Rituximab-associated progressive multifocal leukoencephalopathy after a single cycle of R-CHOP for T-cell/histiocyte-rich large B-cell lymphoma

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Case report/ Kazuistyka

Rituximab-associated progressive multifocal

leukoencephalopathy after a single cycle of R-CHOP for T-cell/histiocyte-rich large B-cell lymphoma

Moa Forssberg

^1,2

, Monika Klimkowska

³

, Maciej Machaczka

^1,4,

*

1Hematology Center Karolinska and Department of Medicine at Huddinge, Karolinska Institutet, Karolinska UniversityHospitalHuddinge,Stockholm,Sweden

2DepartmentofMedicine,NyköpingsHospital,Nyköping,Sweden

3DepartmentofClinicalPathologyandCytology,KarolinskaUniversityHospital,Stockholm,Sweden

4MedicalFaculty,UniversityofRzeszow,Rzeszow,Poland

article info

Articlehistory:

Received:17.07.2017 Accepted:08.08.2017 Availableonline:12.08.2017

Keywords:

JohnCunninghampolyomavirus

Non-Hodgkinlymphoma

Progressivemultifocal leukoencephalopathy

Rituximab

abstract

Progressivemultifocalleukoencephalopathy(PML)isa diseaseofimmunocompromised patients caused by reactivation of the John Cunningham polyomavirus (JCV).

A monoclonal anti-CD20 antibody rituximab is widely used as an important part of therapyforB-cellnon-Hodgkinlymphomasandvariousautoimmunediseases.Itisnot fullyexplainedhowrituximabreactivatesJCV.

In thisreport,we presentthe caseofa 61-year-oldman with T-cell/histiocyte-rich largeB-celllymphomawhowastreatedwithR-CHOPandintrathecalmethotrexate.Two weeksafterthefirstR-CHOPcoursehedevelopeddysarthria,diplopia,anddisturbances inmotorcoordination.Based onCT/MRI resultsshowing3cm2cmlarge hypodense whitematterlesioninleftcerebellarhemisphere,anddetectionofJCVinthecerebros- pinalfluid(14300viralcopies/mL), thepatient wasdiagnosedwithPML. Despitetreat- ment attempt with cidofovirand IVIG,the patient’s neurological status continued to worsen.He developed progressive motorneuron deficits but retained intact cognitive functions.Thepatientdeceasednearlythreemonthsafteronsetofrituximabtreatment.

Rituximabisamilestoneintreatmentofmanyhematologicalandautoimmunedisea- ses.Consideringhowwidespreadhastheuse ofrituximabbecome,the overallriskof developing PML isrelatively low. Nevertheless, sincethe endof1990s several reports werepublishedonPMLdevelopmentinassociationwithusageofrituximab.Theauthors wouldliketoemphasizethatalthoughthetotalriskofPMLoccurrenceinpatientstrea- tedwithrituximabislow,itisimportantthatphysiciansadministratingrituximabthe- rapyareawareofthisseriouscomplication.

*Correspondingauthorat:HematologyCenterKarolinska,M54,KarolinskaUniversityHospitalHuddinge,SE-14186Stockholm,Sweden.

E-mailaddress:maciej.machaczka@ki.se(M.Machaczka).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journalhomepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2017.08.003

zo.o.Allrightsreserved.

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Introduction

Progressivemultifocalleukoencephalopathy(PML)isarare, albeitoftenfatal,centralnervoussystem(CNS)demyelinat- ing disorder caused by reactivation of a latent John Cun- ningham polyomavirus (JCV) [1–3]. The disease was ﬁrst describedin1950sbyaSwedishneuropathologistKarl-Erik Åströmasacomplicationoccurringinpatientswithchronic lymphocytic leukemia (CLL) and Hodgkin lymphoma [1].

Primary JCV infection is usually asymptomatic and occurs inschoolage.Afterthat,thevirusislatentin70–90%ofthe adult population [2]. Latent JCV can be found in kidney epithelial cells, CD34+ hematopoietic cells and possibly early B-cell precursors [4]. It was proposed that hemato- poieticstemcells,whichcarryJCV,canactasTrojanhorses and thus enablethe virus to pass the blood-brain barrier.

During the active phase of the PML, JCV particles are replicated in oligodendrocytes. The virus induces then destructionofmyelinsheathandcelldeath[2].

PML is usually associated with a decreased T-cell response,anditwasveryinfrequent diseaseuntilthetime of HIV-epidemics in the 1980s [5]. The incidence of PML increased50timesbetween1979and1994,but thenit has decreased gradually due to the introduction of antiviral treatmentofHIVinfection.

TherateofPMLprogressionmayinitiallybeslow,making the disease difﬁcult to diagnose. Patients present gradual worsening of cognitive functions, speechand vision [1, 2].

Symptomsbecomemoreprominentwithtime,andpatients develop motor neuron deficits and ataxia. With disease progression,neurologicdeficitsacceleratewithoccurrenceof dementia, blindness, pareses, followed by coma and decease. PML diagnosis is confirmed by JCV detection by polymerasechainreaction(PCR)incerebrospinalfluid(CSF) [2].Magnetic resonanceimaging (MRI)demonstrates typical pictures of multifocal asymmetrical white matter lesions, locatedincerebralhemispheresandlessoftenincerebellum or brain stem. Diagnosis can also be obtained through biopsy, with histopathological analysis of the tissue and complementaryimmunohistochemicalstains(TableI)[2,6].

Rituximabisa monoclonalanti-CD20antibody usedfor treatment of many types of CD20-positive non-Hodgkin lymphomas(NHLs)including CLL [2].Itisalsosuccessfully usedinautoimmunediseases,includingrheumatoidarthri- tis(RA)andsystemiclupuserythematosus(SLE).Expression ofCD20antigenisobservedonbothhealthyandmalignant

B-cells, but not on hematopoietic stem cells. Rituximab produces arapidand almost complete clearanceofB-cells from peripheral blood, with the effect persisting up to 12 monthsaftercompletedtherapy[7].

Case presentation

A 61-year-old previously healthy Swedish man with a periodical alcoholabuse, presented witha three-months- longhistoryofdiffuseabdominalpain,tirednessandweight loss. Computed tomography (CT) imaging revealedabdom- inalandthoraciclymphadenopathyatmultiplesitesaswell as prominent splenomegaly. Lymph node biopsy disclosed inﬁltration of T-cell/histiocyte-rich large B-cell lymphoma.

The patientwas scheduled for 6courses ofR-CHOP (rituximab,cyclophosphamide,doxorubicin,vincristine,predniso- lone) at 14-day intervals and intrathecal methotrexate. He was also found to have undergone hepatitis B, and treat- mentwithlamivudin(Zefﬁx^TM)wasinitiated.

Two weeks afterthe firstR-CHOP-14 coursethe patient came for a follow-up visit and evaluation before the next treatment course. He presented dysarthria and reported experiencing diplopia, disturbances in motor coordination and loss of large muscle group strength for several days before. Lymphomatherapywas postponedand thepatient wasadmittedtothedepartmentofneurology.BrainCTwas performed on the same day,and revealedthe presence of 3cm2cm large hypodense white matter lesion in left cerebellar hemisphere as well as numerous nonspecific white matter lesions.These findings were later confirmed byMRIand tentativeradiologicaldiagnosiswaslymphoma or PML or low grade tumor. Lumbar puncture was performed,withextensiveexaminationforpotentialinfectious agents. Theinitialassessment suggested CNSinvolvement bylymphomasinceonlyonemajorlesionwasdetectedand itslocationwasatypicalforPML.

Results of JCV-PCR analysis in the CSF sample were received3weeksafterinitiationoftheﬁrstR-CHOP-14course, demonstrating 14300viral copies/mL (Fig. 1). Other assays failedtorevealanybacteria,virusorfungalinfection.Abrain biopsy was discussed with neurosurgeons, but they advised againstbiopsyasclearsignsofPMLwerealreadyidentiﬁed.

The patient’s clinical status has gradually improved, and 4 weeks after R-CHOP treatment onset he was in neurologically nearly normal condition apart from minor problemswithhisbodybalance.Atthattime,thenumberof

TableI–Diagnosticsignsandsymptomsofprogressivemultifocalleukoencephalopathy

Clinicalfindings Rapidlyprogressingneurologicaldeficitsandworseningofmotorneuron functions;usuallycognitivedefectandimpairedfieldofvision

Histopathologyofbraintissue(ifbiopsyperformed) Characteristichistopathologicalﬁndings[7]:

Demyelinisation

Bizarreastrocytes

Enlargedoligodendroglialcellnuclei

JCVdemonstratedbyimmunohistochemicalstainorinelectronmicroscopy

Laboratoryﬁndings DetectionofJCVinCSFbymeansofPCR

Radiologicalﬁndings MRIorCT(withcontrast)showsmultifocalwhitematterlesionswithnoor onlydiscretecontrastenhancement

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JCVcopiesinCSFclearlydecreasedto3400copies/mL(Fig.1).

NewbrainMRIscanstakenonthesamedayrevealedthough anewband-likelesionwithcontrastenhancementinproxi- mity to the already known lesion in the left cerebellum hemisphere.

Four weeks after onset of the ﬁrst R-CHOP course the patient received another one, but this time only CHOP without rituximab due to suspected PML. No intrathecal methotrexate was given. He was discharged home, with planned follow-upvisit atthe outpatientclinic two weeks later. However, he did not show up to the appointment, anddidnotanswerphonecalls.

A couple of days later he presented to the emergency department with newly appearing neurological symptoms and inability towalk. Clinical examinationrevealeddysar- thria, decreased strength in large muscle groups and decreasedﬁnemotorneuronfunctionontheleftside,with positive Babinski sign on the left, involuntary movements andinabilitytostandstill.

Acute MRI of the brain was ordered, with suspicion of rapidPML progression. That was confirmed on MRIscans, with new lesions appearing in the upper part of medulla oblongataand pons.Thepreviouslydescribed biglesion in cerebellum has further increased in size, with apparent cysticdegenerationand necrosis. Newlesionsappeared in the right parietal lobe. Multiple plaque-like white matter lesions were still visible. Contrast enhancement was very discrete,a feature characteristicforthe PML (Fig. 2). Radi- ological and clinical findings pointed clearly to PML, with progressionsincethefirstdiagnosis.

Thepatienthasreceivedcidofovir(5mg/kgi.v.)twice,as wellastwodosesofintravenousimmunoglobulin(IVIG).At thetimeofhospitaladmissionnumberofJCVcopiesinCSF increased to 22200copies/mL (i.e., approx. 7 weeks after initiation of R-CHOP therapy) (Fig. 1). CT scans of thorax

and abdomen revealed slight reduction in size of the enlargedlymphnodesascomparedtothestatusbeforethe ﬁrstR-CHOPcourse.FearingthatPMLcanfurtherprogress, a decision was made to abstain from intensive immuno- chemotherapy, and the patient was given a single dose intravenousvincristine(Oncovin^TM).

Unfortunately, thepatient’s clinicalconditioncontinued toworsen.Hedevelopedprogressive motorneurondeficits butretainedintactcognitivefunctions.Thepatientdemon- strated difficultiesinswallowing,wasunabletospeak, and experienced significant problems due tomucus accumula- tion in the respiratory tract in course of an infection for which he was given broad spectrum antibiotics. A total parenteral nutrition was started as he could not swallow withouttheriskofaspirationintoairways.

Three monthsafter thefirst R-CHOP coursethe discus- sionwas commencedon thepossibility oftherapywithT- cells specific againstJCV and patient’s siblings wereHLA- typed.Moreover, experimentalusageofinterleukin7(IL-7) inpatient wasdiscussed.However, this wasconsidered as pointless asthepatient’slymphomawas notinremission, and more intensive treatment would be required which would furtheraggravate the patient’s PML. JCVspecificT- celltherapywasalsoabandonedasthepatient’sstatuswas deemednotcompatiblewiththestudyprerequisites,which among others included performing a positron emission tomographybeforeinfusionofT-cells.Thepatient’sneuro- logical status continued to worsen, and he deceased nearly three months afterthe administration ofrituximab treatment.

Duringthecourseofpatient’scare,areportwassentto the Swedish Medical Products Agency (Läkemedelsverket) concerning PML as a suspected adverse event of therapy withMabThera^TM(rituximab),andanoticewassenttothe drug producer, a pharmaceutical company F. Hoffman-La 0

5000 10000 15000 20000 25000

0 1 2 3 4 5 6 7 8

Number of JCV copies/mL

Weeks aer onset of R-CHOP

Fig.1–Changesinpatient’sJCVlevelsincerebrospinalfluidsamplesovertime

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Roche Ltd. The Agency replied that a relationship can be implied between usage of the medical agent MabThera^TM and the adverse event of PML occurrence. The Agency pointed out that cyclophosphamide, doxorubicin and vincristine shouldalsobe perceivedas other potentialcausa- tiveagents.

Discussion

Monoclonal antibodies have revolutionized treatment of multiple hematological and autoimmune diseases and are currentlyinwidespreaduse.In Sweden,withapopulation of approx. 10 million people, almost 2000 new cases of malignant lymphoma are diagnosed each year in adults, mostoftheserepresentingB-cellNHL withCD20-positivity.

Ofthose,themostcommondiagnosesincludediffuselarge B-cell lymphoma, follicular lymphoma and CLL, which constitutetwo-thirdsofallnewlydiagnosedlymphomas.

PML as a complication of rituximab therapy was ﬁrst notedintheendof1990s[2].Between1997and2008only,57 casesofrituximab-associatedPMLwerereportedworldwide, including 52 patients with B-cell NHL,2 patients withSLE, one patient with RA, one patient with idiopathic autoim- munepancytopenia,andonepatientwithidiopathicthrom-

bocytopenicpurpura(ITP)[8]. Tothebestofourknowledge, only one case of rituximab-associated PML in NHL was reported up till now in Sweden [9]. The case concerned afemalepatientwithatransformedhigh-gradeB-cellNHL.

However, we were not able to identify any Swedish report on rituximab-associated PML in patient withnewly diagnosed B-NHL who developed PML after just a single courseofrituximab.Itisveryunusualwithsuchshorttime betweenadministrationofrituximabandtheonsetofPML, but based on our case, apparently possible. According to the study by Carson et al., median time from the ﬁrst rituximab dose todiagnosis ofPMLwas 16 months(range 1–90 months) [8]. Noteworthy, median time between the last doseofrituximab andsymptomaticJCVviralreactiva- tion was 5.5 months. On average, six doses of rituximab (range1–28doses)wereadministeredbeforePMLdiagnosis was made, and a median survival time following PML diagnosiswas2months(range0.4–122months)[8].

Possible factors predisposing to a more rapid PML progression include lower CD4+ count (<200cells/mL; ref.:

500–1600) and onset of PML signs shortly after the last administered rituximabdose (within 3months) [8, 10]. All the patients who developed PML within 3 months from rituximab infusiondied,ascompared to84%patients who developed PMLmorethan3monthsafterthelastobtained Fig.2–MRIscansofpatient’sbrainwithwidespreadPMLlesionsinleftcerebellarhemisphere,medullaoblongata,andpons

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rituximabdose.Inthe presentcase,the CD4+cell number was not assessed. However, the correlation between a development of PML soon after rituximab infusion and arapidprogressionofthediseasecouldbeobserved.

Currently, there isno effective treatment ofPML avail- able [11]. Cytarabine has been tried in most cases but studies on HIV-positive patients with PML did not reveal any beneﬁcial effect of neither intravenous or intrathecal cytarabine on survival [12, 13]. However, several reports demonstrateda certain improvement ofPMLin HIV-negative patients followingintrathecal administrationof cytarabine [14]. Other reported treatment attempts included administrationofmirtazapine,cidofovir,donorlymphocyte infusion (DLI), IVIG and risperidone [2]. The presented patient unfortunately did not experience any beneﬁcial effectofcidofovirorIVIG.

Mortalityinrituximab-associatedPMLinpatientstreated forNHLisveryhigh[2,11,15].Inthepreviouslymentioned study, Carsonet al.reported that90% patients died dueto PML, and all the survivors had persistent neurological symptoms [8]. A slightly better survival was observed in patientswhodevelopedPMLafterstemcelltransplantation, eitherautologousorallogeneic[8,16].Onecanspeculatethat itmay beduetothefactthat thetransplantedpatient has abetterabilitytorecoverimmunesysteminthelongrun.

RituximabasatriggerofPML

Pathophysiological mechanism behind correlation of ritux- imabtreatmentandPMLisnotwellunderstood.Onetheory suggeststhatdepletionofmatureB-cellsfollowingrituximab administration facilitates expansion of pre-B-cells infected withJCV [2]. Studies have shown thatB-cell reconstitution afterrituximabtherapycausesadisproportionalincreasein immatureB-cells[7,17]buttheexplanationtothisphenom- enonisprobablymorecomplex.

PatientswithITPwhohad beenadministered rituximab hadchangesinT-cellactivityfollowingB-celldepletion[18].

A study done in patients with multiple sclerosis (MS) showed decrease of the total T-cell count in CSF up to 6monthsafterrituximabadministration[19].Otherstudies demonstratedhoweverquiteanoppositeeffectofrituximab onT-cellpopulation[20].

Bennett proposed a hypothesis on the role of bone marrow in rituximab-associated PML [4]. His analysis of bone marrow samples showed that all 5 specimens obtained from patients with lymphoma and PML were positiveforJCV,comparedtoonly2outof86bonemarrow samples from patients who had lymphoma but not PML.

Indeed,JCVremainsinlatentforminCD34+hematopoietic stem cells and most likely also in immature B-cells.

Chemotherapymobilizesstemcellsfrombonemarrowand induces quantitative reduction in the T-cell population.

According to Bennett’s theory rituximab diminishes then thequalitativeT-cellresponse,andprogenitorcellsbearing latentJCVproliferatefollowing the overallB-cell depletion [4]. However, the hypothesis was based on retrospective ﬁndings,andwasneverlaboratoryveriﬁed.

Occurrence of PML was also observed in untreated patientswithlymphomas, it istherefore difﬁculttoassess

how much does rituximab itself increase the risk of the disease.AnItalianstudyof976patientswithNHL demon- strated a signiﬁcantly higher risk of developing PML in subjects treatedwithrituximab[21].Itiscurrentlydifﬁcult to perform similar studies, as rituximab is a part of standard therapy protocols in B-cell NHLs. Besides, PML occurred after rituximab therapy even in patients not havingalymphoma,e.g.insubjectswithSLEorRA.

Another issue is the extent to which chemotherapy included in lymphoma treating protocols contributes to immunomodulation and PMLdevelopment [11, 15]. Carson et al.pointedoutthatallpatients whodevelopedPMLhad previously received treatments affecting the immune sys- tem, including alkylating agents, corticosteroids, purine analogs or immunomodulators for prevention of graft- versus-hostdisease (GvHD)afterallogeneic stemcell trans- plantation [8]. Some of these patients had though been treatedwithrituximabandsteroidsbutnotcytotoxicdrugs.

RituximabseemsthereforetoinducePMLevenwithoutthe contextofchemotherapy.

The present patient had not been treated with che- motherapyuntiladministrationofR-CHOP,buthehadbeen given high dose cortisonepretreatment for3 weeks while awaiting deﬁnitive histopathological conﬁrmation of NHL.

In his case we could not identify an underlying defect in cellular immunity. He developed neurological symptoms already 10 days after receiving ﬁrst R-CHOP cycle, which points to an unusually rapid disease onset. He improved spontaneously after the ﬁrst PML symptoms and 14 days later he was in an apparently normal clinical condition, which is different from a known natural PML course. At thattimeeventhenumberofJCVcopiesdecreasedsponta- neouslyinhisCSFsample(Fig.1).

The patient developed next episode of the disease approx.2–3weeksfollowing the second CHOP course(this time without rituximab), and JCV titer in CSF was even higher than during the ﬁrst symptomatic episode. It is unclear why he initially improved but it can be assumed thatCHOPtreatmentwithoutrituximabcontributedtoPML reactivation.Itwouldbe interestingtoknowifthe patient had lowtitersofCD4+ cellsfromthebeginning,and,if so, was the lymphoma that caused this phenomenon or was there another causative factor. However, a routine infec- tiouswork-upwasperformedatthetimeofNHLdiagnosis, andthepatientwasfoundtobeHIV-negative.

OtheragentsthatmaycausePML

Development of PML can also be induced by monoclonal antibodiesotherthanrituximab[2,22–25].

Natalizumab is an antibodybinding alfa4-integrin on T- cellsand itissuccessfullyusedintherapyofrefractoryMS [2, 22]. The ﬁrst ever case of natalizumab-associated PML wasreported in2005,andtheagent wasremovedfromthe market. Currently, natalizumab is again in use but only understrictcontrolforoccurrenceofanyPML-symptoms[23, 24].Mortalityinnatalizumab-inducedPMLismarkedlylower ascomparedtocaseswhererituximabwasthetrigger[2,22].

OnemayspeculateifitisbecauseMSpatientsareingeneral moreimmunocompetentthanpatientswithlymphomas.

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Efalizumab is an anti-CD11 monoclonal antibody used in treatment of plaque psoriasis. Several cases of efalizumab- associatedPMLwerereportedandasaresulttheantibodywas retrievedfrommarketin2009andisnolongerinuse[2,23].

OtherdrugsthatcanpossiblyinducePMLincludepotent immunosuppressive agents such as tacrolimus or cyclos- porine[25].

Conclusions

Rituximabisamilestoneintreatmentofmanyhematologi- caland autoimmune diseases.Nevertheless, sincetheend of 1990s several reports were published on PML development in association with usage of this antibody. Risk of PMLhasincreasedwith rituximabtherapybut considering how widespread has the use of rituximab become, the overallriskofdevelopingPMLisrelativelylow[2,8].

Furtherstudiesarewarrantedforabetterunderstanding ofrituximabinteractionwithT-cellsanditsimmunomodu- latorymechanisms.Ideally,astrategyshouldbeelaborated toidentify atan early stagepatients atrisk ofdeveloping PML. Measuring the CD4+ cell count at initiation ofritux- imabtreatmentcan beofvalue.During ongoing rituximab therapyacloseclinical follow-upiscrucialso astodetect anydeveloping neurologicalsigns orsymptoms which can pointtoPML,andthediseaseshouldalwaysbeincludedin differentialdiagnosis.

InthedescribedcaseclinicalsuspicionofPMLwasmade earlyaftersymptoms onset,and becauseofthis rituximab was withdrawn from therapy protocol. This however did not improve patient’s outcome, resulting in decease 3monthsafterPMLsymptomonset.

Authors’ contributions/ Wkład autorów

MF– assisted inreport design, gathered and analyzedthe clinical and laboratory data, performed the literature search, drafted the manuscript; MK – gathered and analyzed the laboratory data, drafted the manuscript; MM – planned the report design, gathered and analyzed the clinical and laboratory data, performed the literature search,draftedthemanuscript.

Conﬂict of interest/ Konﬂikt interesu

Nonedeclared.

Financial support/ Finansowanie

Nonedeclared.

Ethics/ Etyka

Thework described inthis article has been carried out in accordancewith The Code ofEthics ofthe World Medical

Association (DeclarationofHelsinki)forexperimentsinvol- ving humans; EU Directive 2010/63/EU for animal experi- ments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

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