I-Chimeric Antigen Receptor (CAR) T-cell therapy

Kuleli khasi sizobe sidingida i-chimeric antigen receptor (CAR) T-cell therapy.

Ishidi leqiniso le-Chimeric antigen receptor (CAR) T-cell therapy

Uhlolojikelele

Ukuqonda ukwelashwa kwe-CAR T-cell ku-lymphoma
UDkt Michael Dickinson, Peter MacCallum Cancer Center

I-Chimeric antigen receptor (CAR) T-cell therapy iwuhlobo lwe-immunotherapy esebenzisa amasosha omzimba womuntu ukuze azame ukucekela phansi amaseli e-lymphoma.

Amasosha omzimba ngokuvamile ayasivikela futhi ayisivikelo somzimba ezifweni nasezifweni, kuhlanganise nomdlavuza. Yakhiwe inethiwekhi yezitho kanye namangqamuzana amhlophe egazi akhethekile abizwa ngokuthi ama-lymphocyte. Kunezinhlobo ezintathu ze-lymphocyte ezihlanganisa:

Ama-lymphocyte B (ama-B-cell) – enza amasosha omzimba ukulwa nokutheleleka
T-lymphocyte (T-cells) -siza ama-B-cell ukuthi enze amasosha omzimba ukuze abone amangqamuzana anamagciwane, alwe nokutheleleka futhi abulale ngokuqondile amangqamuzana anamagciwane noma omdlavuza emzimbeni
Amaseli abulala imvelo (NK). – iphinde ihlasele amangqamuzana omdlavuza, amangqamuzana anamagciwane abulale amagciwane

Lapho ama-lymphocyte ezuza izinguquko ezithile zofuzo, ayahlukana futhi akhule ngokungalawuleki okuholela ku-lymphoma. Lokhu kubangela ukuthi amasosha omzimba angakwazi ukubona amangqamuzana anomdlavuza noma angakwazi ukuwabhubhisa. Amangqamuzana omdlavuza angakwazi nokwenza izindlela zokuvimbela amasosha omzimba ukuba awahlasele. Isibonelo, amanye amangqamuzana omdlavuza enza amaprotheni akhethekile ebusweni bawo atshela ama-T-cell ukuthi angawahlaseli.

I-Chemotherapy kanye nokwelashwa ngemisebe kube izindlela zendabuko zokwelapha umdlavuza. I-Immunotherapy uhlobo lokwelapha oluthuthukisa ikhono lomzimba lokubona nokuhlasela amangqamuzana omdlavuza ngokusebenzisa amasosha omzimba.

Kuyindawo esebenzayo yocwaningo lwezokwelapha futhi kunemithi yokwelapha efakazelwe ye-immunotherapy. Lokhu kufaka phakathi i-monoclonal antibody therapy (i-rituximab noma i-obinutuzumab), ezinye izindlela zokwelapha eziqondisiwe (isb. I-Pembrolizumab ku-Hodgkin lymphoma kanye ne-primary mediastinal B-cell lymphoma), kanye nokwelashwa kwe-T-cell kwe-chimeric antigen yakamuva.

Iyini i-CAR T-cell therapy?

I-CAR T-cell therapy iwuhlobo olusha lwe-immunotherapy esebenzisa ama-T-cell esiguli ukuze abone futhi ahlasele amangqamuzana omdlavuza. Ukwelashwa kwe-CAR T-cell kusebenzisa ama-T-cell ashintshwe ngokukhethekile ukuze aqondise ngokuqondile nangokunembile imidlavuza ethile, okuhlanganisa nezinye izinhlobo ezingaphansi ze-B-cell lymphoma. Ama-T-cell ahlelwe kabusha aqinisa amasosha omzimba ukuze ahlasele futhi abulale amaseli e-lymphoma.

Ingxenyana yama-T-cell esiguli iqoqwa egazini kusetshenziswa inqubo ebizwa ngokuthi i-apheresis. Lawa maseli enziwe kabusha ngokofuzo elabhorethri ekhethekile, ngakho manje athwala izakhiwo ezikhethekile ezibizwa nge-chimeric antigen receptors (CAR) ebusweni bawo. Ama-CAR angamaprotheni aklanyelwe ukunamathela endaweni ethile kumaseli omdlavuza. Emikhiqizweni egunyaziwe njengamanje, lelo phrotheni libizwa nge-CD19 elitholakala phezu kwama-B-cell avamile nanomdlavuza.

Amaseli e-CAR T akhiqiziwe abe esephinde afakwe esigulini (njengokumpontshelwa igazi). Lapho zibopha isamukeli sazo eziqondiwe, ziphindaphindeka ngokushesha, futhi zibulale amangqamuzana aqondiwe kulokhu okuyi-B-cell lymphoma kanye nama-lymphocyte B avamile. Ayaqhubeka nokuphindaphinda futhi ahlasele amangqamuzana omdlavuza aze aphela.

Kwezinye izimo, kucatshangwa ukuthi amangqamuzana e-CAR T ayaqhubeka ephila emzimbeni (okuthiwa “ukuphikelela”) futhi angaqhubeka nokugcina i-lymphoma noma i-leukemia ingekho. Yingakho abaningi becabanga ngama-CAR T-cell 'njengomuthi ophilayo'.

Ubani ofanelekela ukwelashwa kwe-CAR T-cell?

I-CAR T-cell therapy ixhaswa ngokomphakathi e-Australia kubantu abahlangabezana nemibandela eqinile yokufaneleka ezolandelwa yiphaneli yezokwelapha engochwepheshe. Iziguli ezitholwe zinesinye sezifo ezisohlwini ze-B-cell, ezibuye zabuyela emuva ngemva kokungenani izindlela zokwelapha ezingu-2 zangaphambili noma eziphikisayo (azizange zisabele ku-chemotherapy) futhi ziphilile ngokwezokwelapha, zingase zifanelekele ukwelashwa kwe-CAR T-cell. I-CAR T-cell therapy ingaba nemiphumela emibi kakhulu futhi ayifanele wonke umuntu.

Iningi leziguli livamise ukungena enxeleni ngemuva kokuthola ukwelashwa okujwayelekile komugqa wokuqala okuvamise ukuhlanganisa i-chemotherapy kanye ne-monoclonal antibody. Ukwelashwa kwe-CAR T-cell kubiza kakhulu futhi kubiza ngaphezu kuka-$500,000 isiguli ngasinye. Izindleko eziphezulu zidalwe yinqubo yokukhiqiza enguchwepheshe ehilelekile ekwakheni ama-CAR T-cell. Izikhungo ezithile zomdlavuza kuphela ezizoqeqeshwa ngokukhethekile ukuze zifake ukwelashwa kwamaseli e-CAR T nokuphatha ukunakekelwa kwesiguli.

Izinhlobo ezilandelayo ze-lymphoma zingase zifaneleke:

Isabalalisa i-B-cell Lymphoma enkulu
I-Follicular Lymphoma eguquliwe
IBanga lesi-3 le-Follicular Lymphoma
I-Primary Mediastinal B-cell Lymphoma
I-B-cell Acute Lymphoblastic Lymphoma (B-ALL) ye abantu abangaphansi kweminyaka engama-26
I-Mantle Cell Lymphoma.

I-CAR T-cell therapy e-Australia

E-Australia, kube nemikhiqizo emibili eye yaba nesincomo esihle esivela ku-Medical Services Advisory Committee (MSAC) futhi yomibili izoxhaswa esidlangalaleni maduze. Le mikhiqizo ihlanganisa:

UKymriah^TM (tisagenlecleucel) umkhiqizo we-Novartis futhi uxhaswe ngemali esidlangalaleni e-Australia
Yescarta^TM (axicabtagene ciloleucel) umkhiqizo waseGileyadi futhi uxhaswe ngezimali esidlangalaleni e-Australia
UTecartus^TM(brexucabtagene autoeucel) umkhiqizo waseGileyadi oxhaswe esidlangalaleni e-Australia.

Konke ukudluliselwa kuxoxwa ngochwepheshe bezokwelapha emhlanganweni kazwelonke wamasonto onke we-CAR T-cell. Ukuze uthole ulwazi olwengeziwe khuluma nodokotela wakho wegazi noma i-Lymphoma Australia.

Ngingayithola kuphi i-CAR T-cell therapy?

Abantu abadala

Izingane

I-Western Australia

Isibhedlela iFiona Stanley

I-New South Wales

Isibhedlela iRoyal Prince Alfred

Isibhedlela iWestmead

Victoria

Peter MacCallum Isikhungo Somdlavuza

Queensland

I-Royal Brisbane kanye neSibhedlela Sabesifazane

Queensland

Isibhedlela sezingane saseQueensland

I-New South Wales

Isibhedlela Sezingane saseSydney

Victoria

Isibhedlela Sezingane Zasebukhosini

Isibhedlela i-Alfred

Inqubo ye-CAR T-cell

Ngeminye imininingwane bheka

I-Lymphoma Action UK

Ama-CAR T-cell enziwa ngawodwana kumuntu ngamunye. Ungathola ezinye izindlela zokwelapha, ezifana ne-chemotherapy (i-bridging therapy), ukugcina i-lymphoma yakho ilawulwa ngenkathi kwenziwa amaseli e-CAR T (amaviki angu-3-6).

Iqoqo le-T-cell: Igazi lithathwa esigulini. Amangqamuzana egazi amhlophe, ahlanganisa nama-T-cell, ayahlukaniswa futhi lonke igazi libuyiselwa egazini lesiguli nge-apheresis (efana nokuqoqa ama-stem cells). Ama-T-cell esiguli athunyelwa elebhu ukuze akhiqizwe.
Ukukhiqizwa kwamaseli e-CAR T: Ama-T-cell ayashintshwa noma enziwe ufuzo (ashintshiwe) ukuze akwazi ukuthola futhi abulale amaseli omdlavuza. Ama-T-cell akhiwe manje abizwa ngokuthi ama-CAR T-cell. Ama-CAR T-cell esiguli ayaphindaphindeka aze abe yizigidi bese eqandiswa. Ama-CAR T-cells abe esebuyiselwa esibhedlela sesiguli. Le nqubo ingathatha amaviki ambalwa.
I-Chemotherapy: Isiguli sizothola ukwelashwa ngamakhemikhali (i-lymphodepletion), ukuze kuncishiswe inani lama-T-cell ajwayelekile emzimbeni ukuze enze isikhala samaseli e-CAR T, ukuze akwazi ukwanda (aphindaphinde) uma esesetshenzisiwe. Ngokuvamile, le chemotherapy i-fludarabine ne-cyclophosphamide.
I-CAR T-cell infusion: Amangqamuzana e-CAR T esiguli ayancibilika abese ebuyiselwa egazini lesiguli, okufana nokumpontshelwa igazi noma ama-stem cells.
Emzimbeni wesiguli: Amaseli e-CAR T aphindaphindeka ngokushesha egazini lesiguli. I-CAR T-cell ithola futhi ibulale amaseli e-lymphoma. Amaseli e-CAR T angase ahlale emgudwini wegazi ukuze ahlasele uma i-lymphoma ibuya.
Ukubuyisela: Isiguli sizogadwa ngokucophelela ngesikhathi nangemva kokwelashwa. Iziguli ezithola ukwelashwa kwe-CAR T-cell zinesikhathi sokululama cishe izinyanga ezi-2-3. Ngalesi sikhathi, iziguli zizohlolwa imiphumela emibi kanye nokusabela kokwelashwa. Okungenani ezinsukwini zokuqala ezingu-30 ngemva kokukhishwa esibhedlela, iziguli kudingeka zihlale ziseduze (phakathi nemizuzu engama-20) esibhedlela sazo ezelashwayo ukuze zilandelelwe njalo noma ukunakekelwa okuphuthumayo uma kudingeka.

Imiphumela emibi engaba khona ye-CAR T-cell therapy

Yonke imithi nokwelashwa komdlavuza kungabangela imiphumela engemihle. Ukwelashwa kwe-CAR T-cell wuhlobo olusha lokwelapha, futhi njengoba abacwaningi bekuqonda kangcono ukwelashwa, kunjalo nokuphathwa kwale miphumela engemihle. Ukwelashwa kwe-CAR T-cell kungabangela imiphumela emibi kakhulu futhi ukwelashwa kunikezwa kuphela ezibhedlela ezinezikhungo kanye nabasebenzi abangochwepheshe ukuze balawule le miphumela engemihle ngempumelelo.

Kubalulekile ukuqaphela ukuthi akuzona zonke iziguli ezizokwazi ukubekezelela eminye yemiphumela engemihle engase ibe khona ngakho-ke isimo sezokwelapha nempilo yesiguli ngasinye sidinga ukucatshangelwa ngokucophelela ngaphambi kokwenza ukwelashwa kwe-CAR T-cell.

Eminye yemiphumela engemihle evamile ingase ithinte ingxenye enkulu yeziguli futhi ingaholela ekulalisweni isikhathi eside esibhedlela. Imvamisa yale miphumela engemihle ingase ixhunywe kumkhiqizo osetshenzisiwe, kanye nezici ezihambisana nesiguli kanye nesifo. Lokhu kubandakanya:

I-Cytokine release syndrome
Umkhuhlane namakhaza
Umfutho wegazi ophansi kanye namazinga omoya-mpilo aphansi
Izinkinga zesistimu yezinzwa ezihlanganisa; izinkinga zobuchopho (i-encephalopathy), ikhanda elibuhlungu, ukudikizela noma ukuvevezela (ukundindizela) noma isiyezi
Ukushaya kwenhliziyo okusheshayo (tachycardia) kanye nezinguquko zesigqi senhliziyo (arrhythmia)
Ukukhathala (ukukhathala okukhulu)
Isikhukhula
Izimpawu zokugaya ukudla; isicanucanu, ukuhlanza, ukunciphisa ukudla, isifo sohudo nokuqunjelwa
I-Febrile neutropenia (ama-neutrophils aphansi - amasosha omzimba) kanye nezifo

Iyini i-cytokine release syndrome (CRS)?

I-Cytokine release syndrome (CRS) iwumphumela ongase ube mubi kakhulu futhi uhlotshaniswa nokwelashwa kwe-CAR T-cell. Ama-Cytokines ayizithunywa zamakhemikhali ezisiza ama-T-cell enze imisebenzi yawo, akhiqizwa lapho ama-CAR T-cell anda emzimbeni futhi abulale amangqamuzana omdlavuza. Izimpawu ze-CRS zingasukela kumkhuhlane omaphakathi njengezimpawu kuye kuye kuzimpawu ezibucayi kakhulu.

Ama-T-cell aklanyelwe ukukhulula ama-cytokines (izithunywa zamakhemikhali), ezisiza ukuvuselela nokuqondisa impendulo yokuzivikela komzimba. Endabeni ye-CRS, kukhona ukukhululwa okusheshayo nokukhulu kwama-cytokine egazini, okungabangela ukushisa okuyingozi okuyingozi kanye nomfutho wegazi ophansi. Lokhu kungaziwa nangokuthi 'isiphepho se-cytokine'.

Izimpawu ze-cytokine release syndrome

I-CRS ivamise ukuvela phakathi no-1 kuya kwezinsuku ezi-5 ngemva kokuthi amaseli e-CAR T ephinde afakwa esigulini, nakuba kungase kwenzeke ngemva kwamasonto kwezinye izimo. Ezigulini eziningi, isimo sithambile kangangokuba singaphathwa ngokwelashwa okusekelayo nokuqapha.

Izimpawu nezimpawu zingabandakanya:

Fever
Ukukhathala
Ukulahlekelwa kwesifiso
Ubuhlungu besisu nobuhlangene
I-nausea nokuhlanza
Uhudo
Ukuhlambalaza
Ukuphefumula ngokushesha
Ukushaya kwenhliziyo okusheshayo
Umfutho wegazi ophansi
ukuquleka
bekhanda
Ukudideka noma i-delirium
ukusangana
eliqhaqhazelayo
Ukulahlekelwa kokuxhumana

Ukwelashwa kwe-cytokine release syndrome

Ezigulini eziningi, i-CRS ingaphathwa ngemithi yokwelapha ejwayelekile efana nama-steroid noma uketshezi olufakwa emthanjeni. Njengoba abacwaningi bathole ulwazi oluthe xaxa ngokwelashwa kwe-CAR T-cell, bafunda ukuthi bangaphatha kanjani kangcono izimo ezibucayi kakhulu ze-CRS.

Ukwelashwa okujwayelekile kweziguli ukuphatha i-CRS enzima iwukusebenzisa umuthi okuthiwa i-tocilizumab (Actemra^TM). Lona umuthi owaziwa ngaphambilini ukwelapha ezinye izimo ezivuvukalayo, osetshenziselwa ukuvimba i-cytokine ebizwa nge-IL-6. I-IL-6 iyi-cytokine efihliwe emazingeni aphezulu ngama-T-cell ukuphendula ukuvuvukala.

Ezinye iziguli zidinga ukwamukelwa ukuze zilawule imiphumela engemihle futhi zingahlala esibhedlela isonto lonke noma ngaphezulu. Ezinye iziguli zidinga ukwamukelwa ukuze zithole usizo olwengeziwe egunjini labagula kakhulu (ICU).

Izinkinga zesistimu yezinzwa

Abantu abaningi abalashwa nge-CAR T-cell therapy bangaba nezinkinga zesistimu yezinzwa phakathi nezinsuku ezimbalwa zokwelashwa, nakuba izinkinga zingakhula kuze kube amasonto angu-8 ngemva kokwelashwa. Izinkinga zesistimu yezinzwa ngokuvamile ziba mnene futhi ziba ngcono emasontweni ambalwa.

Izinkinga ezivame kakhulu ezenzekayo zingathinta indlela ubuchopho obusebenza ngayo, lapho izimpawu zingase zihlanganisa ukundindizela, ubuhlungu bekhanda, ukudideka, ukulahlekelwa ukulinganisela, ukukhuluma kabi, ukuquleka futhi ngezinye izikhathi ukubona izinto ezingekho. Le miphumela engemihle ngokuvamile iyadamba ngemva kwezinsuku ezimbalwa, nakuba kwabanye ingahlala amasonto.

Ukutholwa kwe-CAR T-cell therapy

Ukululama kungase kuthathe isikhathi njengoba amasosha omzimba esiguli elulama. Isikhathi sokululama esibucayi kanye nokuqapha okuseduze kuvamise ukuba yizinsuku ezingama-30 ngemuva kokujova kwe-CAR T-cell. Ngalesi sikhathi iziguli kufanele zihlale phakathi nemizuzu engama-20 ukusuka esikhungweni sokwelapha umdlavuza. Kufanele futhi babe nomnakekeli kubo ngaso sonke isikhathi ukuze baqaphe izimpawu zomkhuhlane, ukutheleleka kanye nobunzima bemizwa. Iziguli eziningi zizizwa zikhathele futhi azikuthandi ukudla ngalesi sikhathi.

Imiphumela emibi yesistimu yamasosha omzimba

Njengoba ukwelashwa kwe-CAR T-cell kuthinta amasosha akho omzimba, ungase ube sengcupheni enkulu yokutheleleka, okuhlanganisa nezifo ezimbi kakhulu ngemva kokwelashwa. Amaseli akho amhlophe egazi angase abe phansi, futhi abanye abantu banamazinga aphansi e-B-cell kanye namazinga aphansi e-antibody (amasosha omzimba angamaprotheni akhiqizwa ama-B-cell ukuze akusize ulwe nokutheleleka). Lezi zinkinga zingenza kube nzima ukuthi umzimba wakho ulwe nezifo. Ungase unikezwe imithi ukusiza ukuvimbela izifo. Uma unamazinga aphansi e-antibody, ungase udinge ukwelashwa kokubuyisela i-immunoglobulin (ukufakwa kwamasosha omzimba) ukusiza ukuqinisa amasosha akho omzimba.

Ukuhlolwa komtholampilo e-Australia

Ziningi izivivinyo zemitholampilo ezenziwayo njengamanje emhlabeni wonke zomdlavuza wegazi ohlukahlukene kanye nomdlavuza oqinile wesimila. Kuye kwaboniswa ukuthi iphumelela kakhulu kuma-B-cell lymphomas athile. Kukhona okwamanje izivivinyo zomtholampilo ze-B-cell lymphoma e-Australia yonkana ezitholakalayo (kusukela ekwelashweni komugqa wokuqala) za:

Sabalalisa i-B-cell lymphoma enkulu
I-lymphoma elandelayo
I-Mantle cell lymphoma
I-B-cell non-Hodgkin lymphoma
I-Chronic Lymphocytic leukemia

Ukuze uthole ulwazi olwengeziwe bheka ikhasi lewebhu elithi 'Ukuqonda Izilingo Zomtholampilo' noma bheka www.clinicaltrials

Izivivinyo zomtholampilo zamazwe ngamazwe

Ziningi izivivinyo zomtholampilo zokwelashwa kwe-CAR T-cell emhlabeni jikelele. Amazwe ahamba phambili ekuthuthukisweni nasezivivinyweni zokwelashwa atholakala e-USA naseYurophu. Kukhona izivivinyo zomtholampilo ezibheka ama-lymphomas amaningi ahlukene kanye ne-leukemia kusukela ekwelapheni komugqa ongaphambili, futhi esimweni esibuyele emuva noma esiphikisayo.

Izivivinyo zomtholampilo zokwelashwa kwe-CAR T-cell kubantu zaqala ngo-2012. Kwagunyazwa kuphela i-FDA (Ukuphathwa Kokudla Nezidakamizwa e-USA) ngo-2017 esibone inqubekelaphambili yomhlaba wonke esheshayo ekusetshenzisweni kokwelashwa kwe-CAR T-cell.

Abacwaningi basazama ukuqonda ukuthi lokhu kwelashwa kusebenza kanjani, ukuthuthukisa imiphumela emibi kanye nokwenza ngcono imiphumela yeziguli. Yindawo yocwaningo ethuthuka ngokushesha futhi ethokozisayo ukuthi isihambe ibanga elingakanani ngesikhathi esifushane.

Ukuze uthole ulwazi olwengeziwe bheka ikhasi lewebhu elithi 'Ukuqonda Izilingo Zomtholampilo' noma bheka www.clinicaltrials

Ngeminye imininingwane

Khuluma nodokotela wakho wegazi mayelana nokuthi uyafaneleka noma ufanelekile yini ukuthola ukwelashwa kwe-CAR T-cell. Uma kunjalo, udokotela wakho we-hematologist angakuhlelela ukuthi akudluliselwe.
Nganoma yimiphi imibuzo ehlobene nokufaneleka kwesiguli ukuthola ukwelashwa kwe-CAR T-cell noma ukuthi iziguli zingakuthola kanjani lokhu kwelashwa, sicela uthumele i-imeyili: CAR-T.enquiry@petermac.org
Ungathintana neLymphoma Nurse Support Line: T 1800 953 081 noma i-imeyili: nurse@lymphoma.org.au ukuze uthole ulwazi olwengeziwe noma iseluleko.

Izethulo ezirekhodiwe, izingxoxo zochwepheshe kanye nezinsiza

Ukubuyekezwa kwe-CAR T-cell Therapy e-Australia - Iseshini Yezemfundo ebanjwe zingama-21 kuNovemba 2020
UDkt Michael Dickinson, Peter MacCallum Cancer Center

Ukwelapha okunoveli ku-aggressive lymphoma & CAR T-cell therapy
UDkt Michael Dickinson, Peter MacCallum Cancer Center

Ukwelashwa kwe-CAR T-cell nokuthi kusho ukuthini ezigulini

Ukusebenzisana kweLymphoma Coalition kanye ne-Acute Leukemia Advocates Network - 30th June 2022

Izingxoxo zochwepheshe be-American Society of Hematology (ASH).

Izingxoxo zochwepheshe be-European Hematology Association

Incwadi yamahlaya ye-CAR T-cell - CLL Society

Eminye imibuzo okufanele uyibuze udokotela wakho

Ingabe ngiyafaneleka ukuthola ukwelashwa kwe-CAR T-cell?

Ingabe zikhona izivivinyo zomtholampilo ze-CAR T-cell ezitholakalayo e-Australia engingafaneleka ukuzenza?

Ingabe zikhona ezinye izindlela zokwelapha ezingcono kimina?

Ingabe zikhona ezinye izivivinyo zomtholampilo ezitholakalayo kimi?

Leli khasi ligcine ukubuyekezwa ngo-Agasti 2020

Umhlahlandlela wesiguli nomndeni wokwelashwa kwe-CAR T-cell - Okuhlangenwe nakho kwesiguli

Ividiyo engezansi "Umhlahlandlela wesiguli nomndeni we-CAR T-cell therapy" yathuthukiswa nguhulumeni we-NSW. Ngenxa yezilungiselelo zabo zobumfihlo asikwazi ukuyidlala ekhasini lethu lewebhu, kodwa uma wena chofoza inkinobho eluhlaza okwesibhakabhaka "Buka ku-Vimeo" ungafinyelela le vidiyo mahhala.

Mayelana ne-Lymphoma