AJHO Supplement

July 2008Volume 7Number 7

Supplement 1

©2008 Haymarket Media Inc.Supplement of The American Journal of Hematology/Oncology

INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH

®

GIST and AtypicalMyeloid Disorders:

Role of Imatinib and Tyrosine KinaseInhibition in Improving Overall Survival

Faculty

Jonathan C. Trent, MD, PhDAssistant Professor of Medicine

Department of Sarcoma Medical OncologyThe University of Texas M.D. Anderson Cancer Center

Houston, TX

Jeffrey D, Wayne, MDAssistant Professor of SurgeryDivision of Surgical Oncology

Associate Medical DirectorRobert H. Lurie Comprehensive Cancer Center

Northwestern University Feinberg School of MedicineChicago, IL

Srdan Verstovsek, MD, PhDAssociate Professor

Leukemia DepartmentThe University of Texas M.D. Anderson Cancer Center

Houston, TX

GIST and AtypicalMyeloid Disorders:Role of Imatinib and Tyrosine KinaseInhibition in Improving OverallSurvival

Gastrointestinal Stromal Tumors: Update on the 3Therapy of Primary and Metastatic GISTJonathan C. Trent, MD, PhD ➢The University of Texas M.D. Anderson Cancer Center,Houston, TXJeffrey D. Wayne, MD ➢ Robert H. Lurie Comprehensive Cancer Center,Northwestern University

Clinical Update: Atypical Myeloid Disorders 15Srdan Verstovsek, MD, PhD ➢ The University of Texas M.D. Anderson Cancer Center,Houston, TX

Case Study 1: Patient with Systemic Mastocytosis 22

Case Study 2: Patient with Suspected 24Myeloproliferative/Myelodysplastic Disease

Case Study 3: Patient with Hypereosinophilic 26Syndrome (HES)/Chronic Eosinophilic Leukemia(CEL)

INVITED PRESENTATIONS OF PEER-REVIEWED CLINICAL RESEARCH®

®

July 2008 • Vol 7 • No 7 • Supplement 1

PublisherSteve [email protected]

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July 2008 • Vol 7 • No 7 3

Article

Gastrointestinal Stromal Tumors:Update on the Therapy of Primary and Metastatic GIST

Jonathan C. Trent, MD, PhDAssistant Professor of MedicineDepartment of Sarcoma Medical OncologyThe University of Texas M.D. Anderson Cancer CenterHouston, TX

IntroductionGastrointestinal stromal tumor (GIST) is the most

common mesenchymal tumor of the gastrointestinaltract. Nearly 95% of GISTs express the KIT receptortyrosine kinase (stem cell factor receptor or CD117),as shown by immunohistochemical analysis.1 Recentclinical and therapeutic advances have positionedthe KIT inhibitors imatinib and sunitinib as first- andsecond-line therapy, respectively, for patients withadvanced GISTs. Additionally, imatinib has shownpreliminary activity in the adjuvant therapy ofpatients with a resected primary GIST. Systemic ther-apies combined with surgery have shown promise inthe potential curative treatment of primary andmetastatic GIST.

Incidence and Prevalence of GISTFew large epidemiologic studies have been con-

ducted to estimate the incidence and prevalence ofGIST. The largest retrospective study to date by Tranand colleagues estimates the incidence of malignantGISTs at 6.8 per 1 million individuals, although asmaller study reported a slightly higher rate.2 Usingmodern histopathologic methods including im-munohistochemical analysis of KIT expression,Swedish investigators re-evaluated a series of intra-abdominal sarcomas and estimated the incidence ofGIST to be 14.5 cases per million people,3 equating toabout 5,000 new cases per year in the United States.2

The higher rates are linked to the inclusion of small,low-risk GISTs.

The peak incidence of GIST occurs in the late sixthand early seventh decades of life, with a very slightmale predominance. A large retrospective study sug-gested an increased risk among African-Americansand Asian/Pacific Islanders, but this has not beenvalidated in other studies.4 Approximately 60% ofGISTs occur in the stomach, 25% in the small intes-tine, and 10% in the large bowel, rectum, appendix,and esophagus, with rare occurrence in extra-intes-tinal sites such as the gallbladder, omentum, andmesentery.5 GISTs make up 2.2% of all gastric malig-nancies, 13.9% of all small intestine malignancies,and 0.1% of all colonic malignancies.6

Gastric GIST has a better prognosis than extra-gastric GIST.7 The common metastatic sites for GISTinclude the liver and omentum, less frequently thelung, and rarely the regional lymph nodes and bone.4

Diagnosis of GISTThree major histologic subtypes are characteristic

of GIST: spindle cell (70%), epithelioid (20%), and amixed subtype (10%).8 Epithelioid variants are moreoften seen in the stomach and in some studies havebeen linked to expression of Bcl-29 and adverse out-comes.10

Many factors have been evaluated in estimatingthe malignant potential of primary GIST. Whilemany studies have looked at the site of the tumorand mucosal invasion, the two most predictive fac-tors appear to be size of the tumor (greatest diame-ter) and number of mitoses per high-powered field.11

Jeffrey D. Wayne, MDAssistant Professor of SurgeryDivision of Surgical OncologyAssociate Medical DirectorRobert H. Lurie Comprehensive Cancer CenterNorthwestern University Feinberg School of MedicineChicago, IL

4 The American Journal of Hematology/Oncology

Article

Consensus histologic criteria have been formulated(Table 1).12 Despite these criteria, the true malignantactivity of these tumors is unpredictable, as evensmall (<1 cm) tumors may recur 10 years or moreafter diagnosis.

The neoplastic cells in GISTs are thought to arisefrom the interstitial cells of Cajal (ICC) or a cell inthat lineage. Sarlomo-Rikala and colleagues noted in1998 that GISTs stained nearly universally positivefor CD117 as compared to other mesenchymaltumors such as leiomyoma, leiomyosarcomas, andschwannomas. Individuals with germ-line mutationin the KIT gene have been found to have hypertro-phy of the myenteric plexus.13 Hirota, Isozaki, andcolleagues demonstrated gain-of-function mutationsin the KIT gene on chromosome 4.14

It is now estimated that nearly 95% of GISTs stainfor CD117.15 In the small subset of patients who havenegative KIT immunohistochemistry, the use ofreverse transcription-polymerase chain reaction (RT-PCR) can detect mutations in the KIT gene. Thesemutations may lead to decreased or aberrant pheno-typic expression of KIT by immunohistochemistry.Other positive immunohistochemical markersinclude CD34 (70%), smooth muscle actin (35%), S-100 (10%), and, rarely, desmin (5%).5 Epithelioid ormixed morphology GISTs frequently express Bcl-2.9

Although these antigens are useful to distinguishGIST from smooth muscle tumors, desmoid fibro-matosis, and schwannoma, they should not be reliedupon to the exclusion of tumor cell morphology andclinical findings.

Pathophysiology of the KIT Receptor Tyrosine Kinase

The KIT tyrosine kinase receptor, when stimulatedby its native ligand, steel ligand, or stem-cell factor(SCF), functions in a host of cellular processes includ-ing cellular proliferation, differentiation, maturation,survival, chemotaxis, and adhesion. Transmission ofthese various processes is mediated through thehomodimerization, autophosphorylation, and activa-tion of several signal transduction pathways, includ-ing the Phosphoinositide 3’ kinase (PI3K), Jak-Stat,Ras-Erk, and Phospholipase C pathways.15

Genetic mutations in specific exons of the KITgenome lead to a gain of function of this tyrosinekinase receptor in GIST. KIT tyrosine kinase receptoris constitutively active in the absence of stimulationby SCF or via homodimerization resulting ultimate-ly in oncogenesis.15 Most mutations in KIT occur inthe juxtamembrane region encoded by exon 11 (71%)or extracellular region encoded by exon 9 (14%) andless frequently in exon 13 (4%) or 17 (4%), which

Risk Size Mitotic count

Very low < 2 cm < 5/50 hpf

Low risk 2-5 cm < 5/50 hpf

Intermediate risk < 5 cm 6-10/50 hpf

5-10 cm < 5/50 hpf

High risk > 5 cm > 5/50 hpf

> 10 cm Any mitotic rate

Any size > 10/50 hpf

hpf = high-powered field

Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Pathol.2002;10:81-89.

Table 1

Consensus risk of malignancy classification of primary gastrointestinal stromal tumors

July 2008 • Vol 7 • No 7 5

Gastrointestinal Stromal Tumors: Update on the Therapy of Primary and Metastatic GIST

encode the tyrosine kinase domain.16 The remainderof the mutations occur predominantly in anothertyrosine kinase receptor, the platelet-derived growthfactor receptor alpha (PDGFRα).16.17 Many of themutations in PDGFRα correlate with the mutationalhot spots seen in KIT and occurred in patients withwild type KIT tyrosine kinase genes, suggesting thatthese represent two independent, sufficientlytumorigenic mutational events.18 Patients with gas-tric GIST of the epithelioid variant or mixed histolog-ic variant often have PDGFRα mutations.19

Initial Evaluation of the Patient With GISTLaboratory Testing

There are no known serum tumor markers forGIST. Nonetheless, laboratory testing at the time ofdiagnosis and during therapy plays an importantrole in standard care of the patient with GIST. A com-plete blood count will aid in screening for anemia.Patients with GIST may be anemic due to iron defi-ciency as a result of intratumoral or transmucosalhemorrhage, B12 deficiency resulting from malab-sorption after gastrectomy, anemia of chronic dis-ease, or a combination of these mechanisms.Therapy with the tyrosine kinase receptor inhibitorimatinib mesylate (see Systemic Therapy of MetastaticDisease) rarely causes leucopenia or anemia and isunlikely to cause thrombocytopenia. Erythropoietingrowth factors are effective at raising hemoglobinlevels in GIST patients when indicated.

Serum chemistries are useful at baseline todetermine whether a patient has organ involve-ment from the GIST or other disease. This will alsoserve as a baseline for any potential toxicities dueto imatinib. GIST metastases commonly involve theliver, so measurement of bilirubin, transaminases,and alkaline phosphatase is routine. Moreover,hepatotoxicity may occur as a result of imatinibtherapy and may be chemical or autoimmune. (Thedistinction may require a liver biopsy.) Imatinibtherapy may also result in alterations of electrolytemetabolism, resulting in hypokalemia, hypomag-nesemia, hypocalcemia, and hypophosphatemia.20

These parameters should be documented prior tothe use of imatinib and followed every 1-3 monthswhile on therapy, providing replacement as needed.

Computed TomographyComputed tomography (CT) is the most valuable

imaging tool, not only in the initial diagnosis of GISTbut also in assessing the efficacy of therapy. On initial

appearance, GISTs are often large, heterogeneousmasses (Figure 1). The non-enhancing portions of theuntreated GIST contain necrotic tissue.

GISTs tend to grow extraluminally and, as a result,generally do not present as obstructing lesions, withthe exception of large tumors or those that arise inthe esophagus or rectum. GISTs arise in the myen-teric plexus between the circular and longitudinalmuscularis layers, which may give rise to the appear-ance of aneurysmal dilatation of the bowel wall.21

Mucosal ulceration is a finding identified by free airor oral contrast within the tumor. Other findings onCT imaging include intra-tumoral hemorrhage, morecommonly seen in larger tumors. Tumor calcificationand invasion into surrounding viscera andvessels are rare.21

Metastatic disease within the peritoneum is a fre-quent manifestation of GIST but may be underesti-mated by imaging. Peritoneal implants are oftensmall and may be difficult to differentiate fromunopacified bowel, lymph nodes, or small blood ves-sels.21 Although three-phase CT scan is the best imag-ing modality in GIST, additional metastatic lesionsin the liver or peritoneal cavity may be found atlaparotomy.

Metastatic disease of the liver is a common phe-nomenon in GIST. The lesions, unlike their mesen-teric and omental counterparts, are frequently hyper-

Figure 1

GISTs often initially appear as large, heterogeneous masses.


Article

vascular and enhance with contrast. The most sensi-tive means of detecting hepatic metastases remainsthe three-phase CT scan. Single-phase venous con-trast may miss lesions and underestimate the extentof disease in the liver. Ascites in GIST occurs late inthe disease and may be difficult to distinguish fromthe ascites seen as a complication of imatinib therapy.21

Metastases outside the abdomen seldom occur andare associated with advanced disease. Lymphaticspread is also rare, and in the presence of lymphaden-opathy clinicians should entertain other diagnoses.

When patients initiate therapy with imatinib, forexample, lesions that respond to therapy change incharacter on CT imaging. Radiographically, hetero-geneous, hyperattenuating lesions (Figure 2A)become hypoattenuating and appear cystic in nature(Figure 2B). These lesions may initially increase ornot change in size, and when analyzed pathological-ly they change from a cellular tumor (Figure 2C) toone that is composed of myxoid material with mini-mal viable cellular material (Figure 2D).22,23 Even afterseveral months of therapy, the tumor size may notchange appreciably, although there has been markedreduction in the CT radiodensity. Careful tumormeasurement frequently identifies subtle decrease intumor size not qualifying for a partial response bystandard criteria.23

PET ScanPositron emission tomography (PET) is a func-

tional imaging modality with utility in GIST.23 PETimaging evaluates the metabolic rate of tumors bythe uptake of a radiolabelled glucose molecule(FDG, fluourodeoxy glucose). This is particularlyuseful when a baseline scan is compared to oneobtained after therapy. PET imaging has been usedto detect metabolic changes very early in therapy.For instance, Figure 3A depicts a pre-imatinib PETscan showing uptake of FDG by the tumor, whichis completely abrogated after only 8 weeks of ima-tinib therapy (Figure 3B).24 Additionally, PET imaging may be useful in interpreting the results ofan ambiguous CT or MRI study. PET imaging hashelped the medical community understand thelimitations of response criteria commonly em-ployed in clinical trials. RECIST (Response Eval-uation Criteria for use In Solid Tumors).25 Aspatients with GIST are treated with imatinib, en-larging or stable lesions would be misclassified asstable or as an indication of progressive diseaseusing RECIST. However, with the noted metabolicchanges on PET scanning and the correlativepathologic findings of myxoid degeneration andnecrotic tissue, the standard criteria for tumorresponse in this malignancy are invalid.23

Figure 2A

On radiographic analysis, GIST appears heterogeneousand hyperattenuated prior to imatinib therapy.

Figure 2B

After imatinib therapy, lesions become hypoattenuatedand appear cystic.

July 2008 • Vol 7 • No 7 7


Despite the benefit of PET scanning in the man-agement of GISTs, drawbacks and limitations exist.First, CT findings and PET findings do not alwayscorrelate. Hypervascular lesions may be negative onPET scan. Second, smaller tumors may not appear onPET secondary to tumor necrosis, which makes PETscanning not useful in this setting.8 In addition,Scaife and colleagues at The University of Texas M.D.Anderson Cancer Center have questioned the validi-ty of PET scans as a measure of tumor response. Inthis study, 17 patients who received neoadjuvantimatinib had surgery performed on previously non-resectable GIST. The pathologic findings were thencorrelated with the radiologic response to imatinib.Eleven of these patients had a PET scan, and sixdemonstrated no evidence of metabolic activity onFDG-PET scan after imatinib therapy and prior tosurgery.26 The review of the pathologic specimensrevealed viable tumor in five of the six specimens.These scans were obtained within 3 months of surgi-cal intervention, and the therapeutic response mayhave changed during this time to explain this dis-crepancy.26 However, the findings in this study doraise the question of the validity of this imagingmodality in assessing tumor response. Its utility,while promising, requires further investigation.

Therapy of Advanced GISTThe discovery of the KIT tyrosine kinase receptor

and the development of imatinib to block the activi-ty of this receptor have changed the treatment andthe outlook of GISTs. Prior to this discovery, surgery

was the only viable treatment option. Chemotherapyis largely ineffective with poor response rates,27 andradiation therapy was often impractical because ofthe extent and location of disease.

Systemic Therapy of Metastatic DiseaseImatinib Mesylate

The use of imatinib mesylate in the therapy ofmetastatic GIST has changed the course of this dis-ease. From the initiation of its compassionate use ina 50-year-old patient with metastatic GIST in March2000 to its position as the standard of care in patientswith metastatic or unresectable disease, patients cannow experience prolonged disease-free and overallsurvival.22,28,29 The standard dose of imatinib was es-tablished in an EORTC trial by Van Oosterom andassociates, which looked at 36 patients with GIST.30

These patients were randomized to a dose of 400mg/d, 300 mg bid, 400 mg bid, or 500 mg bid.Toxicity and efficacy were monitored, and the find-ings showed that the best tolerated dose was 400mg/d. The side effects were manageable and mostcommonly included edema, nausea, diarrhea,malaise, and fatigue. Rare side effects includedmyelosuppression, hemorrhage, and elevatedtransaminases, which required interruption or dis-continuation of treatment.30

Several phase II and III clinical trials have beendesigned to assess the efficacy of imatinib in themetastatic setting. Based on the data from these stud-ies, the observed response to imatinib ranges from48% to 71%, with disease stabilization in 70% to 85%

Figure 2C

Analyzed pathologically, GIST appears as cellular tumorsbefore imatinib therapy.

Figure 2D

Following therapy, the lesions are composed of myxoidmaterial and minimal viable cellular material.


Article

of patients. The median progression-free survival(PFS) ranges from 18-24 months.28,31-33

Two large international studies randomizedpatients with metastatic GIST to standard-dose orhigh-dose imatinib (400 mg/d versus 800 mg/d,respectively).28,31 The North American SarcomaIntergroup Study S0033 was composed of the US coop-erative oncology groups (Southwest OncologyGroup, Cancer and Leukemia Group B, and theEastern Cooperative Group), The University ofTexas M.D. Anderson Cancer Center, and theNational Cancer Institute of Canada Sarcoma Group.The primary aim of this study was to assess theimpact of imatinib dosing (400 mg compared to 800mg daily) on survival. Secondary aims were to eval-uate response rates and confirm the tolerability ofimatinib therapy in patients with GIST. BetweenDecember 15, 2000, and September 1, 2001, 746patients from 57 institutions were enrolled. Patientsrandomized to receive the 400-mg daily dose wereallowed to cross over to the 800-mg daily dose if theyhad progression of disease. Median overall survivalhad not been reached in either arm after a median

follow-up of 25.6 months. Although the P-value wasgreater than .05, there was a superior PFS rate forpatients with metastatic GIST treated at an initialdose of 800 mg/d. PFS rate estimates at 2 years were50% for the 400-mg arm and 53% for the 800-mg arm.31

Survival estimates after 2 years were equivalentbetween the two arms (78% for the 400-mg arm vs73% for the 800-mg arm). Interestingly, of the 106patients who crossed over to the higher dose afterhaving progression of disease on the 400-mg dailydose, 7% had a partial response and 32% had stabledisease, indicating that patients benefit from doseescalation at the time of progression.31

The EORTC Soft Tissue and Bone Sarcoma Group,Italian Sarcoma Group, and Australasian Gastro-Intestinal Trials Group conducted a similarlydesigned phase III trial of imatinib in patients withunresectable or metastatic GIST. The primary endpoint was PFS, with objective response to treatmentand survival as secondary end points. BetweenFebruary 2001 and February 2002, 946 patients withGIST were randomized to receive imatinib at a doseof either 400 mg daily or 800 mg daily. This trial was

Figure 3A

Pre-imatinib: PET scan revealed uptake of FDG by GISTtumors.

Figure 3B

FDG completely abrogated after only 8 weeks of therapy.

July 2008 • Vol 7 • No 7 9


powered to detect a 10% difference in PFS rates. Theobjective response rates were 45% and 48% for the400-mg and 800-mg arms, respectively.28 The 2-yearoverall survival estimate was 69% for patients treat-ed at an initial daily dose of 400 mg and 74% forthose patients started at 800 mg daily (P=.026).28 PFSrates at 2 years also were significantly superior (52%)for patients allocated to 800 mg daily of imatinibcompared to those who received the lower dose(44%).28 The median PFS among patients taking the800 mg dose was more than 2 years.28

The degree of prolongation of time to progressionseen in the two studies was similar, so it is possiblethat the difference in the statistical significance of theresults in these studies is due to the greater numberof patients enrolled in the EORTC study, thus allow-ing more power to detect statistical differences. Thecombined observations of superior PFS with high-dose imatinib and benefit from dose escalation at thetime of progression suggest a dose-response relation-ship for imatinib in GIST. Determining whichpatients will benefit from higher doses of imatinib isimportant in view of the greater toxicity at higherdoses.

Systemic Therapy of Imatinib-Resistant GISTWidespread progression of disease generally

requires systemic therapy. The initial approachshould be to maximize the dose of imatinib to 800 mgdaily. After progression on the maximum tolerateddose of imatinib, patients should be evaluated for aclinical trial or may be treated with sunitinib, arecently Food and Drug Administration-approvedtyrosine kinase inhibitor. Sunitinib possesses poten-tially both antiangiogenic and anti-oncogenic prop-erties, as it inhibits the vascular endothelial growthfactor receptor and the KIT receptor, respectively.

Sunitinib was investigated in 97 patients withimatinib-resistant GIST. Each patient received suni-tinib 50 mg/d, and after 1 year 22 patients obtainedeither a partial response or stable disease.34 In a phaseIII study in metastatic, imatinib-resistant GIST, suni-tinib was found to have a 7% partial response rateand a 58% stable disease rate after imatinib discon-tinuation. This phase III study randomized patientsto receive either sunitinib or placebo so that the ben-efit of sunitinib over continued imatinib remainsunknown.35

Dasatinib,36 AMG 706, and nilotinib (AMN 107)37

are other multitargeted tyrosine kinase inhibitorswith high affinity for platelet-derived growth factor

receptor and KIT. The efficacy of these agents has notbeen published to date.

Surgical Intervention for GISTSurgical intervention remains the treatment of

choice for localized GISTs. These lesions are submu-cosally based and push, rather than invade, sur-rounding viscera. Thus, minimal, non-anatomic, his-tologically negative margin (R0) resections may oftenbe accomplished. As in other intra-abdominal sarco-mas, lymph node metastasis is rare.38 The classicexample is that of a large, locally advanced gastricGIST, which may be treated by non-anatomic wedgeresection, as opposed to a formal anatomic resectionwith extended lympadenectomy, which would berequired for gastric adenocarcinoma (Figure 4).39,40

Success with this approach has led investigators toapproach these lesions via laparoscopic tech-niques.41,42 While most series are small and from sin-gle institutions, it would appear that as long asappropriate precautions are employed (gentle han-dling of the tumor to prevent rupture, removal of thespecimen in a plastic bag to prevent abdominal wallseeding, and confirmation of histologically negativemargins via gross inspection or frozen section),employing these techniques may allow thesepatients to leave the hospital earlier with equivalentoncologic results.

Contraindications to surgery would include med-ical comorbidities precluding abdominal exploration,evidence of widespread, advanced disease (typically

Figure 4

Wedge resection of GIST emanating from the lesser curveof the stomach.Wayne JD, Bell RH Jr. Surg Clin North Am. 2005;85:1009-1020.


Article

peritoneal or hepatic metastases), and an extensivetumor requiring extended and/or multi-visceral resec-tion. Examples include a large tumor of the 2nd por-tion of the duodenum, which would require a pancre-aticoduodenectomy; a distal rectal tumor that wouldrequire an abdominoperineal resection; and tumors ofthe gastroesophageal junction, which require esopha-gectomy to achieve a margin-negative resection.43

For patients with borderline resectable GISTs, orin whom substantial morbidity may be anticipatedafter resection, considerations should be given to a

preoperative course (neoadjuvant) of imatinib.44 Thisapproach necessitates tissue sampling, which is notalways obtained prior to operative intervention forresectable GISTs. Endoscopic ultrasound with fineneedle aspiration has emerged as the technique ofchoice for biopsy of these often friable lesions.45,46

These patients require close follow-up, given thatdespite imatinib therapy, some tumors may progress,rendering them unresectable. While individual insti-tutional practices vary, the National ComprehensiveCancer Network guidelines would recommend a

Figure 5A

CT shows a 3.5 x 2.2 cm soft tissue mass of the duode-num. Endoscopic ultrasound-guided fine needle aspirationbiopsy confirmed the mass to be a GIST.

Figure 5B

After 6 months of imatinib, the mass had decreased in sizeto 2.7 x 2.3 cm and was deemed resectable.

Figure 5C

The partial duodenal resection specimen, bisected toreveal a typical GIST.Images courtesy of JD Wayne, MD.

Figure 5D

Final pathology revealed a GIST with negative bowel andserosal margins.

July 2008 • Vol 7 • No 7 11


PET scan at 2-4 weeks after starting imatinib therapyto ensure therapeutic effect.47 If no response is found,the patient would proceed to surgery. In stable andresponding patients, however, imatinib is continuedto maximal therapeutic effect. This may take up to 12months.48 Maximal response is typically defined asno further improvement between two succes-sive cross-sectional imaging studies (CT or MRI).Frequent reevaluation of such patients by a multidis-ciplinary team is optimal to determine the best timefor surgical intervention (Figure 5).

Neoadjuvant ImatinibThe role of imatinib in lesions that are surgically

resectable is a controversial matter that is currentlyunder investigation. Preliminary results of theNational Cancer Institute-sponsored RadiationTherapy Oncology Group (RTOG 0132) phase II trialof adjuvant/neoadjuvant imatinib following surgeryfor advanced GIST showed PFS and overall survivalof 82% and 93%, respectively, for locally advanceddisease and 73% and 91%, respectively, for recur-rent/metastatic GIST.49 Thus, until such resultsbecome available, surgery should be considered first-line therapy for primary or recurrent tumors that areresectable without excessive surgical morbidity.

Local Therapy of Metastatic DiseaseLocal therapy may benefit select patients with

metastatic, imatinib-resistant GIST. Limited progres-sion of disease may be amenable to surgical interven-tion depending on the size, number, and location ofprogressing lesions. Modalities potentially useful inthe treatment of limited progression include hepaticarterial embolization (with or without cisplatin),50,51

surgical resection,52 and radiofrequency ablation.53,54

Adjuvant TherapySurvival after surgery alone for GIST is favorable

when compared to other intra-abdominal sarcomas. Aseries of 200 patients with likely GISTs treated at theMemorial Sloan-Kettering Cancer Center were prospec-tively followed from 1983-1997. Of the 93 patients whopresented with a primary tumor and no metastatic dis-ease, 80 (86%) were able to undergo resection of all grossdisease. The 5-year disease-specific survival for thisgroup was 54%, with a median of 66 months.52 Mediantime to recurrence after resection of primary high-riskGIST is about 2 years. Thus, for high- and even interme-diate-risk lesions (> 3 cm in size, and/or > 5 mitoses/hpf), surgery alone can not be considered curative.

These findings have led the American College ofSurgery Oncology Group (ACOSOG) to initiate twotrials examining the role of imatinib in the adjuvantsetting. The first, Z9000, is a single-arm, phase II trialthat accrued 106 patients who had undergone mar-gin-negative resection of a GIST with high-risk fea-tures. Patients were treated with imatinib at 400mg/day for 1 year. The treatment was tolerated well,with no grade 4 or 5 toxicities, and 83% of patientscompleted the prescribed therapy.55 At the 2008American Society of Clinical Oncology Gastro-intestinal Cancers Symposium, results were provid-ed (www.ASCO.org).55 Overall survival for thisgroup was 99%, 97%, and 97% at 1, 2 and 3 years,respectively, an especially favorable response com-pared to the historic controls.55 Also impressive wasthe recurrence-free survival (RFS), which was 94%,73%, and 61%, again at 1, 2, and 3 years, respectively.

The second trial, Z9001, an intergroup, double-blind, randomized, phase III trial of adjuvant ima-tinib (400 mg/day vs. placebo), has also completedaccrual. Interim analysis, included 644 patients from203 sites, with a median follow-up of 1.2 years.56 Oneyear of adjuvant imatinib increased the DFS survivalfrom 83% in the placebo arm to 97% in the treatmentarm (P<.001). This difference in RFS was most pro-nounced in patients with high-risk tumors > 10 cm.There was no statistically significant difference inoverall survival (P = .72). Thus in 2008, adjuvanttherapy with 1 year of imatinib may be considered,especially in high-risk patients. However, mostpatients are best followed by physical examinationand cross-sectional imaging at 3- to 6-month inter-vals for the first 3-5 years.47 Studies are now ongoingin Europe that randomly assign patients to 1 or 3years of adjuvant imatinib or 0 or 2 years of adjuvantimatinib.57,58

DiscussionGIST is the most common mesenchymal tumor of

the gastrointestinal tract. Historically, patients withGIST were often misdiagnosed (as leiomyosarcomas).However, improved understanding of the pathobiol-ogy of this disease has led to revised estimates ofincidence (5,000 new cases/year), which is now recog-nized as much higher than previously thought.3

While many factors play a role in evaluating themalignant potential of primary GIST, tumor size, siteof primary, and the number of mitoses per high-pow-ered field appear to be the most predictive. Notably,the true malignant or nonmalignant activity of these


Article

tumors remains unpredictable, given that even small(< 1 cm) tumors may recur a decade or more after theinitial diagnosis.

The three-phase CT scan remains the most valu-able imaging tool, not only in the initial diagnosis ofGIST but in detecting hepatic metastases. This tech-nology also is the most sensitive means of assessingthe efficacy of therapy. PET scanning provides someutility for the management of GISTs, but this imagingmodality is limited by its inability to detect hyper-vascular lesions, and smaller tumors may not appearon PET secondary to tumor necrosis.

Surgery continues to be the therapy of choice inpatients with resectable GIST. However, it is impor-tant to note that the curative potential of surgery is seldom realized due to a high rate of recurrence and a 5-year survival rate of approximately 50%.47,52

Chemotherapy is largely ineffective,27 with poorresponse rates, and radiation therapy is often imprac-tical because of the extent and location of disease.

Advances in surgery, such as laparoscopic tech-niques, have improved PFS and overall survival inmany patients; however, the discovery of the KITtyrosine kinase receptor and the development of thetyrosine kinase inhibitor imatinib have changed thetreatment and the outlook of GISTs.59,60

The rationale for the use of imatinib in GIST isfounded on the fact that oncogenic mutations of KITor PDGFRα occur in the development of approxi-mately 90% of GISTs and imatinib is a potent andselective inhibitor of these kinases.60

Since 2000 the use of imatinib has become thestandard of care in patients with metastatic or unre-sectable GIST disease. The recent EORTC Soft Tissueand Bone Sarcoma Group, Italian Sarcoma Group,Australasian Gastro-Intestinal Trials Group, and theNorth American Sarcoma Intergroup Study S0033trials have demonstrated that a high percentage ofpatients have experienced prolonged overall sur-vival and more than 50% have achieved 2-year PFSwith 800 mg daily of imatinib.28,31 The recentlyapproved sunitinib and other multitargeted tyrosinekinase inhibitors such as dasatinib36 and nilotinib37

show a high affinity for the PDGFR and KIT and thusmay also have anti-angiogenic and anti-oncogenicpotential for GIST.

Because of its activity in metastatic GIST, imatinibused in an adjuvant setting provides benefits interms of PFS, and, given the favorable efficacy andsafety profile of imatinib, adjuvant therapy may havea role in preventing recurrence and metastasis.44.52.61

The role of imatinib in the neoadjuvant setting, thesubject of current investigation, will be examined inthe Radiation Therapy Oncology Group (RTOG0132) trial, but until these data become available, sur-gery should be considered first-line therapy for pri-mary or recurrent resectable tumors.49

ConclusionsIn summary, recent studies have demonstrated

that imatinib and other tyrosine kinase inhibitors,either alone or in combination with surgery, showconsiderable promise in the management of patientswith metastatic and primary GISTs. Imatinib andother agents in this class will continue to be subjectto ongoing clinical investigation of neoadjuvant,adjuvant, and metastatic GIST for the foreseeablefuture. ■

Editorial assistance and commercial support for this manuscriptprovided by Novartis Pharmaceuticals Corp.

References1. Clary BM, DeMatteo RP, Lewis JJ, Leung D, Brennan MF.

Gastrointestinal stromal tumors and leiomyosarcoma of theabdomen and retroperitoneum: a clinical comparison. AnnSurg Oncol. 2001;8:290-299.

2. Nilsson B, Bèumming P, Meis-Kindblom JM, et al.Gastrointestinal stromal tumors: the incidence, prevalence,clinical course, and prognostication in the preimatinib mesy-late era—a population-based study in western Sweden. Cancer.2005;103:821-829.

3. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastroin-testinal stromal tumors: a consensus approach. Hum Pathol.2002;33:459-465.

4. Emory T, Sobin LH, Lukes L, et al. Prognosis of gastrointesti-nal smooth muscle (stromal) tumors: dependence on anatomicsite. Am J Surg Pathol. 1999;23:82-87.

5. Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointesti-nal stromal tumors. J Clin Oncol. 2004;22:3813-3825.

6. Fletcher CD. Clinicopathologic correlations in gastrointestinalstromal tumors. Hum Pathol. 2002;33:455.

7. Miettinen M, Sobin LH, Lasota J. Gastrointestinal stromaltumors of the stomach: a clinicopathologic, immunohisto-chemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol. 2005;29:52-68.

8. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for themanagement of gastrointestinal stromal tumors: report of theGIST consensus conference 20-21 March 2004, under the aus-pices of ESMO. Ann Oncol. 2005;16:566-578.

9. Steinert DM, Oyarzo M, Wang X, et al. Expression of Bcl-2 ingastrointestinal stromal tumors: correlation with progression-free survival in 81 patients treated with imatinib mesylate.Cancer. 2006;106:1617-1623.

10. Trupiano JK, Stewart RE, Misick C, et al. Gastric stromaltumors: a clinicopathologic study of 77 cases with correlationof features with nonaggressive and aggressive clinical behav-iors. Am J Surg Pathol. 2002;26:705-714.

11. Casali PG, Jost L, Reichardt P. Schlemmer M, Blay JY: ESMOGuidelines Working Group. Gastrointestinal stromal tumors:ESMO clinical recommendations for diagnosis, treatment and

July 2008 • Vol 7 • No 7 13


follow-up. Ann Oncol. 2008;19(suppl 2):ii35-ii38.12. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointesti-

nal stroma tumors: a consensus approach. Int J Surg Pathol.2002;10:81-89.

13. Sarlomo-Rikala M, El-Rifai W, Lahtinen T, et al. Different pat-terns of DNA copy number changes in gastrointestinal stromaltumors, leiomyomas, and schwannomas. Hum Pathol. 1998;29:476-481.

14. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function muta-tions of c-kit in human gastrointestinal stromal tumors. Science.1998;279:577-580.

15. Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R. Normaland oncogenic forms of the receptor tyrosine kinase kit. StemCells. 2005;23:16-43.

16. Heinrich MC, Corless C, Demetri GD, et al. Kinase mutationsand imatinib response in patients with metastatic gastrointesti-nal stromal tumor. J Clin Oncol. 2003;21:4342-4349.

17. Duensing A, Medeiros F, McConarty B, et al. Mechanisms ofoncogenic KIT signal transduction in primary gastrointestinalstromal tumors (GISTs). Oncogene. 2004;23:3999-4006.

18. Bauer S, Corless CL, Heinrich MC, et al. Response to imatinibmesylate of a gastrointestinal stromal tumor with very lowexpression of KIT. Cancer Chemother Pharmacol. 2003;51:261-265.

19. Wardelmann E, Hrychyk A, Merkelbach-Bruse S, et al.Association of platelet-derived growth factor receptor alphamutations with gastric primary site and epithelioid or mixedcell morphology in gastrointestinal stromal tumors. J MolDiagn. 2004;6:197-204.

20. Gleevec [package insert]. East Hanover, NJ: NovartisPharmaceuticals Corp; 2008.

21. Sandrasegaran K, Rajesh A, Rushing DA, et al. Gastrointestinalstromal tumors: CT and MRI findings. Eur Radiol. 2005;15:1407-1414.

22. Joensuu H, Roberts P, Sarlomo-Rikala M, et al. Effect of thetyrosine kinase inhibitor STI571 in a patient with a metastaticgastrointestinal stromal tumor. N Engl J Med. 2001;344:1052-1056.

23. Choi H, Charnsangavej C, Faria SC, et al. Correlation of com-puted tomography and positron emission tomography inpatients with metastatic gastrointestinal stromal tumor treatedat a single institution with imatinib mesylate: proposal of newcomputed tomography response criteria. J Clin Oncol. 2007;25:1753-1759.

24. Trent J. A prospective, randomized, phase II study of preoper-ative plus postoperative imatinib mesylate (Gleevec, formerlySTI-571) in patients with primary, recurrent, or metastaticresectable, Kit-expressing, gastrointestinal stromal tumor(GIST). 2004.

25. Therasse P, Eisenhauer EA, Verweij J. RECIST revisited: areview of validation studies on tumour assessment. Eur JCancer. 2006;42:1031-1039.

26. Scaife CL, Hunt KK, Patel SR, et al. Is there a role for surgeryin patients with “unresectable” cKIT+ gastrointestinal stromaltumors treated with imatinib mesylate? Am J Surg. 2003;186:665-669.

27. Trent JC, Beach J, Burgess MA, et al. A two-arm phase II studyof temozolomide in patients with advanced gastrointestinalstromal tumors and other soft tissue sarcomas. Cancer.2003;98:2693-2699.

28. Verweij J, Casali PG, Zalcberg J, et al. Progression-free survivalin gastrointestinal stromal tumours with high-dose imatinib:randomised trial. Lancet. 2004;364:1127-1134.

29. Blanke CD, Demetri GD, von Mehren M, et al. Long-termresults from a randomized phase II trial of standard- versushigher-dose imatinib mesylate for patients with unresectableor metastatic gastrointestinal stromal tumors expressing KIT.J Clin Oncol. 2008;26:620-625.

30. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacyof imatinib (STI571) in metastatic gastrointestinal stromal

tumours: a phase I study. Lancet. 2001;358:1421-1423.31. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized,

intergroup trial assessing imatinib mesylate at two dose levelsin patients with unresectable or metastatic gastrointestinalstromal tumors expressing the kit receptor tyrosine kinase:S0033. J Clin Oncol. 2008;26:626-632.

32. von Mehren M, Blanke C, Joensuu H, et al. High incidence ofdurable responses induced by imatinib mesylate (Gleevec) inpatients with unresectable and metastatic gastrointestinal stro-mal tumors (GISTs). 2002 American Society of ClinicalOncology; Orlando: Abstract 1608.

33. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy andsafety of imatinib mesylate in advanced gastrointestinal stro-mal tumors. N Engl J Med. 2002;347:472-480.

34. Maki RG, Fletcher JA, Heinrich MC, et al. Results from a con-tinuation trial of SU11248 in patients (pts) with imatinib (IM)-resistant gastrointestinal stromal tumor (GIST). Am Soc ClinOncol. 2005;24:469: Abstract 9011.

35. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy andsafety of sunitinib in patients with advanced gastrointestinalstromal tumour after failure of imatinib: a randomised con-trolled trial. Lancet. 2006;368:1329-1338.

36. Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib(BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits thekinase activity of wild-type, juxtamembrane, and activationloop mutant KIT isoforms associated with human malignan-cies. Cancer Res. 2006;66:473-481.

37. D’Amato G, Steinert DM, McAuliffe JC, Trent JC. Update onthe biology and therapy of gastrointestinal stromal tumors.Cancer Control. 2005;12:44-56.

38. Fong, Y, Coit DG, Woodruff JM, Brennan MF. Lymph nodemetastasis from soft tissue sarcoma in adults. Analysis of datafrom a prospective database of 1772 sarcoma patients. AnnSurg. 1993;217:72-77.

39. Wayne JD, Talamonti MS, Tumors of the Stomach, Duodenum,and Small Bowel. In: American College of Surgeons Surgery:Principles and Practice. Souba WW, Jurkovich GJ, Kaiser LR, etal. Eds. 2006, Web MD, Inc.: New York. pp. 486-498.

40. Wayne JD, Bell RH Jr. Limited gastric resection. Surg Clin NorthAm. 2005;85:1009-1020.

41. Novitsky YW, Kercher KW, Sing RF, Heniford BT. Long-termoutcomes of laparoscopic resection of gastric gastrointestinalstromal tumors. Ann Surg. 2006;243:738-747.

42. Otani Y, Furukawa T, Yoshida M, et al. Operative indicationsfor relatively small (2-5 cm) gastrointestinal stromal tumor ofthe stomach based on analysis of 60 operated cases. Surgery.2006;139:484-492.

43. Blum MG, Bilimoria KY, Wayne JD, et al. Surgical considera-tions for the management and resection of esophageal gas-trointestinal stromal tumors. Ann Thorac Surg. 2007;84:1717-1723.

44. Eisenberg BL, Judson I. Surgery and imatinib in the manage-ment of GIST: emerging approaches to adjuvant and neoadju-vant therapy. Ann Surg Oncol. 2004;11:465-475.

45. Akahoshi K, Sumida Y, Matsui N, et al. Preoperative diagnosisof gastrointestinal stromal tumor by endoscopic ultrasound-guided fine needle aspiration. World J Gastroenterol. 2007;13:2077-2082.

46. Vander Noot MR 3rd, Eloubeidi MA, Chen VK, et al. Diagnosisof gastrointestinal tract lesions by endoscopic ultrasound-guided fine-needle aspiration biopsy. Cancer. 2004;102:157-163.

47. Demetri GD, Benjamin RS, Blanke CD, et al. NCCN Task Forcereport: management of patients with gastrointestinal stromaltumor (GIST)—update of the NCCN clinical practice guide-lines. J Natl Compr Cancr Netw. 2007;5(suppl 2):S1-S29.

48 Bonvalot S, Eldweny H, Péchoux CL, et al. Impact of surgeryon advanced gastrointestinal stromal tumors (GIST) in theimatinib era. Ann Surg Oncol. 2006;13:1596-1603.


Article

49. Eisenberg B, et al. Phase II trial of neoadjuvant/adjuvant ima-tinib mesylate (IM) for advanced primary and recurrent operable GI stromal tumor (GIST) – early results of RTOG0132. The Society for Surgical Oncology 61st Annual CancerSymposium; March 13-16, 2008; Chicago, IL: Abstract 80.

50. Kobayashi K, Gupta S, Trent JC, et al. Hepatic artery chemoem-bolization for 110 gastrointestinal stromal tumors: response,survival, and prognostic factors. Cancer. 2006;107:2833-2841.

51. Rajan DK, Soulen MC, Clark TW, et al. Sarcomas metastatic tothe liver: response and survival after cisplatin, doxorubicin,mitomycin-C, ethiodol, and polyvinyl alcohol chemoemboliza-tion. J Vasc Interv Radiol. 2001;12:187-193.

52. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastroin-testinal stromal tumors: recurrence patterns and prognosticfactors for survival. Ann Surg. 2000;231:51-58.

53. Curley SA. Radiofrequency ablation of malignant liver tumors.Ann Surg Oncol. 2003;10:338-347.

54. Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation ofunresectable primary and metastatic hepatic malignancies:results in 123 patients. Ann Surg. 1999;230:1-8.

55. DeMatteo R et al. Efficacy of adjuvant imatinib mesylate fol-lowing complete resection of localized, primary gastrointesti-nal stromal tumor (GIST) at high risk of recurrence: the USIntergroup Phase II Trial ACOSOG Z9000. American Society ofClinical Oncology – 2008 Gastrointestinal Cancers; January 23-227, 2008; Orlando, FL: Abstract 8.

56. DeMatteo R, Owzar K, Maki R, et al. Adjuvant imatinib mesy-late increases recurrence free survival (RFS) in patients withcompletely resected localized primary gastrointestinal stromaltumor (GIST): North American Intergroup Phase III trialACOSOG Z9001. 2007 American Society of Clinical Oncology;Chicago: Abstract 10079.

57. European Organization for Research and Treatment of Cancer– 62024. Imatinib mesylate or observation only in treatingpatients who have undergone surgery for localized gastroin-testinal stromal tumor. Available at: http://clinicaltrials.gov/ct2/show/NCT00103168. Accessed June 18, 2008.

58. Scandinavian Sarcoma Group and Sarcoma Group of the AIO,Germany. SSG XVIII. Short (12 months) versus long (36months) duration of adjuvant treatment with the tyrosinekinase inhibitor imatinib mesylate of operable GIST with ahigh risk for recurrence – a randomized phase III study.Available at: http://www.ssg-org.net. Accessed June 18, 2008.

59. Heinrich MC, Rubin BP, Longley BJ, Fletcher JA. Biology andgenetic aspects of gastrointestinal stromal tumors: KIT activa-tion and cytogenetic alterations. Hum Pathol. 2002;33:484-495.

60. Manley PW, Cowan-Jacob SW, Buchdunger E, et al. Imatinib: aselective tyrosine kinase inhibitor. Eur J Cancer. 2002;38(suppl5):S19-S27.

61. Trent J, Dhupart J, Zhang W. Imatinib mesylate: targeted ther-apy of gastrointestinal stromal tumors. Current Cancer TherapyReviews. 2005;1:93-108.

July 2008 • Vol 7 • No 7 15

Article

W hen the concept of myeloproliferative dis-orders (MPDs) was first proposed in 1951,1

it comprised five disorders: chronic mye-logenous leukemia (CML), polycythemia vera (PV),essential thrombocythemia (ET), primary myelofibro-sis (PMF), and erythroleukemia. Over the years, ery-throleukemia was redefined as acute erythroidleukemia or its variants. In its 2001 monograph,2 theWorld Health Organization (WHO) Committee for theClassification of Myeloid Neoplasms assigned theremaining classic MPDs to a broader category ofchronic MPDs that also included atypical MPDs,namely, chronic neutrophilic leukemia (CNL), chroniceosinophilic leukemia/hypereosinophilic syndrome(CEL/HES), and chronic MPD, unclassifiable (MPD-U).2,3 The classification was based on a topology thatutilized the morphologic findings of these conditionsas well as their genetic, immunophenotypic, biologic,and clinical features.4,5

The MPDs were, in turn, classified among one ofthe five categories of myeloid neoplasms, the othersbeing: 1) acute myeloid leukemia (AML); 2)myelodysplastic syndromes (MDS); 3) myelodys-plastic/myeloproliferative diseases (MDS/MPD);and 4) mast cell disease (MCD). The central andshared feature among the MPDs is effective clonalmyeloproliferation that is devoid of dyserythro-poiesis, granulocytic dysplasia, or monocytosis. Thepresence of any one of the latter three featuresrequires that the disease be assigned to either theMDS or MDS/MPD category.2

In the revised 2008 WHO classification system forchronic myeloid neoplasms, the phrase disease inboth MPD and MDS/MPD has been replaced by neo-plasm, so that MPD is now referred to as myelopro-liferative neoplasm (MPN) and MDS/MPD asmyelodysplastic/myeloproliferative neoplasm (MDS/MPN).6 In addition, MCD is now included within theMPN category. Other changes are noted in Table 1.6

The 2008 revisions reflect: 1) the neoplastic nature ofMPDs, thus the change from “disease” to “neo-plasm,” 2) the fact that MCD represents another clon-al stem cell disease that is similar to other membersof MPNs; and 3) the presence of molecularly distinctcategories among patients with primary eosinophil-ia. All the atypical neoplasms represented in therevised WHO classification system category MPN,and all those in the MDS/MPN category, are veryrare and can be life-threatening. They are, for themost part, refractory to treatment and, to date, havefew established therapies.7

MDS/MPNAlthough MDSs and MPDs appear to have entirely

different pathophysiologic mechanisms, the existenceof conditions with overlapping features is well estab-lished. This led WHO to introduce the category ofmyeloplastic/myeloproliferative diseases (MDS/MPD,now MDS/MPN), which includes myeloid disordersthat have both dysplastic and proliferative featuresat the time of initial presentation and that are diffi-cult to assign to either the myelodysplastic or chron-ic myeloproliferative group of diseases.8 The WHOgroup proposed the new category to allow for morefocused clinical and laboratory investigations ofmyeloid proliferation, abnormal proliferation, anddysplasia, and a less restrictive view of myeloid dis-orders, which in some cases clearly overlap.4

The MDS/MPN are clonal myeloid disorders thatpossess both dysplastic and proliferative features butare not properly classified as either MDS or MPN.1

The MDS/MPN category includes three majormyeloid disorders: chronic myelomonocytic leukemia(CMML), atypical chronic myeloid leukemia (aCML),and juvenile myelomonocytic leukemia (JMML).Myeloid disease that shows features of both MDS andchronic MPN but does not meet the criteria for any of the three major MDS/MPN entities is designated

Clinical Update: Atypical Myeloid Disorders

Srdan Verstovsek, MD, PhDAssociate ProfessorLeukemia DepartmentThe University of Texas M.D. Anderson Cancer CenterHouston, TX


Article

as myelodysplastic/myeloproliferative neoplasm,unclassifiable (MDS/MPN-U).

The etiology of MDS/MPN is not known. Theincidence varies widely, ranging from approximately3 per 100,000 adults annually for CMML9 to as few as0.13 per 100,000 children annually for JMML.10

Reliable data concerning the incidence of aCML arenot available, and the incidence of MDS/MPN-U isunknown. The pathophysiology of MDS/MPNinvolves abnormalities in the regulation of myeloidpathways for cellular proliferation, maturation, and

survival. Clinical symptoms are caused by complica-tions resulting from cytopenia(s), dysplastic cells thatfunction abnormally, leukemic infiltration of variousorgan systems, and general constitutional symptoms,such as fever and malaise.11 Patients with MDS/MPNhave no Philadelphia (Ph) chromosome or BCR/ABLfusion gene. No specific genetic defects have been iden-tified for any of these entities, although abnormalitiesin regulation of the ras pathway of signaling proteinsappear to be a common finding in CMML, aCML, andJMML, and may have some role in the abnormalmyeloid proliferation associated with these diseases.6

In general, treatment of these diseases depends onwhether the manifestation is primarily myeloprolifera-tive or myelodysplastic.

Chronic Myelomonocytic Leukemia (CMML)CMML is a clonal disorder of a bone marrow stem

cell, and monocytosis is a major defining feature.CMML exhibits heterogeneous clinical, hematologic,and morphologic features, varying from predomi-nantly myelodysplastic to predominantly myelopro-liferative. It accounts for approximately 15% to 20%of myelodysplastic syndromes, and the median sur-vival is 14 to 18 months.12 The red cell precursors inthe marrow appear normal; however, mild anemiamay be present. In addition, mild thrombocytopeniaassociated with morphologically normal mega-karyocytes may also be present. The bone marrowcontains up to 20% blasts, and the circulating mono-cyte count is ≥ 1,000/mm3. Hepatosplenomegaly mayalso be present.11 Clinical features of CMML includefever, fatigue, night sweats, weight loss, infection,and thrombocytopenia-related bleeding as well ashepatomegaly and/or splenomegaly (in patientswith higher WBC count). In patients with a normal orslightly decreased white blood cell count, clinical fea-tures may be identical to MDS.4

There is general agreement that the higher the blastcount in patients with CMML, the more unfavorablethe prognosis. Therefore, WHO criteria divide CMMLinto two prognostic categories, CMML-1 and CMML-2,based on the number of blasts in the blood and bonemarrow (Table 2). Approximately 30% of patients withCMML progress to acute leukemia.13

Atypical chronic myeloid leukemia (aCML)The term “atypical chronic myeloid leukemia”

(aCML) implies that the associated disorder is an atyp-ical variant of chronic myelogenous leukemia (CML).However, the nomenclature is based on the fact that

1. Acute myeloid leukemia

2. Myelodysplastic syndromes (MDS)

3. Myeloproliferative neoplasms (MPN)

3.1 Chronic myelogenous leukemia

3.2 Polycythemia vera

3.3 Essential thrombocythemia

3.4 Primary myelofibrosis

3.5 Chronic neutrophilic leukemia

3.6 Chronic eosinophilic leukemia, not otherwisecategorized

3.7 Hypereosinophilic syndrome

3.8 Mast cell disease

3.9 MPNs, unclassifiable

4. MDS/MPN

4.1 Chronic myelomonocytic leukemia

4.2 Juvenile myelomonocytic leukemia

4.3 Atypical chronic myeloid leukemia

4.4 MDS/MPN, unclassifiable

5. Myeloid neoplasms associated with eosinophilia andabnormalities of PDGFRα, PDGFRβ, or FGFR1

5.1 Myeloid neoplasms associated with PDGFRαrearrangement

5.2 Myeloid neoplasms associated with PDGFRβrearrangement

5.3 Myeloid neoplasms associated with FGFR1rearrangement (8p11 myeloproliferative syndrome)

Reprinted with permission from: Tefferi A, Vardiman JW. Classificationand diagnosis of myeloproliferative neoplasms: The 2008 World HealthOrganization criteria and point-of-care diagnostic algorithms. Leukemia.2008;22:14-22.

Table 1

The 2008 World Health OrganizationClassification Scheme for Myeloid Neoplasms

July 2008 • Vol 7 • No 7 17

patients with aCML lack the Ph chromosome andBCR/ABL fusion gene that are the hallmarks of classicCML. Furthermore, aCML is associated with a markedgranulocytic and frequently multilineage dysplasia thatis not seen during the chronic phase of CML. The inci-dence of aCML in patients presenting with clinical andhematologic features of CML but lacking the Ph chro-mosome is estimated to be 1 to 2 per 100 patients.14 Thefew clinical studies published to date indicate thataCML is clinically a very aggressive disease. Medianage at onset is 65 years, and median survival times areonly 11 to 18 months. Clinical features of aCML includeanemia, thrombocytopenia, and splenomegaly (in up to75% of cases); thrombocytopenia and marked anemiaare considered poor prognostic factors.7,15,16 AtypicalCML evolves to acute leukemia in approximately 25% to 40% of patients;7 in the remainder, fatal compli-cations include resistant leukocytosis, anemia, throm-bocytopenia, hepatosplenomegaly, cerebral bleedingassociated with thrombocytopenia, and infection.17

Juvenile myelomonocytic leukemia (JMML)JMML is a clonal hematopoietic disorder character-

ized by proliferation principally of the neutrophil and monocytic lineages. The Ph chromosome andBCR/ABL fusion gene are absent. JMML typicallymanifests as a leukemic disorder in infants and youngchildren (mean age approximately 1 year), but occa-sionally it occurs in adolescents as well. JMML is morecommon in boys, with a male to female ratio of approx-imately 2.5:1. The cause of JMML is not known.18

The clinical and morphologic features of JMML canclosely mimic those of a variety of infectious diseases,including those caused by the Epstein-Barr virus,cytomegalovirus, human herpesvirus 6, histoplasma,

mycobacteria, and toxoplasma. Laboratory testing dis-tinguish JMML from infectious diseases.18,19 Childrenwith neurofibromatosis type 1 (NF1) are at increasedrisk for developing JMML, and up to 14% of cases ofJMML occur in children with NF1.20 Morphologically,the peripheral blood picture in this disease showsleukocytosis, anemia, and frequently, thrombocytope-nia.16,21 Although cytogenetic abnormalities, includingmonosomy 7, occur in 30% to 40% of patients, none isspecific for JMML.16,19 The median survival times forJMML vary from approximately 10 months to morethan 4 years, depending partly on the type of therapychosen.22 Prognosis is related to age at the time of diag-nosis and is better in children younger than 1 year atthe time of diagnosis. Children older than 2 years at thetime of diagnosis have a much worse prognosis.16

Treatment of MDS/MPNThe standard therapy for patients with CMML is

hydroxyurea, combined with supportive care tomanage symptoms. Hematopoietic growth factors,particularly erythropoietin, may be beneficial forsome patients. No other treatment except allogeneicstem-cell transplantation has been demonstrated toimprove the natural history of this disease, althoughrelapse and graft versus host disease are not uncom-mon.23,24 In recent years, several therapeutic agentshave been approved as therapy for CMML. Thehypomethylating agents 5-azacytidine and decitabinehave been approved by the US Food and DrugAdministration, and are commonly used to treatpatients with advanced CMML. One recent study ofdecitabine at three different dosing schedules (20 mg/m2 IV daily 2 5; 20 mg/m2 SC daily 2 5; and10 mg/m2 IV daily 2 10) in CMML reported a com-plete response rate of 34%.25 Nausea/vomiting, liverdysfunction, and fatigue were the most commonlyreported side effects. The incidence of myelosup-pression associated complications and of prolongedmyelosuppression tended to be worse with the 10-day IV protocol, as was the incidence of hospitaliza-tion. Several case reports suggested that imatinibmesylate induces positive hematologic and cytoge-netic responses in selected patients with CMML,24,26-28

including one patient who, at the time of reporting,achieved a complete remission with the administra-tion of imatinib 400 mg/day.26 Among other com-mercially available agents with potential significantactivity in CMML are topoisomerase I inhibitors.23

The optimal treatment of aCML is uncertainbecause of the rare incidence. Treatment with

CMML-1: Blasts fewer than 5% in blood and fewer than10% in bone marrow

CMML-2: Blasts are 5% to 19% in blood or 10%-19% inmarrow or Auer rods are present and blastsare fewer than 20% in blood or marrow

CMML-1 or CMML-2 with eosinophilia: Above criteria present with an eosinophil count in theperipheral blood greater than 1.5 x 109/L

Data from: Vardiman JW, Harris NL, Brunning RD. The World HealthOrganization (WHO) classification of the myeloid neoplasms. Blood.2002;100:2292-2302.

Table 2

Differential Criteria for CMML-1 and CMML-2



Article

hydroxyurea may lead to short-lived partial remis-sions of 2- to 4-months’ duration.17 Atypical CMLappears to respond poorly to treatment with inter-feron-alfa.17 Several case reports show excellent cyto-genetic and hematologic response with the adminis-tration of imatinib with minimal side effects.28-30

A small proportion of patients with MDS/MPN,either with CMML or aCML, have a chromosomalbreakpoint on chromosome 5 (5q33) causing consti-tutive activation of a gene coding for a platelet-derived growth factor receptor beta (PDGFRβ)‚ tyro-sine kinase. Others may have a chromosomal break-point on chromosome 4 (4q12) causing activation ofa gene for PDGFRα tyrosine kinase. Both PDGFRtyrosine kinases are particularly sensitive to ima-

tinib. Cytogenetic testing is mandatory for allpatients with MDS/MPD, and confirmation of thesetranslocations should support the use of imatinib inMDS/MPD patients. FDA-approved imatinib mesy-late at a dose of 400 mg/day is recommended for thetreatment of adults with forms of MDS/MPD associ-ated with PDGFR gene rearrangements.31 for thetreatment of adults with forms of MDS/MPD associ-ated with PDGFR gene rearrangements.31

No consistently effective therapy is available forJMML. Historically, more than 90% of patients havedied despite the use of chemotherapy.32 Bone-mar-row transplantation (BMT) seems to offer the bestchance of cure for JMML. In a review of 91 patientswith JMML treated with BMT in 16 different reports,41% were still alive at the time of reporting, includ-ing 50% of the patients who received grafts fromHLA-matched or one-antigen mismatched familialdonors, 17% with mismatched donors, and 32% withmatched unrelated donors.32

Myeloproliferative NeoplasmsThe upcoming 2008 edition of the WHO classifica-

tion6 makes changes to the category now known asMPN (Table 1). The MPN category now includesmast cell disease (MCD); and the four classic myelo-proliferative disorders: chronic neutrophilic leukemia(CNL), chronic eosinophilic leukemia/ hypereosino-philic syndrome (CEL/HES) and CMPN, unclassifiable.

Chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES)

HES is a heterogeneous group of rare disorderscharacterized by prolonged and sustained peripheralblood and tissue eosinophilia leading to end-organdamage. While HES is a diagnosis of exclusion, forwhich no cause of elevated eosinophils can be found,patients with hypereosinophilia who are found tohave clonal diseases (ie, cytogenetic or molecularabnormality proving the existence of malignant clone)are said to have CEL. HES and CEL have similar clin-ical presentations, and distinguishing between thetwo can be difficult unless proper testing for a molec-ular/cytogenetic marker is done. CEL is estimated tobe the cause of eosinophilia in 20% of patients withelevated eosinophils in blood.33

The generally accepted diagnostic criteria for HESare sustained overproduction of eosinophils, absenceof other causes of eosinophilia, and organ systeminvolvement.34,35 Because most patients with HEShave secondary eosinophilia, due to infection, atopy,

1. Cutaneous mastocytosis (CM):

a. Maculopapular CM

b. Diffuse CM

c. Mastocytoma of skin

2. Indolent systemic mastocytosis (ISM):

a. Smoldering systemic mastocytosis (SSM)

b. Isolated bone marrow mastocytosis

3. Systemic mastocytosis with an associated clonalhematologic non-mast-cell lineage disease(SM-AHNMD)

a. SM-MDS

b. SM-MPD

c. SM-CEL

d. SM-CMML

e. SM-NHL

4. Aggressive systemic mastocytosis (ASM) With eosinophilia (SM-eo)

5. Mast cell leukemia (MCL)Aleukemic MCL

6. Mast cell sarcoma

7. Extracutaneous mastocytoma

MDS: myelodysplastic syndrome; MPD: myeloprolifer-ative disorder; CMML: chronic myelomonocyticleukemia; CEL: chronic eosinophilic leukemia; NHL:non-Hodgkin lymphoma

Reprinted with permission from: Valent P, Horny HP, Escribano L, et al.Diagnostic criteria and classification of mastocytosis: a consensus pro-posal. Leuk Res. 2001;25:603-625.

Table 3

World Health Organization Variants ofMastocytosis, 2001

July 2008 • Vol 7 • No 7 19

drug reactions, connective tissue disorders, or vas-culitis, these reactive causes of peripheral bloodeosinophilia should be ruled out before consideringa diagnosis of HES.36

HES strikes nine times as many men as women,and patients with this disease usually present betweenthe ages of 20 and 50 years.35 HES has an annual inci-dence of one to two cases per 100,000 and is charac-terized by a high degree of clinical heterogeneityregarding manifestations and prognosis.37 The diseasecan range from minimal symptoms with a long sur-vival probability to rapidly fatal due to sudden, severe heart failure or acute leukemia.37,38 Organ dam-age in patients with HES results from tissue infiltra-tion by eosinophils and their subsequent release oftoxic substances via degranulation.39,40 Biopsies of tis-sue from patients with HES who died of cardiac disease have revealed heart tissue damage attributa-ble to eosinophilia.41 Although the most severe com-plications of HES involve the heart and the centralnervous system, any organ system can be affected.35,41

Aggressive systemic mastocytosisMast cell disease, or mastocytosis, comprises a

heterogeneous group of hematologic diseases char-acterized by an overabundance of active mast cellsand their accumulation in tissues.3 Mast cell diseaseusually involves the skin but can affect other organsas well, with symptoms caused by cellular infiltrationand release of chemical mediators from mast cells.3 If

the disease involves other organs, it is called systemicmastocytosis (SM); the organ involved may includebone marrow, liver, spleen, lymph nodes, and the gas-trointestinal tract. Symptoms associated with SM varywidely and may include flushing, tachycardia, pruri-tus, anemia, abdominal cramping, peptic ulcer disease,and diarrhea. The diagnosis of SM is based on identifi-cation of abnormal mast cells by morphologic,immunophenotypic, and/or molecular criteria in vari-ous organs.42 This is most frequently established by his-tologic and immunohistochemical examination of bonemarrow aspirate and biopsy specimens.

Adults account for most cases of SM; patients usual-ly present between the ages of 20 and 40 years.43 Thecourse of SM can range from presentation with onlyminor symptoms and stable disease not affecting organ function (therefore called indolent SM), to mastcell leukemia (MCL), a life-threatening condition.Aggressive systemic mastocytosis (ASM) is one ofseven WHO-defined variants of mast cell disease (Table3) in which an involved organ function is affected.42 InASM, malignant mast cell infiltration into organs maycause cytopenias, osteoporosis, pathologic fractures,hepatosplenomegaly, lymphadenopathy, and malab-sorption.44 Patients with MCL typically will live nomore than 12 months after the initial diagnosis.45

TreatmentBecause of their complex clinical course, the man-

agement of MPNs remains challenging. Currently,

Therapy Indications/comment

Alkylating agents Chlorambucil and others; may be administered in 4-day pulse doses repeated as dictatedby magnitude of blood eosinophilia

Corticosteroids First-line agent for those with organ involvement; if effective, dose may be tapered orchanged to every other day

Hydroxyurea Used in patients with organ involvement and eosinophilia unresponsive to corticosteroids;anemia and/or thrombocytopenia common with chronic therapy

Imatinib Effectiveness demonstrated in clinical studies, with minimal toxicity

Vincristine Especially useful for acute reductions when total eosinophil counts are excessive (≥50,000–75,000/µL); can be administered episodically to control hypereosinophilicsyndrome, often with amelioration of thrombocytopenia

Other Interferon-alfa; cyclosporine; cladribine; bone-marrow transplantation

Cardiac surgery Indicated for serious mitral valve regurgitation with bioprosthetic mitral valve replacement;less commonly, thrombectomy or endomyocardectomy

Reprinted with permission from Cortes J, Kantarjian H. Beyond chronic myelogenous leukemia: potential role for imatinib in Philadelphia-negative myeloproliferative disorders. Cancer. 2004;100:2064-2078.

Table 4

Therapies Used in the Treatment of Idiopathic Hypereosinophilic Syndrome



Article

there is no known, curative medical therapy forpatients with HES or MCD.41,46 For patients with HES,clinical management has focused on the preventionor palliation of disease morbidity and prevention ofdisease progression (Table 4).7,38,41,43,47 The first-linetreatment of HES is usually prednisone, with aresponse rate of nearly 70%. However, relapses oftenoccur on cessation of therapy, requiring the patient toseek alternative drug options, such as interferon-alfaor hydroxyurea, which are considered to be the sec-ond-line drugs of choice. The first treatmentapproach for patients with MCD should be pharma-cologic inhibition of mediators of inflammation,including blockade of histamine H1 and H2 receptors.Patients may also benefit from treatment with anti-inflammatory drugs, such as cyproheptadine,48 andfrom treatment with adrenaline to combat anaphy-lactic shock. Histamine H2 receptor inhibition alsocan help to reduce excessive gastric secretions thataccompany this disease. Systemic corticosteroids canaid in the management of skin disease, malabsorp-tion, or ascites of SM. First-line therapeutic agents forASM include interferon-alfa49 and cladribine.50

Some HES patients have been found to possess adeletion in chromosome 4, not seen by conventionalcytogenetic testing, which fuses the FIP1-like1 gene(FIP1L1) to the PDGFRα gene. These cases are nowreclassified as CEL, as the resulting FIP1L1-PDGFRαrearrangement gene has become a marker of diseaseclonality. Resulting constitutive active PDGFRα tyro-sine kinase can be effectively inhibited by treatmentwith imatinib. It appears that although imatinib ismuch less effective in HES without the FIP1L1-PDGFRα marker, the drug may also have a nonspe-cific but beneficial myelosuppressive effect. Otherpatients with CEL may have a chromosomal abnor-mality with a breakpoint involving a site wheregenes for PDGFR tyrosine kinases are found (4q12and 5q33, for PDGFRα and PDGFRβ, respectively).These tyrosine kinases are constitutively active inthese cases and sensitive to imatinib therapy. It isimperative that testing for the FIP1L1-PDGFRαrearrangement by polymerase chain reaction (PCR),and cytogenetic testing be performed in all patientswith suspected HES/CEL.

In the United States, imatinib is indicated for use in adults with HES/CEL associated with FIP1L1-PDGFRα fusion kinase, and for patients withHES/CEL who are FIP1L1-PDGFRα fusion kinase-negative or unknown. The recommended dosage of ima-tinib in HES/CEL patients is 400 mg daily. However, a

daily starting dosage of 100 mg imatinib is recommend-ed for HES/CELpatients with the FIP1L1-PDGFRα, withpotential to increase to 400 mg daily in the absence ofadverse effects or insufficient response to drug therapy.

The great majority of SM patients exhibit a mutationin the c-KIT oncogene, resulting in ligand-independentmast cell growth through autophosphorylation of theKIT tyrosine kinase. The most common KIT mutation isthe D816V mutation, which is not sensitive to imatinib.Sporadic cases of alternate KIT mutations have beendescribed, which are usually imatinib-sensitive.Therefore, testing for KIT D816V mutational status byPCR in patients suspected of having SM is highly rec-ommended. If positive, it helps in confirming the diag-nosis (it is part of diagnostic criteria) and may help thephysician select proper therapy. A subgroup of SMpatients, usually those with associated eosinophilia,have also been found to express the imatinib-sensitiveFIP1L1-PDGFRα rearrangement gene. Patients withASM and associated eosinophilia, therefore, shouldhave PCR testing done to document the possible pres-ence of FIP1L1-PDGFRα rearrangement.

In the United States, imatinib is approved for thetreatment of adults with ASM who either lack theD816V KIT mutation or are of unknown KIT mutation-al status. The recommended dosage of imatinib is 400mg a day. A starting dosage of 100 mg imatinib daily isrecommended for patients with ASM associated witheosinophilia, with the potential to increase to 400 mgdaily in the absence of adverse effects or insufficientresponse to drug therapy. ■

Editorial assistance and commercial support for this manuscriptprovided by Novartis Pharmaceuticals Corp.

References1. Dameshek W. Some speculations on the myeloproliferative

syndromes. Blood. 1951;6:372-375.2. Jaffe ES, Harris NL, Stein H, et al. World Health Organization

Classification of Tumours of Hematopoietic and Lymphoid Tissues.IARC Press: Lyon, France, 2001, 1-351.

3. Vardiman JW, Brunning RD, Harris NL. WHO histologicalclassification of chronic myeloproliferative diseases. In: JaffeES, Harris NL, Stein H, Vardiman JW, eds. World HealthOrganization Classification of Tumours: Tumours of theHaematopoietic and Lymphoid Tissues. International Agency forResearch on Cancer (IARC) Press: Lyon, France, 2001, 17-44.

4. Vardiman JW, Harris NL, Brunning RD. The World HealthOrganization (WHO) classification of the myeloid neoplasms.Blood. 2002;100:2292-2302.

5. Malcovati L, Cazzola M. Myelodysplastic/myeloproliferative dis-orders. Haematologica. 2008;93:4-6.

6. Tefferi A, Vardiman JW. Classification and diagnosis of myelo-proliferative neoplasms: the 2008 World Health Organization cri-teria and point-of-care diagnostic algorithms. Leukemia.2008;22:14-22.

7. Cortes J, Kantarjian H. Beyond chronic myelogenous leukemia:potential role for imatinib in Philadelphia-negative myeloprolif-erative disorders. Cancer. 2004;100:2064-2078.

8. Voglová J, Chrobák L, Neuwirtová R, et al. Myelodysplastic andmyeloproliferative type of chronic myelomonocytic leukemia—distinct subgroups or two stages of the same disease? Leuk Res.2001;25:493-499.

9. Vardiman JW, Pierre R, Imbert M, et al. Juvenile myelomono-cytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.:Pathology and Genetics of Tumours of Haematopoietic and LymphoidTissues. Lyon, France: IARC Press, 2001. World HealthOrganization Classification of Tumours, 3, 17-31; 47-52.

10. Hasle H, Niemeyer CM, Chessells JM, et al. A pediatricapproach to the WHO classification of myelodysplastic andmyeloproliferative diseases. Leukemia. 2003;17:277-282.

11. Bain BJ. The relationship between the myelodysplastic syndromesand the myeloproliferative disorders. Leuk Lymphoma.1999;34:443-449.

12. Germing U, Kündgen A, Gattermann N. Risk assessment inchronic myelomonocytic leukemia (CMML). Leuk Lymphoma.2004;45;1311-1318.

13. Onida F, Beran M. Chronic myelomonocytic leukemia: myelopro-liferative variant. Curr Hematol Rep. 2004;3:218-226.

14. Breccia M, Biondo F, Latagliata R, et al. Identification of risk fac-tors in atypical chronic myeloid leukemia. Haematologica.2006;11:1566-1568.

15. Hernández JM, del Cañizo MC, Cuneo A, et al. Clinical, hemato-logical and cytogenetic characteristics of atypical chronic myeloidleukemia. Ann Oncol. 2000;11:441-444.

16. Costello R, Sainty D, Lafage-Pochitaloff M, et al. Clinical and bio-logical aspects of Philadelphia-negative/BCR-negative chronicmyeloid leukemia. Leuk Lymphoma. 1997;25:225-232.

17. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al. BCR rearrange-ment-negative chronic myelogenous leukemia revisited. J ClinOncol. 2001;19:2915-2926.

18. Niemeyer CM, Fenu S, Hasle H, et al. Response: differentiatingmyelomonocytic leukemia from infectious disease. Blood.1998;91:365-367.

19. Vardiman JW, Pierre R, Imbert M, et al. Juvenile myelomonocyticleukaemia. In: Jaffe ES, Harris NL, Stein H, et al, eds. Pathology andGenetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon,France: IARC Press, 2001. World Health OrganizationClassification of Tumours, 3, 55-57.

20. Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocyticleukemia in childhood: a retrospective analysis of 110 cases.European Working Group on Myelodysplastic Syndromes inChildhood (EWOG-MDS). Blood. 1997;89:3534-3543.

21. Passmore SJ, Hann IM, Stiller CA, et al. Pediatric myelodysplasia:a study of 68 children and a new prognostic scoring system. Blood.1995;85:1742-1750.

22. Luna-Fineman S, Shannon KM, Atwater SK, et al.Myelodysplastic and myeloproliferative disorders of childhood: astudy of 167 patients. Blood. 1989;93:459-466.

23. Cortes J. CMML: a biologically distinct myeloproliferative dis-ease. Curr Hematol Rep. 2003;2:202-208.

24. Magnusson MK, Meade KE, Nakamura R, et al. Activity of STI571in chronic myelomonocytic leukemia with a platelet-derivedgrowth factor beta receptor fusion oncogene. Blood. 2002;100:1088-1091.

25. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a ran-domized study of 3 schedules of low-dose decitabine in high-er-risk myelodysplastic syndrome and chronic myelomonocyt-ic leukemia. Blood. 2007;109:52-57.

26.Pitini V, Arrigo C, Teti G, et al. Response to STI571 in chronicmyelomonocytic leukemia with platelet derived growth factorbeta receptor involvement: a new case report. Haematologica.2003;88:ECR18.

27. Apperley JF, Gardembas M, Melo JV, et al. Response to imatinibmesylate in patients with chronic myeloproliferative diseaseswith rearrangements of platelet-derived growth factor receptorbeta. N Engl J Med. 2002;347:481-487.

28. Cortes J, Giles F, O’Brien S, et al. Results of imatinib mesylate ther-apy in patients with refractory or recurrent acute myeloidleukemia, high-risk myelodysplastic syndrome, and myeloprolif-erative disorders. Cancer. 2003;97:2760-2766.

29. Garcia JL, Font de Mora J, Hernandez JM, et al. Imatinib mesylateelicits positive clinical response in atypical chronic myeloidleukemia involving the platelet-derived growth factor receptorbeta. Blood. 2003;102:2699-2700.

30. Safley AM, Sebastian S, Collins TS, et al. Molecular and cytoge-netic characterization of a novel translocation t(4:22) involvingbreakpoint cluster region and platelet-derived growth factorreceptor-alpha gene in a patient with atypical chronic myeloidleukemia. Genes Chromosome Cancer. 2004;40:44-50.

31. Gleevec [package insert]. East Hanover, NJ: NovartisPharmaceuticals Corp; 2008.

32. Aricò M, Biondi A, Pui CH. Juvenile myelomonocytic leukemia.Blood. 1997;90:479-488.

33. Gotlib J. Molecular classification and pathogenesis of eosinophilicdisorders: 2005 update. Acta Haematol. 2005;114:7-25.

34. Chusid MJ, Dale DC, West BC, et al. The hypereosinophilic syn-drome: analysis of fourteen cases with review of the literature.Medicine (Baltimore). 1975;54:1-27.

35. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syn-drome. Blood. 1994;83:2759-2779.

36. Peros-Golubicic T, Smojver-Jezek S. Hypereosinophilic syndrome:diagnosis and treatment. Curr Opin Pulm Med. 2007;13:422-427.

37. Roufosse F, Cogan E, Goldman M. The hypereosinophilic syn-drome revisited. Annu Rev Med. 2003;54:169-184.

38. Anghel G, De Rosa L, Ruscio C, et al. Efficacy of imatinib mesy-late in a patient with idiopathic hypereosinophilic syndrome andsevere heart involvement. Tumori. 2005;91:67-70.

39. Sasano H, Virmani R, Patterson RH, et al. Eosinophilic productslead to myocardial damage. Hum Pathol. 1989;20:850-857.

40. Schwartz RS. The hypereosinophilic syndrome and the biology ofcancer. N Engl J Med. 2003;348:1199-1200.

41. Fauci AS, Harley JB, Roberts WC, et al. NIH conference. The idio-pathic hypereosinophilic syndrome. Clinical, pathophysiologic,and therapeutic considerations. Ann Intern Med. 1982;97:78-92.

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

43. Hartmann K, Henz BM. Mastocytosis: recent advances in defin-ing the disease. Br J Dermatol. 2001;144:682-695.

44. Hennessy B, Giles F, Cortes J, et al. Management of patients withsystemic mastocytosis: review of M. D. Anderson Cancer Centerexperience. Am J Hematol. 2004;77:209-214.

45. Quintas-Cardama A, Aribi A, Cortes J, et al. Novel approaches inthe treatment of systemic mastocytosis. Cancer. 2006;107:1429-1439.

46. Mesa RA. Clinical and scientific advances in the Philadelphia-chromosome negative chronic myeloproliferative disorders. Int JHematol. 2002;76(suppl 2):193-203.

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

48. Enomoto U, Kusakabe H, Matsumura T, et al. Diffuse cutaneousmastocytosis responding to cyproheptadine. Clin Exp Dermatol.1999;24:16-18.

49. Casassus P, Caillat-Vigneron N, Martin A, et al. Treatment of adultsystemic mastocytosis with interferon-alpha: results of a multicen-tre phase II trial on 20 patients. Br J Haematol. 2002;119:1090-1097.

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

July 2008 • Vol 7 • No 7 21



CaseStudy

Case Study 1: Patient with Systemic Mastocytosis

Chief complaint: Worsening symptoms of systemicmastocytosis

History of present illness: A 50-year-old man pre-sents to the office for a second opinion. He was diag-nosed with urticaria pigmentosa approximately 5years ago. Three years ago, he suffered an L1 com-pression fracture after lifting a box. Following a bonebiopsy, he was diagnosed with systemic mastocyto-sis. He states that his current medications do not con-trol his symptoms very well. He is unable to endureany physical exercise as elevation of body tempera-ture precipitates mastocytosis “attack” with symp-toms that include flushing, hives, rash, and frequentdiarrhea. He is requesting a second opinion andwants to discuss treatment options.

Past medical history: The patient states that he suf-fers from fatigue, chronic skin rash, and diarrhea (4-6 times per day). He has osteoporosis with proximallower extremity bone pain. Dual energy x-rayabsorptiometry scan reveals a bone density equiva-lent to that of an 87-year-old man.

Current medications:1. Fexofenadine 60 mg twice daily2. Ranitidine 150 mg twice daily3. Doxepin 25 mg once daily.4. Cromolyn sodium 100 mg four times daily5. Teriparatide 20 µg once daily6. Calcium 600 mg plus vitamin D 1800 mg once

daily7. Multivitamin twice daily

Allergies: The patient has no known drug allergies.However, he states various over-the-counter medica-tions can set off a mastocytosis attack.

Review of systems: See history of present illness. Thepatient notes poor exercise tolerance secondary toexacerbation of symptoms, chills, and fatigue. He alsocomplains of mild skin erythema and dermatographia.

Physical examination: General: Temperature 36.5o C; pulse 57 beats/min;respirations 18/min; blood pressure 132/74 mm Hg.Height: 170 cm. Weight: 80.9 kg. Performance status= 1. Well-developed, well-nourished, 50-year-oldman in no acute distress; awake, alert, and orientedtimes three. Head, eyes, ears, nose, throat (HEENT):Normocephalic, atraumatic. Pupils equal, round,reactive to light and accommodation (PEERLA).Extraocular movements intact. Oral and nasalmucosa are pink and moist without lesion. Neck: Supple, with full range of motion. No lym-phadenopathy. No bruits noted. Chest: Lungs clear to auscultation bilaterally. Norales, rhonchi, or wheezing. Heart: Regular rate and rhythm plus S1, S2; no mur-murs, rubs, or gallops. Abdomen: Soft, nontender, and nondistended.Positive bowel sounds times four. No rebound, rigidi-ty or guarding. No hepatosplenomegaly noted.Extremities: No clubbing, cyanosis, or edema. Pedaland radial pulses are +2 bilaterally. Neurologic: Deep tendon reflexes +2. Muscle strengthis 5/5 in upper and lower extremities bilaterally.Lymph nodes: No cervical, clavicular, axillary, oringuinal lymphadenopathy is noted bilaterally. Skin: Diffuse erythema. Demonstrated positive der-matographia. No obvious signs of extreme or local-ized erythema or bruising and no signs of rash ortrauma.

Laboratory data: Complete blood count (CBC): White blood cell count(WBC) 4.2 x 109/L; hemoglobin level 14.4 g/dL;hematocrit 41.5%. Platelet count 197,000/mm3.Normal differential. The electrolyte profile is unre-markable with normal liver and renal indices.Tryptase 66 ng/mL (normal ≤10).

July 2008 • Vol 7 • No 7 23

CaseStudy

Bone marrow differentialBlasts 2% (0-5)Progranulocytes 1% (2-8)Myelocytes 15% (5-20)Metamyelocytes 12% (13-32)Granulocytes 14% (7-30)Eosinophils 2% (0-4)Basophils 1% (0-1)Lymphocytes 16% (3-17)Plasma cells 1% (0-2)Monocytes 2% (0-5)Reticulum cells 0% (0-2)Pronormoblasts 2% (1-8)Normoblasts 30% (7-32)M:E ratio 1.4 (3-4)Mast cells 2%

Bone marrow biopsyCellularity: 20%Infiltrate: Increased spindle cells with cytoplasmic

granules, consistent with mast cells, com-prising approximately 5% of total cellularelements.

Stains on biopsyReticulin: Minimally increased (0-1+). Collagen: Negative.Tryptase: Approximately 5% of the cells are

positive. CD117: 5% of the cells are positive.CD25: Rare cells are positive.

Bone marrow clotQuality: Adequate, morphology similar to

that of the biopsy.

Bone marrow smearsQuality/cellularity: Adequate Granulocytes: Show maturation Erythrocytes: Show maturationMegakaryocytes: Normal morphology Lymphocytes: Small, mature-appearingOthers: Mast cells are present (5%).

These cells are oval to spin-dle-shaped.

Bone marrow diagnosis Mastocytosis comprising approximately 2%-5% oftotal cellular.Adequate trilineage hematopoiesis.

Flow cytometryFlow cytometry studies identified a mast cell populationcoexpressing CD117, CD2, CD25, CD11c, and CD59.

Cytogenetic and molecular testingNo chromosomal abnormalities identifiedNo mutation at codon 617 of JAK2 identified.No mutation at codon 816 of KIT identified.No evidence of the FIP1L1-PDGFRα fusion tran-script detected.

Assessment and treatment plan:Patient with aggressive systemic mastocytosis,without D816V KIT mutation. The patient wasstarted on imatinib 400 mg once daily.

3-month follow-up The patient complains of fatigue, nausea, and a

slight increase in weight. His eyelids are somewhatpuffy. He states that his skin is “a little better,” withdecreased inflammation. He appears to be tolerat-ing imatinib relatively well and is instructed toreturn in 3 months and to call if any problems occurprior to that time. He is to continue to check hisblood cell count and chemistries with his referringdoctor monthly.

6-month follow-up The patient has continued taking imatinib 400

mg once daily. On follow-up, his performance sta-tus is 0, and he reports feeling “the best he has feltin approximately 4 years.” He denies pruritus andstates that the rash is unchanged in surface area butit is less intense in color. He reports that he has nogastrointestinal (GI) symptoms other than occasion-al diarrhea and has completely discontinued all hisGI medications.

12-month follow-upThe patient remains on imatinib 400 mg daily.

His performance status is still 0. Fatigue, skin rash,and diarrhea are completely resolved and energylevel is much improved. Other than a mild edema ofthe legs, he notes no side effects. Recent bone mar-row study shows results similar to pretreatmentbone marrow study, with serum tryptase decreasedslightly from 66 to 55 ng/mL. Although bone mar-row study shows no decrease in mast cells, thepatient is advised to continue on imatinib 400 mgdaily to maintain good clinical response. ■


CaseStudy

Case Study 2: Patient with SuspectedMyeloproliferative/Myelodysplastic Disease

Chief complaint: Fatigue, shortness of breath onexertion, weight loss of approximately 40 pounds inthe past year, night sweats, minimal swelling inlower extremities

History of present illness: The patient is a 63-year-old man who was in his normal state of health until4 years ago, when he developed fatigue, shortness ofbreath, weight loss, and night sweats. A CBC per-formed at that time showed anemia. Colonoscopy andupper GI endoscopy findings were both negative.Because of his worsening anemia and subsequentdevelopment of eosinophilia, he underwent a bonemarrow aspiration and biopsy, which showed hyper-cellular bone marrow with eosinophilia. Weekly injec-tions of epoetin alfa were started for anemia, and thepatient has received approximately 12 injections. Hewas referred to an infectious disease specialist to ruleout an infectious process. He underwent an extensiveworkup and was suspected to have Q fever; doxycy-cline was started. A computed tomography (CT) scanof the chest was performed and showed small pul-monary nodules. He then underwent a bronchoscopywith biopsy, which showed focal fibrosis with chronicinflammation and scattered eosinophils. There was noevidence of vasculitis.

Past medical history: The patient has benign pro-static hypertrophy and hypertension and has hadchronic asthma since childhood. He underwentcholecystectomy 7 years ago and has also had leftknee arthroscopic surgery.

Current medications:1. Epoetin alfa 60,000 units subcutaneously weekly2. Tamsulosin 0.4 mg daily3. Dutasteride 0.5 mg daily4. Montelukast 10 mg daily5. Fluticasone two puffs daily6. Albuterol as needed for shortness of breath7. Hydrochlorothiazide 25 mg daily8. Doxycycline 100 mg by mouth (daily for 30 days,recently completed)

Allergies: The patient has no known drug allergies.

Review of systems: See history of present illness.The rest of the review is not contributory.

Physical examination: General: Well-developed, well-nourished man in noacute distress. Performance status = 1. Temperature36o C, pulse 76, respirations 20/min; blood pressure128/65 mm Hg. Weight 94.4 kg. Height 186 cm.HEENT: Normocephalic, atraumatic. Pupils equal,round reactive to light and accommodation. Extraocularmovements intact. Sclerae are anicteric. Buccal mucosais pink and moist without lesions.Neck: Supple. No jugular venous distention. No pal-pable lymphadenopathy.Heart: Regular rate and rhythm, normal S1, S2, with-out murmurs, rubs, or gallops.Chest: Lungs clear to auscultation bilaterally. Nowheezes, rales, or rhonchi. Abdomen: Soft, nontender, and nondistended, withnormoactive bowel sounds times four. No palpablehepatosplenomegaly. No other abdominal massesare noted.Extremeties: No cyanosis, clubbing, or edema. Pedalpulses are 2+ bilaterally.Neurologic: Intact. No focal neurologic deficits.Lymph nodes: No cervical, clavicular, axillary, oringuinal lymphadenopathy is noted bilaterally. Skin: No rashes, lesions, or cutaneous nodules.

Laboratory data: Complete blood count (CBC): WBC 8.3 × 109/L; hemo-globin level 9.4 g/dL; platelet count 150,000 mm3; 49%neutrophils, 22% lymphocytes, 15% monocytes, 13%eosinophils, 1% metamyelocytes. Chemistries andelectrolytes are within normal limits.

Bone marrow differentialBlasts 1% (0-5)Progranulocytes 0% (2-8)Myelocytes 2% (5-20)Metamyelocytes 1% (13-32)

July 2008 • Vol 7 • No 7 25

CaseStudy

Granulocytes 36% (7-30)Eosinophils 22% (0-4)Basophils 0% (0-1)Lymphocytes 16% (3-17)Plasma cells 1% (0-2)Monocytes 15% (0-5)Reticulum cells 0% (0-2)Pronormoblasts 0% (1-8)Normoblasts 6% (7-32)M:E Ratio 8.5 (3-4)

Bone marrow smearsGranulocytes: MaturingErythrocytes: DecreasedMegakaryocytes: NormalLymphocytes: Relatively increased, unre-

markable morphologyOthers: Increased eosinophils and

monocytes

Bone marrow diagnosis Bone marrow, biopsy, clot section, aspirate smears,and touch imprint, right side: Myeloproliferative disease with eosinophilia and monocytosis (possiblechronic myelomonocytic leukemia with eosinophilia).

Cytogenetic and molecular testingCytogenetic analysis* showed46,XY,t(5;12)(q33;q13)[9]/46,XY[11].No mutation at codon 617 of JAK2No mutation at codon 816 of KITNo monoclonal T-cell receptor gamma chain generearrangements detected by PCR analysis.

Assessment and treatment plan:Patient with monocytosis and eosinophilia, withcytogenetic abnormality, suggesting either chronicmyelomonocytic leukemia or chronic eosinophilicleukemia. However, according to newly revisedWorld Health Organization classification of myeloidmalignancies, this case is best classified as PDGFRß-rearranged myeloid neoplasm with eosinophilia.Imatinib 400 mg once a day was started.

4-week follow-up (Table 1) The patient reports that he is feeling better and

having no adverse effects from the imatinib. Hestopped taking epoetin alfa.

8-week follow-up (Table 1)Patient again reports feeling better, having much

more energy.

12-week follow-up (Table 1) The patient is being treated with imatinib 400 mg a

day. He has been on treatment now for 12 weeks andfeels well. He has had no red blood cell transfusionsand has taken no epoetin alfa for the past 2 months.He denies any symptoms and has performance statusof 0. He has repeat bone marrow aspirate and biopsydone showing 2% eosinophils and 4% monocytes.

Bone marrow diagnosisNormocellular bone marrow with trilineage

hematopoiesis. Cytogenetic findings normal.

Patient achieved complete hematologic, bonemarrow, and cytogenetic response, and continueson therapy with imatinib 400 mg a day. ■

Baseline Week 4 Week 8 Week 12WBC(K/mL) 8.3 8.4 7.4 4.7Hemoglobin (g/dL) 9.4 10.9 13.0 14.5Platelet count/mm3 150,000 280,000 233,000 232,000Neutrophils 49% 37.4% 38.2% 56.6%Lymphocytes 22% 47.6% 49.4% 42.4%Monocytes 15% 11% 7.9% 3.8%Eosinophils 13% 3.7% 3.9% 2%Basophils -- 0.3% 0.6% 0.2%

WBC, white blood cell count.

Table 1

Key Hematologic Values, Baseline – Week 12

*Chromosomal breakpoint on chromosome 5 (5q33) causes con-stitutive activation of a gene coding for platelet-derived growthfactor receptor beta (PDGFRß) tyrosine kinase.


CaseStudy

Case Study 3: Patient with HypereosinophilicSyndrome (HES)/Chronic Eosinophilic Leukemia (CEL)

Chief complaint: A 50-year-old man presents with thediagnosis of eosinophilic leukemia.

History of present illness: He states that his prob-lems started approximately 1 year ago when hebegan to experience right hip pain that became pro-gressively more severe, leading to migratory arthral-gias. He underwent MRIs of the abdomen, pelvis,and hips but nothing of significance was found. Healso experienced swelling in his wrists and back withredness and warmth. He suffered migratory arthral-gias throughout the year and experienced approxi-mately a 13-kg weight loss over the past 6 to 8months. He has night sweats, and his wife hasnoticed that his face and nose are constantly flushed.Six months ago, he had a CBC and a bone marrowaspiration that showed increased eosinophils. Hisoutside CBC 2 months ago showed 3.2 x 109/Leosinophils (normal 0.4 × 109/L). At that time, hebegan to take steroids for his pain. He continued onthe steroids for pain relief and has seen improvementin his eosinophil count. He presents today, accompa-nied by his wife, to discuss diagnosis and treatmentoptions.

Current medications:1. Prednisone 20 mg daily2. Multivitamin 3. Ibuprofen as needed4. Aspirin

Allergies: The patient has no known drug allergies.

Review of systems: See history of present illness.The remainder of the review of symptoms is nega-tive. He has no history of heart disease, hyperten-sion, neuropathies, chest pain, shortness of breath,asthma, pneumonia, or GI distress.

Physical examination: General: Temperature 36.6o C; pulse 81 beats/min;respirations 20/min; blood pressure 119/82 mm Hg.

Height: 188 cm. Weight: 84.9 kg. Alert and orientedman in no acute distress, but appears uncomfortable. HEENT: Facial flushing. Sclerae anicteric. PEERLA. Neck: Supple. No palpable adenopathy. His orophar-ynx is clear. Heart: Regular rate and rhythm. No rubs or gallops. Chest: Lungs clear to auscultation and percussion.No rales or rhonchi detected. Abdomen: Soft, nontender. No rebound or ascites.No hepatosplenomegaly detected. Positive bowelsounds in all four quadrants. Extremities: Without edema or deformity. Nocyanosis. Skin: No breakdown, but mild rash over torso. Nolesions or petechiae. Neurologic: No focal neurologic deficits are detected.

Laboratory data: CBC: WBC 8.6 × 109/L; hemoglobin level 12.2 g/dL;hematocrit 37.6%; platelet count 345,000/mm3.Eosinophils 22%. Chemistry panel: Mildly elevateduric acid at 8.1 mg/dL; otherwise; within normalparameters.

Bone marrow differentialBlasts 2% (0-5)Progranulocytes 0% (2-8)Myelocytes 13% (5-20)Metamyelocytes 6% (13-32)Granulocytes 23% (7-30)Eosinophils 25% (0-4)Basophils 1% (0-1)Lymphocytes 14% (3-17)Plasma cells 2% (0-2)Monocytes 0% (0-5)Reticulum Cells 0% (0-2)Pronormoblasts 0% (1-8)Normoblasts 14% (7-32)M:E Ratio 4.9 (3-4)

July 2008 • Vol 7 • No 7 27

CaseStudy

Bone marrow biopsyCellularity: 20%-40%, on average 30%Infiltrate: Numerous eosinophils observed.

Bone marrow clotQuality: AdequateCellularity: 30%-40%Megakaryocytes: UnremarkableInfiltrate: Numerous eosinophils

noticed. Hyperplasia ofmyeloid cells noted.

Bone marrow smearsGranulocytes: Predominant, maturing.

Unremarkable morphology. Eosinophilia 25%.

Erythrocytes: Unremarkable morphologyMegakaryocytes: Unremarkable morphologyLymphocytes: Small and matureBlasts: Not increased

Bone marrow diagnosis Bone marrow, core biopsy, clot specimen, and aspi-rate smears

Cellular (30%-40%) bone marrow with granulocytichyperplasia and marked eosinophilia consistentwith chronic eosinophilic leukemia/hyper-eosinophilic syndrome. No evidence of malignantlymphoma.

Cytogenetic and molecular testingDiploid normal cytogenetics. FIP1L1-PDGFRα detected by molecular testing (PCR).No mutation detected in codon 816 of the KIT gene.JAK2 mutation analysis negative.

Assessment and treatment plan:Patient with chronic eosinophilic leukemia, PDGFRα−positive, anemic. Multiple symptoms related to thedisease, including significant weight loss. Thepatient was started on imatinib 100 mg once daily.

2-week follow-upPatient reports feeling better and not taking prednisoneanymore.

5-week follow-up Patient has no symptoms or signs of disease, andno side effects from imatinib therapy.

Laboratory data: WBC7.0 × 109/L (4.0-11.0)Hemoglobin 13.2 g/dL (14.0-18.0)Hematocrit 37.6% (40.0-54.0)Platelet count 230 × 109/L (140-440)Neutrophil percent 72.0% (42.0-66.0)Lymphocyte percent 15.0% (24.0-44.0)Monocyte percent 11.0% (2.0-7.0)Eosinophil percent 2.0% (1.0-4.0)Neutrophil absolute count 5.04 × 109/L (1.70-7.30)Lymphocyte absolute count 1.05 × 109/L (1.00-4.80)Monocyte absolute count 0.77 × 109/L (0.08-0.70)Eosinophil absolute count 0.14 × 109/L (0.04-0.40)

Bone marrow biopsy:Bone marrow, left side, biopsy, aspirate smears,

clot section, and touch preparation: Cellular (40%)bone marrow showing trilineage hematopoiesiswith 3% eosinophils. PCR for PDGFRα is negative.

Patient achieved complete hematologic and bonemarrow response, including molecular negativity forPDGFRα and continues on imatinib 100 mg a day. ■

Editorial assistance and commercial support for these case studiesprovided by Novartis Pharmaceuticals Corp.

©2008 Haymarket Media Inc.Supplement of The American Journal of Hematology/Oncology

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