w w w . h t c t . c o m . b r
Hematology, Transfusion and Cell Therapy
Original article
Outcome of hairy cell leukemia patients treated with cladribine – a 10-year single-center
experience in Pakistan
Mohammad Faizan Zahid
a, Mohammad Qasim Mehdi
b, Natasha Ali
c,∗aTempleUniversityHospital,Philadelphia,PA,USA
bMedicalCollege,AgaKhanUniversity,Karachi,Pakistan
cAgaKhanUniversity,Karachi,Pakistan
a r t i c l e i n f o
Articlehistory:
Received3July2018 Accepted13August2018
Availableonline31December2018
Keywords:
Hairycellleukemia Outcome
Cladribine
2-Chlorodeoxyadenosine
a bs t r a c t
Introductionand objective:Hairycellleukemia isanuncommon, indolentB-celllympho- proliferativedisorder.Therapywithcladribine(2-chlorodeoxyadenosine)isabletoinduce completeremission(CR)inthemajorityofpatientsafterasinglecourseoftreatment.We reporttheoutcomesofpatientstreatedatAgaKhanUniversityHospital,Karachi,Pakistan.
Methods:Thiswasaretrospectivereview.Medicalrecordsofpatientswereusedtocollect data.
Results:Atotalof21patientswithhairycellleukemiaweretreatedwithcladribine.All patientsachievedaninitialCR.Fourpatients(19%)requiredhospitalizationandtherapyfor neutropenicfever.Sixpatients(29%)relapsedatamedianof48months.All6patientswere treatedforrelapse,outofwhich4achievedCR,1hadpartialresponseand1hadrefractory disease.Theoverallsurvivalratewas90.5%,withamedianfollow-upof35months.
Conclusion:AsinglecourseofcladribineisabletoinduceCRinavastmajorityofpatients.
Unfortunately,relapseisnotuncommon.Patientswhorelapsecanbesuccessfullyretreated withcladribine.Cladribinehasimpressiveefficacyandafavorableacuteandlong-term toxicityprofilewhenadministeredtopatientswithHCL.
©2018Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Hairycell leukemia isan uncommon, indolent B-celllym- phoproliferativedisorder. OriginallydescribedbyBournocle et al.1 in 1958, it derives its name from the “hair-like”
∗ Correspondingauthorat:DepartmentofPathologyandLaboratoryMedicine/Oncology,TheAgaKhanUniversityHospital,P.OBox3500, StadiumRoad,Karachi74800,Pakistan.
E-mailaddress:natasha.ali@aku.edu(N.Ali).
cytoplasmicprojectionsemergingfromitscellsurfacemem- brane.ThemedianatagediagnosisforHCLrangesfrom41 to55years(muchyoungerthanforotherB-cellmalignancies, suchaschroniclymphocytic leukemia),witha predilection forthe malegender(male tofemaleratio 4:1).2,3 HCL usu- ally presents with splenomegaly with varying degrees of
https://doi.org/10.1016/j.htct.2018.08.006
2531-1379/©2018Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
cytopenia(s)anddiffusebonemarrowinvolvementbyabnor- mallymphocytesexpressingCD11c,CD25,CD103,panB-cell antigens(CD19,CD20and/orCD22)andtartrate-resistantacid phosphatase.4,5
Although indolent, HCL is considered incurable. The therapeuticstrategyforHCLhasevolvedoverdecades.His- torically, not all newly diagnosed patients need treatment upfront.6 For those requiring treatment (usual indications for initiating treatment were cytopenias and/or symp- tomatic splenomegaly), splenectomy was the standard of care7 until1984, when Quesadaet al.8 explored interferon as treatment for HCL, though interferon had disappoint- ing outcomes, with infrequent and short-lived complete responses(CR).9Subsequently,nucleosideanalogs,suchas2- deoxycoformycin(pentostatin)and 2-chlorodeoxyadenosine (cladribine),emergedandarepopulartherapeuticoptionsfor HCLincurrentpractice.Infact,monotherapywithanucle- osideanalog isnow the first-line therapyfor HCLpatients requiringtreatment.7
Cladribineisadeoxyadenosineanalogthatresistsdeam- ination by adenosine deaminase, leading to intracellular accumulationofdeoxygenatedadenosinetriphosphate,caus- ingDNAstrandbreaks,disablingofDNArepairandeventual apoptosis,withlymphoidcellsparticularlyvulnerabletoits moleculareffects.6,10 Althoughcladribineisnotcurative, it hasdemonstratedimpressiveresultsinHCL,achievinglong- lastingCRinamajorityoftreatment-naïvepatientsandhas shownremarkableactivityinrelapseddisease.5–7
Previously Bilwani et al.11 reported the outcomes of patientstreatedatAga KhanUniversity(AKU) from 1990to 2003.Sevenpatientsweretreated,6ofwhom(85.7%)achieved CR,whileonepatienthadrefractorydiseaseanddiedofsepsis.
Wereporttheoutcomeof21HCLpatientsdiagnosedatAKUH andtreatedwithcladribinefrom January2006toDecember 2016.
Patients and methods
Weconductedadescriptive, retrospectivereviewofpatient medicalrecordsatAKU,whichisa560bedtertiarycarecenter inKarachi,Pakistan.TheEthicalReviewCommitteeatAKUH reviewedandapprovedthestudydesign,undertheprotocol number“3771-Pat-ERC-15”.
AllcasesofHCLwere identifiedbytheICD-10 codingof medicalrecords(ICD-10code:C91.4).Onlyadult,treatment- naïvepatientchartswerereviewed.ThediagnosisofHCLwas confirmedbyreviewofdiagnosticbonemarrowmorphology, trephinebiopsyandImmunophenotypingbyflowcytometry.
Standard criteria were used to initiate treatment, define treatment response and re-treatment in patients with a diagnosis of HCL.12,13 Briefly, asymptomatic patients with cytopenia(s) (hemoglobin<10.0g/dL, platelet count<100×109/L and/or absolute neutrophil count
<1.0×109/L) and patients symptomatic from cytopenias and/orsplenomegalywerestartedonanti-HCLtreatment.
CRwasdefinedasthenormalizationofperipheralblood counts and resolution of splenomegaly. Partial response (PR) was defined as ≥50% improvement in the peripheral bloodcountsorsplenomegalycomparedtothatatdiagnosis.
Relapsewasdefinedbythedevelopmentofneworprogres- siveperipheralbloodcytopenias,recurrenceofsplenomegaly ornewclinicalsymptomsattributabletoHCL.
DatawereanalyzedusingtheStatisticalPackageforSocial Sciences20(SPSSInc,Chicago,IL,USA).Categoricalvariables were reported asfrequenciesand percentage distributions, whilemeans,standarddeviationsandmedianswereusedto describecontinuousvariables.
Results
We identified a total of 26 treatment-naïve patients who received treatment for HCL at AKU between January 2006 andDecember2016.Twenty-onepatientsreceivedtreatment withcladribineandwereincludedinthisstudy.Allpatients weremale,withthemedianageatdiagnosisbeing52years (range31–75).Feverwasthemostcommonpresentingsymp- tom(76%patients),followedbyfatigue(43%)andsymptomatic splenomegaly(38%).ThemediandurationfromHCLdiagno- sistotreatmentwithcladribinewas1month(range1–11).The medianfollow-updurationwas35months(range1–182).The baselinecharacteristicsofthesepatientsareshowninTable1.
Cladribinewasgivenasasinglecontinuousintravenous infusion.Eighteenpatients(86%)receivedcladribineatadose of 0.1mg/kg/day over the course of7 days, 1 patient(4%), 0.09mg/kg/dayoverthecourseof7days,and2patients(10%),
Table1–Baselinecharacteristicsof21HCLpatients treatedwithcladribine.
Characteristics n(%)
Malegender 21(100)
Medianage(range),years 52(31–75)
Initialsymptoms
Fever 16(76)
Fatigue 9(43)
Symptomaticsplenomegaly 8(38)
Weightloss 4(19)
Marrowfailure 4(19)a
Other 6(29)b
Peripheralbloodcountsatdiagnosis
Hemoglobin,median(range),g/dL 9.1(6.7–19.4) WBCcount,median(range),×109/L 6.0(0.7–53.1) ANC,median(range),×109/L 0.8(0.02–4.6) Platelets,median(range),×109/L 56(24–185) Medianbonemarrowinfiltrationby
hairycells(range),%
49(14–78)
Diseasetype
ClassicalHCL 20(95)
VariantHCL 1(5)
Mediantimefromdiagnosisto2CdA therapy(range),months
1(0–11) Medianfollowup(range),months 35(1–182) 2CdA:cladribine;ANC:absoluteneutrophilcount;HCL:hairycell leukemia;WBC:whitebloodcell.
a 2patientshadrecurrentinfections,1hadpallorandfatigue,1 hadrecurrentbleeding.
b 3patientshadkneejointpain,2hadgeneralizedbodyaches,1 hadgeneralizedlymphadenopathy.
Table2–Characteristicsof7patientswhorelapsedafterinitialtherapywithcladribine.
Patient number
Timeofrelapse afterinitial cladribine therapy, months
Treatment ofrelapse
Neutropenicfever Outcomeof relapse treatment
Second relapse
Treatmentof secondrelapse
Finaloutcome
1 9 2CdA No CR Yes None Alivewith
activedisease
2a 37 2CdA Yes–A.fumigatus
pneumoniatwice treatedwith amphotericinB
CR CR
3 40 Radiation No CR CR
4 55 2CdA No PR Alivewith
activedisease
5a 74 Interferon Yes–unknown
sourceofinfection
Refractory disease
Died
6 104 2CdA No CR CR
2CdA:cladribine;CR:completeresponse;PR:partialresponse.
a Treatedwith2CdA0.09mg/kg/dayover7days.
0.14mg/kg/day over the course of 5 days. All 21 patients achieved a CR under cladribine therapy. During cladribine therapy,4patients(19%)requiredhospitalizationandtherapy withIVantimicrobialsforneutropenicfever.Twopatientshad Staphylococcusaureusskinsinfections,1patienthadKlebsiella pneumoniaepneumoniaand1patienthadAspergillusfumiga- tuspneumonia.Therewerenodeathsduringorafterinitial therapywithcladribineinthe21patientstreated.
Sixpatients(29%)relapsedatamedianof48months(range 9–104)afterinitialtherapywithcladribine.Theonepatient withvariantHCLdidnotexperiencerelapseduringthefollow- upperiod.Allsixpatientsreceivedtreatmentforrelapse.Only onepatientexperiencedasecondrelapse,butdidnotreceive treatment.Twopatientswereadmittedforneutropenicfever duringtherapyduetosubsequentrelapse(Table2).Onedeath occurredinthe6patientsreceivingtreatmentforrelapsedue tosepticshock.Thetreatmentdetailsandoutcomesareelab- oratedin Table 2. All but 2 patients receivedcladribine at 0.1mg/kg/dayover7days(similartotheinitialtherapy).
Atamedianfollow-upof35months,1patientdied.This patient had a relapse after initial therapy with cladribine (patient5inTable2).Hisdiseasewasrefractorytotherapy forrelapseandhediedofsepticshock.Theoverallsurvivalin ourpatientcohortwas90.5%(Figure1).
Discussion
Thepresentstudyelaboratesthecharacteristicsandoutcomes of21HCLpatientswhoweretreatedwithcladribineatAKU between2006and2016.Theefficacyofcladribineintreating HCLwasfirstreportedbyPiroetal.14in1990.Twelvepatients weretreatedand11(92%)achievedCRwithnorelapses,at amedianfollow-upof16months.Astudyof88patientsby Rosenbergetal.7 reporteda CRof88%.Other studies have alsoreportedveryimpressiveresponsesaftertreatmentwith cladribine,withoverallresponseandCRratesrangingfrom 75to100%and72to98%,respectively.3,5,6,15,16The100%CR ratein ourcohort isin concordancewiththese previously
reportedfigures.Unfortunately,relapseisnotinfrequentin theclinicalcourseofpatients,despitetheexcellentresponse tocladribine.Twenty-ninepercentofthepatientsinourstudy suffered from disease relapse. Somestudies have reported similarrelapserates(26–38%),3,5,17 whileotherstudieshave reportedrelativelyhigherpercentages(58%).7Arecentstudy16 reportedasurprisinglylow(16%)relapserateinHCLpatients treated with cladribine, although one must note that the medianfollow-upinthisstudywasrelativelyshorterthanthe follow-upinstudiesreportinghigherrelapserates,indicating thatrelapsetendstobecomeevidentlaterratherthansooner.
ThisislikelyduetotheindolentnatureofHCL,indicatingthat themalignantclonethatsurvivesinitialtherapywithcladrib- inetakestimetoachieveenoughmasstoproduceanevident relapse.
ApriorexperienceatourcenterhighlightedaCRrateof 85.7%in6patients,witharelapserateof50%.11Othercen- tersinPakistanhavealsoreportedoutcomesinHCLtreated withcladribine.Buttaretal.,15reportedaCRrateof82.3%in 17patientstreatedwithcladribineintheircohortof22HCL patients, withasurprisinglylow(5.8%)relapserate. Jameel etal.18reportedCRwithnorelapsein2patientstreatedwith cladribineintheircohortof7HCLpatients.
Themostnotabletoxicityassociatedwithcladribinether- apyismyelosuppressionleadingtosusceptibilitytoinfectious complications. The incidence of neutropenic fever during first-linecladribinetherapyinourcohortwas19%,whichis lowerincomparisontothereported26–50%incidenceinprior studies.4,6,19Differentdosingroutesandschedulesofcladrib- inehavebeenstudiedinanattempttomodifytheincidence and severity ofneutropenia andtreatment-related toxicity;
however,thesehaveshowncomparableoutcomesintermsof treatmentresponseandtoxicity.6Whileonewouldthinkthat adjunctuse offilgrastimmay helpminimize theincidence ofneutropenic fever,aphase IIstudy20 showedno clinical benefitin terms ofincidenceofneutropenic fever and the need forhospitalization or longerhospitalization duration, despiteanincreasedabsoluteneutrophilcount(ANC)nadir anddecreasedtimetoANCrecoveryaftercladribinetherapy.
Kaplan−Meier survival estimate
Overall Survival =90.5% (19/21) 1.00
0.75
0.50
0.25
0.00
0 20 40 60 80 100 120 140 160 180 200
0 (0) (0)
(0)
(2) 5 5 2
21 Number at risk
Survivor function Outcome Duration of Survival in “Months”
Proportion of Survival function
Figure1–Overallsurvivalinn=21patients.Theoverallresponserate(ORR)wasdefinedastheproportionofpatients achievingabestclinicalresponse.Overallsurvivalrate(OS)wasdefinedastimewithbeginningtilldeath;patientsstillalive atthetimeofgatheringthedatawerecensoredatthedateofthelastpresentedmedicalrecord.Descriptiveanalyseswere appliedtomeasurethespecifictreatmentpatternsandORR.andoverallsurvivalrateweredescriptivelyanalyzedusing Kaplan–Meiersurvivalmethodsalongwiththelog-ranktesttechniqueandBreslowtestforstatisticalsignificance.Data wassetata95%confidenceintervalata5%levelofsignificance.
Inthe case ofrelapseddisease (specifically forrelapses occurring between 2 and 5 years after initial therapy), chemoimmunotherapywith rituximaband cladribineis an effectiveoption,21withtherituximabandcladribinecombina- tionyieldingveryimpressiveCRrates(withlongerlastingCR incomparisontopriorcladribinemonotherapy)andfailure- freeandoverallsurvival.22Unfortunately,wearesituatedin a developing country and due toits heavy costs and lim- itedavailability,23rituximabcouldnotbeusedinanyofthe patientsinourcohort.
To conclude, cladribine demonstrates highly impressive activityagainstHCL.Althoughourstudyshowsaremarkable 100%CRrate tofirst-linecladribinetherapy witharelapse rateofjust29%,ourfindingsarelimitedbyasmallnumber ofpatientsinourcohortandwithashortmedianfollow-up periodincomparisontootherpublishedstudies.Itispossi- blethattherelapserateinourstudyisunderestimatedbythe shortfollow-upduration.Thiswarrantslargerstudies with extensivefollow-upperiodsintreatedpatients toascertain howeffectivecladribineisinHCL,notjustupfrontininducing CR,butalsoinhowlongtheCRlasts.Multicentercollabora- tionsandprospectivestudiesarethebestwayofachieving thisgoaland providinginsightinto maximizingthebenefit derivedfromcladribinetherapy.
Conflicts of interest
Theauthorsdeclarenoconflictsofinterest.
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