A Decade Experience

Treating CML with TKIs:

Lesson Learned
PIT PAPDI Jogya
20 March 16
Alana Hotel

Johan Kurnianda
Division of Hematology-Medical Oncology
Department of Internal Medicine
Gadjah Mada University/Dr. Sardjito Hospital
Yogyakarta, Indonesia
 CML : Burden of Disease
Age-Adjusted Incidence Rate
New Cancer Cases Worldwide (as defined by SEER)
20121 2008-20122

97%
3% 87%
13%

1 to 2 new cases of CML are diagnosed per 100,000 people annually3

The prevalence of CML is increasing annually due to reduced mortality

with newer treatments4,5
SEER, Surveillance, Epidemiology, and End Results Program.
1. International Agency for Research on Cancer. GLOBOCAN 2012: estimated cancer incidence, mortality and prevalence worldwide in 2012.
http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. Accessed July 20, 2015; 2. Surveillance Epidemiology, and End Results Program. SEER Cancer Statistics Review,
1975-2012. http://seer.cancer.gov/csr/1975_2012/. Accessed July 20, 2015; 3. Baccarani M, et al. Ann Oncol. 2009;20(suppl 4):105-107; 4. Rohrbacher M, Hasford J. Best Pract
2 Res Clin Haematol. 2009;22(3):295-302; 5. Huang X, et al. Cancer. 2012;118(12):3123-3127.
 CML : Natural History

Accelerated Phase
Spleen enlargement

Chronic phase Blast Crisis Phase

Goals of treatment
 Philadelphia Chromosome Is the Hallmark of CML

Chromosome 9

Chromosome 22 BCR-ABL transcripts (qualitative

PCR) are also confirmatory
t(9;22)
BCR ABL evidence of
Ph+ CML1
Fusion containing
BCR-ABL gene
(Philadelphia chromosome) Presence of the Philadelphia
chromosome is a diagnostic
marker of CML in most patients2,3
BCR-ABL protein

Deregulated tyrosine kinase activity

5 1. Baccarani M, et al. Blood. 2013;122:872-884; 2. Faderl S, et al. N Engl J Med. 1999;341(3):164-172; 3. Baccarani M, et al. Ann Oncol. 2009;20(suppl 4):105-107.
 Ph Chromosome is
An Oncogene Addicted

Genes and Developement 21, 3214-31, 2007

 Mechanism of Action of STI571

Bcr-Abl
Bcr-Abl
Substrate
Substrate
STI571
P
ATP P
P

Y = Tyrosine
P = Phosphate
P

Goldman JM. Lancet. 2000;355:10311032.

Various Generations of TKIs
 Survival in Early Chronic-Phase
CML
1.0 Year Total Dead
93% Imatinib 302 15
84% (censored for non-CML death)
0.8 Imatinib 302 31
1990-2000 963 425
1982-1989 364 273
Proportion Alive

0.6 1975-1981 132 129

1965-1974 123 123

0.4

0.2

0
0 3 6 9 12 15 18 21 24 27
Yrs From Referral
The University of Texas M. D. Anderson Cancer Center database. Reprinted with permission.
 CML: Overview of Historical vs
Modern Perspective
Parameter Historical Perspective Modern Perspective
(Until 2000) (Since 2000)
Course Fatal Indolent
Prognosis Poor Excellent
10-yr survival 10% 84% to 90%
Frontline treatment Allogeneic SCT, Imatinib or dasatinib or
interferon alfa nilotinib
Second-line treatment Not established Allogeneic SCT or
novel TKIs

Faderl S, et al. Ann Intern Med. 1999;131:207-219.

Druker BJ, et al. N Engl J Med. 2001;344:1031-1037.
 Measurement of Treatment Response
Hematologic response (HR)1
Measure of blood counts and differentials
Complete HR (CHR)
- WBCs < 10 109/L, basophils < 5% - Platelet count < 450 109/L
- No blasts in the differential - Nonpalpable spleen

Cytogenetic response (CyR)

Chromosome banding analysis of BM cell metaphases2
Partial CyR (PCyR): 1%-35% Ph+ metaphases, with 20 metaphases examined1,2
Complete CyR (CCyR): no Ph+ metaphases, with 20 metaphases examined1,2

Molecular response (MR)

Measurement of BCR-ABL transcript levels relative to those of a control gene2,3
Major MR (MMR): ratio of BCR-ABL expression to that of a control gene 0.1%
according to the International Scale (IS)1,2

11 1. Baccarani M, et al. J Clin Oncol. 2009;27(35):6041-6051; 2. Baccarani M, et al. Blood. 2013;122(6):872-884; 3. Cross NCP. Best Pract Res Clin Haematol. 2009;22(3):355-365.
 Correlation Between
Response and Disease Burden
Number of Leukemic Cells1

1012 Hematologic
Cyto-

BCR-ABL Transcripts, log101-3

1011 CHR (< 1-log) genetic

1010 CCyR (2-log)

109 MMR (3-log) Molecular

108 MR4 (4-log)

107 5-log reduction Deep molecular

response2
106 Undetectablea
BCR-ABLIS
Diagnosis Time

a Definition
depends on assay sensitivity, which varies by study.
12 1. Baccarani M, et al. Blood. 2006;108:1809-1820; 2. Baccarani M, et al. Blood. 2013;122:872-884; 3. Radich JP. Blood. 2009;114(16):3376-3381.
 TKI in Sardjito Hospital
2004, GIPAP, Imatinib, limited access
2007, ASKES, Imatinib +Nilotinib,
wider access
2014, BPJS, Imatinib +Nilotinib,
universal coverage
 Lesson Learned (1) :
Prolonged Survival Can Be Achieved
 Lesson Learned (1) :
Prolonged Survival Can Be Achieved

A Haryanto et al 2015
 Lesson Learned (1) :
Prolonged Survival Can Be Achieved
Mr.IDP, born 8/04/1962, CHR + MMR, IM,

ST March 2003

Mr. MA, born 26/01/1985, CHR + MMR,IM,

ST March 2004

Mr. CS, born 21/06/1964, CHR + MMR,IM

ST May 2007
 Lesson Learned (2) :
Aggresive Type Can Be Managed
 Lesson Learned (2) :
Aggresive Type Can Be Managed
 Lesson Learned (2) :
Aggresive Type Can Be Managed
Calculation Form of Relative Risk of Sokal,
Euro & EUTOS Score

Z Tao et al 2014
Calculation Form of Relative Risk of Sokal,
Euro & EUTOS Score

Z Tao et al 2014
 Proposed schema for individualizing therapy based on comorbidities, goals of therapy, and
disease risk profile.

*)

*) 2 years of monitoring in which every test

demonstrated an absence of BCR-ABL by quantitative
RT-PCR with sensitivity of at least 4.5 logs
2013 by Amern Society of Hematology
Hughes T , and White D Hematology 2013;2013:168-175
 Lesson Learned (2) :
Aggresive Type Can Be Managed
 Lesson Learned (2) :
Aggresive Type Can Be Managed
 Lesson Learned (2) :
Aggresive Type Can Be Managed
 Lesson Learned (3) :
Molecular Discordant
Is a Sign of Poor Response
N Ide Clinical Marrow Molecula Cytogen
o ntit presentation r assay etic
y assay
1 S, F, Hepatosplenomegaly G: blast 3%, displastic granulopoesis Bcr-abl b3a2
57 L 25, Hb 21, Hmt 63.9, E: displastic erythropoetic
P 400 P: Cluster of megakaryocyte, displastic
thrombocyte
2 S, F, Splenomegaly G: Dicreased of granulopoetic series with all Bcr-abl b3a2
51 L 42.6, Hb 14.5, P 379 maturation stages; blast 6%
E: decreased of erythropoetic series with
binucleated RBC
3 SH, Splenomegaly (?) G: increased granulopoetic, blast (-) Bcr-abl b3a2;
M, L 40, Hb 12.6, P 54 E: polichromatic erythroblasts V617F JAK2
63 mut.
4 RM, P 1387 G: maturation of granulocyte series, blast 1% Bcr-abl b3a2
M, E: binucleated normoblasts, Howell-Jolly
61 bodies
P: giant thrombocyte, megakaryocyte,
megakaryoblast (+) ET with displasia (?)
5 I, M, Hepatosplenomegaly G: increased granulopoetic, all maturation Bcr-abl b3a2 Dominant
59 L 22.8, Hb 11.4, P 400 stages exist, blast 2% hipoploidy
E: normoblast basophilic-polichromatophilic, (68%)
acidophilic
P: many megakaryocytes
6 T, F, L 4.7, Hb 11.5, P 526 NA Bcr-abl b3a2 Ph
63 chromosom
(-)
7 J, M, L 8.8, Hb 17, Hmt NA Bcr-abl b3a2
70 53.2, P 264
S: Suharti, S: Sugiarti; SH: Sahid Hidayat; RM: Rahaju Murti; I: Istamar; T: Tijem; J: Japar
 Lesson Learned (3) :
Molecular Discordant Is a Sign of Poor Response
N Identity Previous Clinical response after Current
o (Initial, assess Imatinib treatment treatment
sex, age) ment

1 S, F, 57 PV-ET CHR in 3 mo was not achieved, TKI stop in Hydroxyurea 1 g

mo 7
2 S, F, 51 PHR in 5 mo, In mo 8 no CHR Hydroxyurea 2 g

3 SH, M, 63 MF CHR was not achieved in 3 mo, TKI stop in Hydroxyurea 1 g

mo 5
4 RM, M, 61 MPD CHR was not achieved in 3 mo, TKI stop in Imatinib 400 mg +
mo 6 Hydroxyurea 1 g till mo 6
5 I, M, 59 DD: CML, CHR was not achieved in 3 mo, TKI stop in Hydroxyurea 1,5 g
Leukemoid reaction mo 5

6 T, F, 63 ET CHR was not achieved in 3 mo, worsed in Imatinib 400 mg +

mo 5 Hydroxyurea 1,5 g
Imatinib 400 mg
7 J, M, 70 PV CHR was not achieved in 3 mo, in mo 9 he Hydroxyurea 1,5 g
had a stroke event

All with low BCR-ABL < 10% at diagnosis

 Lesson Learned (4) :
Managing Toxicity Is Crucial

Marin D 2012
 Lesson Learned (4) :
Managing Toxicity Is Crucial

Skin RashToxicity on Nilotinib Tx

 Take Home Messages
TKIs have changed CML from fatal disease to
become indolent disease
Always treat CML patients with BCR-ABL
confirmation
Personalized medicine is future of CML
patients
Managing toxicity is crucial in CML
management
Thank You for Your Kind Attention