1. No category

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 (GAZYVAROTM) 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
CD1
9
Ig Ig
P
Lyn
P
Syk
P PI3K
P
Btk
PLC-
P
PLC-
PIP2
IP3
Ca2
DAG
+
PKCβ
IK
K
ERK
NF-κB
Business Intelligence : Priority CLL Abstracts Anticipated at 2014 ASCO
Type
BCL-2
Inhibitors
Poster
Oral
Session
Abst. #
7015
LBA7008
Title
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
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.
7014
Independent evaluation of ibrutinib efficacy 3 years
post-initiation of monotherapy in patients with chronic
lymphocytic leukemia/small lymphocytic leukemia
including deletion 17p
Poster
7010
Association of disease progression on ibrutinib therapy
with the acquisition of resistance mutations: A singlecenter experience of 267 patients
Syk
inhibitors
Oral
Session
7007
Phase 2 trial of GS-9973, a selective Syk inhibitor, in
chronic lymphocytic leukemia (CLL)
Anti-CD20
mAbs
Poster
7052
Is obinutuzumab cost-effective in the first-line treatment
of CLL?
BTK
Inhibitors
Oral
Session
Author
John Seymour
John Byrd
Susan O'Brien
Jennifer Woyach
Jeff Sharman
David Veenstra
Details
Sat, May 31
1:15 PM - 4:15 PM
S405
Tues, Jun 3
11:57 AM – 12:09 PM
E354a
Tues, Jun 3
11:33 AM – 11:45 AM
E354a
Sat, May 31
1:15 PM - 4:15 PM
S405
Tues, Jun 3
11:45 AM – 11:57 AM
E354a
Mon, Jun 2
1:15PM – 5:00 PM
S Hall A2
13
Key Highlights and Implications
Insights
Ibrutinib
•
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
CLL
•
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.
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.
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.
14
Key Highlights and Implications
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.
CLL
• 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
ŠT.
CR
(%)
PR
(%)
ORR
(%)
Bcl-2 ant
ABT-199
Bcl-2
Sindrom lize tumorja,
nevtropenija
56
13
72
85
TKI
Idelalisib
(CAL-101)
PI3 kinaza
Pljučnica, dispneja, FN,
pireksija
54
4
52
56
Ibrutinib
Bruton TK
diareja
85
2
68
71
IBRUTINIB: NOVA MALA
MOLEKULA, INHIBITOR OF BTK
• Tvori specifične, irreverzibilne vezi z
cisteinom-481 v Btk
O
NH
• Močna inhibicija Btk pri IC50 = 0.5 nM
• Peroralna oblika z dnevnim jemanjem
in 24-urno tarčno inhibicijo
2
N
• Inhibira receptorsko odvisno
signaliziranje v B celicah in je aktiven
pri spontanih pasjih B-celičnih limfomih
N
N
N
• V celicah KLL vzpodbuja apoptozo,
inhibira ERK1/AKT fosforilacijo, NF-κB
DNA vezavo, s CpG posredovano
proliferacijo in zaščito strome
N
O
PCI-32765
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: 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
CD244; CD160, PD1:
BOLEZNIH
CTLA4, TIM3,LAG3:*
CLL CD8+ T proliferacija:
CLL CD8+ citotoksičnost:
Pakiranje grancimov:
Interferon-γ, TNFα:*
T celica
KLL
IL2:*
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
SIMPTOMATSKI
•  NE ZDRAVITI!
•  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.
CIRS OPREDELJUJE
KOMORBIDNOST BOLNIKOV
S komorbidnostmi
Brez večjih soobolenj
25
Bolniki (%)
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
STANJE
ZMOGLJIVOSTI
Del (17p)
p53mut
ZDRAVLJENJE
Neaktivna bolezen,
Binet A-B, Rai 0-II
Nepomembno
Nepomembno
Ni indicirano
Aktivna bolezen,
Binet C, Rai III-IV
Go-Go
ne
FCR
da
Ibrutinib, ABT-99, AloTKMC
ne
Clb + obinutuzumab
(R, ofatumumab)
da
Ibrutinib, Al, HD R, O
Slow-go
ZDRAVLJENJE PONOVITVE ALI
REFRAKTARNE KLL
M. Halek, EHA 2014
Del(17p) ali p53 mutacija
ali relaps < 2 leti
Go-Go
Ibrutinib, alemtuzumab, ABT-199, alo-TKMC
Slow go
Ibrutinib, alemtuzumab
Brez del (17p) ali mutacije
p53 ali relaps > 2leti
Go-Go
Ponoviti 1. linijo, BR po FCR
Slow go
Ponoviti 1. linijo, BR
RELAPS ALI REFRAKTARNA KLL
(DO 2014)
STANJE
ZMOGLJIVOSTI
ZDRAVLJENJE
STANDARDNO
ALTERNATIVNO
(KL. ŠTUDIJA)
REFRAKTARNI/
GO-GO
PROGRES < 2LETI ali
Del(17p) ali p53
mutacija
SLOW-GO
Al-Dex, FA,
FCR 
Alo-TKMC
Len, BR, BR2,
kombinacije z
inhibitorji kinaz
spremeni Z, kl. študija
Al za del(17p), FCRlite,
BR, Bendamustin, len,
ofatumumab, HD-R,
inhibitorji kinaz
PROGRES > 2LETI
Ponovi 1. linijo
VSI
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.
•
•
•
•
1-2 meseca
6-12 mesecev
1 leto 
Ant
lenalidomid
Kinazni inh.
Bcl antag.
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!