Parimet e kimioterapise

Prof. A. Ivanaj
Cancer care
C. June, EHA 2018
The cell of origin in AML. During normal myelopoiesis, HSC differentiate into mature blood cells via progenitor populations in a series of lineage
restriction steps.

Horton S J , Huntly B J Haematologica 2012;97:966-974

Targeting the LSC. Knowledge of the initiating genetic lesion and the downstream driver mutations will allow the delivery of specifically
tailored targeted therapies.

Horton S J , Huntly B J Haematologica 2012;97:966-974

AML
Traditional chimiotherapy (klasat kryesore)
• Alkylantet
• Antimetabolitet
• Interkalantet (inhibitoret e topoisomerases I dhe II)
• Medikamentet qe veprojne me tubulat
Alkilantet shkaktojne modifikime covalente te ADN

• Mutarda e Azotit ( clorambucili, malphalani, cyclophosphamidi, etj)

• Nitroso-ure (lomustine, fotemustine, etj)
• Organoplatine (cisplatine, carboplatine, oxaliplatine)
• Ethylene- imines (thiotepa, altretamine)
• Triazene (procarbazine, temozolomide, dacarbazine)
• Alkilante te tjere (busulfani, bendamustina etj.)
Antimetabolitet veprojne ne biosintezen e ADN
• Antifoliniket (metrotrexati etj.)
• Antipuriniket (mercaptopurina, pentostatina, cladribina, fludarabina
etj.)
• Antipirimidiket (azacytidina, 5-fluoro-urocili, capecitadina, cytarabina,
decitabina)
• Te tjera antimetabolite (hydroxyurea, gemcitabine)
Mekanizmi i veprimit te antimetabolikeve, disa nga medikamentet e kesaj familje

• Metrotrexati vepron si analog i acidit folik, duke vepruar si substrak

zevendesues duke frenuar nga kompetiviteti dihydrofolate-reduktazen
dhe bllokon sintezen e bazave purinike dhe pirimidike.
• Fludarabine vepron si derivat fluorine i adenosine-arabinosine
monophosphorile, resistent i adenosinedesaminazes dhe i
transformuar ne substrat te gabuar (2-F-ara_ATP)
• Aracytina, antimetabolit pyrimidique (nucleoside pyrimidique i
sintezes i ngjashem me cytidine, ku ribosa eshte zevendesuar me
arabinoze, duke frenuar sintezen e AND nga inkorporimi i AND dhe
frenimi direkt i AND polimerazes
Interkalantetet veprojne duke shaktuar dhe stabilizuar keputje
te ADN

• Inhibitoret e topoisomerazes I, camptothecina (irinotecan, topotecan)

• Inhibitoret e topoisomerazes II frenojne sintezen e acideve nukleike,
jane jo faze dependente, por veprojne me shume ne fazen S.
Antracyclinat (epirubicine, idarubicine, daxorubicine, daunorubicine)
Antracenedione (mitoxantrone, etj.)
Te tjere interkalante (etoposide, actinomycine)
Medikamente ndares (bleomycina) prodhohet nga streptomyces
verticillus, vepron duke fragmentuar AND.
Toxiciteti cardiak i doroxicilines
Medikamente qe veprojne me tubulat
• Alcaloidet e pervenches ose vinca-alcaloide (vincristina, vinblastina,
vindesina, etj) veprojne duke u fiksuar ne tubulat dhe blokojne
qelizen ne metaphaze.
• Stabilizantet e fuseau (taxanet), derivate te if te paqesorit duke
blokuar replikimin qelizore duke frenuar depolimerizimin e tubulines
dhe rritur polimerizimin e saj
• Frenuesit e mikrotubulave
 Moduluesit e senescence

Cellular senescence is a
highly stable cell cycle arrest
initiated in response to a
variety of stress signals to
prevent the replication of
old, damaged or
preneoplastic cells. The
implementation of the
senescence growth arrest
depends on the activation of
the p21CIP1/WAF1/p53 and
p16 INK4A/RB tumour
suppressor pathways.

Molecular Oncology, Volume: 16, Issue: 21, Pages: 3855-3880, First published: 05 September 2022, DOI: (10.1002/1878-0261.13312)
Targeting senescence as
an anticancer therapy

Molecular Oncology, Volume:

16, Issue: 21, Pages: 3855-
3880, First published: 05
September 2022, DOI:
(10.1002/1878-0261.13312)
The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of acute myeloid leukemias

Haematologica; Vol. 107 No. 11 (2022): November, 2022

Medikamente diferencuese, Retinoidet (acidi gjithe - trans-retinoike, ATRA) eshte
metabolite natural i retinol, qe vepron si agjent defirencues, i cili shkakton
diferencimin e granulociteve funksionale te linjes qelizore ne LAM3
Antitrupat monoklonale jane selektive dhe shkaterrojne vetem qelizat
malinje mbartese te antigjenit ndaj te cilit jane prodhuar, njeri nder
me te perdorurit eshte anti – CD 20, i pari ne perdorim klinik

• Imunoterapia bazohet ne
perdorimin e nje proteine te
qelizes malinje si antigjen,
ndaj se ciles prodhojme in
vitro nje antitrup
monoklonal, perdorimi i te
cilit in vivo do te njohe
antigjenin e tij, duke formuar
kompleksin antitrup –
antigjen, i cili drejton qelizen
drejt shkaterrimit te saj

Critical Reviews in Oncology / Hematology. 97: p. 275-290

 Potential Mechanisms of Action of Monoclonal Antibodies
(Mekanizmi i veprimit te antitrupave monoklonale).)

Cheson BD, Leonard JP. N Engl J Med 2008;359:613-626.

Immunomodulatoret
• Thalidomidi, i cili ka efekte immunomodulatore, anti-angiogjenike,
anti-inflamatore dhe potencialisht anti-tumorale, vecanersiht nga
prodhimi i anti-TNF alfa.
• Lenalidomidi, immunomodulator anti-angiogjenike, anti-tumoral dhe
pro-erytropoietike, vecenerisht nga prodhimi I anti-TNF alfa, mee
theksuar ne qelizat e linjes myeloide dhe blastet me delecionin e
kromozomit 5
lenalidomide

J Hematol Oncol. 2009; 2: 36.

Anti methylizantet
Targeting DNA Methylation Clin Cancer Res. 2009 Jun 15; 15(12): 3938–3946.
Targeting DNA Methylation
Clin Cancer Res. 2009 Jun 15; 15(12): 3938–3946.
Inhibitoret e proteasome
• Carfilizomib frenues selektive dhe i pakthyeshem i nen-unitetit beta
te proteasome 20S me te cilen lidhet dhe frenon aktivitetit e saj
chymotrypsique dhe shkakton apoptozen e qelizave myeloide.
• Bortozomib frenon proteazome 26S (proteazome e implikuar ne
degradimin e proteinave qelizore) duke stimuluar apoptozen e
qelizave malinje.
“One size fits all” versus Precision Medicine

Medical diagnostics and treatments have long been focused on the general principles that work
for the majority of patients, but not for all patients of a specific group
Who can benefit from FCR?
MRD +
(40%)

IgHV UNMUTATED (+/- gene abnormalities) (60%)

7%
AGE > 65 yrs & COMORBIDITIES (60%)

NO NEEED FOR TREATMENT (30%)

Target terapy
• Inhibitoret e tyrozine kynaze parimi i veprimit te tyre bazohet duke
frenuar mekanizmin e veprimit te produktit (TK) te prodhuar nga
demtimi gjenetik, i cili eshte karektaristike e kancerit te dhene.

• Shembulli me i mire eshte Leucemia Myeloide Kronike, por jo vetem.

Therapeutic targets in CLL
BCR PATHWAY

APOPTOTIC PATHWAY

del13q14 (miR15/16)

CD79A
CD79B
Venetoclax
Ibrutinib covalent
Acalabrutinib
BTK Zanubrutinib
TP53

Pirtobrutinib non covalent

cyt C Nemtabrutinib
Bak
Bak
Bak

TP53 Bcl2 PLCƴ2

tBid

Bcl2 Bcl-xl
TP53
Bcl-xl
ERK
Bcl2
Bak

cypD

Bcl-xl NF-kB
TP53
activation
PTP
MAPK

TP53
ROS
Biology of CML
Chromosome 22 Chromosome 9 Philadelphia (Ph) Cytogenetics
chromosome

9
BCR t (9;22)

BCR
ABL ABL
22 Ph+

BCR-ABL + Signaling pathways Deregulation CML

(Tyrosine kinase) • Ras • Cell proliferation • WBC (myeloid) é
• AKT • Cell survival • RBC ê
• PI3K > • DNA repair > • Platelets ê
• Other pathways

-
Tyrosine kinase inhibitors (TKIs)
CGP57148; STI571; imatinib; Glivec
TK inhibitory activity
Stability to hydrolysis

H H N

N N N N
Solubilisation

N O

No PKC inhibition
• Potent inhibition of Abl-K, c-kit and PDGF-R
• Salts are soluble in water
• Orally bioavailable
N • Not mutagenic

Cellular permeability

1992
Treatment landscape of triple-negative breast cancer-expanded options evolving needs

https://www.nature.com/articles/s41571-021-00565-2
future
Inhibitoret e bcl-2
• venetoclax
Antikanceroze te ndryshem
• Asparginaza enzyme cytostatike me origjine bakteriale, frenon
sintezen proteinike nga mungesa e aspargines ne nivelin e qelizave
leucemike
Hormonoterapia (tumoret solide kryesisht)
• Inhibitoret e lidhjeve te oestradiolit, aromatazes etj
Cytokinat
• Faktoret e rritjes qelizore, filgrastim, etj
Trajtimi qelizore
• Car-T cell therapy
Procedure illustration….
A little story ….
 Chimeric Antigen Receptor T-Cell Therapy.

Panel A shows the general steps in

chimeric antigen receptor (CAR) T-
cell therapy, in which white cells
are first isolated from the patient by
means of leukapheresis and then
are taken to a Good Manufacturing
Practice (GMP) production facility,
where T cells are activated and
genetically engineered with a
retrovirus encoding the CAR.
CAR T cells are further expanded,
harvested, and finally reinfused into
the patient, who has undergone a
preparative lymphodepletion
regimen before infusion.
In the ZUMA-1 study by Neelapu et
al., the entire process took a
median of 17 days.
Panel B shows the differences in
design of the anti-CD19 CARs used
in the study by Neelapu et al. and
those used in the study by Schuster
et al. TCR denotes T-cell receptor.

Tran E et al. N Engl J Med 2017;377:2593-2596.

C. June, EHA 2018
 Chimeric Antigen Receptor (CAR) T Cells Engrafting, Trafficking to
Tumor, and Proliferating Extensively after Infusion.
Chimeric Antigen Receptor
(CAR) T Cells Engrafting,
Trafficking to Tumor, and
Proliferating Extensively
after Infusion.
After infusion, CAR T cells
leave the blood and travel
to sites of tumor, where
they identify and kill tumor
cells.
This can trigger extensive
proliferation of CAR T cells
and the release of tumor
antigens, which activates
the immune system to
recruit non–CAR T cells,
thus eliciting further
antitumor responses in a
process known as cross
CH June, M Sadelain. N Engl J Med 2018;379:64-73.
priming.
C. June, EHA 2018
Pra si t’i perdorim te gjitha keto ???
• Parimi kryesor e i perdorimit te kimioterapise klasike ka qene dhe
mbetet efekte maksimale mbi qelizen malinje me efekte sa me te
pakta sekondare mbi organizmin.
• Perdorimi i preperateve te cilat kane sinegjizemin njeri me tjetrin, pra
qe rrisin efektin e njeri-tjetrit mbi qelizen malinje pa rritur toksicitetin
mbi organizmin (ose toksicitet te pranueshem).

• Me qellim per te arritur jetegjatesi me te larte te mundshme dhe

jetegjatesi pa semundje maksimale per te semurin.
Kombinimi i ”te vjetres me te rene”
rruga e duhur, kimioterapia klasike
me target terapy.
The Goal of the Chemotherapy SoC is to
achieve And Maintain remission
The current AML chemotherapy SoC for
newly diagnosed fit adult patients consists of

Induction Therapy
Consolidation Therapy Stem Cell Transplant
(7+3)

• 1–2 cycles • Up to 4 cycles • Determined on a case-by-

• Cytarabine • Cytarabine case basis
– 100–200 mg/m2/d IV – 1000–3000 mg/m2 IV q12h • Ideally in first CR, and for
– Days 1–7 – Days 1, 3, 5 higher-risk patients
• Anthracycline
– 60–90 mg/m2/d IV
daunorubicin, or
– 12 mg/m2/d IV idarubicin
– Days 1–3

CR = complete remission; depending on age, 40–85% of patients will achieve a CR; SoC = standard of care.
Döhner H, Weisdorf DJ, Bloomfield CD. N Engl J Med. 2015;373(12):1136-1152.
Anti-flt3

RYDAPT® (midostaurin) Brings the first Significant advance to the aml standard of care in
decades
Date of first approval Drugs Approved for Newly Diagnosed AML1,2*

1969 1979 1987 1990 2005 2008 2012 2017 2018

Daunorubicin Idarubicin Azacitidine RYDAPT®

CPX-351
Cytarabine Mitoxantrone
Histamine Decitabine Gemtuzumab
dihydrochloride ozogamicin†

2017: RYDAPT is the first and only EMA-approved targeted therapy for adult
patients with newly diagnosed AML who are FLT3 mutation-positive

*Timeline excludes therapies specific for APL. For AML, the standard of care is induction with 3 days of an anthracycline and 7 days of cytarabine
followed by consolidation therapy3. †Reapproved after market withdrawal in 2010.
1. Drugs@FDA: FDA Approved Drug Products. Food and Drug Administration Website. http://www.accessdata.fda.gov/scripts/cder/daf/. Cytarabine: NDA ID 016793,
Daunorubicin: NDA ID 050484, Mitoxantrone: NDA ID 019297, Idarubicin: NDA ID 050661, Midostaurin: NDA ID 207997, CPX-351: NDA ID 209401, Gemtuzumab
ozogamicin: NDA ID 021174. Accessed February 21, 2018; 2. European Medicines Agency Website. http://ema.europa.eu/. Histamine dihydrochloride: orphan
decision number EU/3/05/272, Azacitidine: agency product number EMEA/H/C/000978 and ATC code L01BC07, Decitabine: agency product number
EMEA/H/C/002221 and ATC number L01BC08. Accessed March 2, 2017. 3. Referenced with permission from the 2017 ELN recommendations for diagnosis and
management of AML in adults. Döhner H, Estey E, Grimwade D, et al. Blood. 2017;129(4):424-447.
New directions for emerging therapies in acute myeloid leukemia: the next chapter 7 + 3, 7 days of standard-dose cytarabine
plus 3 days of anthracycline; ADC
antibody-drug conjugate; AHD antecedent
hematologic disorder; AML acute myeloid
leukemia; AML-MRC AML with
myelodysplasia-related changes; CBF core
binding factor; CLIA cladribine–idarubicin–
Ara-C; CPX-351 liposomal formulation of a
fixed combination of daunorubicin and
cytarabine; GO gemtuzumab ozogamicin;
FLAG-Ida fludarabine–Ara-C–filgrastim plus
idarubicin; FLT3 FMS-like tyrosine kinase;
HMA hypomethylating agent; IDH
isocitrate dehydrogenase; LDAC low-dose
cytarabine; NGS next-generation
sequencing; SCT stem cell transplantation;
t-AML therapy-related AML.

Blood Cancer JournalISSN 2044-5385 (online) October 2020

Kombinimi i
kimioterapise klasike me
immunoterapine,
trajtimin qelizore, apo
target terapy me
immunoterapi etj.
Treatment basis today, anti- CD20 in B cell malignancies,
Perdorimi i ant-CD20 i kombinuar me kimioterapine klasike. CD20 eshte proteine e kudo ndodhur ne limfocitet
malinje, perdorimi I nje antitrupik kunder kesaj protein ka hapur nje mundesi reale ne trajtimin e ketyre
semundjeve.

CHOP DLBCL
DHAP
EPOCH
ICE

CLL CVP FL, MCL

Bendamustine
Bendamustine
Lenalidomide
FC Anti-CD20 CHOP
PC MCP
FCM
Alemtuzumab FCM CHVP
F
Chlorambucil Lenalidomide

PCM FND
Treatment of NHL (DLBCL)
kombinime te ndryshme te kimioterapise klasike ne trajtimin e LMNH dhe kombinimi i tyre me
mjekimet e reja sipas viteve

CHOP Ottlieb J and al. Cancer res. 1973 CHOP Fisher R and al. NEJM, in 1993

R- CHOP Coiffer R and al. NEJM 2002

C. June, EHA 2018
Konkluzione
• Trajtimi kancerit mbetet shume kompleks, progresi i trajtimit te tij
kalon nga te kuptuarit gjithenje dhe me mire te oncogenezes.

• Kombinimi i kimioterapise klasike me target terapine apo

immunotherapine apo dhe terapine qelizore mbetet rruga e duhur ne
progresin e trajtimit te semundjes malinje.