Atypical Myeloproliferative

Mayo Clin Proc. • April 2006;81(4):553-563 • www.mayoclinicproceedings.com 553

ATYPICAL MYELOPROLIFERATIVE DISORDERS

From the Division of Hematology, Mayo Clinic College of Medicine, Rochester,Minn.

Address correspondence to Ayalew Tefferi, MD, Division of Hematology, MayoClinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail:[email protected]). Individual reprints of this article and a bound bookletof the entire Symposium on Oncology Practice: Hematological Malignancies willbe available for purchase from our Web site www.mayoclinicproceedings.com.

© 2006 Mayo Foundation for Medical Education and Research

Atypical Myeloproliferative Disorders: Diagnosis and Management

AYALEW TEFFERI, MD; MICHELLE A. ELLIOTT, MD; AND ANIMESH PARDANANI , MBBS, PHD

Myeloid disorders constitute a subgroup of hematological malig-nancies that is separate from lymphoid disorders. The WorldHealth Organization system for classification of tumors of thehematopoietic system divides myeloid disorders into acute my-eloid leukemia and chronic myeloid disorders based on thepresence or absence, respectively, of acute myeloid leukemia—defining morphological and cytogenetic features including thepresence of 20% or more myeloblasts in either the bone marrow orthe peripheral blood. A recently proposed semimolecular classifi-cation system for chronic myeloid disorders recognizes 3 broadcategories: the myelodysplastic syndrome, classic myeloprolifera-tive disorders (MPD), and atypical MPD. Classic MPD includespolycythemia vera, essential thrombocythemia, myelofibrosiswith myeloid metaplasia, and chronic myeloid leukemia. Bothmyelodysplastic syndrome and BCR/ABL-negative classic MPDwere previously discussed as part of the current ongoing sympo-sium on hematological malignancies. The current review focuseson the diagnosis and treatment of both molecularly defined andclinicopathologically assigned categories of atypical MPD:chronic myelomonocytic leukemia, juvenile myelomonocytic leu-kemia, chronic neutrophilic leukemia, chronic basophilic leuke-mia, chronic eosinophilic leukemia, idiopathic eosinophilia includ-ing hypereosinophilic syndrome, systemic mastocytosis, unclassi-fied MPD, and eosinophilic/mast cell disorders associated withmutations of platelet-derived growth factor receptors ααααα (PDGFRA)and βββββ (PDGFRB), FGFR1, and KIT.

Mayo Clin Proc. 2006;81(4):553-563

AML = acute myeloid leukemia; ASCT = allogeneic stem cell transplan-tation; CEL = chronic eosinophilic leukemia; CMD = chronic myeloiddisorders; CML = chronic myeloid leukemia; CMML = chronic myelo-monocytic leukemia; CNL = chronic neutrophilic leukemia; EMS = 8p11myeloproliferative syndrome; ET = essential thrombocythemia; FGFR 1 =fibroblast growth factor receptor 1; FISH = fluorescence in situ hybridiza-tion; HES = hypereosinophilic syndrome; IL = interleukin; JMML = juvenilemyelomonocytic leukemia; MDS = myelodysplastic syndrome; MMM =myelofibrosis with myeloid metaplasia; MPD = myeloproliferative disor-ders; NF1 = neurofibromatosis type 1; PCPD = plasma cell proliferativedisorders; PDGFR = platelet-derived growth factor receptors; PV =polcythemia vera; SM = systemic mastocytosis; UMPD = unclassifiedMPD; WHO = World Health Organization

The term myeloproliferative disorders (MPD) was firstintroduced by Dr William Dameshek in 1951 to em-

phasize the clinicopathological similarities between chron-ic myeloid leukemia (CML), essential thrombocythemia,(ET), polycythemia vera, (PV), and with myeloid metapla-sia (MMM) (aka, chronic idiopathic myelofibrosis or pri-mary myelofibrosis).1 Accordingly, these 4 disorders arecurrently referred to as “classic” MPD. However, severalMPD-like clinicopathological entities have since been de-scribed and, at present, the World Health Organization(WHO) system for classification of myeloid neoplasmsorganizes MPD and the related chronic myeloid disorders(CMD) into 4 broad categories: myelodysplastic syndrome

(MDS), MPD, MDS/MPD, and systemic mastocytosis(SM).2 The WHO MPD category includes the 4 classicMPD (CML, ET, PV, MMM) as well as chronic neutro-philic leukemia (CNL), chronic eosinophilic leukemia(CEL), hypereosinophilic syndrome (HES), and unclassi-fied MPD (UMPD). On the other hand, the MDS/MPDcategory includes chronic myelomonocytic leukemia(CMML), juvenile myelomonocytic leukemia (JMML),and the so called atypical CML. In contrast to the WHOclassification scheme, an alternative semimolecular classi-fication system organizes CMD first into MDS and MPDand subsequently subdivides MPD into classic and atypicalvariants (Table 1). In other words, the latter system treatsclassic MPD as a completely separate category, an actionsupported by both historical connotation and the presenceof fundamental differences in disease biology.3 Both clas-sic and atypical MPD represent stem cell–derived clonalmyeloproliferation, and the primary clonogenic mutationhas been identified in some of the disease subentities.4 Thishas allowed further classification of “atypical” MPD into“molecularly defined” and “clinicopathologically assigned”disease categories (Table 1).5

MOLECULARLY DEFINEDATYPICAL MYELOPROLIFERATIVE DISORDERS

PDGFRA-REARRANGED EOSINOPHILIC DISORDERS

Blood eosinophilia represents either a primary or second-ary process depending on the respective absence or pres-ence of conditions known to be associated with reactiveeosinophilia.6 Primary eosinophilia is in turn subclassifiedinto clonal or idiopathic eosinophilia depending on therespective presence or absence of either a cytogenetic ab-normality or bone marrow histological evidence of an oth-erwise defined acute leukemia or CMD.6 Hematologicaldisorders that can be accompanied by clonal eosinophiliainclude acute myeloid leukemia (AML),7 acute lympho-cytic leukemia,8 CML,9 MDS,10 and both “classic” and

SYMPOSIUM ON ONCOLOGY PRACTICE: HEMATOLOGICAL MALIGNANCIES

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“atypical” MPD.11,12 Atypical MPD phenotypes that areknown to be associated with clonal eosinophilia includeCEL, SM, CMML, and UMPD.

TABLE 1. Modern Classification of Chronic Myeloid Disorders

1. Myelodysplastic syndrome (MDS)Diagnosis of MDS is considered in the presence of erythroid and other myeloid dysplasia and the absence of

peripheral blood monocytosis (monocyte count, ≥1 × 109/L). Diagnosis also requires the absence of 20% blastsor more in either the bone marrow or peripheral blood

2. Myeloproliferative disorders (MPD)Diagnosis of MPD is currently operational and requires the exclusion of both MDS and acute leukemia.

Clinical phenotype in MPD is markedly variable, and in some instances, the disease-causing mutation hasbeen identified. The term myeloproliferative disorder was first coined by Dr William Dameshek in 1951 and atthat time included polycythemia vera (PV), essential thrombocythemia (ET) myelofibrosis with myeloidmetaplasia (MMM), and chronic myeloid leukemic (CML). Accordingly, these 4 disorders are now classifiedas classic MPD, and all other MPD-like diseases are operationally labeled as atypical MPD. Both classic andatypical MPD are subsequently divided into molecularly defined and clinicopathologically assignedcategories depending on whether the disease-causing mutation is known

Classic MPDI. Molecularly defined

At present, only 1 (ie, CML) of the 4 classic MPD is molecularly defined. However, CML can mimicboth other classic or atypical MPD in its presentation. Therefore, the first step in the diagnosticevaluation of a chronic myeloid disorder is to perform mutation screening for BCR/ABL withcytogenetic and fluorescence in situ hybridization studies. The absence of the mutation rules out thepossibility of CML, and its presence, in the context of a chronic myeloid process, is diagnostic of CML

II. Clinicopathologically assignedCurrently, no molecular marker is diagnostic of the other 3 classic MPD, including PV, ET, and MMM.

Their diagnosis is currently based on consensus-defined bone marrow and clinical criteria. Mostrecently, a new mutation, JAK2V617F, was described in almost all patients with PV and half of thosewith either ET or MMM. As a result, modern diagnostic criteria for these disorders incorporatescreening for the specific JAK2 mutation

Atypical MPDThe atypical MPD category includes all chronic myeloid disorders that cannot be clearly classified as

either MDS or classic MPD. Similar to the case with CML, the oncogenic mutation in some of the entitiesincluded in this category has been characterized

I. Molecularly defined atypical MPDMost cases with molecularly defined atypical MPD are accompanied by prominent blood eosinophilia

and involve mutations that affect either 1 of the 2 platelet-derived growth factor receptorsPDGFR (α and β) or the fibroblast growth factor receptor 1. It is unusual to detect these mutations inthe absence of eosinophilia. The clinical phenotype of these eosinophilia-associated, molecularlydefined atypical MPD includes systemic mastocytosis (SM), hypereosinophilic syndrome, chroniceosinophilic leukemia, chronic myelomonocytic leukemia, and unclassified MPD. On theother hand, molecularly defined SM with KIT mutation may or may not be accompanied by bloodeosinophilia1. PDGFRA-rearranged eosinophilic/mast cell disorders (eg, FIP1L1-PDGFRA)2. PDGFRB-rearranged eosinophilic disorders (eg, TEL/ETV6-PDGFRB)3. 8p11 Myeloproliferative syndrome (eg, ZNF198/FIM/RAMP-FGFR1)4. SM associated with KIT mutation (eg, KITD816V )

II. Clinicopathologically assigned atypical MPDClinicopathologically assigned atypical MPD includes several entities that await molecular

characterization. Current diagnosis is based primarily on bone marrow histological appearance. Thediagnosis of SM requires demonstration of morphologically and immunophenotypically abnormalmast cells in the bone marrow. However, as elaborated above, the SM clinical phenotype may ormay not be accompanied by a putatively disease-causing mutation, Accordingly, SM can be eithermolecularly defined or clinicopathologically assigned depending on the respective presence or absenceof the specific mutant molecule. The same holds true for an atypical MPD associated with prominentblood eosinophilia1. Chronic neutrophilic leukemia2. Chronic eosinophilic leukemia, molecularly not defined3. Hypereosinophilic syndrome4. Chronic basophilic leukemia5. Chronic myelomonocytic leukemia6. Juvenile myelomonocytic leukemia (associated with recurrent mutations of RAS signaling

pathway molecules including PTPN11 and NF1)7. SM, molecularly not defined8. Unclassified MPD

Modified from Tefferi and Gilliland,5 with permission.

Recent studies have revealed an invariable associationbetween activating mutations of the genes for both platelet-derived growth factor receptors α (PDGFRA) and β




(PDGFRB) and clonal eosinophilia that accompanies asubset of patients with an HES, SM, CEL, CMML, orUMPD phenotype.13-16 PDGFRA-rearrangement usuallyoccurs as a result of a small (~800 bp) interstitial deletioninvolving the chromosome 4q12 region and resulting inthe fusion of the PDGFRA gene to the centromericFIP1L1 gene (FIP1L1-PDGFRA).13 However, PDGFRAcan also be activated by a chromosomal translocationsuch as t(4;22)(q12;q11) that produces BCR/PDGFRAfusion.17-19 Either way, the protein product of the alteredgene is a constitutively activated receptor tyrosine kinase(PDGFRA) that has been shown to transform hematopoi-etic cells and produce an MPD disease phenotype inmice.13,20,21

To date, FIP1L1-PDGFRA has been demonstrated inpatients with the clinical phenotypes of HES,13 SM,22 andCEL.23 However, on close scrutiny, all such cases mightrepresent a subset of patients with eosinophilia-associatedSM.22 In a systematic study of prevalence and clinicopatho-logic correlation, FIP1L1-PDGFRA was detected by fluo-rescence in situ hybridization (FISH) in approximately14% of patients with primary eosinophilia, and almost allsuch cases were histologically classified as SM.22 There-fore, the contemporary nomenclature for the disease asso-ciated with FIP1L1-PDGFRA is SM-CEL.

The diagnosis of FIP1L1-PDGFRA+ SM-CEL shouldbe suspected in any patient who presents with a diseasephenotype that suggests HES, eosinophilia-associated SM,or CEL. Either peripheral blood or bone marrow screeningfor the FIP1L1-PDGFRA abnormality should be done in allsuch cases. Of note, standard cytogenetic methods are notcapable of revealing the FIP1L1-PDGFRA abnormality.This must be sought with either a FISH or reverse tran-scriptase–polymerase chain reaction–based laboratorytechnique.13,14

With rare exceptions,23 all patients described so far withFIP1L1-PDGFRA+ SM-CEL have been males.23-25 Themost relevant aspect of FIP1L1-PDGFRA+ SM-CEL is itsexquisite sensitivity to treatment with imatinib mesy-late.13,19,22,24,26 In one of the largest studies to date of imatinibtherapy for FIP1L1-PDGFRA+ SM-CEL, all 8 treated pa-tients achieved complete and durable remissions with rela-tively low drug dosage levels (100 mg/d).14,22,27 A similarexperience has been reported with PDGFRA rearrange-ments resulting from cytogenetic translocations involvingchromosome 4q12; t(4;22)(q12;q11.2).17,19 Treatment withimatinib is recommended even in the absence of symptomsbecause of the potential to prevent cardiovascular com-plications.24,28,29 Finally, imatinib therapy for FIP1L1-PDGFRA+ SM-CEL has been associated with drug-in-duced cardiogenic shock that might be prevented by theconcomitant use of systemic corticosteroid therapy (1 mg/

kg per day) during the initial 1 or 2 weeks of imatinibtherapy.30

PDGFRB-REARRANGED EOSINOPHILIC DISORDERS

The PDGFRB gene is located on chromosome 5q33 andwhen activated by various chromosomal translocations in-volving 5q33 and other partner chromosomes, such ast(5;12)(q33;p13), produces a rare MPD that is usually asso-ciated with prominent eosinophilia and sometimes withmonocytosis.31 Accordingly, the clinical phenotypes asso-ciated with PDGFRB-rearranged MPD have included bothCMML and CEL.7,15,31-34 Similar to the case with FIP1L1-PDGFRA+ SM-CEL, women are rarely affected withPDGFRB-rearranged MPD, and imatinib is therapeuticallyeffective. Imatinib drug dosages used in this instance havebeen higher (400 mg/d), and it is currently unknown iflower doses would have the same effect.15 Diagnosisshould be suspected in the presence of an abnormal karyo-type that involves a 5q33 chromosomal translocation,whereas it is unusual to encounter karyotypically occultcases.11,15,35-37 Finally, it is underscored that both PDGFRB-rearranged MPD and FIP1L1-PDGFRA+ SM-CEL arerelatively rare disorders, and clinicians should refrain fromthe indiscriminate use of imatinib therapy for primary eosi-nophilia or SM.38,39

8P11 MYELOPROLIFERATIVE SYNDROME

The 8p11 myeloproliferative syndrome (EMS), also knownas human stem cell leukemia/lymphoma syndrome, is asso-ciated with fibroblast growth factor receptor 1 (FGFR1)rearrangement that results from cytogenetic translocationsinvolving chromosome 8p11 and multiple other partnerchromosomes, which juxtaposes the tyrosine kinase do-main of FGFR1 to a dimerization domain from the partnergene, resulting in constitutive kinase activation.40 The clini-cal phenotype includes eosinophilia, both myeloprolifera-tive and myelodysplastic features, lymphadenopathy, and ahigh incidence of T-cell nonHodgkin lymphoma with pro-gression to AML.40,41 As is the case with PDGFRB-rear-ranged MPD, diagnosis is facilitated by the fact that EMS isoften karyotypically apparent. On the other hand, currentlyavailable treatment agents, including imatinib, are ineffec-tive in EMS, and patients are best served by referral forparticipation in clinical trials.

SM ASSOCIATED WITH KIT MUTATION

Systemic mastocytosis, as is the case with most MPD, is aclonal stem cell disorder that is clinically characterized byurticaria pigmentosa, mast cell mediator release symptoms(diarrhea, urticaria, pruritus, flushing, syncope), osteoporo-sis, hepatosplenomegaly, ascites, and cytopenia. At least 2genes (KIT and PDGFRA) are involved in mutations that




are currently considered pathogenetically relevant in SM.Most“molecularly defined” SM is linked to activating KITmutations involving the kinase, juxtamembrane, or trans-membrane domains, and their distinction is therapeuticallyrelevant.42-47 For example, wild-type KIT is inhibited byimatinib, whereas such drug sensitivity is displayed bysome (eg, V560G) but not other (eg, D816V) mutantKIT.42,48-50 Accordingly, imatinib is used as first line ther-apy in SM associated with either PDGFRA or non-D816VKIT mutations, whereas it is unlikely to be effective inKITD816V-positive cases. In the latter instance, treatment issimilar to that of molecularly undefined SM; cytoreduc-tive therapy is not recommended for indolent SM, whereaseither interferon alfa or cladribine is used as first-linetherapy for aggressive disease.51-53 We await with greatinterest the results from currently ongoing treatment stud-ies in SM that use second-generation kinase inhibitors in-cluding dasatinib and AMN107. The former but not thelatter drug displays in vitro activity against KITD816V-posi-tive mast cell lines and primary cells.54 At present, in mostplaces, mutation screening for KIT is available only in aresearch setting.

CLINICOPATHOLOGICALLY ASSIGNED ATYPICALMYELOPROLIFERATIVE DISORDERS

CHRONIC NEUTROPHILIC LEUKEMIA

Chronic neutrophilic leukemia (CNL) is characterized bymature neutrophilic leukocytosis with few or no circulatingimmature granulocytes, monocytosis, or basophilia.55 Af-fected patients usually have splenomegaly, and bone mar-row histology reveals granulocytic hyperplasia withoutevidence of dysplasia or substantial reticulin fibrosis.56,57

Both cytogenetic and molecular analysis are negative forBCR/ABL. In addition, diagnosis of CNL requires the ab-sence of typical features that are characteristic of otherMPD.58 The disease is rare, with approximately 150 re-ported cases to date.59 Median age at diagnosis is approxi-mately 67 years, and the disease is equally prevalent in bothsexes. Most patients are asymptomatic at diagnosis. Fa-tigue is the most common presenting symptom. Other re-ported symptoms include weight loss, easy bruising, bonepain, and night sweats. Most patients have palpable spleno-megaly at diagnosis.

By definition, patients with CNL feature “right-shifted”neutrophilia with less than 5% immature granulocytes(promyelocytes, myelocytes, and metamyelocytes). Diag-nosis requires the absence of circulating blasts, absolute orrelative monocytosis, eosinophilia, or basophilia. Most pa-tients are mildly anemic at presentation, and the plateletcount is often normal. However, later in the clinical course,thrombocytopenia accompanies progressive splenomeg-

aly. The leukocyte alkaline phosphatase score is elevated inmost patients. Bone marrow examination reveals hyper-cellular marrow with relatively mature granulocytic hyper-plasia without excess blasts, dysplasia, or Auer rods. Cyto-genetic study results are abnormal in approximately 23% ofpatients at diagnosis, and specific lesions have included20q–, 21+, 11q–, and trisomy 9.60-62

The differential diagnosis of CNL includes reactive leu-kocytosis, plasma cell proliferative disorders (PCPD), andother MPD. Reactive leukocytosis might accompanychronic infections and inflammatory or malignant condi-tions.63,64 Interestingly, the incidence of PCPD in CNL hasbeen reported to be as high as 32%.65 It is currently thoughtthat neutrophilia seen in association with PCPD represents areactive phenomenon,66-68 and current CNL diagnosis there-fore requires the absence of clonal plasma cells in either theperipheral blood or the bone marrow or, if present, theconfirmation of myeloid cell clonality by cytogenetic ormolecular studies.58,69 Similarly, the possibility of otherwisedefined CMD, including neutrophilic CML,70 must be ex-cluded before a working diagnosis of CNL is made.

The disease course is heterogeneous and includes aclinically indolent chronic phase followed over a variableperiod by an accelerated or blast phase. Disease accelera-tion is heralded by progressive treatment-refractory neutro-philia, marked splenomegaly, anemia, thrombocytopenia,and the appearance of immature myeloid progenitor cells,including myeloblasts, in the peripheral blood. Median sur-vival is approximately 2 years, and causes of death includeblast transformation (always myeloid), progressive diseasewithout blast transformation, bleeding, and infection.

Treatment reports of CNL have included splenic irradia-tion, splenectomy, cytoreductive agents including hydrox-yurea, busulfan, 6-thioguanine, low-dose cytarabine,cladribine, AML-like induction chemotherapy, and alloge-neic stem cell transplantation (ASCT). In general, we donot recommend splenectomy because of the potential forexacerbating leukocytosis.71 Based on anecdotal experi-ence, we favor the use of hydroxyurea as first-line therapyand expect response in 75% of patients with either leukocy-tosis or splenomegaly. Responses often last for a median of12 months. For second-line treatment, we use interferonalfa based on reports of successful use in a small number ofpatients.72-74 Acute myeloid leukemia–like induction che-motherapy is ineffective in CNL, whereas ASCT is a po-tentially curative treatment modality for transplant-eligiblerecipients who are still in chronic phase.59,71,75

CEL, MOLECULARLY NOT DEFINED

Chronic eosinophilic leukemia is a subset of clonal eosino-philia that is neither molecularly defined (see previoussections) nor classified as an alternative clinicopathologi-




cally assigned myeloid malignancy such as acute leukemia,MDS, classic MPD, SM, or CMML.76,77 We prefer to usethe term strictly in patients with an “HES” phenotype whoalso display either a clonal cytogenetic/molecular abnor-mality or excess blasts in the bone marrow or peripheralblood.77,78 The WHO defines CEL in the presence of ablood eosinophil count that is 1.5 × 109/L or higher accom-panied by either the presence of myeloblast excess (either>2% in the peripheral blood or 5%-19% in the bone mar-row) or evidence of myeloid clonality.79 The distinc-tion between CEL and UMPD associated with eosinophiliacan be challenging and is arbitrarily based on the prom-inent myeloproliferative component seen in the latter in-stance.12,76,77 Reported cytogenetic abnormalities in CEL,other than those associated with molecularly defined eosi-nophilic disorders, include trisomy 8 (the most frequent),t(10;11)(p14;q21), and t(7;12)(q11;p11).12,76,78 In general,molecularly undefined CEL does not respond to imatinib,and treatment strategies are often not different from thoseused in other similar MPD: ASCT for transplant-eligiblerecipients with poor risk factors and participation in experi-mental treatment protocols otherwise.

HYPEREOSINOPHILIC SYNDROME

Blood eosinophilia that is neither secondary nor clonal isoperationally labeled as “idiopathic.” Hypereosinophilicsyndrome is a subcategory of idiopathic eosinophilia thatrequires documentation of both a target organ damage andan absolute eosinophil count of 1.5 × 109/L or higher for atleast 6 months.79-81 Many patients with idiopathic eosino-philia are asymptomatic at diagnosis, whereas HES re-quires, by definition, the presence of eosinophilia-associ-ated tissue damage, including cardiomyopathy, gastroen-teritis, cutaneous lesions, sinusitis, pneumonitis, neuritis,and vasculitis. In addition, some patients manifest throm-boembolic complications, hepatosplenomegaly, and eithercytopenia or cytosis. An HES phenotype with episodicangioedema, urticaria, fever, weight gain, and elevatedlevels of serum IgE, IgM, and polyclonal γ globulins isassociated with a relatively benign, corticosteroid-respon-sive disease (Gleich syndrome).82

In the strict sense, true HES should be devoid of anymolecular or cytogenetic marker of clonality.76 In addition,the bone marrow histology in true HES must not display anabnormal population of mast cells, monocytosis, or evi-dence of trilineage myeloproliferation or dysplasia.76

Therefore, both bone marrow histological and cytogenetic/molecular studies should be performed before a workingdiagnosis of HES is made. Additional blood studies that arecurrently recommended during the evaluation of possibleHES include serum tryptase (an increased level suggestsSM and warrants molecular studies to detect FIP1L1-

PDGFRA),22,83 T-cell immunophenotyping and T-cell re-ceptor antigen gene rearrangement analysis (a positivetest suggests an underlying clonal or phenotypically abnor-mal T-cell disorder and warrants measurement of inter-leukin (IL)-5 as well as consideration of T-cell–directedtherapy),84,85 serum IL-5 (an elevated level requires carefulevaluation of the bone marrow as well as T-cell gene re-arrangement studies for the presence of a clonal T-celldisease),84 and serum IgE level (patients with an increasedIgE level might be at a lower risk of developing eosino-philia-associated heart disease).86 In addition, initialevaluation in HES should include an echocardiogram andmeasurement of serum troponin levels to screen for myocar-dial involvement by the disease.87 Specific therapy for HESis indicated in the presence of eosinophil-mediated tissueinjury, and first-line therapy in this regard is prednisonealone (1 mg/kg per day) or in combination with hydroxyurea(starting dosage, 500 mg twice daily).88,89 In corticosteroid-refractory or corticosteroid-dependent patients, interferonalfa (starting dosage, 1 million units 3 times a week) iscurrently considered second-line treatment of choice.90-103

Modern treatment considerations for patients with HES whoare refractory to conventional therapy include imatinib,13,104

mepolizumab (monoclonal antibody to IL-5),28,87,105-107 andalemtuzumab (monoclonal antibody to CD52).108,109 In drug-refractory cases, ASCT can be considered.110-119

CHRONIC BASOPHILIC LEUKEMIA

In addition to his well-established prowess in plasma cellproliferative disorders, Dr Robert A. Kyle is also creditedfor the first clinical description of chronic basophilic leuke-mia.120 More recently, this rare disease was fully character-ized, and its features include prominent blood and bonemarrow basophilia in the absence of the BCR/ABL generearrangement.121 In the few patients that have so far beendescribed with the disease, clinical presentation includedbasophil mediator release symptoms including gastrointes-tinal ulcers, diarrhea, pruritus, and urticaria. The bone mar-row typically shows marked dysmegakaryopoiesis withnumerous small mononucleated and binucleated forms,prominent basophilia, and lesser degrees of peripheralblood and bone marrow eosinophilia.121 Granulocyte matu-ration is usually left-shifted with a slight increase in myelo-blasts. The disease is usually aggressive with the potentialto transform into AML. Information is limited on aspects ofclonality, cytogenetics, and treatment. We recommendtherapy similar to that for molecularly undefined CEL (seesection entitled CEL, Molecularly Not Defined).

CHRONIC MYELOMONOCYTIC LEUKEMIA

The sine qua non for CMML diagnosis is the presence of anabsolute monocytosis of greater than 1 × 109/L. This abso-




lute peripheral blood monocytosis is accompanied by evi-dence of both effective (myeloproliferative) and ineffective(myelodysplastic) hematopoiesis. The WHO committee onclassification of hematological malignancies recently re-classified CMML as an MDS/MPD overlap syndrome re-quiring (1) a peripheral blood monocyte count greater than1 × 109/L, (2) the absence of more than 20% blasts in eitherthe peripheral blood or the bone marrow, and (3) the pres-ence of dysplasia in 1 or more myeloid lineages or cytoge-netic abnormality or persistent unexplained monocytosis.2

We prefer to label CMML as atypical MPD but maintainthe WHO criteria for diagnosis.

Little is currently known about the primary oncogenicevents that lead to CMML. Nonspecific cytogenetic abnor-malities are seen in approximately 20% to 30% of patientsat diagnosis and include monosomy 7, trisomy 8, and com-plex abnormalities.122-125 Despite earlier speculations,36 theincidence of TEL/PDGFRB mutation or its cytogeneticcounterpart in CMML is very low; 1 of 27 consecutivecases in one series126 and none of 203 cases in anotherseries.124 Although not conclusive, FISH-based clonalitystudies in CMML have suggested pan-myeloid but notlymphoid lineage clonal involvement.127,128 Finally, in aseries of 119 patients with CMML, JAK2V617F was detectedin only 3% of the patients.129

Chronic myelomonocytic leukemia is approximately 2-fold more prevalent in men compared with women andprimarily affects elderly people with median age at presen-tation that ranges from 65 to 75 years.124,130 Common symp-toms and signs of the disease include fatigue, weight loss,fever and night sweats, splenomegaly, and hepatomegaly.Serositis is another CMML characteristic, but relatively in-frequent, disease feature and might involve the joints (arthri-tis), pericardium (pericarditis and pericardial effusion),pleura (pleural effusion), or peritoneum (ascites).131,132 Thebone marrow is often hypercellular with granulocytic prolif-eration as the predominant feature. Monocytic proliferation,although invariably present, may be difficult to appreciatewithout the use of specific cytochemical stains. Dysplasia isusual and may involve 1, 2, or all myeloid lineages.

According to a recent meta-analysis of reported series ofCMML, both median survival and median time to transfor-mation into AML (usually M4 or M5) were 1.5 to 2years.133 For practical purposes, we consider increasedbone marrow blast percentage (>5%), presence of anemia(hemoglobin level <10 g/dL), and presence of abnormalkaryotype as the main predictors of shortened survival.134

At present, hydroxyurea and supportive care (red blood celland platelet transfusions, erythropoietin) remain the stan-dard of care for most patients with CMML. Further supportfor such a treatment strategy comes from a recent random-ized trial in which hydroxyurea performed better than oral

etoposide.135 Similarly, it is unclear at this time whetherother investigational agents (eg, topotecan,136 combinationtopotecan and intermediate-dose cytarabine,137 AML-typeinduction)138 are superior to hydroxyurea monotherapy. Onthe other hand, ASCT is a viable treatment option fortransplant-eligible recipients with poor prognostic features.In this regard, in the largest study reported so far, a total of50 adult patients with CMML underwent ASCT from ei-ther related (n=43) or unrelated (n=7) donors.139 Twenty-six patients (52%) died of treatment-related causes. After amedian follow-up of 40 months, the 5-year estimated over-all and disease-free survival were 21% and 18%, respec-tively.139 Whether reduced intensity conditioning ASCTcan overcome treatment-related mortality and morbidity inCMML remains to be seen.140

JUVENILE MYELOMONOCYTIC LEUKEMIA

Juvenile myelomonocytic leukemia is primarily a diseaseof early childhood and is included, along with CMML, inthe “MDS/MPD” WHO category of CMD.2 Both CMMLand JMML feature leukocytosis, monocytosis, and hepato-splenomegaly. Additional characteristic features in JMMLinclude thrombocytopenia and elevated fetal hemoglobinlevels.141 Myeloid progenitors display granulocyte-macro-phage colony-stimulating factor hypersensitivity in JMMLthat has been attributed to deregulated RAS/MAPK signal-ing as a result of mutually exclusive mutations affectingone of the pathway regulatory molecules, including thegenes for RAS, PTPN11 (encoding for the nonreceptorprotein tyrosine phosphatase, SHP-2, that transmits signalsfrom growth factor receptors to Ras), and NF1 (neurofibro-matosis type 1 encoding for neurofibromin protein thatinactivates Ras).142,143 A third of patients with JMML that isnot associated with Noonan syndrome carry PTPN11 mu-tations,142,144 whereas the incidence of NF1 mutations (inpatients without neurofibromatosis, type 1)143 and RAS145

mutations is approximately 15% to 20% each. The afore-mentioned molecular information has been exploited inrecent clinical trials in JMML that used drugs with thepotential to interfere with the RAS signaling pathway.146

At present, however, the treatment of choice for JMMLremains ASCT that results in a 5-year survival of approxi-mately 50%.147,148

SM, MOLECULARLY NOT DEFINED

Mast cell disease is defined as tissue infiltration by mor-phologically and immunophenotypically abnormal mastcells. It is classified into 2 broad categories, cutaneousmastocytosis and SM.149,150 Mast cell disease in adults isusually systemic, and the clinical course can be eitherindolent or aggressive, depending on the respective ab-sence or presence of impaired organ function. Symptoms




and signs of the disease include urticaria pigmentosa, mastcell mediator release symptoms (headache, flushing, light-headedness, syncope, anaphylaxis, pruritus, urticaria, an-gioedema, nausea, diarrhea, abdominal cramps), and organdamage (lytic bone lesions, osteoporosis, hepatospleno-megaly, cytopenia).151 Aggressive SM can be associatedwith either another MPD or, rarely, mast cell leukemia.149,150

In general, life expectancy is nearly normal in indolent SMbut significantly shortened in aggressive SM includingMPD-associated SM.149,152

Molecularly defined SM, associated with either FIP1L1-PDGFRA or KIT mutations, has been discussed in previoussections of the current paper. However, these mutations arenot detected in a substantial proportion of adult patientswith SM, thus forming the group of patients with molecu-larly undefined SM.45 Regardless, diagnosis is based onbone marrow examination that shows clusters of morpho-logically abnormal spindle-shaped mast cells that are bestevaluated with the use of immunohistochemical stains thatare specific to mast cells (tryptase, CD117).153,154 In addi-tion, we recommend mast cell immunophenotyping in sus-pected cases to search for aberrant CD25 expression byneoplastic mast cells.155 Other laboratory findings in SMinclude increased levels of serum tryptase, histamine, cal-citonin, and urine histamine metabolites including methyl-imidazoleacetic acid and prostaglandins.151

Patients with either indolent or aggressive SM mightexperience mast cell mediator release symptoms, which aresuboptimally managed by both H-1 and H-2 histaminereceptor blockers as well as cromolyn sodium.156 In addi-tion, patients with a propensity to vasodilatory shockshould wear a medical alert bracelet and carry an epineph-rine self-injector pen for self administration of subcutane-ous epinephrine.157 Urticaria pigmentosa shows variableresponse to both topical and systemic corticosteroidtherapy.158 Cytoreductive therapy is not recommended forindolent SM.159 In aggressive SM, either interferon alfa(starting dosage, 1 million units 3 times weekly) or clad-ribine (2-hour infusion of 5 mg/m2 per day for 5 days re-peated every 4 weeks for 4 to 6 cycles) is considered first-line therapy and benefits most patients.51,52 In contrast,imatinib is ineffective in the treatment of molecularly un-defined SM.160

UNCLASSIFIED MYELOPROLIFERATIVE DISORDER

The category of UMPD serves to accommodate MPD- orMDS-like disorders that cannot be clearly assigned one ofthe aforementioned CMD diagnoses. Some cases displayfeatures of both MPD and MDS, whereas others mimicCML without the disease-defining BCR/ABL mutation(aka, atypical or BCR/ABL-negative CML).161-164 A French-American-British Cooperative Group analyzed 51 cases of

CML- or CMML-like cases and constructed a statisticalmodel that separates “atypical” CML from both CMMLand BCR/ABL-positive CML.163 Accordingly, atypicalCML was characterized by a higher degree of granulocyticdysplasia and a lesser rate of basophilia and monocytosis.However, we favor reserving the term chronic myeloidleukemia to refer to only those cases with detectable BCR/ABL and encourage the use of the term unclassified myelo-proliferative disorders otherwise. Patients with UMPD aremanaged in a similar fashion to those with either MDS ormolecularly undefined atypical MPD. Whether the rela-tively frequent (25%) JAK2V617F mutation in UMPD willhave therapeutic relevance during future targeted treat-ments remains to be seen.165

CONCLUSION

It is only a matter of time before the molecular underpin-nings of all CMD, including atypical MPD, are fully char-acterized, thus paving the way for a molecular classifica-tion system as well as the development of pathogenesis-targeted diagnostic and therapeutic approaches. In this re-gard, the most recent exciting development concerns anovel JAK2 somatic point mutation (a G-C to T-A transver-sion, at nucleotide 1849 of exon 14, resulting in the substi-tution of valine to phenylalanine at codon 617; JAK2V617F)that was described in both classic and atypical, BCR/ABL-negative MPD.3,129,165-173 Although the pathogenetic rel-evance of this mutation remains uncertain at this point,the discovery has provided guidance for both areas offocus for additional pathogenetic studies and develop-ment of targeted therapeutics. In the meantime, currentdiagnostic work-up for atypical MPD should always startwith screening, both by cytogenetic and other molecularstudies, for therapeutically relevant mutations includingBCR/ABL, FIP1L1-PDGFRA, rearrangements involvingeither FGFR1 or PDGFRB, and KITD816V. In the absence ofsuch well-defined molecular markers, diagnosis is made onthe basis of a constellation of clinical, bone marrow histo-logical, cytochemical, chromosomal, and immunopheno-typic features.

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The Symposium on Oncology Practice: Hematological Malignancieswill continue in the May issue.


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Atypical Myeloproliferative