beyond chronic myelogenous leukemia : potential role for imatinib in philadelphia-negative...

Beyond Chronic Myelogenous LeukemiaPotential Role for Imatinib in Philadelphia-Negative Myeloproliferative Disorders

Jorge Cortes, M.D.

Hagop Kantarjian, M.D.

Department of Leukemia, The University of TexasM.D. Anderson Cancer Center, Houston, Texas.

Dr. Cortes is a Clinical Research Scholar for theLeukemia and Lymphoma Society.

Address for reprints: Jorge Cortes, M.D., Depart-ment of Leukemia, The University of Texas M. D.Anderson Cancer Center, 1515 Holcombe Boule-vard, Houston, TX 77030-4009; Fax: (713) 794-4297; E-mail: [email protected]

Received February 17, 2004; accepted February20, 2004.

The myeloproliferative disorders (MPDs) are chronic malignant conditions origi-

nating from the clonal expansion of a multipotential hematopoietic stem cell.

These diseases include polycythemia vera (PV), essential thrombocythenia, atypi-

cal chronic myeloid leukemia, idiopathic hypereosinophilic syndrome (HES), ag-

nogenic myeloid metaplasia with myelofibrosis, and others. Receptor tyrosine

kinases—the platelet-derived growth factor receptors (PDGFRs) and c-Kit—and

their respective ligands have been implicated in the pathogenesis of MPDs. For

example, a constitutively activated PDGFR fusion tyrosine kinase (FIP1L1-PDG-

FRA) was identified in some patients with HES, a disease characterized by sus-

tained overproduction of eosinophils that has been classified by the World Health

Organization as a chronic subtype of the MPDs. Imatinib is a selective inhibitor of

PDGFRs, c-Kit, Abl and Arg protein-tyrosine kinases, as well as Bcr-Abl, the onco-

genic tyrosine kinase that causes chronic myeloid leukemia. The efficacy of ima-

tinib in treating HES, systemic mast cell disease, chronic myelomonocytic leuke-

mia associated with PDGFR� fusion genes, and (to a lesser extent) PV and

idiopathic myelofibrosis was reviewed from institutional experience and a review

of the literature. In 3 studies that involved 11 patients with PV, 10 patients had

reductions in phlebotomy with imatinib. Eight studies of 42 patients with HES

indicated that 70% achieved complete hematologic remissions with imatinib. Four

studies of 6 patients with MPD indicated responses with imatinib in 5 patients.

Insight into the molecular pathogenesis of MPDs will improve the definitions of

different disease categories and suggests that signal transduction inhibition is

likely to be an increasingly important treatment option in the future. Cancer 2004;

100:2064 –78. © 2004 American Cancer Society.

KEYWORDS: myeloproliferative disorders, polycythemia vera, idiopathic myelofibro-sis, hypereosinophilic syndrome, drug therapy, imatinib.

The myeloproliferative disorders (MPDs) are a group of chronicmalignant conditions that originate from the clonal expansion of

a multipotential hematopoietic progenitor cell. They are character-ized by overproduction of one or more cell types of the myeloeryth-roid lineages (Table 1).1,2 Although chronic myeloid leukemia (CML)is included nosologically among the MPDs, CML is distinguishedfrom them by a unique chromosomal abnormality, the Philadelphiachromosome (Ph), and a well-characterized pathogenetic defect atthe molecular level, expression of the Bcr-Abl fusion oncoprotein.Therefore, the Ph–negative MPDs—including polycythemia vera (PV);idiopathic myelofibrosis (IMF), also referred to as agnogenic myeloidmetaplasia; and essential thrombocythemia (ET)— often are consid-ered separately from CML.3–7 In addition, patients with clinical char-acteristics of CML in whom neither the Ph chromosome nor thebcr-abl rearrangement are present constitute a unique category; their

2064

© 2004 American Cancer SocietyDOI 10.1002/cncr.20211Published online 19 April 2004 in Wiley InterScience (www.interscience.wiley.com).

disease has been referred to as true Ph–negative CMLand, more recently, atypical CML (a-CML).8

Idiopathic hypereosinophilic syndrome (HES) is arare MPD of unknown etiology.9,10 The 3 definingcharacteristics of HES are sustained overproduction ofeosinophils (� 1.5 � 109/L for � 6 months), signs andsymptoms of organ damage (especially to the heart),and no identifiable underlying cause of eosinophilia(e.g., malignancy, allergy, parasitic infection).9,11 How-ever, the varied clinical presentation of chronic hy-pereosinophilia and its elusive etiology continue tomake its definition and classification difficult.12

Mast cell disease (MCD), or mastocytosis, in-cludes a heterogeneous group of MPDs characterizedby excessive growth and accumulation of mast cells inthe skin and other organs, such as the heart, nervoussystem, lungs, liver, and kidneys.13,14 Mast cell degran-ulation and release of cellular chemical mediators areresponsible for the array of symptoms that accompanythese diseases.

Because of their complex clinical course, involvingthrombocytosis, thrombotic and hemorrhagic phe-nomena, constitutional symptoms, and the potentialfor progression to myelofibrosis and/or acute leuke-mia, the management of MPDs remains challenging.Currently, there is no known, curative medical therapyfor patients with PV, IMF, ET, HES, MCD, ora-CML.5,7,9 Clinical management has focused on theprevention or palliation of disease morbidity and pre-vention of disease progression.5,9 With increasing in-sight into the molecular pathogenesis of the MPDs, ithas become apparent that signal transduction-inhib-itor therapy targeted to specific protein-tyrosine ki-nases may provide an important new approach to thetreatment of MPDs.15

Dysregulated protein-tyrosine kinase activity has

been implicated in the development of MPDs. Plate-let-derived growth factor receptor (PDGFR) activationstimulates eosinophils. Constitutive activation of aPDGFR is present in some MPDs and perhaps in asignificant proportion of patients with HES. PDGF ap-pears to have a pathogenetic role in MPD-associatedmyelofibrosis.10,16,17 The protein-tyrosine kinase c-Kit,the product of the c-Kit protooncogene, is the receptorfor stem cell factor (SCF) and is expressed normally bya variety of cell types, including hematopoietic pro-genitor cells.18 The presence of constitutively activatedc-Kit, resulting from a c-Kit gain-of-function muta-tion, is the hallmark of gastrointestinal stromal tumor(GIST).19 Significant levels of c-Kit have been found ineosinophils, and the c-Kit ligand, SCF, may induceeosinophil proliferation, activation, and degranula-tion.20 Synergism between erythropoietin and severalgrowth factors, including SCF, leads to the maturationand proliferation of erythroid precursors.21–24

Imatinib (formerly STI571; Glivec�, Gleevec�; No-vartis Pharmaceuticals, Basel, Switzerland) is an orallybioavailable 2-phenylaminopyrimidine compoundthat was designed rationally to inhibit adenosinetriphosphate binding to protein-tyrosine kinases and,thus, to block the activation of kinase-mediated intra-cellular signal transduction pathways.18,25–28 Thesepathways control fundamental cellular processes,such as growth, metabolism, differentiation, adhesion,and apoptosis.29 Dysregulated tyrosine kinase activityplays a central role in the pathogenesis of CML, GIST,and other human malignancies.29,30 In CML, the for-mation of the bcr-abl oncogene leads to constitutiveexpression of the Bcr-Abl oncoprotein with increasedtyrosine kinase activity, causing the disease.31 Ima-tinib specifically inhibits the kinase activity of Ablprotein-tyrosine kinases and the Abl-related gene(ARG) protein as well as PDGFR-� (PDGFRA),PDGFR-� (PDGFRB), and c-Kit.18,25–28

Therapy with imatinib has resulted in unprece-dented rates of hematologic, cytogenetic, and molec-ular remissions in patients with CML. It is now thepreferred agent for first-line use.32,33 It also has dem-onstrated remarkable activity in the treatment of ma-lignant metastatic or unresectable GIST, with durableresponses and prevention of disease progressionachieved in 82% of patients in clinical trials at 9months of follow-up.34,35 Imatinib therapy is toleratedwell, producing mostly mild-to-moderate side effects.The efficacy and safety results have prompted inves-tigations of the potential role of imatinib for otherdiseases that carry molecular targets known to be sen-sitive to this agent, such as metastatic dermatofibro-sarcoma protuberans, a fibrohistiocytic tumor with anassociated COL1A1-PDGFB fusion.36

TABLE 1Myeloproliferative Diseases (World Health OrganizationClassification)

CML, Ph-positive: t(9;22)(q34;q11), Bcr-AblChronic neutrophilic leukemiaChronic eosinophilic leukemia/HESa

Chronic idiopathic myelofibrosisPolycythemia veraEssential thrombocythemia

CML: chronic myelogenous leukemia; HES: hypereosinophilic syndrome; Ph: Philadelphia chromo-

some.a Some authors classify hypereosinophilic syndrome as an atypical chronic myeloid disorder related to

the myeloproliferative diseases (see Vardiman et al.94). Note that only Ph–positive disease is called

chronic myelogenous leukemia. Ph–negative diseases are referred to as atypical chronic myelogenous

leukemia and are assigned to the newly created myelodysplastic/myeloproliferative group. Other

myelodysplastic/myeloproliferative diseases include chronic myelomonocytic leukemia and juvenile

myelomonocytic leukemia (see Harris et al.57).

Treatment of MPDs with Imatinib/Cortes and Kantarjian 2065

This review summarizes recent results of imatinibtreatment for PV, IMF, MCD, and HES after an over-view of the principal features of these diseases and abrief summary of approaches to their treatment. ET,which has a more favorable natural history and isassociated less frequently with chromosomal abnor-malities than other Ph–negative MPDs, is not consid-ered in detail.37–39

OVERVIEW OF MPDEpidemiologyTable 2 shows the annual incidence, demographicfeatures, and median survival reported in the litera-ture for PV, IMF, HES, and MCD.

Pathogenetic FeaturesBecause the MPDs are disorders of a multipotent my-eloid stem cell, they are characterized by trilineageclonal expansion and panhyperplasia of all myeloidcompartment lineages.7,40 Some MPDs have potentialfor transformation into acute leukemia. In approxi-mately 2% of long-term survivors of PV, the diseaseprogresses to acute myeloid leukemia.4 In 1 large se-ries of IMF patients, leukemic conversion caused 27%of all deaths.41

Bone marrow fibrosis is a predominant character-istic of IMF but occurs in other MPDs to various de-grees. In all of these diseases, the bone marrow fibro-sis is polyclonal in origin, suggesting that it is areactive process stimulated by activity of an abnormalstem cell clone, e.g., PDGF production.2,20,40,42– 45 Witheffective therapy, fibrosis may be reversible (e.g., in-terferon-� [IFN-�] in hairy cell leukemia [HCL], IFN-�

IFN/Gleevec in CML).

Clinical Features and ManagementPVThe etiology of PV is unknown; however, PV is char-acterized by the accumulation of morphologically nor-mal erythrocytes, leukocytes, platelets, and their pro-genitors in the absence of an identifiable stimulus andto the exclusion of nonclonal hematopoiesis.46,47 Signsand symptoms of PV are related to increased red cellmass and may include headache, dizziness, dyspnea,fatigue, visual problems, paresthesias, abdominal dis-comfort, weight loss, and night sweats.3,46,48 General-ized pruritus, often exacerbated by a hot bath, is acommon symptom, occurring in up to 50% of pa-tients.7

Life-threatening complications of PV include vas-cular events and evolution into postpolycythemic my-elofibrosis/myeloid metaplasia (the so-called spentphase) or acute leukemia.3 Thromboses occur in ap-proximately 20% of patients and include transientischemic attacks, retinal vein thrombosis, central ret-inal artery occlusion, myocardial infarction, angina,pulmonary embolism, hepatic and portal vein throm-bosis, deep venous thrombosis, and peripheral arterialocclusion. At autopsy, it has been found that approx-imately 6% of patients with PV have Budd-Chiari syn-drome.48 Bleeding, usually gastrointestinal, is less fre-quent.3 It was found recently that treatment withaspirin given at a dose of 100 mg daily versus placebolowered the risk of cardiovascular death, nonfatalmyocardial infarction, nonfatal stroke, and all majorarterial and venous thromboses in PV patients understandard cytoreductive treatment.49

The risk of PV transformation to acute leukemia istreatment dependent, with overall rates of 1.5%, 9.6%,

TABLE 2Incidence, Demographics, and Median Survival of Patients with Polycythemia Vera and Idiopathic Myelofibrosis

VariablePolycythemiaveraa

Idiopathicmyelofibrosisb HESc MCDd

Annual incidence 2.3/100,000 0.5–1.5/100,000 1–2/200,000 1/4000–8000Male:female ratio 1.2:1 �1:1 9:1 1:1Median age at diagnosis (yrs) 60 65 40e Cutaneous, infancy; systemic, adultMedian survival (yrs) � 10 5 � 5f Benign systemic MCD, normal life span; malignant MCD, 1–2 years

after diagnosisg

HES: hypereosinophilic syndrome; MCD: mast cell disease.a See Tefferi.7

b See Tefferi44 and Bilgrami and Greenberg.48

c See Karnak et al.95

d See Pullen and Wright,14 Alto and Clarcq,62 and Valent et al.96

e See Chusid et al.11

f See Lefebvre et al.97

g See Stone and Bernstein.63

2066 CANCER May 15, 2004 / Volume 100 / Number 10

and 13.2% for patients treated with phlebotomy alone,radiophosphorus 32P, or chlorambucil, respectively.50

The risk of transformation to postpolycythemic my-eloid metaplasia has been estimated as 10% over 10years and 20% over 25 years.40 The Polycythemia VeraStudy Group (PVSG) studies show a median survival of12.6 years for patients who were treated with phlebot-omy alone compared with 10.9 years and 9.1 years forpatients who were treated with 32P and chlorambucil,respectively.7,50 The different survival intervals are at-tributable to differences in the incidence of acute leu-kemia.

Diagnosis. The PVSG originally defined two categoriesof diagnostic criteria for PV: 1) blood count and otherlaboratory values and 2) palpable splenomegaly.48

More recent algorithms have advocated the use ofcytogenetics, serum erythropoietin levels, and ery-throid colony–forming assays to distinguish PV fromsecondary polycythemia.51 In a proposed modificationof the original PVSG criteria, the diagnosis of PV isestablished if any one of the following categories ofcriteria is present in addition to red blood cell mass� 25% of the mean predicted value4: 1) absence ofcauses of secondary erythrocytosis with splenomegalyon palpation, 2) abnormal bone marrow karyotype asa clonality marker, or 3) absence of causes of second-ary erythrocytosis plus any 2 of the following: throm-bocytosis with platelet count � 400 � 109/L; neutro-philic leukocytosis � 10 � 109/L; splenomegalydemonstrated by imaging techniques; and either char-acteristic, erythroid, burst-forming unit growth or re-duced serum erythropoietin.

The differential diagnosis of PV includes spuriouserythrocytosis and reactive (secondary) erythrocyto-sis. Spurious erythrocytosis can be distinguished fromPV by determination of red cell mass. Reactive eryth-rocytosis is characterized by elevated levels of serumerythropoietin and retention of erythropoietin depen-dence in erythroid colony–forming assays. In addition,bone marrow biopsy in patients with PV demonstratespanhyperplasia, whereas pure erythroid hyperplasia isseen in secondary erythrocytosis.52

Treatment. PV is treated with phlebotomy and, occa-sionally, with myelosuppressive drugs to reduce thered blood cell count. In addition, hydroxyurea andIFN-� therapy can reduce splenomegaly and otherrelated symptoms of PV. Treatment approaches for PVare summarized in Table 3.

IMFIn addition to bone marrow fibrosis, defining featuresof IMF include pancytopenia, leukoerythroblastosis,

dacryocytosis (inflammation of the lacrimal gland),hepatosplenomegaly, and extramedullary hematopoi-esis.40 Symptoms in patients with IMF are caused byanemia and/or splenomegaly and include fatigue,early satiety, and left upper quadrant discomfort. Hy-permetabolism, often in patients with marked spleno-megaly, can manifest as weight loss, night sweats, andfever. Bleeding occurs in 25% of patients as a result ofvarious pathogenetic mechanisms, including intrinsicplatelet dysfunction, thrombocytopenia, disseminatedintravascular coagulation, and esophageal varices. Oc-casionally, patients with IMF may have symptomscaused by extramedullary hematopoiesis in the spinalcord, brain, lung, small intestine, and abdominal cav-ity. In some patients, osteosclerosis can cause perios-titis and severe bone and joint pain.40

The median survival of patients with IMF is ap-proximately 5 years, with � 20% of patients reportedlyalive at 10 years.37,40 Causes of death include heartfailure, infection, and leukemic transformation, whichoccurs in approximately 10% of patients.3

Diagnosis. Because fibrosis of the bone marrow maybe reactive to other processes, IMF can be difficult todistinguish from other conditions in which bone mar-row fibrosis is present.47 The presence of osteosclero-sis favors a diagnosis of IMF.44 Chromosomal abnor-

TABLE 3Therapies Used in the Treatment of Polycythemia Vera

Therapy Indications/comment

Phlebotomy Mainstay of therapy for polycythemia vera; the goal is to reduceRBC mass and to maintain a hematocrit level of � 45% formen and � 42% for women (see Tefferi3); for patients withrisk factors for thrombosis, add myelosuppressive therapywith 32P or busulfan for patients age � 70 yrs or addmyelosuppressive therapy with hydroxyurea for patients age� 70 yrs; consider interferon for younger patients at risk forleukemogenicity with long-term myelosuppression and forpatients of childbearing age (see Tefferi,3,7 Bilgrami andGreenberg,48 and Pearson et al.98)

Hydroxyurea In addition to the above indications, may be useful forsplenomegaly, bone pain, intractable pruritus, and poorvenous access (see Bilgrami and Greenberg48)

Interferon-� In addition to the above indications, may be useful forerythrocytosis, splenomegaly, and intractable pruritus (seeTefferi7)

Aspirin Use is somewhat controversial. In a PVSG study, high doses(900 mg/day) plus dipyridamole increased the rate of serioushemorrhage (see Tartaglia et al.99) and failed to protect fromThrombosis; a subsequent study using low-dose aspirin (40mg/day) showed no increased risk of bleeding; however,efficacy remains unproven (see Tefferi7 and Landolfi andMarchioli100)

RBC: red blood cells; PVSG: Polycythemia Vera Study Group.


malities, including 20q�, 13q�, and �21, are presentin 30% of patients.40 Necessary diagnostic criteria forIMF include diffuse bone marrow fibrosis and absenceof the Ph or bcr-abl rearrangement. Features that maysuggest the diagnosis include splenomegaly; aniso-poikilocytosis with teardrop erythrocytes; circulatingimmature myeloid cells, or erythroblasts; clusters ofmegakaryoblasts and anomalous megakaryocytes inbone marrow specimens; and myeloid metaplasia.53

Treatment. Therapy for patients with IMF is directedmainly toward palliation of symptoms and improve-ment in quality of life.40 These objectives can be ad-dressed with blood transfusions, androgen therapy,glucocorticoids, and erythropoietin. For patients withsplenomegaly that is painful, splenectomy can be con-sidered. Other treatments for patients with IMF in-clude thalidomide, radiation therapy, and allogeneicstem cell transplantation (SCT). Treatment ap-proaches are summarized in Table 4.

Idiopathic HESThe distinctive clinical feature of HES, in addition tosustained eosinophilia of unknown cause, is its predi-lection for damage to specific organs, particularly theheart and lungs. Other sites of organ damage includethe nervous system, skin, lungs, gastrointestinal tract,and eyes. Tissue toxicity may be mediated by cationic

granule proteins in the eosinophils or the elaborationof cytokines that contribute to inflammation and fi-brosis.9,54 Usually, patients present with normalkaryotype.

Cardiac disease is the major source of morbidityand mortality in patients with HES.54 Heart damagemanifests as congestive heart failure (CHF) and canevolve through 3 stages: 1) acute necrosis, 2) a subse-quent thrombotic stage, and 3) a late fibrotic phase.9

Moreover, heart failure can result from accumulationsof eosinophils in the heart, blocking venous return.Neurologic manifestations include diffuse central ner-vous system (CNS) dysfunction, cerebrovascular acci-dents, peripheral neuropathy, and focal CNS deficitsfrom cardiac emboli or other hematologic disturbanc-es.54 Patients also may present with rashes; pulmonaryinfiltrates; chronic cough; visual symptoms; arthral-gias and joint effusions; and gastrointestinal distur-bances, including diarrhea.9,54

Hallmarks of HES are its clinical heterogeneityand highly variable prognosis. Some patients have apaucity of symptoms, require no treatment, and haveprolonged survival. Others suffer a rapidly fatal coursedue to sudden, severe CHF or to the development ofacute leukemia.55

Diagnosis. Like IMF, HES has no specific diagnosticmarker and, thus, is a diagnosis of exclusion.56 Itshould be noted that eosinophilia can occur in bothPh-positive and Ph-negative MPDs. The World HealthOrganization (WHO) classification system recom-mends that the presence of a clonal cytogenetic ab-normality reclassifies cases as chronic eosinophilicleukemia rather than idiopathic HES.56 The diagnosisof idiopathic HES, once an underlying MPD is ex-cluded, depends on the 3 criteria discussed above,which originally were proposed by Chusid and col-leagues.11 Some authors have classified HES as anatypical chronic myeloid disorder related to theMPDs,7 whereas the most recent WHO classificationof the neoplastic hematopoietic tissue diseases pairschronic eosinophilic leukemia and HES as chronicmyeloproliferative subtypes (Table 1).57 Chronic eo-sinophilic leukemia is a hypereosinophilic diseasecharacterized by clonal cytogenetic abnormalities.58

The most common abnormality is a break in the q31-5region of chromosome 5, the locus for genes thatencode for the cytokines interleukin-3 (IL-3), IL-5, andgranulocyte-macrophage– colony stimulating factor,which stimulate eosinophil production. Although, bydefinition, HES has no known cause, it has beenshown recently that, at least in some patients, it hasdysregulated tyrosine kinase activity arising from agene rearrangement as a possible etiologic factor.10,12

TABLE 4Therapies Used in the Treatment of Idiopathic Myelofibrosis


Blood transfusion, androgentherapy, glucocorticoids,erythropoietin

Useful in treatment of anemia (see Tefferi3 andHasselbalch et al.101); androgen therapyrequires careful monitoring of liver function,virilizing effects in women, and prostateeffects in men (see Tefferi et al.40)

Danazol Ameliorates anemia and thrombocytopenia(see Tefferi et al.40)

Splenectomy For patients in whom splenomegaly is causingpain, mechanical discomfort, refractorythrombocytopenia, hypercatabolicsymptoms, or forward-flow hypertension;however, may increase risk of leukemictransformation (see Tefferi et al.102 andAkpek et al.103

Radiation therapy Useful for management of complicationsassociated with extramedullaryhematopoiesis (see Tefferi3); splenicirradiation is an alternative for poorsplenectomy candidates

Allogeneic stem celltransplantation

For patients age � 45 yrs with a poorprognosis; however, associated with highmorbidity and mortality (see Tefferi,43 Fauciet al.,54 and Roufosse et al.55


Confirming earlier findings that eosinophils are clonalin origin in a subset of HES patients,59,60 these resultssuggest the definitions applied in the diagnosis ofchronic eosinophilic syndromes and HES may requirerefinement as the molecular events responsible for thegenesis of HES are identified. The WHO criteria indi-cate that a diagnosis of chronic eosinophilic leukemiashould be given to patients with clonally derived eo-sinophils. Consequently, new data demonstrating thatan appreciable subgroup of patients with HES have aunique molecular abnormality and, hence, a clonaldisorder suggest that these patients should be classi-fied with chronic eosinophilic leukemia rather thanHES. Resolution of these classification issues awaitsfurther study.

Treatment. Table 5 summarizes therapies used in HES.The objective of the therapeutic approaches to datehas been long-term maintenance to control organdamage, thus, making the disease manageable as achronic condition.9 In patients without evidence oforgan involvement, specific therapy usually is notneeded. Patients who have evidence of organ damageare treated initially with prednisone, 1 mg/kg daily.54

For patients who have continuing end-organ damage,therapy with a variety of cytotoxic agents has provedeffective.9 IFN-� also has been used with success in alimited number of patients.61 Patients with cardiacinvolvement have undergone surgery with valve re-

placement and with endomyocardectomy. Patientswith thrombosis have undergone thrombectomy.9

MCDMCD is characterized by an overabundance of activemast cells, usually localized to skin, and can occur inother organs as well, signifying a systemic disorder.62

Ninety percent of patients with MCD present with acutaneous disorder that consists of skin lesions withinfiltrates of mast cells. In contrast, systemic MCD canaffect other organs, such as the liver, spleen, lymphnodes, and gastrointestinal tract. This disease canpresent with minor symptoms or may be life-threat-ening as a consequence of organ damage associatedwith systemic disease. The spectrum of MCDs spansfrom mast cell hyperplasia, to benign neoplasms thatare not characterized by unregulated proliferation, tomalignant neoplasms.63 Malignant mastocytosis is anaggressive form of systemic mastocytosis with apoorer prognosis compared with nonmalignant vari-ants. Acute leukemia eventually develops in 15–30% ofpatients who have malignant mastocytosis, with one-third of patients developing mast cell leukemia andthe remaining two-thirds of patients developing acutemyeloid leukemia or chronic myelomonocytic leuke-mia (CMML). A recent proposed classification identi-fied 2 broad categories: cutaneous and systemic mas-tocytosis. The later is classified further into 4 majorvariants: indolent systemic mastocytosis; systemicmastocytosis with an associated clonal, hematologic,nonmast cell lineage disease; aggressive systemic mas-tocytosis; and mast cell leukemia.64

Diagnosis. MCD is difficult to diagnose, with 3 criteriathat must be considered during the diagnostic processfor MCD: 1) histopathology of the skin lesion, 2) his-tologic evidence of systemic involvement with or with-out an underlying hematologic disorder, and 3) bio-chemical markers of mast cell activity.14 Bone marrowbiopsies are necessary to demonstrate an increase inmast cells for the diagnosis of systemic MCD. Markersof mast cell membranes include CD117 (c-Kit) andCD25, which may be detected in circulation. Elevatedserum tryptase and histamine levels are used com-monly as diagnostic markers for MCD. Recently pro-posed criteria are presented in Table 6.

Treatment. Pharmacologic inhibition of mediators ofinflammation is the first approach in the treatment ofMCD, including the blockade of histamine H1 and H2

receptors. Patients can benefit from treatment withantiinflammatory drugs, such as cyproheptadinegiven at a dose of 4 mg 2–3 times daily,65 and fromtreatment with adrenaline to combat anaphylactic

TABLE 5Therapies Used in the Treatment of Idiopathic HypereosinophilicSyndromea


None No evidence of organ involvementAlkylating agents Chlorambucil and others; may be administered in 4-day pulse

doses repeated as dictated by magnitude of bloodeosinophilia

Corticosteroids First-line agent for those with organ involvement; if effectivedose may be tapered or changed to every other day

Hydroxyurea Used in patients with organ involvement and eosinophiliaunresponsive to corticosteroids; anemia and/orthrombocytopenia common with chronic therapy

Imatinib Effectiveness demonstrated in clinical studies, with minimaltoxicity

Vincristine Especially useful for acute reductions when total eosinophilcounts are excessive (� 50,000–75,000/�L); can beadministered episodically to control hypereosinophilicsyndrome, often with amelioration of thrombocytopenia

Other Interferon-�; cyclosporine; cladribine; bone marrowtransplantation

Cardiac surgery Indicated for serious mitral valve regurgitation withbioprosthetic mitral valve replacement; less commonly,thrombectomy or endomycardectomy

a Data from Weller and Bubley,9 Cools et al.,10 and Cortes et al.84


shock. Histamine H2 receptor inhibition also can helpto reduce excessive gastric secretions that accompanythis disease. Systemic corticosteroids can aid in themanagement of skin disease, malabsorption, or as-cites of systemic mastocytosis.

IMATINIB IN MPDSPathophysiologic RationaleImatinib may be effective treatment in some MPDs,such as PV, IMF, MCD, and HES. Imatinib specificallyinhibits the PDGFRs and c-Kit in addition to ARG andBcr-Abl.18 It has been proposed that both the PDGFRsand their ligand and c-Kit and its ligand, SCF, may beimplicated in the pathogenesis of MPDs.

It is believed that PDGF plays a role in the patho-genesis of fibrosis in IMF and in other MPDs, as dis-cussed earlier.16 There also is evidence for the consti-tutive activation of the PDGFRs in MPDs. A relativelysmall number of patients with MPD have transloca-

tion fusions of the PDGFRB gene. Most frequently,these result from a t(5;12) (q33;p13) cytogenetic ab-normality associated with an ETV6-PDGFRB fusiongene. At least 3 other PDGFRB fusion genes have beendescribed.15,17,66 These include t(5;7)(q33;q11), t(5;10)(q33;q21.2), and t(5;17)(q33;p13), which fuse HIP1,H4/D1OS1, and Rab5 to PDGFRB, respectively. Afourth fusion gene, t(5;14)(q33;q32), which fusesCEV14 to PDGFRB, was described in a patient withacute myeloid leukemia who acquired the gene as asecondary abnormality at recurrence. In addition, itwas shown that t(1;5)(q23;q33) fused PDGFRB to thecoiled-coil domains of a novel partner protein, myo-megalin, in a patient who had MPD with eosino-philia.67 Both published and unpublished results indi-cate that other translocations also target PDGFRB andsuggest that several fusion genes remain to be char-acterized.66 Clinically, most patients who carry a t(5;12)(q31 � 33;p13) present with a myelodysplastic orMPD picture that includes eosinophilia, eosinophilicleukemia, or CMML.66 PDGFRB fusion proteinsformed by the t(5;12) (q33;p13) abnormality and re-lated translocations no longer are controlled by nor-mal interaction with PDGF but, instead, are activeconstitutively.17,66 In mouse models, the fusion geneinduced an MPD that closely resembled humanCMML.68

Constitutive activation of PDGFRA resulting fromthe fusion of the Fip1-like 1 (FIP1L1) gene to thePDGFRA gene was identified as the cause of HES in 9of 16 patients in a recent report.10 A t(1;4) (q44;q12)translocation found in 1 patient pointed to a role for amolecular-level oncogenic lesion. Further investiga-tion revealed an interstitial deletion on the long arm ofchromosome 4 (q12) that was repaired through thejoining of elements of FIP1L1 and PDGFRA, which waspresent in 9 patients. The protein product of the fu-sion gene, FIP1L1-PDGFRA, is a continuously activetyrosine kinase that transforms hematopoietic cellsand is inhibited by low concentrations of imatinib(50% inhibitory concentration, 3.2 nM).10 This repre-sents a 2-log higher sensitivity to inhibition by ima-tinib compared to Bcr/Abl. It is noteworthy that clin-ical recurrence and resistance to imatinib in 1 patientwith HES were associated with acquisition of a T6741mutation in the ATP-binding domain of the FIP1L1-PDGFRA fusion protein.10 The site of this point muta-tion corresponds to that of the T3151 bcr-abl muta-tion, which confers resistance to imatinib in patientswith CML. This supports the view that FIP1L1-PDG-FRA is the therapeutic target of imatinib in some pa-tients with HES.

In 2002, a t(4;22)(q12;q11) translocation fusingBCR to PDGFRA was reported in 2 patients with a-

TABLE 6Proposed Criteria to Diagnose Mastocytosis64

Cutaneous mastocytosisTypical skin lesions � typical clinical signs (UP/MPCM, DCM, mastocytoma) and

positive histology with typical infiltrates of MC (diagnostic infiltratepattern: multifocal or diffuse)

Systemic mast cell disease: “SM criteria”Major

Multifocal, dense infiltrates of MC (� 15 MC aggregating) detected in section ofBM and/or of other extracutaneous organ(s) by tryptase-immunohistochemistry or other stains

Minora. In MC infiltrates detected in section of BM or other extracutaneous organs,

� 25% of MC are spindle-shaped or, in BM smears, atypical MC (Type Iplus Type IIa) comprise � 25% of all MC

b. Detection of a c-kit point mutation at codon 816 in BM or blood or otherextracutaneous organ(s)

c. Kit-positive mast cells in BM or blood or other extracutaneous organ(s)coexpress CD2 or/and CD25

d. Serum total tryptase concentration persistently � 20 ng/mL (in case of anAHNMD, d. is not valid)b

If one major and one minor or three minor criteria are fulfilled3Then the diagnosis is SM

UP/MPCM: urticaria pigmentosa/maculopalular cutaneous mastocytosis; DCM: diffuse cutaneous

mastocytosis; MC: mast cell; BM: bone marrow; AHNMD: associated hematologic clonal, nonmast cell

lineage disease; SM: systemic mastocytosis.a Atypical mast cell Type I has two or three of the following: 1) prominent surface projections (special

form: spindle-shaped cell); 2) oval nucleus with or without eccentric position; and 3) hypogranulated

cytoplasm with focal accumulations of granules with or without granule fusions, but no signs of

degranulation. These cells may exhibit a more mature or immature morphology. Atypical mast cell Type

II is a variable form of cell with bilobar or polylobar nuclei, with a high (immature) or low (mature)

nuclear-to cytoplasmic ratio, with fine (immature) or condensed (mature) nuclear chromatin, with

nucleoli that may be present, and the cytoplasm often is hypogranulated (without signs of degranula-

tion).b In patients with acute myeloid leukemia, myeloproliferative syndrome, or myelodysplastic syndrome,

elevated serum tryptase levels have been detected without increases in mast cell numbers or signs of

mastocytosis.


CML, representing the first known translocation ofthis gene.69 Both patients had an unusual in-frameBCR-PDGFRA fusion mRNA, with either BCR exon 7 orexon 12 fused to short BCR intron-derived sequences,which, in turn, were fused to part of PDGFRA exon 12.More recently, the same translocation was reported ina third patient with a-CML, although this case wascharacterized by a distinct breakpoint fusing BCRexon 1 with PDGFRA exon 13. In view of the involve-ment of PDGFRA, the patient was treated with ima-tinib and subsequently achieved a rapid clinical andmolecular response, demonstrating in vivo activity ofthis agent against PDGFRA.70

Mutations of c-Kit and altered c-Kit function inMPD may contribute to neoplastic clonal prolifera-tion.21 SCF acts synergistically with erythropoietin tosupport the proliferation of erythroid precursors, sug-gesting a possible role in the pathogenesis of PV.24,71

Red blood cells isolated from patients with PV formerythroid burst-forming units even in the absence oferythropoetin. This autonomous erythropoiesis wasinhibited by exposure of PV patient cells in vitro toimatinib, suggesting that imatinib-sensitive kinase ac-tivity may be responsible for inducing proliferation.72

Recently a newly identified, imatinib-sensitive ty-rosine kinase was reported in leukocytes from patientswith PV.73 This kinase appears to be different from anyknown imatinib targets. The potential roles of c-Kitand SCF in the pathophysiology of HES have not beendefined clearly to date. However, it has been demon-strated that human eosinophils express c-Kit, and SCFinduces eosinophil activation and degranulation.20

Clinical ResultsPVSmall amounts of preliminary data are available re-garding the use of imatinib to treat PV. In one study,seven patients with PV received therapy with imatinibaccording to diagnostic criteria of the PVSG.24 Priortreatments included phlebotomy alone or phlebotomyplus hydroxyurea (n � 1 patient), IFN (n � 1 patient),or anagrelide (n � 2 patients). The starting dose ofimatinib was 400 mg daily, with dose escalation to amaximum of 800 mg daily permitted for persistentphlebotomy requirements, thrombocytosis, or spleno-megaly. During treatment, 6 of 7 patients achievedreductions in phlebotomy requirements comparedwith baseline. Of 2 patients who had palpable spleno-megaly, 1 patient had a 75% reduction in spleen size,and the other patient (whose spleen was smaller atbaseline) had complete regression. Four patients hadreductions in platelet counts � 600 � 109/L. The ima-tinib dose was increased for 6 of 7 patients, with 5patients receiving doses � 500 mg daily. The medica-

tion was tolerated well except in 1 patient, who dis-continued treatment because of Grade 3 dermatitis.

The elimination of phlebotomy was achieved in asecond study in 2 patients with PV who were treatedwith 400 mg daily of imatinib.76 One of those patients,who had undergone phlebotomy 2 or 3 times per yearand had splenomegaly 17 cm below the costal marginprior to receiving imatinib, remained phlebotomy freeduring 8 months of therapy. Imatinib administrationwas discontinued in this patient after 32 weeks be-cause of lack of reduction in spleen size. The secondpatient had required phlebotomy every 2– 4 monthsand had no splenomegaly before starting treatmentwith imatinib; this patient was continuing on therapyat 63 � weeks, requiring only 1 phlebotomy at thistime.

A recent case report described excellent responsesto imatinib in 2 patients with PV who were treatedwith imatinib after discontinuation of hydroxyureaand IFN therapy because of intolerable side effects.75

The first patient achieved normalization of the hemat-ocrit level and blood cell counts within 1 week ofbeginning treatment with 200 mg of imatinib daily,and she remained asymptomatic during 14 months offollow-up. The second patient had no PV symptomsand maintained normal blood values from the timewhen her therapy was switched from IFN to imatinib,400 mg daily, through 6 months of follow-up; her onlysymptom was mild diarrhea, probably related to ima-tinib. Studies of imatinib for the treatment of PV aresummarized in Table 7.23,75,76

IMFFour centers have reported results of clinical trials ofimatinib for the treatment of patients with IMF. In 1study of 8 patients who were treated with 400 mgdaily, 6 patients had improvements in platelet counts,and 3 patients had resolution of splenomegaly.74 Noreduction in transfusion requirements or bone mar-row fibrosis was noted.

In a Phase II trial that involved 14 patients who weretreated with 400 mg daily of imatinib, some improve-ments in anemia and thrombocytopenia were seen;however, treatment was discontinued in 8 patients inwhom increasing thrombocytopenia, bleeding, diseaseprogression, lung fibrosis, or pneumonia developed dur-ing the study.77 In another study among 18 patients withIMF who received imatinib 400 mg daily, 10 patients hadreductions � 30% in spleen size, including 4 patientswho had complete resolution of splenomegaly.76 Threepatients demonstrated improvements in anemia orthrombocytopenia, including one patient who had atransient trilineage response.

In a Phase II study of 23 patients with IMF who


were treated with imatinib 400 mg daily, therapy wasdiscontinued in 16 patients because of side effects,including musculoskeletal pain, thrombocytosis,edema, diarrhea, and hyperbilirubinemia.78 None ofthose patients experienced improvements in anemia,and 2 patients had partial responses in the form ofreduced splenomegaly. Increases in platelet countswere documented in 11 patients, but not in patientswho had baseline platelet counts � 100 � 109/L. It ispossible that initiation of imatinib treatment earlier inthe disease course, a longer duration of imatinib treat-ment (� 6 months), or the use of imatinib in combi-nation with other agents may improve the result.74,78

In another Phase II study of 19 patients with chronicIMF who were treated with 400-mg imatinib, bonemarrow biopsies performed every 3 months did not

show a decrease in the degree of myelofibrosis in anypatient.79 Results of those studies are summarized inTable 7.74,76 –79

MPD with eosinophiliaFour patients (all male) with chronic MPD, eosino-philia, and chromosome rearrangements involving thePDGFRB gene were treated with imatinib 400 mgdaily.17 The first 3 patients, whose clinical featuresincluded leukocytosis, mild anemia, and eosinophilia,had the classic t(5;12)(q33;p13) translocation andETV6-PDGFRB fusion. The fourth patient had leuko-cytosis, eosinophilia, and a t(5;12)(q33;q13) transloca-tion that involved PDGFRB and an unknown partnergene. The patient had presented at age 6 years withcutaneous involvement, thrombocytosis, and eosino-

TABLE 7Treatment of Polycythemia Vera, Idiopathic Myelofibrosis, Myeloproliferative Disorders, and Idiopathic Hypereosinophilic Syndrome withImatinib

StudyNo. ofpatients Dosage (mg/day) Follow-up Response rate

A. Polycythemia veraSilver, 200323 7 400 3 800 �4–9 mos 6/7Cortes et al., 200376 2 400 32 and 63 weeks 2/2Jones and Dickinson, 200375 2 200 and 400 14 and 6 mos 2/2

B. Idiopathic myelofibrosisHo et al., 200274 8 400–800 3 mos 6/8; 3/8a

Gisslinger et al., 200277 14 400 NR Mixedb

Cortes et al., 200376 18 400 Up to 58 weeks 13/18c

Tefferi et al., 200278 23 400 � 3 mos 11/23d

De Angelo et al., 200379 19 400–800 NR 1/19e

C. Myeloproliferative disordersApperley et al., 200217 4 400–800 9–12 mos 4/4Pardanini et al., 200380 2 100–400 Median, 17 weeks; range, 10–33 weeks 1f/2Magnusson et al., 200281 1 400 Up to 6 mos 1Wilkinson et al., 200367 1 NR NR 1

D. Idiopathic hypereosinophilic syndromeAult et al., 200282 1 100 �2 mos 1/1Gleich et al., 200283 5 100 97–166 days 4/5Gotlib et al., 200285 5 100–400 NR 5/5Nolasco et al., 200286 1 100 NR 1/1Pardanani et al., 200380 5 100–400 Median, 17 weeks; range, 10–33 weeks 3/5Cools et al., 200310g 11 100–400 NR 9/11h

Cortes et al., 200384 9 100i Median, 13 weeks; range 6–36 � weeks 5/9Schaller and Burkland, 2001104 1 — Weeks 1/1

NR: not reported.a Six patients had sustained platelet count improvement; three patients had resolution of splenomegaly.b There were improvements in some symptoms in some patients (notably, thrombocytopenia), but imatinib was discontinued in 8 patients after a median duration of 5.5 months because of toxicity.c Objective improvements were seen in clinical or hematologic parameters.d Some increased platelet counts were seen in patients with counts � 100 � 109/L; there was no clinical benefit overall, and imatinib was discontinued in 16 patients because of toxicity.e Clinical improvement was seen as a result of a decrease � 25% in spleen size.f This may have been a patient with hypereosinophilic syndrome.g Some of these patients are included in the other published series listed in this table.h Complete hematologic remission lasted � 3 months.i One patient required dosage escalation to 400 mg/day, which was allowed under the protocol for lack of objective response after 4 weeks of therapy at the 100-mg starting dose; dose escalation to 400 mg/day also

was permitted at any time for disease progression. The patient’s peripheral blood eosinophil count was sustained at normal levels after the dosage increase.


philia. The patient’s skin condition progressed despitetreatment (corticosteroids, hydroxyurea, and IFN-�);and, at age 20 years, he was started on imatinib. Bloodcounts normalized in 2 of the first 3 patients within 1week of starting imatinib, and bone marrow cytoge-netics showed elimination of the t(5;12) abnormalityby 12 weeks. In the third patient, blood count andbone marrow morphology were normal by 12 weeks,and the cells became cytogenetically normal at 36weeks. In the fourth patient, the white cell and eosin-ophil counts normalized within 5 days of the start ofimatinib therapy, and the t(5;12) abnormality was un-detectable after 4 weeks. However, thrombocytosispersisted, and bone marrow aspirate remained hyper-cellular after 8 weeks of therapy. With gradual escala-tion of the imatinib dose from 400 – 800 mg daily be-tween Week 8 and Week 20 of treatment, this patientexperienced normalization of blood counts, regressionof skin lesions, and normalization of bone marrowhistology. Responses in all 4 patients were durable at9 –12 months of follow-up.

In addition, 2 patients with a similar eosinophilia-associated chronic myeloid disorders but without thet(5;12) translocation have been reported.80 One pa-tient, who was treated with 100 mg daily of imatinib,had a dramatic response, with resolution of eosino-philia and a clinical and histologic remission demon-strated by bone marrow biopsy; this probably was apatient with HES. A second patient with a bone mar-row karyotype that showed trisomy 8 and whose clin-ical condition was markedly worse (e.g., a prior historyof CHF and treatment with prednisone, hydroxyurea,and cyclosporine), did not respond to treatment withimatinib 400 mg daily.

It has been shown, as noted above, that a varianttranslocation, t(1;5)(q23;q33), fuses PDGFRB to thecoiled-coil domains of a partner protein (myomega-lin), and 1 patient with MPD and this translocationresponded to imatinib.67 The patient, who had refrac-tory and progressive disease, achieved complete clin-ical and hematologic remissions and had a major cy-togenetic response.

A novel PDGFRB fusion oncogene, rabaptin-5–PDGFRB, was identified recently in a patient withCMML81 who underwent allogeneic SCT and achieveda molecular remission 5 months after transplantation.At 15 months post-SCT, signs of molecular recurrencedeveloped. After an in vitro demonstration of imatinibactivity against cells transformed with rabaptin-5–PDGFRB, the patient began therapy with imatinib.Molecular remission was achieved after 6 weeks ofimatinib administration and was continuing at 6months of treatment, providing further evidence ofthe effectiveness of imatinib in treating diseases in

which PDGFRB fusion oncogenes are implicated. Re-sults of the studies of imatinib in MPD with eosino-philia are summarized in Table 7.17,67,80,81

Idiopathic HESStudies of imatinib for the treatment of HES are sum-marized in Table 7.10,80,82– 86 Cortes et al.84 found that5 of 9 patients responded to imatinib, with completeremissions (i.e., normalization of peripheral bloodcounts, including eosinophils; disappearance of allHES signs and symptoms) that were durable beyond36 weeks (median, 13 weeks) achieved in 4 patients.Responses occurred rapidly, with normalization of theeosinophil count usually achieved within 4 weeks.Only 1 responding patient required an increase fromthe initial dosage of 100 mg daily to 400 mg daily.Treatment was tolerated well. One patient discontin-ued therapy because of a rash that was consistent withexacerbation of preexisting psoriasis, and 1 patient incomplete remission required a dosage reduction to100 mg every other day because of abdominal symp-toms while continuing to have a sustained response.All other side effects were mild (Grade 1) and wereconsistent with those observed in previous studies ofimatinib.

In 2 other studies that were based on a commoncohort of patients with HES who were treated with 100mg imatinib, 4 of 5 patients had complete hematologicresponses.83,87 The initial observation was that onlypatients with normal IL-5 levels responded to ima-tinib, but this was not confirmed with further follow-up, and it was found that patients responded despiteelevated IL-5 levels.

In both that study and others (Table 7), patientswith HES who responded to imatinib usually did so atdoses lower than those required for induction of he-matologic and cytogenetic responses in patients withBCR-ABL-positive CML (i.e., 100 mg vs. 400 mg daily).This difference corresponds to the lower 50% inhibi-tory concentration of PDGFRA compared with BCR-ABL.10

Cools and associates10 reported on 16 patientswith a diagnosis of HES from several institutions, 11 ofwhom were treated with imatinib. Ten of 11 patientsachieved a complete hematologic remission, with res-olution of eosinophilia, after a median of 4 weeks.Remissions were sustained for 3 months or longer(median, 7 months; range, 3–15 months) in 9 patients.One patient had a t(1;4) (q44;q12) translocation. DNAfrom the 16 patients in the study was analyzed forabnormalities in PDGFRA, PDGFRB, and c-Kit, all ofwhich are proven targets of imatinib. The FIP1L1-PDGFRA fusion gene, which encodes the constitu-tively activated FIP1L1-PDGFRA tyrosine kinase, was


found in 9 of 16 patients (56%) analyzed and in 5 of 9patients (56%) who responded to imatinib and re-mained in remission for at least 3 months. Why 4patients without the FIP1L1-PDGFRA fusion geneachieved a sustained complete hematologic responseto imatinib is not clear at this time, but yet-to-be-identified molecular abnormalities, probably affectingimatinib-sensitive tyrosine kinases, may be involved.The investigators noted that the FIP1L1-PDGFRA generearrangement is clonal, possibly warranting recon-sideration of the WHO classification of the eosino-philic proliferative disorders.

None of the patients in the reported investigationsof imatinib therapy for HES who were tested for evi-dence of t(5;12) (q33;p13) or mutations in c-Kit dem-onstrated these abnormalities.80,83,85 Many patients inthose studies received prior treatments, including glu-cocorticoids, hydroxyurea, IFN, and cytotoxic agents.In 1 patient, left ventricular dysfunction and cardio-genic shock developed within 1 week after the initia-tion of imatinib treatment and were reversedpromptly with corticosteroid therapy.80 Endomyocar-dial biopsy showed eosinophilic myocarditis with ev-idence of eosinophil degranulation and focal myocytedamage. Imatinib administration was continued, withgood clinical response. An additional patient discon-tinued imatinib treatment because of profound fa-tigue. Studies of the effect of imatinib on eosinophilsurvival and differentiation and of the activation sta-tus of c-Kit in HES patients are ongoing.

MCDIn a study in which patients with systemic MCD weretreated with imatinib at 100 mg or 400 mg per day,50% of patients had measurable responses.88 In thatstudy, it was found that 2 patients who did not re-spond to imatinib therapy had gain-of-function mu-tations of c-Kit. These findings suggested that the ef-ficacy of imatinib could be attributed to the inhibitionof wild-type Kit kinase activity or to another oncogenickinase, perhaps PDGFRA. It has been shown that Kitgain-of-function mutations in the kinase domain areless sensitive to imatinib compared with mutations inthe juxtamembrane region.89

The finding that at least some instances of HESare myeloproliferative clonal disorders was expandedrecently in a study that examined the utility of serumtryptase levels in identifying HES patients with anunderlying MPD.90 In that study, levels of serumtryptase, a mast cell– derived product found in MPDsand systemic mastocytosis, were elevated in 9 of 15patients with HES and were associated with othermarkers of myeloproliferation, including elevated B12

levels and splenomegaly. It is noteworthy that each of

5 patients with HES and elevated serum tryptase levelswho were assessed for the presence of FIP1L1-PDG-FRA harbored the fusion gene, whereas no patientwith HES and a normal tryptase level displayedFIP1L1-PDGFRA. Furthermore, patients who had ele-vated tryptase levels, compared with patients who hadnormal levels, had more severe disease and a highermortality rate. Six patients with HES and elevatedtryptase levels were treated with imatinib 400 mgdaily, and all 6 patients (including 4 patients withFIP1L1-PDGFRA) achieved clinical and hematologicresponses.

Although the patients with HES and elevated se-rum tryptase levels displayed several minor character-istics associated with systemic mastocytosis and eo-sinophilia, these patients could be distinguished frompatients with classic systemic mastocytosis by theirclinical manifestations, lack of mast cell aggregates,lack of a somatic kit mutation, and presence ofFIP1L1-PDGFRA.90 These differences suggested differ-ences in the underlying etiologies and pathogenesis ofthe 2 syndromes. However, it is known that mast cellproducts activate eosinophils and, conversely, that eo-sinophil products activate mast cells, suggesting a di-rect action between mast cells and eosinophils in thepathogenesis of severe disease associated with HES.91

In summary, the investigators noted that serumtryptase levels may be useful as a clinical marker ofMPDs characterized by a poor prognosis and imatinibresponsiveness.90

An examination of the prevalence of FIP1L1-PDG-FRA fusion in eosinophilia-associated disorders indi-cated that this fusion gene may be associated exclu-sively with systemic MCD rather than with HES.92 Inthat study, among 8 patients who achieved remissionwith imatinib therapy, all 8 patients were positive forFIP1L1-PDGFRA, and 7 of 8 patients had a diagnosis ofsystemic MCD.

In a complementary study, deletion of the CHIC2locus at 4q12 was detected in bone marrow cells from3 of 5 patients with systemic MCD with eosinophilia.93

Deletion at this locus, which was detected by fluores-cence in situ hybridization technology, is considered asurrogate for fusion of the FIP1L1 and PDGFRA genes.According to the investigators, identification of theFIP1L1-PDGFRA fusion gene in systemic MCD sug-gests an overlap between MCD and HES with respectto clinical presentation and molecular pathogenesis.In view of the demonstrated activity of imatinib inHES patients with FIP1L1-PDGFRA, identification ofthis gene in patients with systemic MCD provides arationale for their treatment with this agent. The studyalso demonstrated the CHIC2 deletion and expressionof the FIP1L1-PDGFRA fusion in eosinophils, neutro-


phils, and mononuclear cells, suggesting that the le-sion occurs in an early progenitor, which may explainthe similarities between HES and systemic mast celleosinophilias.

SUMMARY AND CONCLUSIONSEarly clinical results of imatinib therapy for selectedMPDs and HES are encouraging. Patients with HEShave a high response rate with imatinib(50 – 80%).10,80,82– 86 The numbers of patients with PVtreated with imatinib to date have been small. How-ever, some patients with PV appear to respond toimatinib, as evidenced by a reduction of phlebotomyrequirements.23,75,76 Results in patients with IMF havebeen more variable, which is consistent with the his-torically refractory nature of the illness. Longer follow-up, adjustments in dosing or patient selection, andimatinib-based combinations may improve re-sponses. Imatinib treatment has been found to beeffective in patients with chronic MPDs characterizedby eosinophilia and genetic rearrangements, leadingto constitutive PDGFR tyrosine kinase activity. Results,particularly in these patients, demonstrate the impor-tance of accurate clinical and molecular diagnosis andthe potential role of mutational analysis. The discov-ery of a new molecular abnormality—the FIP1L1-PDGFRA fusion gene, after the clinical observation ofthe efficacy of imatinib in HES—provided a remark-able example of translational research and suggestedthe possibility that other, similar molecular eventsmay be generated by this unique mechanism.

Insight into the molecular pathogenesis of MPDsis increasing. The pathogenetic role of constitutivelyactive PDGFRA and PDGFRB fusion proteins has beendemonstrated clearly in a subgroup of patients withMCD, HES, and MPD. Evidence indicates that PDGFRand c-Kit mutations may play a role in the pathogen-esis of IMF, and preliminary information suggests apotential contribution of SCF and c-Kit to the patho-genesis of PV and HES. These advances have led to theintroduction of molecularly targeted therapy for pa-tients with these challenging diseases. Identificationof an imatinib target provides support for therapeuticuse of the drug. The results of larger clinical studiesand additional investigations into potential mecha-nisms of action are awaited.

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