KRONIČNA LIMFOCITNA LEVKEMIJA ASH 2013 ASCO 2014 EHA 2014 Prim. Nataša Fikfak, dr.med., spec. int. med. in hematologije
ASH 2013: Tait Shanafelt: Zdravljenje KLL pri starejših bolnikih; ključna vprašanja in trenutni odgovori ASCO 2014: Susan O Brian: Novosti in priporočila o uporabi novejših zdravil pri zdravljenju KLL EHA 2014: Michael Halek: Novejši pristop k zdravljenju KLL; bodočnost brez kemoterapije?
NOVA ZDRAVLJENJA KLL Nova zdravila CAR-modificirane T celice Priporočila (NCCN smernice 2014, verzija 4)
KLL = heterogena bolezen Prepoznavanje kliničnih, genetskih, bioloških kazalcev bolezni Prepoznavanje značilnosti bolnikov (sočasne druge bolezni, telesna in psihična zmogljivost, funkcionalnost organov. CIRS) Dostopnost do zdravil in zdravstvene oskrbe ZDRAVLJENJE KLL V 2014
CITOSTATIKI KLORAMBUCIL ANALOGI PURINA: fludarabin, pentastatin, kladribin DRUGA KONVENCIONALNA KT: CHOP, COP BENDAMUSTIN
PROTITELESA RITUXIMAB RITUXIMAB + KT OFATUMUMAB OBINUTUZUMAB ALEMTUZUMAB
OFATUMUMAB GSK and Genmab Receive EU Authorization for Arzerra (ofatumumab) as First-Line Treatment for Chronic Lymphocytic Leukemia (CLL) in Combination with Chlorambucil or Bendamustine for Patients Ineligible for Fludarabine-based Therapy OBINUTUZUMAB Evropska agencija za zdravila je odobrila novo biološko zdravilo obinutuzumab (GAZYVARO TM ) za zdravljenje odraslih bolnikov s predhodno nezdravljeno najpogostejšo obliko levkemije ( KLL )
KOMBINACIJE PT + KT FC R-FC FCR-LITE +/- vzdrževanje z R/3 mesece R-klorambucil Obinutuzumab + klorambucil (CLL11) CFAR Mitoxantron + RFC
KOMBINACIJE PT + KT Kombinacije s pentostatinom Kombinacije z bendamustinom: BR Druge kombinacije: kladribin-r, metilprednisolon-r A; RA Kombinacije z alemtuzumabom: - FCA - FA - A + HDMP (CLL20)
NOVA ZDRAVILA S CILJNIM DELOVANJEM NA PATOGENETSKE MEHANIZME KLL
SIGNALNE POTI V B CELICI Bcl-2 Mcl-1 Bcl-xL Proliferacija, migracija, rast in preživetje celic Young RM, Staudt LM. Nat Rev Drug Discov. 2013;12:229-43.
TERAPEVTSKA MODULACIJA RECEPTORSKO ODVISNEGA SIGNALIZIRANJA V B CELICAH PRI KLL pre-bcr Ig Ig CD1 9 P Lyn P Syk P PLC- P PI3K Btk PLC- P PIP 2 DAG IP 3 Ca 2 + PKCβ ERK IK K NF-κB
Business Intelligence : Priority CLL Abstracts Anticipated at 2014 ASCO Type Abst. # Title Author Details BCL-2 Inhibitors Poster 7015 ABT-199 (GDC-0199) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL): High complete-response rate and durable disease control John Seymour Sat, May 31 1:15 PM - 4:15 PM S405 Oral Session LBA7008 Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. John Byrd Tues, Jun 3 11:57 AM 12:09 PM E354a BTK Inhibitors Oral Session 7014 Independent evaluation of ibrutinib efficacy 3 years post-initiation of monotherapy in patients with chronic lymphocytic leukemia/small lymphocytic leukemia including deletion 17p Susan O'Brien Tues, Jun 3 11:33 AM 11:45 AM E354a Poster 7010 Association of disease progression on ibrutinib therapy with the acquisition of resistance mutations: A singlecenter experience of 267 patients Jennifer Woyach Sat, May 31 1:15 PM - 4:15 PM S405 Syk inhibitors Oral Session 7007 Phase 2 trial of GS-9973, a selective Syk inhibitor, in chronic lymphocytic leukemia (CLL) Jeff Sharman Tues, Jun 3 11:45 AM 11:57 AM E354a Anti-CD20 mabs Poster 7052 Is obinutuzumab cost-effective in the first-line treatment of CLL? David Veenstra Mon, Jun 2 1:15PM 5:00 PM S Hall A2 13
Key Highlights and Implications CLL Ibrutinib Insights Interim RESONATE (Ph III, Ibrut vs. Ofa in R/R CLL, NCT01578707) and RESONATE-17 (Ph II, Ibrut in R/R del17p CLL, NCT01744691) results presented show Ibrutinib as a beneficial therapy for R/R CLL/SLL patients irrespective of del17p. The ORR in del17p was not significantly different than those pts with all other cytogenetic risk. NPP available for R/R CLL in Europe but only eligible for del17p pts till end of September according to one KOL. Idelalisib Study 116 data (Ph III, Idela + R vs. R in R/R CLL, NCT01539512) was presented demonstrating Idela +R retained robust efficacy across all high-risk subpopulations including highest risk patients who were positive for both del17p and TP53mut (76.5% ORR and PFS HR 0.13) Study 117 (extension study of study 116, NCT01539291) is the only EAP for idelalisib for CLL patients in Europe. ABT-199 Poster presentation demonstrated changes implemented in the dosing schedule and pt monitoring reduce the risk of clinically relevant TLS. Ph I results after protocol modification shows ABT-199 was tolerable and active in R/R CLL including del17p and fluda refractory disease. 23% of pts achieved CR out of which some were evaluated for MRD and found to be MRD negative. ABT-199 monotherapy & combination trials in CLL have commenced. ONO-4059 Ph I trial showed a ONO-4059 has a favourable safety profile along with promising efficacy in heavily pre-treated CLL (best ORR 84%), with responses observed in 17p deleted patients and/or TP53 mutated patients. Implications Novel agents targeting various pathways are jostling to demonstrate robust efficacy in R/R CLL and high risk groups. This has set a high barrier for new entrants. Other product profiles such as toxicity, durability, combinability and accessibility will likely play a role in treatment decisions. 14
Key Highlights and Implications CLL Insights Other novel agents Ph I results of abexinostat demonstrates the agent has a safe toxicity profile and encouraging efficacy (ORR 30%) in R/R HL, NHL and CLL. KOL perception KOLs chooses to prescribe novel agents based on their efficacy, toxicity, combination with other agents and accessibility. Ibrutinib s properties of single agent activity, bleeding side effects and accessibility are highlighted by KOLs. Idelalisib has more promising efficacy than ibrutinib in terms of OS rate and durability in TP53 mutant patients when used in combination with rituximab. ABT-199 is perceived to have the highest CR rate. MRD is considered an important clinical marker of curability and indicator to cease treatment especially in the front line setting. It is considered more important than CR. Some KOL believe accessibility/cost will be a key factor in prescription choice. Implications Treatment paradigm for R/R CLL will change in the near future with the entry of novel agents. MRD particularly in the first line setting is increasingly being recognized as an important clinical marker to guide treatment and will be leveraged as a key differentiators by competitors. It should be considered to be part of the analysis in future trials. 15
KLINIČNA UČINKOVITOST IN GLAVNI NEŽELENI UČINKI IZBRANIH TARČNIH ZDRAVIL PRI KLL SKUPINA ZDRAVILO TARČA AE STOPNJE 3, 4 ODGOVOR PRI R-KLL Bcl-2 ant ABT-199 Bcl-2 Sindrom lize tumorja, nevtropenija TKI Idelalisib (CAL-101) PI3 kinaza Pljučnica, dispneja, FN, pireksija ŠT. CR (%) PR (%) ORR (%) 56 13 72 85 54 4 52 56 Ibrutinib Bruton TK diareja 85 2 68 71
Honigberg LA, et al. Proc Natl Acad Sci USA.2010;107(29):13075-80. Herman SE, et al. Blood. 2011;117(23):6287-96. IBRUTINIB: NOVA MALA MOLEKULA, INHIBITOR OF BTK O Tvori specifične, irreverzibilne vezi z cisteinom-481 v Btk Močna inhibicija Btk pri IC 50 = 0.5 nm N N H 2 N N N N O Peroralna oblika z dnevnim jemanjem in 24-urno tarčno inhibicijo Inhibira receptorsko odvisno signaliziranje v B celicah in je aktiven pri spontanih pasjih B-celičnih limfomih V celicah KLL vzpodbuja apoptozo, inhibira ERK1/AKT fosforilacijo, NF-κB DNA vezavo, s CpG posredovano proliferacijo in zaščito strome PCI-32765
IBRUTINIB: ŠTUDIJE Faza 2: ibrutinib + BR Ibrutinib + R Registracijske študije v ZDA: -- relaps/refr KLL: ibrutinib / ofatumumab -- relaps/refr:br+/-ibrutinib -- 1.zdravljenje: ibrutinib / klorambucil
IBRUTINIB( IMBRUVICA 140mg kaps) Doza : 420mg/d Začetna limfocitoza ( >50% povečanje ) Neželeni stranski učinki : - diareja - krvavitve - okužbe - mielosupresija - nefrotoksičnost - sekundarni malignomi
IDELALISIB (CAL 101) Neželeni učinki: hiperglikemija, povečana aktivnost transaminaz; mielosupresija, večje tveganje za okužbe Odmerjanje: 2x/d p.o. Kombinacije: + ofatumumab + R + bendamustin + BR
IDELALISIB: ŠTUDIJE Relaps/refr, not fit za KT: R+/- idelalisib Relaps/refr: ofatumumab +/- idelalisib Relaps/refr: BR+/-idelalisib
IMUNOMODULATORJI Lenalidomid R-len R-len-F R-len-Bendamustin (CLL2P protokol) Flavopiridol-len Len-ofatumumab
IZČRPANJE LIMFOCITOV T PRI B CELIČNIH LIMFOPROLIFERATIVNIH BOLEZNIH CD244; CD160, PD1: CTLA4, TIM3,LAG3:* CLL CD8+ T proliferacija: CLL CD8+ citotoksičnost: Pakiranje grancimov: Interferon-γ, TNFα:* T IL2:* celica KLL Te spremembe izniči lenalidomid Riches JC, et al. Blood. 2013;121:1612-21.
CARS Chimeric Antigen Receptor Modified T cells Genetsko spremenjeni T limfociti na površini anti CD-19 CD 19 na LyB celična smrt Priprava lastnih LyT Rezultati na 25 bolnikih (OR 47%, CR 17%, PR 22%) Toksičnost: hepatotoksičnost, ledvična okvara, sindrom tumorskega razpada (CRS), aplazija B limfocitov, hipogamaglobulinemija Sindrom sprostitve citokinov: povečana TT, mialgija, hipotonija, respiratorna insuficienca ukrep: tocilizumab
ALGORITEM ZDRAVLJENJA Z ODOBRENIMI ZDRAVILI Klinični stadij bolezni (Binet, Rai) Telesna (+ psihična) zmogljivost bolnika: CIRS; OGFR Stopnja zdravljenja: 1. zdravljenje zdravljenje ponovitve bolezni odzivnost na 1. zdravljenje
BOLNIK ASIMPTOMATSKI NE ZDRAVITI! SIMPTOMATSKI 1. ZDRAVLJENJE del(17p) ali p53 mutacija zmogljivost bolnika (go-go; slow go)
NI DOBRIH STANDARDOV ZDRAVLJENJA ZA BOLNIKE S SLABIM PS Go: CIRS 6 in OGFR 70 ml/min Slow: CIRS > 6 in OGFR < 70 ml/min Ne: hujše spremljajoče bolezni in kratka pričakovana življenjska doba Gribben JG, et al. Blood. 2009;114(16):3359-3360. Goede V, et al. Blood. 2013;122: Abstract 6.
CIRS TABELA Linn BS, et al. J Am Geriatr Soc 1968; 16:622 626. Parmelee PA, et al. J Am Geriatr Soc 1995; 43:130 137.
Bolniki (%) CIRS OPREDELJUJE KOMORBIDNOST BOLNIKOV 25 Brez večjih soobolenj S komorbidnostmi 20 15 10 5 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 CIRS celokupni seštevek Extermann M, et al. J Clin Oncol 1998; 16:1582 1587.
ZDRAVLJENJE KLL: 1. LINIJA STADIJ Neaktivna bolezen, Binet A-B, Rai 0-II Aktivna bolezen, Binet C, Rai III-IV STANJE ZMOGLJIVOSTI Del (17p) p53mut ZDRAVLJENJE Nepomembno Nepomembno Ni indicirano Go-Go ne FCR da Ibrutinib, ABT-99, AloTKMC Slow-go ne Clb + obinutuzumab (R, ofatumumab) da Ibrutinib, Al, HD R, O
ZDRAVLJENJE PONOVITVE ALI REFRAKTARNE KLL M. Halek, EHA 2014 Del(17p) ali p53 mutacija ali relaps < 2 leti Brez del (17p) ali mutacije p53 ali relaps > 2leti Go-Go Slow go Go-Go Slow go Ibrutinib, alemtuzumab, ABT-199, alo-tkmc Ibrutinib, alemtuzumab Ponoviti 1. linijo, BR po FCR Ponoviti 1. linijo, BR
RELAPS ALI REFRAKTARNA KLL (DO 2014) REFRAKTARNI/ PROGRES < 2LETI ali Del(17p) ali p53 mutacija STANJE ZMOGLJIVOSTI GO-GO STANDARDNO Al-Dex, FA, FCR Alo-TKMC ZDRAVLJENJE ALTERNATIVNO (KL. ŠTUDIJA) Len, BR, BR2, kombinacije z inhibitorji kinaz SLOW-GO spremeni Z, kl. študija Al za del(17p), FCRlite, BR, Bendamustin, len, ofatumumab, HD-R, inhibitorji kinaz PROGRES > 2LETI VSI Ponovi 1. linijo
M.HALEK: SEQUENTIAL TRIPLE T TREATMENT ailored argeted otal eradication of MRD
M.HALEK: SEQUENTAL TRIPLE T TREATMENT Debulking Indukcija MRD prilagojeno vzdrževanje Šibka KT (bendamustin, fludarabin) Kinazni inh. protitelesa Bcl 2 antag. Ant lenalidomid Kinazni inh. Bcl antag. 1-2 meseca 6-12 mesecev 1 leto
LIMFOME ZDRAVIMO V SBG
AMERIŠKE SMERNICE NCCN http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site
AMERIŠKE SMERNICE NCCN DEL 17P http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site
EVROPSKE SMERNICE ESMO Eichhorst B, et al. Annals of Oncology. 2011;22(Supplement 6):vi50 vi54.
ZDRAVLJENJE KLL PRI STAREJŠIH
STAREJŠI BOLNIKI SO RAZLIČNI Starejši & v dobri kondiciji Starejši & v slabši kondiciji Starejši & šibki
CILJI ZDRAVLJENJA PRI STAREJŠIH Shanafelt T. Hematology Am Soc Hematol Educ Program 2013;2013:158-67.
ALGORITEM ZDRAVLJENJA PRI STAREJŠIH > Shanafelt T. Hematology Am Soc Hematol Educ Program 2013;2013:158-67.
PODPORNO ZDRAVLJENJE Screening za maligne bolezni: pregled kože letno; dojke, širokega črevesa, materničnega vratu Cepljenje: 13-valentno cepivo ob Dg, po 8 tednih dodatno 23 (Pneumovax), ponoviti po 5 letih; letno proti gripi; izogibati živim atenuiranim vakcinam Fatigue: ocena telesne zmogljivosti neodvisno od KLL; depresija, drugi raki, hipotiroza, sleep apnea, anemija, nepovezana s KLL Druga priporočila: Vit D, prenehanje kajenja
HVALA ZA POZORNOST!