Rev. Bras. Hematol. Hemoter. vol.39 número2

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revbrashematolhemoter.2017;39(2):167–169

w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Case

Report

Concomitant

chronic

myeloid

leukemia

and

monoclonal

B

cell

lymphocytosis

–

a

very

rare

condition

Sara

Duarte

a,b,∗

,

Sónia

Campelo

Pereira

a

,

Élio

Rodrigues

a

,

Amélia

Pereira

a a_Internal_Medicine_Service,_District_Hospital_of_Figueira_da_Foz,_EPE,_Figueira_da_Foz,_Portugal

b_Clinical_Hematology_Department,_University_Hospital_Center_of_Coimbra,_Coimbra,_Portugal

a

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Articlehistory:

Received3November2016

Accepted13February2017

Availableonline11March2017

Introduction

Chronic lymphocytic leukemia (CLL) is the commonest

leukemiainadults.Itisdefined,accordingtothelatest

guide-lines,as>5×103/␮LcirculatingBlymphocytes(BL)expressing

atypicalcellsurfacemarkersignature(CD5+_,_CD10−_,_CD19+

and CD20dim_, _surface _{immonuglobulin}dim_, _CD23+_, _CD43+/−

and cyclin D1−_).1 _If _lymph _node _enlargement _and/or

hep-atosplenomegaly is present in a patient with <5×103/␮L

monoclonalcirculating BL,the diagnosis ofsmall

lympho-cytic lymphoma (SLL) is reached and treatment may be

required.2_The_{identification}_of_CLL-like_cells_in_healthy

peo-pleduetoincreasinglymoresensitiveimmunophenotyping

methods led to the definition in the 2008 World Health

Organization(WHO)classificationoflymphoidneoplasmsof

monoclonalBcell lymphocytosis (MBL) asup to5×103/␮L

monoclonal BL in peripheral blood (PB), phenotypically

similartoCLLcells,butwithoutcytopeniasorpalpable

lym-phadenopathies.MBLissubdividedintotwosubgroups,

“low-count”MBL(<0.5×103/␮L),witharesidualchancetoboostinto

CLL/SLLand“high-count”MBL,whichsharephenotypicand

molecular/geneticfeatureswithRaistagingsystem0CLLand

∗ _{Corresponding}_author_at_:_Internal_Medicine_Service,_District_Hospital_of_Figueira_da_Foz,_EPE,_Gala,_3094-001_Figueira_da_Foz,_Portugal.

E-mailaddress:sarafrduarte@gmail.com(S.Duarte).

requireroutinefollow-up.IthasbeenshownthatCLLisalways

precededbyMBL,however,despiteitsprevalenceof12%inthe

healthypopulation,MBLprogressestoovertCLL/SLLinonly

1–2%ofcasesyearly.1

Chronic myeloid leukemia (CML) is a myeloproliferative

disease characteristicallyexpressing the aberrant

Philadel-phia chromosome, a product of the translocation of the

Abelsonmurineleukemia1(ABL1)genefromchromosome9to the breakpointclusterregion(BCR)geneonchromosome22–

t(9;22)(q3.4;q1.1).ThisresultsintheBCR-ABL1fusiongenethat

codesforanoncoproteinthatconstitutivelytriggerstyrosine

kinaseactivity.TheincidenceofCMLisgraduallyrisingdueto

thehighefficiencyoftyrosine-kinaseinhibitorsusedtotreat

andprolongthelifeexpectancyofpatients.

Rarely,CMLandCLLorCLL-relatedneoplasmscoexistin

the same patient. To date, only a few dozens of cases of

simultaneousCMLandCLLhavebeenreportedandonlyin

aminorityofpatients,theyarediagnosedconcomitantly.3_In

addition, onlyonecaseofsimultaneousCMLand MBLhas

beenreported,whereCMLfollowedMBL.4

Hereinwedescribeararecaseofsimultaneousdiagnosis

ofCMLand“high-count”MBL.Aftercompletingsixyearsof

treatmentusingimatinib,ourpatientdevelopedpancytopenia

http://dx.doi.org/10.1016/j.bjhh.2017.02.004

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168

andmultipleadenopathies,stronglysuggestingdisease

pro-gressiontoSLL.Weadditionallydemonstratethatmyeloidand

lymphoidneoplasticcellsoriginatefromdistinctprogenitors.

Case

report

Wereportonan82-year-oldmanwithcardiovasculardisease

andobstructivesleepapnea,whowasseenintheemergency

room(ER)inApril2008forleukocytosisinhisroutineblood

testsandcomplaintsoffatigue,osteoarticular pain,sweats

andanxietyforseveralweeks.Onphysicalexamination,he

had a BMI of 30.0kg/m2_, _and _presented _with _a _sad _facies

anddepression.Lungandheartauscultationswerenormal.

Athoroughexaminationofthehead,earsandneckexcluded

enlargement of regional lymph nodes. No organomegalies

were found on abdominal palpation. Infectious and acute

inflammatoryconditionswereexcluded.Hehadnohistoryof

expositiontomyelotoxicdrugsorradiation.

A complete blood count (CBC) confirmed leukocytosis

of 26.6×103/␮L, with neutrophilia (14.44×109/L),

lympho-cytosis (4.73×109/L), a platelet count of 282×109/L and

hemoglobinof13.7g/dL.Serumchemistryshowedunaltered

renalandhepaticparametershowever,lactatedehydrogenase

waselevatedat636U/L. Aperipheralbloodsmearrevealed

leukocytosiswithimmaturegranulocytes(2%ofmyelocytes,

4% of metamyelocytes and 11% of band cells).

Addition-ally,bonemarrow(BM)aspirationidentifiedhypercellularity,

<1%ofblasts and myeloid hyperplasia withpredominance

of immature cells, rare orthochromatic erythroblasts with

Howell-Jollybodiesandaratioofmyeloidtoerythroid

precur-sorsof4:1.Strikingly,phenotypicanalysisoftheBMshowed

5%of lymphocytes, of which 90% were monoclonal, small

sizedBlymphocytesco-expressingCD5,CD43,CD38andCD20

atlowlevels.CD23washeterogeneously expressed.The

B-cellclonewasnegativeforZap-70,CD79b,FMC7,CD10and

theKappaimmunoglobulinlightchain.Thirtypercentofthe

clonewaspositiveforCD11c. Apoptosisregulator Bcl2was

expressed atnormal levels, whilelambda chains were

lit-tleexpressed.ABMbiopsywasinconclusive.Computerized

tomography (CT) excluded generalized lymphadenopathies

andhepatosplenomegaly.

Altogether,theanalysesabovesuggestedthediagnosisof

“high-count”MBL.

Inagreementwiththe observationofcirculating

imma-turemyeloidcellsbutatoddswiththeimmunophenotypic

study, cytogenetic analysis revealed the presence of the

t(9;22)(q3.4;q1.1) translocation in all metaphases analyzed

andreversetranscriptasepolymerasechainreaction(RT-PCR)

showedBCR-ABL1transcripts,establishing,concurrentCML

inadditiontotheMBLdiagnosis.

Welostcontactwiththepatientfor14monthsatwhich

timehewasreadmittedtotheERduetoactivebleeding

sub-sequenttoadentalimplantprocedure.Onthisoccasion,the

CBCshowedanescalationofleukocytosisto170.0×103/␮L,

with neutrophilia shifted to the left (109.65×₁₀9_/L),

lym-phocytosis(14.28×103/␮L)andthrombocytosis(532.0×109/L).

Hemoglobin haddropped to12.1g/dL.A secondPB

pheno-typicstudywaspursuedrevealing1.7%ofBcellswithaCLL

phenotype.Moreover,91%ofneutrophils(60%ofthesein

mat-uration)were detectedanda slightincreaseofCD34+ _cells

(0.12%).

Thedefinitivediagnosisofconcomitant“high-count”MBL

andCMLwasreached.

The patient completed six days of cytoreduction with

hydroxyurea (1g per day) and the absolute leukocyte

countdroppedto16.3×103/␮L(10.81×109/Lneutrophilsand

3.19×103/␮Llymphocytes).Treatmentwithimatinib(400mg

perday)wasinitiatedonemonthlater.Complete

hematolog-icalandmolecularresponseswereachievedwithsixmonths

oftreatment(ratioofBCR-ABL1toABL10.04%byRT-PCR)and

sustainedfor5.5yearsoffollowup.

During thefirst semesterof2015,the patientdeveloped

leukopenia while lymphocytes boosted to over 70% of all

whitebloodcells,plateletsreachedcountsbetween84.0and

140.0×109/Landhemoglobinlevelsdroppedfrom9.9g/dLin

November 2014 to 8.5g/dL in June 2015. A supraclavicular

adenomegalywasdetectedonphysicalexamination.

Never-theless, the patient was asymptomatic.Revaluation ofBM

aspirate showed 90% of clonalBcells, positive forlambda

immunoglobulinlightchainandacharacteristicphenotypeof

B-CLL.PBimmunophenotypicanalysisshowed15%ofB

lym-phocytesofwhich99%hadthe phenotypeCD19+_, _CD20low_,

CD5+_, _CD38het_, _CD23+_, _CD200+_, _CD43+_, _CD10−_, _CD79b− _and

expressed lambda chain. Cytogenetic studies of PB for

tri-somy12,del11q23,BCR/ABL1fusiongene,del17p13.1(p53)and

del13q14.3molecularabnormalitiesonfluorescence-activated

cell sorting purified CLL-like lymphocytes and monoclonal

blasts were all negative, demonstrating that characteristic

genomic abnormalities for CLL were absent inthis patient

andthattheBCR/ABL1translocationoccurredexclusivelyin

CMLcells.Thoraco-abdomino-pelvicCTrevealedlymphnode

enlargement(>1.5cm)ofsubcarinal,para-aortic,axillary

bilat-erally,lowercervicalandabdominal(celiacandhepatic)lymph

nodes.Liverandspleenpresentedwithnormaldimensions.

Nevertheless,theratioofBCR-ABL1/ABL1was≤0.0011%.All

together,theaboveeventsstronglysuggestanexpansionof

theMBLconditiontoSLL,stageIIIofLuganomodificationof

AnnHarborstagingsystemforprimarynodallymphomas2

besidesacompletemolecularresponseofCMLwithimatinib.

Inaddition,resultsshowthatCMLandMBLcloneshave

dis-tinctorigins.

Imatinibtreatmenthasbeensuspendedwhilethepatient’s

clinicalconditionisre-stagedandanewtreatmentstrategyis

beingappraised.

Discussion

Previousstudieshavesuggestedthatpatientswith

Philadel-phianegativemyeloproliferativeneoplasms(Ph−_MPN)_are_at

higherriskofdevelopingBcelllymphoidneoplasmsthanthe

generalpopulation.Thisnotionwassubstantiatedbyarecent

reportdemonstratingthatMBLoccursmorefrequentlyinPh−

MPN comparedtoacontrolgroup.5 _Altogether,_these

stud-iesmayindicateasharedpathophysiologybetweenthePh−

MPNandlymphoidmalignancies.Contrastingly,Ph+_CML_and

CLL/SLLorMBLinthesamepatientisaveryrareconditionand

evenrareristheirsimultaneousdiagnosis.Whensequentially

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169

CML.3,4_Leukemogenic_effects_of_chemotherapy_drugs_used_to

treatCLLaswellasimmunodeficiencyassociatedtoCLLhave

beensuggestedasplausible causesforthe developmentof

CMLfollowingCLLdiagnosis.6_{Nevertheless,}_secondary_solid

tumorsare muchmorelikelytooccurinCLLpatientsthan

hematologicalmalignancies.SimultaneousMBLandCMLhas

only been reported once, where CML onset followed MBL

diagnosis.4 _{Contrastingly,}_CML_often_evolves_to_a_blast_crisis

andsecondaryneoplasmsarenotcommonlyfoundinthese

patients.7_{Nevertheless,}_the_above_arguments_have_no_place

incasesofconcomitantoccurrenceofCMLand matureBL

neoplasms,ashereinreported.

Thoughonlyoccasionallyfound,itisofgreatinteresttothe

fieldandclinicallyimportanttounderstandthecausesand

molecular mechanisms underlying the concomitant

occur-renceofhematologicalmalignancies.Itisgenerallyaccepted

thatmyeloidandlymphoidneoplasmsemergeandprogress

independently, however studies unequivocally

demonstrat-ingabiclonaloriginofthetwolymphoidandmyeloidclones

arestilllacking.D’Arenaetal.have,forthefirsttime,sorted

myeloidandlymphoidcellsaparttoshowthateachcelltype

carriescharacteristicandmutuallyexclusivegenomic

aber-rations(BCR-ABLanddel17q11,respectively),demonstrating

therefore,thatCLLandCMLcellshavedistinctorigins.8

Simi-larly,inourstudy,werancytogeneticsonseparatedcirculating

lymphocytesand provedthatBcell andmyeloid neoplasm

populationsoriginatefromdistinctprogenitors.Thus,todate,

evidenceislackingforacommonanduniquestemcellcapable

oforiginatingbothleukemiclymphoidandmyeloidclones.

Finally, as previously mentioned,MBL is aprecursor of

virtuallyall cases ofCLL and the diagnosis ofthelatter is

establishedwhen >5.0×103/␮LmonoclonalBLare detected

inPB.However,clinicaldatasupportingthis arbitrary

labo-ratory cut-off value is lacking. Nevertheless, it ispowerful

enough to stratify patients between having the diagnosis

ofMBL,abenignconditiondespiteitspotentialtoprogress

tomalignancy,againstpatientswithCLL/SLL.Infact, 1–2%

of“high-count”MBL patientsprogresstoovertCLL/SLLper

year.1_In_our_case,_although_a_lymph_node_biopsy_is_required

fordefinitivediagnosis,analyticalandimagingdatastrongly

suggest the progression ofMBL to SLL six years after the

diagnosis ofconcomitant MBL and CML. Itis legitimate to

hypothesizethatimatinibmayberesponsibleforthis

trans-formation.However,mostadverseeffectsoftyrosine-kinase

inhibitorssuchasimatinib,usedasfirst-linetreatmentdrugs

forCML,resultinlow-gradetoxicitiesandgenerallyoccurat

anearlyphaseofthetreatment.Furthermore,although

stud-ieshavesuggestedaninteractionbetweenimatinibandDNA

repairmechanismsanditspotentialtoinhibitT-lymphocytes

and dendritic cells,9 _as _of _today, _there _is _no _irrefutable

evidence that tyrosine-kinase inhibitors induce secondary

malignancies.Incontrast,BCR-ABL1expressingcellssecrete

severalcytokines,includinginterleukin-3,whichmayleadto

increasedproductionofimmatureBcellsthat,inturn,may

resultinthedevelopmentofCLL.10

Conclusion

Ourstudyisaveryimportantcontributiontothesparse

num-berofcasesofsimultaneousdiagnosesofmyeloproliferative

and lymphoproliferativeneoplasmsfoundin theliterature,

particularlyconcomitantoccurrenceofPh+_CML_and_MBL;_this

isthe first caseeverreportedin Portugal.Wealso

demon-stratethatclonallymphoidandmyeloidcellsoriginatefrom

distinctprogenitors.Furtherworkisnecessarytounderstand

themolecularpathogenesisunderlyingthisconditionand

dis-coveracommonandefficienttherapytotreatpatientswho

progresstosimultaneousmyeloidand lymphoid

malignan-cies.

Conflict

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

TheauthorsacknowledgeDr.ArturPaiva.

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