Clinical aspects of prophylaxis and treatment of CNS disease in lymphoma patients

Review/Praca poglądowa

Clinical aspects of prophylaxis and treatment of CNS disease in lymphoma patients

Małgorzata Krawczyk-Kuliś *, Sławomira Kyrcz-Krzemień

School of Medicine in Katowice, Medical University of Silesia, Department of Hematology and Bone Marrow Transplantation,Poland

Centralnervous system(CNS)involvement inlymphoproli- ferative tumors is considered a negative prognostic factor influencingshortenedsurvival[1–3].Thepathophysiologyof leukemic/lymphoma infiltrations in the CNS has not been sufficientlyelucidated,despiteprogressinbasicresearch.It is believedthat leukemia cells can migrate from the skull bonemarrowinto thesubarachnoidspacethroughbridging veinsandreachthecerebrospinalfluidthroughthechoroid

plexus, then penetrate into the brain tissue through the capillariesof the brain orinfiltratemeninges throughskull bone damage. Leukemia/lymphoma cells can also pass through nerve roots and occupy the subarachnoid space through nerve openings. Tumor masses can move into the epidural space through intervertebral spaces. Finally, the leukemic/lymphoma cells can infiltrate the CNS both throughbleeding(ifthereareblastsintheblood)andinan article info

Articlehistory:

Received:04.09.2014 Accepted:28.11.2014 Availableonline:05.12.2014

Keywords:

 Lymphoma

 Treatmentandpreventionof centralnervoussystem involvement

 Intrathecaltriplechemotherapy

 Liposomalcytarabine

 Radiotherapy

abstract

Currently,infiltrationof thecentralnervous system (CNS)inlymphoma patientsisan unfavorableprognosticfactorcontributingtoshortersurvival.Inthesecases,immunophe- notypisationhasbecomeimportantforevaluationofcerebrospinalfluidcells–especially intheso-called‘‘subclinicalformofCNSinvolvement.’’Othermethodsusedinthesecases includediagnosticimagingandcytologicalexamination.Therapyprotocols,includingthe prophylacticintrathecal administrationofdrugs, are usedfor treatment ofsome lymp- homasubtypes characterizedbyfrequentCNSinfiltrations,eitheratdiagnosisorduring relapse(lymphoblasticlymphoma/acutelymphoblasticleukemia,Burkitt'slymphoma,dif- fuselargeBcelllymphoma,andlymphomainHIV+patients).Incurrentclinicalpractice, prophylacticirradiationoftheCNSisusedlessfrequently.Inadditiontolocaltreatmentof the CNS, systemic therapy with high-dose methotrexate and cytosine arabinoside is recommended.Theintrathecal treatmentofchoice isliposomal cytosinearabinoside or tripletherapy:methotrexate,cytarabine,anddexamethasone.Becauseliposomalcytosine arabinosidehassustainedactivityintheCSFfor2weeks,thenumberofintrathecaladmi- nistrationsnecessarytoeradicateCNSinfiltrationsmaybereduced.

Thispapersummarizesourcurrentfindingsandrecommendationsontheprevention andtreatmentofCNSinvolvementinlymphomapatients.

©2015PolskieTowarzystwoHematologówiTransfuzjologów,InstytutHematologiii Transfuzjologii.PublishedbyElsevierUrban&PartnerSp.zo.o.Allrightsreserved.

*Correspondingauthorat:ul.Dabrowskiego25,40-032Katowice,Poland.Tel.:+48322562858;fax:+48322554985.

E-mailaddress:kulism@interia.pl(M.Krawczyk-Kuliś).

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journal homepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2014.11.003

0001-5814/©2015PolskieTowarzystwoHematologówiTransfuzjologów,InstytutHematologiiiTransfuzjologii.PublishedbyElsevier Urban&PartnerSp.zo.o.Allrightsreserved.

iatrogenic way, during the traumatic diagnostic lumbar puncture. Symptomatologyof changesis diverse, from the absence of clinical manifestations, when CNS involvement is detected incidentally during diagnostic puncture, to presentationofsymptomssuchasCNSbleeding,neurologi- caldeficits,orsymptomsofspinalcordcompression.

Diagnostic methods used in cases of suspicion of CNS infiltration

CNS involvement ismost commonly diagnosedin the pre- senceof clinicalsymptoms.Theseincludeheadaches,beha- vioraldisorders,cranialor peripheralnervepalsies,balance impairments,seizures,andcoma.Fordiagnosticpurposes,in addition to neurological examination, medical imaging is used,including:computedtomography,magneticresonance, andmorerecently,positronemissiontomographycombined with computed tomography (FDG PET/CT). In each case of suspected CNS involvement, cerebrospinal fluid cytological assessmentis recommended.Although this type of assess- mentisahighly specific method,it maygivefalse-negative results in 20–60% of cases. Complementary methods to cytology include immunophenotyping and cytogenetic and molecular techniques [4–6]. Immunophenotyping of cere- brospinal fluid cells hasits methodological limitations and requirespropertechniqueof performanceandanalysis.The useof11-parameterflowcytometryinaprospectiveevalua- tion of CNS involvement in patients with aggressive non- HodgkinB-celllymphomaledtoanearlyfourfoldincreasein detection[7].Detection intheCSF of morethan 20%of the cellscorrespondingtothephenotypeofBorTcelltumorcells isconsideredevidenceofCNSinfiltration[6].

Cerebrospinal fluid analysis with immunophenotypic characterizationof cells isparticularlyuseful inprevention of CNS infiltration in diffuse large B-cell lymphoma and otherprecursorB-cell lymphoidtumors withincreasedrisk of CNS involvement [8]. Confirmation of the presence of

tumor cells inthe cerebrospinal fluidcanalso beobtained withtheuseofgeneticanalysismethodssuchasFISH.The presence of t(14;18), t(8;14), and DNA hyperdiploidy was found in cases of transformed follicular lymphoma and lymphoblasticlymphoma.Inthesecases,thecoexistenceof BCL6andc-MYCrearrangementwasfound[6].

There have also been reports about the possibility of usingbiomoleculartests(suchasPCR)incerebrospinalfluid analysis. Identification of microRNA (MiR21, miR-19, and miR92a)byRT-PCRwith95.7%sensitivityand96.7%specifi- city is considered as a new, noninvasive biomarker for diagnosis of primary central nervous system lymphoma (PCNSL)[9].

Progress in basic science, the implementation of new diagnosticmethodstoeverydayclinicalpractice,andadjust- ment of therapy in the treatment of leukemia/lymphoma justify the need to analyze the methods of diagnosis and treatment for CNSinvolvement, as well asthe previously usedmethodsofprevention.

The incidence of CNS infiltration is differentdepending onthesubtypeof lymphoproliferativetumor.Suchchanges are mostfrequentlyobservedinacutelymphoblasticleuke- miaand other aggressivelymphomas,and leastfrequently in indolent lymphomas and chronic lymphocytic leukemia (TableI).

Prevention and treatment of CNS infiltration in acute lymphoblastic leukemia in adults

Treatment of acutelymphoblastic leukemia(ALL) inadults can achievecomplete remission (CR) inmore than 74–92%

ofthepatientswith5-yearoverallsurvivalinapproximately 37%[10–14].Inrecentyears,manyresearchgroupsusedALL treatment protocols taking into account the so-called risk factors inpatients.Oneof the factorswithpoorprognostic impact is CNS involvement both at diagnosis and during treatment[15].CNSinvolvementat diagnosisisreportedin

TableI–Incidenceofinfiltratesinthecentralnervoussystemincertaintypesoflymphoproliferativeneoplasms(datafrom variouspublications,inthecitedliterature)

Diagnosis Theincidence

atdiagnosis

Theincidenceatrelapse

Acutelymphoblasticleukemia 5% Upto50%intheabsenceofprevention

Approximately5–6%,despiteprevention

Lymphoblasticlymphoma 2–7% 4.3%(withCHOPtreatmentandMtx12mg

ITprophylaxis)

Burkitt'slymphoma App.7% 24.4%(with:CHOP,Mtx12mg6–8applications

IT,MTX2.0g/m²IV) DiffuselargeB-celllymphoma Oftensubclinical,

theincidence difficulttodetermine

App.5%(2.1–10.4%)

AggressivelymphomasinHIV patients(DLBCL,Burkitt's, plasmoblastic,anaplastic)

3–15% 4–5%despiteroutineprophylaxis

Mantlecelllymphoma 0.9% 4.1%–inthecourseofthedisease(noroutine

prophylaxis)

Chroniclymphocyticleukemia Occasionally Occasionally,usuallyatprogression,Richter's transformation(lowfrequency)

approximately 3–7% of the patients. Risk factors for the occurrence of CNS leukemia are T-cell subtype, ‘‘mature B cells’’ phenotype, high leukocytosis in peripheral blood, mediastinal lesions, and elevated levels of serum LDH (1, www.nccn.org, NCCN Clinical Practice Guidelines in Oncology, Acute Lymphoblastic Leukemia, Version I.2014, accessedon 25.11.2014).The published analysisof 380 ALL patients treated in prospective studies of the Polish Adult LeukemiaGroup (PALG) showed that primaryCNSinvolve- ment was present in 5.3% of the patients [16]. In the absence of CNS-directed prophylaxis, CNS relapses may affect even 30–50% of patients and the five-year survival rate is less than 10% [17, 18]. For manyyears, an integral partoftheprogramsofmultidrugintensiveALLchemother- apy inadults has been CNSinvolvement prophylaxis.It is usedregardlessofALLsubtype,bothinTandBcelltumors, inPhiladelphia/BCR-ABLpositiveleukemia,andinPhiladel- phia/BCR-ABL negative leukemia, regardless of the age of the patient [19]. Prophylaxis involves administration of cytotoxicdrugsdirectlyintothecerebrospinalfluid,intrave- nous high doses of CNS-penetrating cytosine arabinoside and methotrexate, corticosteroids, and skull base irradia- tion.Asaresult,theCNSrelapserateinALLislowanditis estimated at about 5–9% [16]. In everydayclinical practice, preventionof CNSinfiltrationinALLhasbecome aroutine practice. Prophylaxis is applied in all stages of treatment, during the induction, consolidation, and during mainte- nance therapy. It is also recommended in patients after bone marrow transplantation, mainly after autologous hematopoietic cell transplantation (www.palg.pl, Grupy Robocze,dsleczeniaostrejbiałaczkilimfoblastycznej,PALG ALL6 protokół, accessed on 25.11.2014). Published data from prospective studies typically concern triple therapy (with the use of 40–50mg cytosine arabinoside, 15mg methotrexate,4mgdexamethasone).Thenumberofappli- cations of intrathecal drugs into the cerebrospinal fluid during lumbar puncture is different in various research protocols and ranges from 7–8 (PALG protocols) to 12–14 (Northern-Italian Leukemia Group – NILG, German Multi- centerStudyGroupforAdultALL–GMALL).Currently,the use of liposomal cytosine arabinoside is preferred in clinical practice [20, 21], which allows a reduction in the number of punctures, thus increasing adherence to ALL treatmentprotocols.Reportedtoxicitywhen theDepoCyte was administered concomitantly with high-dose systemic chemotherapyadvisedthe carefulnesswiththiscombined treatment. In the paper serious unexpected neurotoxicity duringhyper-CVADtreatmentwas reportedandliposomal cytarabine IT administration 16% of patients experienced seriousneurotoxicity[22].

In the global NCCN guidelines, CNS prophylaxis is a mandatory element of intensive ALL therapy inchildren andadults(www.nccn.orgNCCNClinicalPracticeGuidelines inOncology,AcuteLymphoblasticLeukemia,VersionI.2014, accessedon25.11.2014). Theriskof CNSrecurrence canbe evaluated based on the degreeof blastosisincrease inthe cerebrospinal fluid (CNS1 – no blasts in the cerebrospinal fluid,CNS2–<5cellsperml,CNS3–5cellsperml).In2008, PALGpublishedrecommendationsfor CNSprophylaxispol- icyforALLinadults[16].Therecommendationsconcerning

drugsforCNSprophylaxis,basedonsomepublicizedclinical observations also including the authors experience, pro- posedthe administrationof liposomal cytosinearabinoside (DepoCyte) instead of triple therapy [20, 23]. Long-term (2weeks)maintenanceofthedruginthecerebrospinalfluid allowed for a reduction of the number of prophylactic punctures during intensive treatment. This makes it even morecrucial thathemostasisismaintainedwhenperform- ing a lumbarpuncture; platelet count shouldexceed 50G/l and anticoagulants should not beused [21]. Current PALG recommendations(www.palg.pl,GrupyRobocze,dsleczenia ostrej białaczki limfoblastycznej, PALG ALL6 protokół, accessed on 25.11.2014; ALL-6 PALG protocol) recommend 5 intrathecal drug applications during induction and con- solidationtherapyand every3monthsduringthefirstyear ofmaintenancetherapy.TheuseofDepoCyteinprevention reducestheriskofcomplicationsbyreducingthenumberof lumbarpuncturesandcontributestothestrictadherenceto the therapy regimen. Although there are no published results of ongoing prospective controlled trials comparing the effectiveness of triple prophylaxis (12 doses of metho- trexate,cytarabine,andprednisolone)withDepoCytemono- therapy (6 doses in B-cell subtype and 8 doses in T-cell subtype; researchconductedbytheEuropeanLeukemiaNet, ALL-NILG10/07protocol,www.leukemia-net.org/www.leuke- mia-registry.eu), with the newly developed recommenda- tions, some research groups prefer the use of liposomal cytosine arabinoside. CNSprophylaxistherapy withliposo- mal cytarabine in elderly patients ina prospective GMALL studyprovedtobeeffectiveandwelltolerated[24].

CNSirradiationisbecominglesspopularinCNSprophy- laxis; although this procedure isstillunder discussion,the increasing proportion of patients for whom hematopoietic cell transplantation is planned and where the optimal conditioningtreatmentinALListotalbodyirradiation(TBI), CNS prophylaxis should not include irradiation. Therefore, properly conducted CNS preventive cytostatic treatmentis becomingmoreimportant[25].

CNS recurrence in ALL may be isolated or occur in parallel with the overallactivity of leukemia. Isolated CNS recurrence of leukemia usually precedes systemic recur- rence. Changes are located mostly within the meninges.

However, infiltratesmay occur inbrain tissue,making the efficacy of intrathecally administered drugs lower due to suboptimalbrain penetration.Inthesecases,the treatment of choice is high doses of intravenous methotrexate or cytosine arabinoside and liposomal cytosine arabinoside administered into the cerebrospinal fluid. DepoCyte has extendedactivitybothintheentirespaceofthespinalcord andinbrainfluidchambers(TableII).

InthetreatmentofCNSleukemia,mostfrequentlymani- festedbymeningealinvolvement,thesamedrugsareusedas inprophylaxis.Tripletherapy(methotrexate,cytosinearabi- noside, dexamethasone) is routinely administered into the cerebrospinal fluid at intervals of several days by lumbar puncture oftheintervertebralspace,inpractice,atleast2–3 times aweek. The currentlyaccepted treatment, with high clinical efficacy,isliposomalcytarabine[18,26,27].Because of its long-lasting presence in the cerebral spinal fluid (2 weeks),cytosinearabinosidemaybeadministeredeverytwo

weeks. This treatment is well tolerated and neurological complicationsarerelativelyrare,asalsoconfirmedinPolish observations:in56%ofthetreatments,therewerenoadverse clinicaleffects,whilesevereheadachesandfeveroccurredin 7%ofthecases[28,29].ObservationsfromaEuropeanmulti- center phase II trial (GMALL) have shown that the use of liposomal cytarabine with dexamethasone prophylaxis (administered intrathecally or as a systemic treatment for 2weeks)resultedintotalremissionintheCSFin86%ofthe patientswith ALL andin 40%ofthepatients with Burkitt's lymphoma.Sideeffectswereobservedin89%ofthepatients, mainly headaches: III–IV grade headaches occurred in 32%

[26]. Intrathecal treatment can be completed if in two consecutivepuncturesthecerebrospinalfluidisnegativefor blasts. Continuation of maintenance treatment is then recommended with prolonged intervals between IT drug administrations;however,thedurationof CNSmaintenance therapyhasnotbeendetermined.Theuseofradiotherapyfor CNS treatment is recommended in cases with a lack of chemotherapy effect and as the treatment of choice when infiltratesarepresentinbraintissue.

Prevention and treatment of CNS infiltration in lymphoblastic lymphoma and Burkitt's lymphoma

In the treatment of highly aggressive lymphomas, inten- siveinductionchemotherapyisusedtogetherwithpreven- tion of CNS involvement. Principles of treatment are similar to ALL. Prophylaxis of CNS infiltration involves administration of high doses of CNS penetrating cyto- staticsandadministration ofdrugs into the cerebrospinal fluid(triple therapyofchoice or liposomalcytosine arabi- noside). CNS irradiation is not recommended. Treatment ofCNSinfiltrationbylymphomaiscarriedout inthesame way as in treatmentof ALL.In cases of resistance to the chemotherapy ofchoice,CNSirradiation can alsobeused [29,30].

Treatment of CNS infiltration in mature B-cell neoplasms

BothprimaryandsecondaryinvolvementsbymatureB-cell lymphomasoccursporadically.Inrecentyears,theneedfor a detailedassessment ofthe increasedriskof CNSinfiltra- tionbylargeB-celllymphoma(DLBCL)isemphasized.

In 2010, the Polish Lymphoma Research Group and the PALG published recommendations presenting an algorithm for diagnosis and therapy of patients with DLBCL [8].

Primary CNS involvement in DLBCL is rare; the estimated incidence of recurrence in this location is about 5%.

Increasedriskfactors for CNSinvolvementare:raisedLDH level, involvement of at least 2 extranodal sites, and involvement of so-called specific sites (testis, mammary glands,orbit,paranasalsinuses, andthespine).Theriskof CNS involvement is enhanced in the primary mediastinal large B-cell lymphoma (PMLBCL) and intravascular large B-celllymphoma[17].ThepublishedPolishguidelinesfocus on theuse offlow cytometryincerebrospinalfluidevalua- tion for detaileddiagnosis inpatientswithno neurological signsandthepresenceofatleastoneoftheriskfactors.In the case of PMLBCL and intravascular large B-cell lym- phoma, aswell asin DLBCLwithat leasttwo riskfactors, intrathecal administration of drugs is recommended pro- phylactically during the first lumbar puncture. In CNS involvement, prophylaxisliposomal cytosinearabinosideor 15mgmethotrexateisrecommended.Goodefficacyandlow toxicityofDepoCyteinprevention,assessedintheobserva- tion of 79 patients treated in two Polish centers [31], encouragetheuseofthisdrugineverydayclinicalpractice.

However, insome publications neurotoxicitywas reported:

four of thefourteen patients(25%) developedgrades 2and 3 neurotoxicity manifested as conus nedullaris/cauda equine syndrome [32]. In cases where lymphoma cells are detected in the cerebrospinal fluid by flow cytometry, continuation of intrathecal treatment is recommended in TableII–DrugsusedinprophylaxisandtreatmentofCNSinvolvementinlymphoproliferativeneoplasms

Drug PreventionofCNSinvolvement TreatmentofCNSinfiltrations

Intravenouscytosinearabinoside–doses

>0.5–1.0g/m²

Inmonotherapy Frequentlyinmonotherapy

Methotrexateintravenously–doses>1.0 g/m²

Inmonotherapy Frequentlyinmonotherapy

Intrathecalcytosinearabinoside,40–50mg dose

Inmonotherapyorincombination withprednisone40mg,dexamethasone 4mg,andmethotrexate12–15mg (tripleregimen)

Inmonotherapyorincombination withprednisone/dexamethasone andmethotrexate(tripleregimen);

2–3dosesperweek Intrathecalmethotrexate12–15mgdose Incombinationwithprednisone/

dexamethasone(dualregimen)or additionallywithcytosine(tripleregimen)

Incombinationwithprednisone/

dexamethasoneandcytosine arabinoside(tripleregimen) Cytosinearabinoside–liposomal(DepoCyte)

50mgdose

Inmonotherapyorincombinationwith dexamethasone4mgusedduringasingle ITpuncture(note:thedrugsinseparate syringes)

Inmonotherapyorincombination withdexamethasone,every2 weeksuntileradicationof pathologicalpleocytosisfollowed by2additionaldoses

Radiationtherapytoskullbaseandmedulla oblongata/CNS(inadultsalsousedless frequently)

Procedureofchoice,supplementing chemoprophylaxisinpatientsnoteligible forbonemarrowtransplantwithTBI preparation

Procedureofchoice,usuallyinlack ofeffectofaforementioned chemotherapeutictreatment

parallelwithsystemictherapy, and useof liposomalAra-C ispreferredduetofavorablepublishedclinicalobservations and the smallernumber of lumbar punctures requiredfor effectivetreatment[8].

Inlymphocyticlymphoma/chroniclymphocyticleukemia (CLL/SLL) with CNSinvolvement in the form of meningeal infiltration,symptomsofsystemicprogressionandRichter's transformation are often present. The analysis of 2514 Norwegian patients with various lymphoma subtypes showed thatthe frequencyof CNSlow-grade recurrence in NHL according to the Kiel classification (time period of analysis:1980–1996)was2.8%withinfiveyears,comparedto 4.3% in the high-grade lymphomas and 24.4% in Burkitt's lymphomaorlymphoblasticlymphoma[33].Inmultivariate analysis,independentriskfactorsforCNSinvolvementwere B symptoms, bonemarrow involvement, and skininvolve- ment.Thecoexistenceoftwo/threeofthesefactorsinlow- grade lymphomaincreased therisk of CNSinvolvementto about7%inthe5-yearfollow-up.Thisisoneofthelimited datashowingtheincidenceofCNSinvolvementinCLL.Due to the low incidence of CNSinvolvement in the course of CLL/SLL,prophylacticadministration of intrathecaldrugsis notrecommended.However,treatmentof CNSinvolvement isbasedonthegeneralrulesapplicabletoothersubtypesof lymphoma,butreportsofefficacyarecasereports[34].

Observations of the Spanish group published in the British Journal of Hematology in 2010 concerning effective treatmentofintrathecalliposomalcytarabine,thepossibility ofusingamodern,effectivetherapywasindicatedin7cases of meningeal involvementin Richter'ssyndrome. On aver- age,5doses ofintrathecalliposomal cytarabine (range2–9) wereusedtoobtainblastcellclearanceinthecerebrospinal fluid. Only 3/7 of them had previous triple intrathecal therapy or CNS irradiation [33]. In another published case ontheeffectiveuseofliposomalcytarabineinthetreatment of CNS, recurrence preceding systemic recurrence in CLL lasting over 10 years, the use of liposomal cytarabine as consolidation and maintenance treatment allowed long- termmaintenance andcomplete remissionwithin theCNS [35].

Mantle cell lymphoma – localization of changes in the CNS

Interesting observations concerning CNS involvement in mantlecelllymphoma(MCL)werepresentedintheanalysis of the European Mantle Cell Lymphoma Network (EMCLN) involving1396patientswithMCL[36].TheincidenceofCNS involvement at diagnosis was 0.9% (0.5–1.6%, n=13) and 4.1% overthe course of the disease (3.2–5.2%, n=44). Only 15caseshadisolatedCNSinvolvement.Themedianfollow- up of patientswith CNSinvolvement was17 months (0.2– 170).Themajorhigh-riskfactorswereblastoidsubtype(28%

of patientswithCNSinvolvement),thepresence ofgeneral B symptoms (53%),clinical stageIV(91%), highMIPI (61%), andelevatedLDHactivity(75%).In37%,CNSrecurrencewas isolatedandin63%, coexistedwithsystemicrecurrence.In most cases of treatment of CNS involvement, systemic chemotherapy was used (72%). In 13%, combination with

radiation wasused, in4%,onlyradiationwas used,andin 10%, palliative treatment was used. The most commonly useddrugswere:high-dosemethotrexate,cytosinearabino- side(eitheralone orinmultidrugregimens),acombination of rituximab with chemotherapy, and in 79%, the use of intrathecal therapy(triple, dualorsingleagent:methotrex- ate or liposomal cytarabine). The median overall survival from diagnosis of CNS involvement was 3.7 months (0.2– 69.3). Some patients achieved complete remission within the CNS. The overall survival was 3.9 months, but some patientslivedover2years[36].

CNS involvement in MCL is rare, but its occurrence is associatedwithpoorprognosis.Untilresultsoftheprospec- tivestudyareobtained, thereare noclearrulesconcerning thepreventionofCNSinvolvementinthisdisease.

Autotransplantation of hematopoietic cells in lymphomas with CNS involvement

SecondaryCNSinvolvementinthe courseof lymphomais, inmostcases,associated withpoorprognosisandreduced survival. The use of intensive induction chemotherapy basedonhighdosesofmethotrexateandcyclophosphamide with dexamethasone in combination with intrathecal administration of liposomal cytarabine prior to autologous hematopoietic cell transplantation (phase II prospective study, for conditioning treatmentthiotepa and BCNU were used) resulted in CR in 63% of the patients with a 2-year Time toTreatment Failure(TTF) rateof 5822%[37]. This procedure may be used in everyday clinical practice as atreatmentofchoice.

Non-Hodgkin lymphoma in patients with HIV infection and CNS involvement

Patients withHIV infectionhave anincreased incidence of lymphomaandahighgradeofdiseaseisindicatedinthese patientswheninitialclinicalsymptomspresent.At diagno- sis, mostpatientsare inCSIII/IV andin>70–98%,thereis involvementatextranodalsites,mainlyinthegastrointest- inal tract, bonemarrow,and CNS[38]. CNSinvolvementat diagnosis ranges from 3 to 15% and is most common in Burkitt's histological subtype in cases of extranodal site involvementandduringtheuseofantiretroviraldrugs.CNS involvementisoftenasymptomatic.Takingintoaccountthe high risk of progression in the CNS during treatment or recurrence in this location during NHL remission, a mandatorypartof lymphomatreatmentprotocolsinHIV patientsincludesuse ofintrathecalCNSprophylaxis.Based on theliteraturedataonthelow toxicityand goodefficacy ofintrathecalDepoCyte,aprospectiveanalysiswasperformed in30patientswithNHLtreatedwithHAART.Thenumberof intrathecal applications of liposomal cytarabine varied dependingonthetypeofsystemicchemotherapyused.With polychemotherapy regimens:Rituximab+Cyclophosphamide +Adriblastin+Oncovin+Prednison (R-CHOP), CHOP, and Rituximab+Cyclophosphamide+Doxorubicin+Etoposide (R- CDE)andthe‘‘Stanfordchemotherapy’’regimenthedrugwas

administeredintrathecallyevery3weeksupto6applications IT,butofeachR-CODOX-Msystemicpolychemotherapycycle, upto3applications.Duetoaccumulationof toxicityduring concomitantsystemicuseofhighdosesofAra-Cinthecourse of the ‘‘R-IVAC’’ cycles, DepoCyte was not administered intrathecally. Such a procedure was considered effective prophylaxis,despitethereductioninthenumberofintrathe- calapplicationsofdrugscomparedtotripleprophylaxisregi- men. CNS relapses occurred in 3% ofthe patients and the incidence did not differ from the general population of patients with lymphoma. In cases of lymphoma in HIV patients, the use of liposomal cytarabine as the agent of choicebothinprophylaxisandtreatmentofCNSinvolvement ispreferred[38].

Inrecent years, therehave beennumerous publications onthediagnosisandtreatmentofprimarylymphomaofthe brain.Thestandardfirstlinetherapyistheuse ofsystemic high-dosemethotrexateandcytarabine[39–41].Accordingto published observations of Sierra Del Rio, the prophylactic use of intrathecal drugshad no effecton improvement of therapy effectiveness [42]. Therefore, in everyday clinical practice, neither the prophylactic administration of cyto- staticsintocerebrospinalfluidnorprophylacticradiotherapy isused.Clinicalobservationreported24%occurrenceofthe serious neurotixic side effect during the treatment with high-dosesystemicmethotrexate andAra-Cbasedpolyche- motherapycombinedwithliposomalAra-C[43].Conclusions basedonsmallnumberofpatientsandshouldbeconfirmed on the larger group of the patients. In resistance and relapses,DHAPandESHAPrituximabarerecommendedas salvagetherapies,which resultedinresponseinabout27%

of the patients. CNS irradiation was used to treat che- motherapy-resistantcases [44].Anotherproposed approach is the use of consolidation treatment with high-dose che- motherapy(theuseof BCNUandthiotepaisrecommended in conditioning) with autologous hematopoietic cell trans- plantation. This treatment led to 5-year survival in more than80%ofthepatients[45].

Despite the higher costs of liposomal cytarabine, the treatment is comparable in efficacy and according to the clinicalexperienceoftheauthorsand canbeconsideredas treatment of choice because lower number of intrathecal dosesgivethesame resultswhich canimprovethe quality of life of oncologic patients. The total costs of intrathecal therapy using liposomal Ara-C can be even lower due to reduced cost of hospitalization and concomitant therapy during the treatment. Up to now pharmacoeconomic ana- lysesoftheproblemarenotavailable.

Summary

1. PreventionofCNSinvolvementisafundamentalelement of intensive treatment of neoplasms originating from precursor B and T-cells (acute lymphoblastic leukemia/

lymphoblasticlymphoma)andBurkitt'slymphoma.

2. In cases of large B cell lymphoma (DLBCL), the risk of CNS involvement should be assessed. When increased riskfactorsoccur,it isadvisabletoprevent CNSinfiltra- tionwithintrathecaladministrationofdrugs.

3. Prevention of CNS involvement is recommended in all casesof lymphomainHIV-positivepatients,whereinthe useofliposomalcytosinearabinosideispreferred.

4. In the treatment of CNS involvement in tumors of the lymphatic system, theadministration of liposomal cyto- sine arabinoside shows the same efficacy as intrathecal triple therapy with fewer intrathecal punctures and comparableorlowertoxicitybuttheneurologiccomplica- tions after the treatment must be considered as well, especiallyduringtheconcomitantsystemictherapy.

5. Based onthepublishedresultsofthe clinicalexperience and retrospectiveanalysis,theuse of liposomalcytosine arabinoside is recommended in the prevention of CNS involvement.

Authors' contributions/Wkład autorów

Accordingtoorder.

Conflict of interest/Konflikt interesu

Nonedeclared.

Financial support/Finansowanie

ThispaperwassponsoredbyMundipharmaPolskaSp.z.o.o., Warsaw,Poland.

Theauthorsreportnootherdisclosuresandnofinancial support.

Ethics/Etyka

The work described in this articlehas been carried out in accordance with The Code of Ethics of the World Medical Association (Declarationof Helsinki)for experiments invol- ving humans; EU Directive 2010/63/EU for animal experi- ments;UniformRequirementsformanuscriptssubmittedto Biomedicaljournals.

Acknowledgements/Podziękowania

Thetechnicalsupportandlanguageassistancewereprovided byProperMedicalWriting,Warsaw,Poland.

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