The patient with 5q minus syndrome and V617F mutation with the presence of ringed erythroblasts meeting the criteria of RARS-T effectively treated with lenalidomide – A case report

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Case report/Kazuistyka

The patient with 5q minus syndrome and JAK2 V617F mutation with the presence of ringed erythroblasts meeting the criteria of RARS-T

effectively treated with lenalidomide – A case report

Marcin Kruszewski

^1,

*, Adriana Czyż

²

, Krzysztof Lewandowski

³

, Monika Prochorec-Sobieszek

⁴

, Jarosław Czyż

^1,2

1UniversityHospitalNo.2–BizielMemorialHospital,Bydgoszcz,Poland

2NicolausCopernicusUniversity,CollegiumMedicum,Bydgoszcz,Poland

3MedicalUniversityofGdansk,DepartmentofClinicalChemistryandBiochemistry,Gdansk,Poland

4InstituteofHematologyandTransfusionMedicine,Warsaw,Poland

Introduction

5qminussyndrome(5qminus)isaformofmyelodysplastic syndrome (MDS) characterized by the presence of an

isolateddeletionof longarmof thechromosome5[1]. The diseasehasarelativelygood prognosis,theoverallsurvival rateisestimatedatapproximately145monthsandtherisk of transformation to acute myeloid leukemia is less than 10% [2, 3]. In a small percentage of cases, patients with acta haematologica polonica 47 (2016)29–32

article info

Articlehistory:

Received:14.06.2015 Accepted:28.12.2015 Availableonline:07.01.2016

Keywords:

5qminus

JAK2V617Fmutation

RARS-T

MDS

Lenalidomide

abstract

5q minussyndrome is a form ofmyelodysplastic syndrome characterized by the pre- senceofanisolateddeletionoflongarmofthechromosome5.Patientswith5qminus respondwelltothetreatmentwithlenalidomide.ThepresenceoftheJAK2V617Fmuta- tionisacommonfeatureofrefractoryanemiawithringsideroblastsandmarkedthrom- bocytosis.Muchlessisknownabouteffectivenessoflenalidomideinthesepatients.We presentthepatientwith5qminussyndromeandJAK2V617Fmutationaccompaniedby thepresenceof ringederythroblasts meetingthecriteria ofRARS-T. Wecouldidentify onlytwosuchpatientsreportedintheliterature;nodetailsweregivenabouteffective- nessoflenalidomidein thatgroup. Weobserved goodresponse tothe treatmentwith lenalidomidewith transfusion independence9months afterstarting ofthe treatment;

however,therewasnocompleteeradicationofdel(5)(q13q31)clonenortheclonewith JAKV617Fmutation.

*Corresponding author at: Oddział Kliniczny Hematologii i Chorób Rozrostowych Układu Krwiotwórczego Szpital Uniwersytecki nr2imdr.JanaBiziela,ul.Ujejskiego75,Bydgoszcz85-168,Poland.Tel.:+48504012507;fax:+48523655559.

E-mailaddress:marcin.kruszewski5@wp.pl(M.Kruszewski).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journalhomepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2015.12.002

zo.o.Allrightsreserved.

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5q- syndrome may exhibit JAK2 V617F mutation [4]. The authors of the fourth edition of WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues (WHO 2008) separated JAK2 V617F mutated form that emerged fromthetypical5qminussyndrome.Intheiropinion,there is not enough data collected for accurate classification of thissubgroup.Itwasdecidedthattemporarilythediagnosis should be classified as MDS, not as a myeloproliferative disease,withtheadditionofinformationaboutthepresence of the JAK2 V617F mutation [5, 6]. On the other hand, the presence of theJAK2V617F mutation isacommon feature of refractory anemia with ring sideroblasts and marked thrombocytosis (RARS-T),which was includedinto “Myelo- dysplastic/myeloproliferative neoplasm, unclassifiable” as a provisional entity grouping together patients with the diseaseshavingfeaturesofmyelodysplasticandmyeloproli- ferative disease [7, 8]. Patients with 5q minus syndrome usuallyrespondwelltothetreatmentwithlenalidomide[9–

11]. Much less is known about its effectiveness in the patients meeting the criteria of RARS-T [12, 13]. In this paper, we present the case of a patient with 5q minus syndrome with JAK2 V617F mutation features and ringed erythroblasts accompanied by thrombocytosis effectively treatedwithlenalidomide.

A case report

A 59-year-old female patient was admitted to the depart- ment of hematology due to persistent macrocytic anemia with hemoglobin 9.9g/dl (mean cell volume – MCV – 104.3ﬂ), white cell count 9.50G/l, and with platelet count

94410⁹/l. Before shewas referredto a hematologist, she had been unsuccessfully treated with vitamin B12. At the timeofherﬁrstpresentation,thebonemarrowshowed60%

cellularity with numerous dysplastic megakaryocytes pre- senting large hypolobated nuclei and with features of erythroid dysplasia (Fig. 1). Ringed sideroblasts accounted for 18% of her erythroid precursors (Fig. 2). Blast cells expressingCD34antigenaccountedforapproximately3%of Fig.1–Fiveerythroblasts(arrows),atdifferentstageof maturation,showdysplasticfeatures(megaloidchanges, cytoplasmicvacuoles,irregularshapeofnucleus,abnormal hemoglobinisation)

Fig.2–Tworingedsideroblasts(arrows) acta haematologica polonica47(2016)29–32

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all nucleated cells and numerous megakaryocytes were present, including some with hypolobated nuclei (Fig. 3).

Thecytogeneticanalysisrevealedadeletionofthelongarm of chromosome 5: 46, XX, del (5)(q13q31) [13]/46, XX. PCR studies did not show the presence of the JAK2 V617F mutationatthattime.

Oncethediagnosiswasestablished,thepatientremained under observation, with a sporadic, intermittent require- mentof abloodtransfusion, andrequiredoccasionalblood transfusions.After21monthsof follow-upoutpatientmon- itoring, signiﬁcant worsening of the anemia was noticed and it was decided to commence the treatment with lenalidomide.Atthattime,thebiopsyshowed70%marrow cellularitywithlarge,dysplasticmegakaryocytes,anddyser- ythropoiesis.Noincreaseinblastpercentwasfound.Atthis point, the PCR test revealed the presence of JAK2 V617F mutationfortheﬁrsttime.

Lenalidomidetherapy wasintroduced,initiallyatadose of 10mg per day, later reduced to 5mg per day due to neutropenia.After 12weeks of that treatmentanindepen- dence from blood transfusions was achieved. The current levelofhemoglobin,evaluated9monthsafterthetreatment was ﬁrst introduced, is 11.8g/dl at MCV of 95.7ﬂ and the plateletcountof 12610⁹/L.Thelenalidomidetreatmentis continued at the dose of 5mg per day. Despite clinical improvements, the 5q ( ) clone is still present and the molecular analysis shows the presence of JAK2 V617F mutation.Dysplasticfeaturesalsocontinuetopersistinthe marrow.

Discussion

The accurate classiﬁcation of 5q minus syndrome with aJAK2V617Fmutation isyet notdetermined,especiallyin patients withadditional presence of ring sideroblasts. The casedescribedabove respondedwell tothetreatmentwith lenalidomide, which is commonly seen in patients with

isolated 5q minus deletion MDS but much less often in patientswithother typesof lowgrade MDS[9,13].Itison the other hand very difficult to compare the response to lenalidomide treatment observed in our patient to similar cases describedin literature. In oneof the largest studies, 190 patients with 5q minus syndrome were described by researchers from the Mayo Hospital. It represented 1% of over24000uniquepatientcytogeneticstudiesperformedat that institution between 1989 and 2009. Among them, 78 patientswiththe5qminus syndromewereidentified.JAK2 V617Fmutationwasshownin5(6.4%)ofthemanddidnot seemtoaffectthephenotypeorprognosis.Only oneof the presented cases had additional feature of RARS, similarto thatwhichisobservedinourpatient[14].Inanotherstudy, Szpurka et al.described146patientswithRARS, 13carried JAK2V617Fmutationsandonlyoneofthemfulfilledcriteria of5qminussyndrome[8].Noseparateinformationconcern- ing theoutcomeofthe patient'streatmentwasgiven.Huls et al. described twopatients with RARS-twithJAK2 V617F mutation, who responded to the treatment with lenalidomide, with one of them achieving complete molecular remission[15].

The effectiveness of lenalidomide has also been con- ﬁrmed inthe presented case. Despite the reduction of the initial doseof 10mg/dto5mgperday duetoneutropenia, the patientbecamecompletelyindependentof bloodtrans- fusions.However,therewasnocompleteeradicationofdel (5)(q13q31)clonenortheclonewithJAKV617Fmutation.In a study reported by Fenaux et al. among patients with classic 5q minus syndrome, cytogenetic remission was observed in 50% of them treated with10mglenalidomide daily.Yet,only25%ofpatientsthatreceivedadoseof5mg perdaywentintocytogeneticremission[11].Atthepresent stage,wearenotabletoﬁndanydifferenceinresponseto the treatment with lenalidomide between our patient and othercaseswithisolated5qminusdeletedMDS.

Authors’ contributions/Wkład autorów

MK, JC – study design, data collection and interpretation, statistical analysis, manuscript preparation, literature search.KL,MP-S–datacollection.AC–manuscriptprepara- tion.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Financial support/Finansowanie

Nonedeclared.

Ethics/Etyka

The work described in this articlehas been carried out in accordance with The Code of Ethics of the World Medical Fig.3–Twolargehypolobatedandonesmaller,bi-nuclear,

immaturemegakaryocytes

acta haematologica polonica47(2016) 29–32

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Association(Declaration of Helsinki)for experimentsinvol- ving humans; EU Directive 2010/63/EU for animal experi- ments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

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