptase > 20 ng/mL (does not count in patients who have an associated clonal hematologic non-mast cell disease [AHNMD])

* From Valent et al.20

References

1. Kirshenbaum AS, Goff JP, Dreskin SC, Irani AM, Schwartz LB, Metcalfe DD. IL-3-dependent growth of basophil-like cells and mastlike cells from human bone marrow. J Immunol. 1989;142:2424- 2429.

2. Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD. Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol. 1991;146:1410-1415.

3. Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that human mast cells arise from a progenitor cell population that is CD34(+), c-kit(+), and expresses aminopeptidase N (CD13). Blood. 1999;94: 2333-2342.

4. Agis H, Willheim M, Sperr WR, et al. Monocytes do not make mast cells when cultured in the presence of SCF: characterization of the circulating mast cell progenitor as a c-kit+, CD34+, Ly-, CD14- , CD17-, colony-forming cell. J Immunol. 1993;151:4221-4227.

5. Rottem M, Kirshenbaum AS, Metcalfe DD. Early development of mast cells. Int Arch Allergy Appl Immunol. 1991;94:104-109.

6. Mitsui H, Furitsu T, Dvorak AM, et al. Development of human mast cells from umbilical cord blood cells by recombinant human and murine c-kit ligand. Proc Natl Acad Sci U S A. 1993;90:735-739.

7. Irani AM, Nilsson G, Miettinen U, et al. Recombinant human stem cell factor stimulates differentiation of mast cells from dispersed human fetal liver cells. Blood. 1992;80:3009-3021.

8. Valent P, Spanblochl 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; 80:2237-2245.

9. Orfao A, Escribano L, Villarrubia J, et al. Flow cytometric analysis of mast cells from normal and pathological human bone marrow samples: identification and enumeration. Am J Pathol. 1996;149:1493-1499.

10. Escribano L, Orfao A, Villarrubia J, et al. Immunophenotypic characterization of human bone marrow mast cells: a flow cytometric study of normal and pathological bone marrow samples. Anal Cell Pathol. 1998;16:151-159.

11. Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy Clin North Am. 2006;26:465-485.

12. Brunning RD, McKenna RW, Rosai J, Parkin JL, Risdall R. Systemic mastocytosis: extracutaneous manifestations. Am J Surg Pathol. 1983;7:425-438.

13. Horny HP, Parwaresch MR, Lennert K. Bone marrow findings in systemic mastocytosis. Hum Pathol. 1985;16:808-814.

14. Stevens EC, Rosenthal NS. Bone marrow mast cell morphologic features and hematopoietic dyspoiesis in systemic mast cell disease. Am J Clin Pathol. 2001;116:177-182.

15. Escribano L, Orfao A, Diaz-Agustin B, et al. Indolent systemic mast cell disease in adults: immunophenotypic characterization of bone marrow mast cells and its diagnostic implications. Blood. 1998;91:2731-2736.

16. Schernthaner GH, Jordan JH, Ghannadan M, et al. Expression, epitope analysis, and functional role of the LFA-2 antigen detectable on neoplastic mast cells. Blood. 2001;98:3784-3792.

17. Pardanani A, Kimlinger T, Reeder T, Li CY, Tefferi A. Bone marrow mast cell immunophenotyping in adults with mast cell disease: a prospective study of 33 patients. Leuk Res. 2004;28:777-783.

18. 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;32:545-552.

19. 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;28:1319-1325.

20. Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25:603-625.

21. Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow haematopoietic 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;108:2366-2372.

22. Pardanani A, Akin C, Valent P. Pathogenesis, clinical features, and treatment advances in mastocytosis. Best Pract Res Clin Haematol. 2006;19:595-615.

23. Furitsu T, Tsujimura T, Tono T, et al. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993;92: 1736-1744.

24. Nagata H, Worobec AS, Oh CK, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995;92:10560-10564.

25. Longley BJ Jr, Metcalfe DD, Tharp M, et al. Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis. Proc Natl Acad Sci U S A. 1999;96:1609-1614.

26. Pullarkat VA, Pullarkat ST, Calverley DC, Brynes RK. Mast cell disease associated with acute myeloid leukemia: detection of a new c-kit mutation Asp816His. Am J Hematol. 2000;65:30-7309.

27. Pignon JM, Giraudier S, Duquesnoy P, et al. A new c-kit mutation in a case of aggressive mast cell disease. Br J Haematol. 1997;96:374-376.

28. Hartmann K, Wardelmann E, Ma Y, et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology. 2005;129:1042-1046.

29. Tang X, Boxer M, Drummond A, Ogston P, Hodgins M, Burden AD. A germline mutation in KIT in familial diffuse cutaneous mastocytosis. J Med Genet. 2004;41:e88.

30. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. Blood. 2004;103:3222-3225.

31. Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer. 2001;92:657-662.

32. Zhang LY, Smith ML, Schultheis B, et al. A novel K509I mutation of KIT identified in familial mastocytosis-in vitro and in vivo responsiveness to imatinib therapy. Leuk Res. 2006;30:373-378.

33. Akin C. Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagn. 2006;8:412-419.

34. Valent PHH, Li CY, Longley JB, et al. Mastocytosis (mast cell disease). In: Pathology and Genetics of Tumours of the Haematopoietic and LymphoidTissues. Lyon, France: IARC Press; 2001:291-302. World Health Organization Classification of Tumours; vol 1.

35. Hartmann K, Henz BM. Cutaneous mastocytosis-clinical heterogeneity. Int Arch Allergy Immunol. 2002;127:143-146.

36. Hartmann K, Henz BM. Classification of cutaneous mastocytosis: a modified consensus proposal. Leuk Res. 2002;26:483- 484; author reply 485-486.

37. Soter NA. Mastocytosis and the skin. Hematol Oncol Clin North Am. 2000; 14:537-555, vi.

38. Kettelhut BV, Metcalfe DD. Pediatric mastocytosis. J Invest Dermatol. 1991; 96:15S-18S.

39. Azana JM, Torrelo A, Mediero IG, Zambrano A. Urticaria pigmentosa: a review of 67 pediatric cases. Pediatr Dermatol. 1994;11:102-106.

40. Middelkamp Hup MA, Heide R, Tank B, Mulder PG, Oranje AP. Comparison of mastocytosis with onset in children and adults. J Eur Acad Dermatol Venereol. 2002;16:115-120.

41. Czarnetzki BM, Kolde G, Schoemann A, Urbanitz S, Urbanitz D. Bone marrow findings in adult patients with urticaria pigmentosa. J AmAcad Dermatol. 1988;18:45-51.

42. Castells M, Austen KF. Mastocytosis: mediator-related signs and symptoms. Int Arch Allergy Immunol. 2002;127:147-152.

43. Cherner JA, Jensen RT, Dubois A, O’Dorisio TM, Gardner JD, Metcalfe DD. Gastrointestinal dysfunction in systemic mastocytosis: a prospective study. Gastroenterology. 1988;95:657-667.

44. Cherner JA. Gastric acid secretion in systemic mastocytosis. N Engl J Med. 1989;320:1562.

45. Horan RF, Austen KF. Systemic mastocytosis: retrospective review of a decade’s clinical experience at the Brigham and Women’s Hospital. J Invest Dermatol. 1991;96:5S-13S; discussion 13S-14S.

46. Lawrence JB, Friedman BS, Travis WD, Chinchilli VM, Metcalfe DD, Gralnick HR. Hematologic man\ifestations of systemic mast cell disease: a prospective study of laboratory and morphologic features and their relation to prognosis. Am J Med. 1991;91:612-624.

47. Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee RG. Systemic mast cell disease: analysis of 58 cases and literature review. Medicine (Baltimore). 1988; 67:345-368.

48. Parwaresch MR, Horny HP, Lennert K. Tissue mast cells in health and disease. Pathol Res Pract. 1985;179:439-461.

49. Horny HP, Ruck P, Krober S, Kaiserling E. Systemic mast cell disease (mastocytosis). General aspects and histopathological diagnosis. Histol Histopathol. 1997;12:1081-1089.

50. Lennert K, Parwaresch MR. Mast cells and mast cell neoplasia: a review. Histopathology. 1979;3:349-365.

51. Li CY. Diagnosis of mastocytosis: value of cytochemistry and immunohistochemistry. Leuk Res. 2001;25:537-541.

52. Horny HP, Sillaber C, Menke D, et al. Diagnostic value of immunostaining for tryptase in patients with mastocytosis. Am J Surg Pathol. 1998;22:1132-1140.

53. Horny HP, Valent P. Histopathological and immunohistochemical aspects of mastocytosis. Int Arch Allergy Immunol. 2002;127:115- 117.

54. Horny HP, Sotlar K, Sperr WR, Valent P. Systemic mastocytosis with associated clonal haematological non-mast cell lineage diseases: a histopathological challenge. J Clin Pathol. 2004;57:604- 608.

55. Sperr WR, Escribano L, Jordan JH, et al. Morphologic properties of neoplastic mast cells: delineation of stages of maturation and implication for cytological grading of mastocytosis. Leuk Res. 2001;25:529-536.

56. Escribano L, Garcia Montero AC, Nunez R, Orfao A. Flow cytometric analysis of normal and neoplastic mast cells: role in diagnosis and follow-up of mast cell disease. Immunol Allergy Clin North Am. 2006;26:535-547.

57. Escribano L, Diaz-Agustin B, Nunez R, Prados A, Rodriguez R, Orfao A. Abnormal expression of CD antigens in mastocytosis. Int Arch Allergy Immunol. 2002;127:127-132.

58. Escribano L, Orfao A, Villarrubia J, et al. Sequential immunophenotypic analysis of mast cells in a case of systemic mast cell disease evolving to a mast cell leukemia. Cytometry. 1997;30:98- 102.

59. Elliott MA, Pardanani A, Li CY, Tefferi A. Immunophenotypic normalization of aberrant mast cells accompanies histological remission in imatinib-treated patients with eosinophilia-associated mastocytosis. Leukemia. 2004;18:1027-1029.

60. Escribano L, Diaz-Agustin B, Lopez A, et al. Immunophenotypic analysis of mast cells in mastocytosis: when and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry B Clin Cytom. 2004;58:1-8.

61. Nunez-Lopez R, Escribano L, Schernthaner GH, et al. Overexpression of complement receptors and related antigens on the surface of bone marrow mast cells in patients with systemic mastocytosis. Br J Haematol. 2003;120:257-265.

62. Diaz-Agustin B, Escribano L, Bravo P, et al. The CD69 early activation molecule is overexpressed in human bone marrow mast cells from adults with indolent systemic mast cell disease. Br J Haematol. 1999;106:400-405.

63. Escribano L, Orfao A, Diaz Agustin B, et al. Human bone marrow mast cells from indolent systemic mast cell disease constitutively express increased amounts of the CD63 protein on their surface. Cytometry. 1998;34:223-228.

64. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316:1622-1626.

65. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26:451-463.

66. Schwartz LB, Min HK, Ren S, et al. Tryptase precursors are preferentially and spontaneously released, whereas mature tryptase is retained by HMC-1 cells, Mono-Mac-6 cells, and human skin- derived mast cells. J Immunol. 2003;170: 5667-5673.

67. Schwartz LB, Sakai K, Bradford TR, et al. The alpha form of human tryptase is the predominant type present in blood at baseline in normal subjects and is elevated in those with systemic mastocytosis. J Clin Invest. 1995;96:2702-2710.

68. Sperr WR, Jordan JH, Baghestanian M, et al. Expression of mast cell tryptase by myeloblasts in a group of patients with acute myeloid leukemia. Blood. 2001;98:2200-2209.

69. Sperr WR, Hauswirth AW, Valent P. Tryptase a novel biochemical marker of acute myeloid leukemia. Leuk Lymphoma. 2002;43:2257-2261.

70. Sperr WR, Stehberger B, Wimazal F, et al. Serum tryptase measurements in patients with myelodysplastic syndromes. Leuk Lymphoma. 2002;43:1097-1105.

71. Samorapoompichit P, Kiener HP, Schernthaner GH, et al. Detection of tryptase in cytoplasmic granules of basophils in patients with chronic myeloid leukemia and other myeloid neoplasms. Blood. 2001;98:2580-2583.

72. Sotlar K, Fridrich C, Mall A, et al. Detection of c-kit point mutation Asp-816[arrow right]Val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res. 2002;26:979-984.

73. Pardanani A, Reeder T, Li CY, Tefferi A. Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia. Leuk Res. 2003;27:883-885.

74. Yavuz AS, Lipsky PE, Yavuz S, Metcalfe DD, Akin C. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood. 2002;100:661-665.

75. Lawley W, Hird H, Mallinder P, et al. Detection of an activating c-kit mutation by real-time PCR in patients with anaphylaxis. Mutat Res. 2005;572:1-13.

76. Sotlar K, Escribano L, Landt O, et al. One-step detection of c-kit point mutations using peptide nucleic acid-mediated polymerase chain reaction clamping and hybridization probes. Am J Pathol. 2003;162:737-746.

77. Mutter RD, Tannenbaum M, Ultmann JE. Systemic mast cell disease. Ann Intern Med. 1963;59:887-906.

78. Lawrence JB, Friedman BS, Travis WD, Chinchilli VM, Metcalfe DD, Gralnick HR. Hematologic manifestations of systemic mast cell disease: a prospective study of laboratory and morphologic features and their relation to prognosis. Am J Med. 1991;91:612-624.

79. Travis WD, Li CY, Bergstralh EJ, Yam LT, Swee RG. Systemic mast cell disease: analysis of 58 cases and literature review. Medicine (Baltimore). 1988; 67:345-368.

80. Pardanani A, Baek JY, Li CY, Butterfield JH, Tefferi A. Systemic mast cell disease without associated hematologic disorder: a combined retrospective and prospective study. Mayo Clin Proc. 2002;77:1169-1175.

81. Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1- PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. 2004;104:3038-3045.

82. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348:1201-1214.

83. Robyn J, Lemery S, McCoy JP, et al. Multilineage involvement of the fusion gene in patients with FIP1L1/PDGFRA-positive hypereosinophilic syndrome. Br J Haematol. 2006;132:286-292.

84. Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003;101:4660-4666.

85. Klion AD, Robyn J, Akin C, et al. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood. 2004;103:473-478.

86. 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 therapy. Blood. 2003;102:3093-3096.

87. 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; 102:3093-3096.

88. Bain BJ. Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis. Am J Hematol. 2004;77:82-85.

89. Valent P, Sperr WR, Samorapoompichit P, et al. Myelomastocytic overlap syndromes: biology, criteria, and relationship to mastocytosis. Leuk Res. 2001; 25:595-602.

90. Tefferi A, Pardanani A. Clinical, genetic, and therapeutic insights into systemic mast cell disease. Curr Opin Hematol. 2004;11:58-64.

91. Tefferi A, Pardanani A. Systemic mastocytosis: current concepts and treatment advances. Curr Hematol Rep. 2004;3:197-202.

92. Caplan RM. The natural course of urticaria pigmentosa: analysis and follow-up of 112 cases. Arch Dermatol. 1963;87:146- 157.

93. Horan RF, Sheffer AL, Austen KF. Cromolyn sodium in the management of systemic mastocytosis. J Allergy Clin Immunol. 1990;85:852-855.

94. Turk J, Oates JA, Roberts LJ II. Intervention with epinephrine in hypotension associated with mastocytosis. J Allergy Clin Immunol. 1983;71:189-192.

95. 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;119:1090-1097.

96. Butterfield JH. Interferon treatment for hypereosinophilic syndromes and systemic mastocytosis. Acta Haematol. 2005;114:26-40.

97. Tefferi A, Li CY, Butterfield JH, Hoagland HC. Treatment of systemic mastcell disease with cladribine. N Engl J Med. 2001;344:307-309.

98. Pardanani A, Hoffbrand AV, Butterfield JH, Tefferi A. Treatment of systemic mast cell disease with 2- chlorodeoxyadenosine. Leuk Res. 2004;28:127-131.

99. Kluin-Nelemans HC, Oldhoff JM, Van Doormaal JJ, et al. Cladribine therapy for systemic mastocytosis. Blood. 2003;102:4270- 4276.

100. Gotlib J. KIT mutations in m\astocytosis and their potential as therapeutic targets. Immunol Allergy Clin North Am. 2006;26:575- 592.

101. Ma Y, Zeng S, Metcalfe DD, et al. The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wildtype kinases and those with regulatory-type mutations. Blood. 2002;99:1741-1744.

102. Akin C, Brockow K, D’Ambrosio C, et al. Effects of tyrosine kinase inhibitor STI571 on human mast cells bearing wild-type or mutated c-kit. Exp Hematol. 2003;31:686-692.

103. Pardanani A, Elliott M, Reeder T, et al. Imatinib for systemic mast-cell disease. Lancet. 2003;362:535-536.

104. Musto P, Falcone A, Sanpaolo G, Bodenizza C, Carella AM. Inefficacy of imatinib-mesylate in sporadic, aggressive systemic mastocytosis. Leuk Res. 2004; 28:421-422.

105. Pardanani A, Ketterling RP, Li CY, et al. FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res. 2006;30:965-970.

106. Frost MJ, Ferrao PT, Hughes TP, Ashman LK. Juxtamembrane mutant V560GKit is more sensitive to Imatinib (STI571) compared with wild-type c-kit whereas the kinase domain mutant D816VKit is resistant. Mol Cancer Ther. 2002; 1:1115-1124.

107. Shah NP, Lee FY, Luo R, Jiang Y, Donker M, Akin C. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in the majority of patients with systemic mastocytosis. Blood. 2006;108:286-291.

108. Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wildtype, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006;66:473- 481.

109. Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell. 2002;1:433-443.

110. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54-60.

111. Chen J, Deangelo DJ, Kutok JL, et al. PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci U S A. 2004;101: 14479-14484.

112. Cools J, Stover EH, Boulton CL, et al. PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRalpha- induced myeloproliferative disease. Cancer Cell. 2003;3:459-469.

113. Gotlib J, Berube C, Growney JD, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005;106:2865-2870.

114. Corbin AS, Demehri S, Griswold IJ, et al. In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit. Blood. 2005;106:227-234.

115. Corbin AS, Griswold IJ, La Rosee P, et al. Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970. Blood. 2004;104:3754-3757.

116. Liao AT, Chien MB, Shenoy N, et al. Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors. Blood. 2002;100:585-593.

117. von Bubnoff N, Gorantla SH, Kancha RK, Lordick F, Peschel C, Duyster J. The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107. Leukemia. 2005;19:1670-1671.

118. Petti F, Thelemann A, Kahler J, et al. Temporal quantitation of mutant Kit tyrosine kinase signaling attenuated by a novel thiophene kinase inhibitor OSI-930. Mol Cancer Ther. 2005;4:1186- 1197.

119. Garton AJ, Crew AP, Franklin M, et al. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res. 2006;66:1015-1024.

Mrinal M. Patnaik, MD; Michelle Rindos, MD; Peter A. Kouides, MD; Ayalew Tefferi, MD; Animesh Pardanani, MD, PhD

Reprints: Animesh Pardanani, MD, PhD, Mayo Clinic, Division of Hematology, 200 First St SW, Rochester, MN 55905 (e-mail: Pardanani.animesh@mayo.edu).

Copyright College of American Pathologists May 2007

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