1. DR. VARUN GOEL
MEDICAL ONCOLOGIST
RAJIV GANDHI CANCER INSTITUTE, DELHI

2. Overview
 Introduction
 Prognostic Factors
 Conventional Drugs
 Presently First-line Therapy in CML
 Toxicity Profiles of TKI Therapy
 Monitoring of Patients With CML
 Resistance and Second-line Therapy in CML
 Allogeneic Hematopoietic Stem Cell Transplantation
in CML

3. INTRODUCTION
 Chronic myeloid leukemia is a clonal hematopoietic
disorder caused by an acquired genetic defect in a
pluripotent stem cell.
 The disease usually evolves into an accelerated phase
that often terminates in acute phase
chronic phase (90%) 3-5 years
accelerated phase 6-12 months
Blastic phase 3-6 months

4. Baseline Prognostic Factors
 Phase of Disease
 CML-CP  blast crisis (5 - 10% cases in the first 2 yrs
after diagnosis),
 the annual progression rate increased to 20 - 25%.
 To guide patient management, various prognostic scales
have been developed to predict the probability of disease
progression.
 Risk stratification
 Sokal
 Hasford

5. WHO criteria of the different
phases of CML

6. Risk stratification
 Sokal Score:
 Exponential of Total (Age, Spleen, Platelet count, Blood
myeloblasts)
 = (11x age + 35x spleen + 89x blasts + 0,4x platelet – 550)/1000
 Hasford Score:
 Applicable to patients treated with interferons
 Includes above factors + blood basophils and eosinophils
 Expressed as total x 1000
 = (0,666x age /0 when age <50, 1 when >/ + 0,0420x spleen +
0,0584x blasts + 0,0413x eosinophils + 0,2039x basophils /0
when basophils <3%, 1 when basophils >3%/ + 1,0956x
platelet /0 when platelet <15000G/l, 1 when >/) x 1000

7. Calculation of Disease RR
Relative Risk Sokal score Hasford Score
Low <0.8 <780
Intermediate 0.8-1.2 781-1480
High >1.2 >1480
Low intermediate and high risk of disease progression,
with median survivals of 5, 4 and 3 years, respectively.

8. Historical treatment
 Historically, mainstays of therapy for CML
were
 busulfan,
 hydroxyurea and
 interferon-α

9. Conventional Drugs
Busulphan Hydroxyurea
 Alkylating agent ● Often used initially for white cell count
 acts on stem cell reduction
 Side effect : ● Acts by inhibiting the enzyme
ribonucleotide reductase
 prolonged
myelosuppression ● Dose: 1-6g/d orally, depending on the
 Pulmonary fibrosis
white cell count
 Skin pigmentation ● Side effects: suppression of
 infertility hematopoiesis, often with megaloblastic
erythropoiesis
● It does not alter long-term prognosis

10. INTERFERON
5yr Survival
Chemotherapy 42%
IFN alpha 57%
The Chronic Myeloid leukemia Trialists’ Colaborative group. Interferon alpha Vs chemotherapy for
CML: a meta-analysis of seven randomised trials. J Natl Cancer Inst 1997;89:1616-20.
clinical use of IFN-α is limited by its toxicity profile
INTERFERON + CYTOSINE ARABINOSIDE
Cyogenetic Response IFN+AraC IFN
Complete 15% 9%
Partial 26% 15%
Minor 25% 28%
3 yr survival 85.7% 79.1%
Guilhot et al. N Engl J Med 1997;337:223-29

11. 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.

12. Treatment of Chronic Phase
Disease
 The basis of current therapy for CML in CP is the three
TKIs— imatinib, dasatinib, and nilotinib—and
alloHSCT.
 Allogeneic HCT is regarded as the only curative therapy
but associated with morbidities.
 Ability of tyrosine kinase inhibitor therapy to achieve
long-term disease control have made these drugs the
treatment of choice.

13. Definition of Response in CML
Response by Type Definitions
Hematologic
Complete WBC < 10 X 109/L
Basophils < 5%
No myelocytes, promyelocytes, myeloblasts in the differential
Platelet count < 450 x 109/L
Spleen nonpalpable
Cytogenetic
Complete No Ph+ metaphases
Partial 1% to 35% Ph+ metaphases
Minor 36% to 65% Ph+ metaphases
Minimal 66% to 95% Ph+ metaphases
None > 95% Ph+ metaphases
Molecular
Complete Undetectable BCR-ABL mRNA transcripts by real time
quantitative and/or nested PCR in 2 consecutive blood samples
of adequate quality (sensitivity > 104)
Major Ratio of BCR-ABL to ABL (or other housekeeping genes)
≤ 0.1% on the international scale
Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.

15. Imatinib(Gleevec)
 first tyrosine kinase inhibitor
developed
 approved by the U.S. FDA in 2001
 targets the molecular pathogenetic
event in CML
 Imatinib functions by
blocking the binding of ATP
to the BCR-ABL tyrosine
kinase, inhibiting its activity.

16. The IRIS Study Design
R Imatinib
A (n = 553)
N
D Crossover
O
M IFN- +
I Ara-C
Z (n = 553)
E Crossover for:
Lack of response
Loss of response
Intolerance of treatment
Druker BJ, et al. N Engl J Med. 2006;355:2408-2417.

17. Summary of 19 Month Data
Imatinib vs. INF/ARAC
<0.001
100 97 95
92 <0.001
80 74 76
60
Imatinib
40 INF/ARAC
20 15
8.5
3.3
0
FFP OS AP/BC CCR
Quality of Life
O’Brien S.G. N Engl J Med. 348:994. Hahn, E.A. et al. JCO 2003;21:2138-46

18. IRIS Study – 8 year follow-up
Event-free survival 81%
Overall survival 85%
Transformation-free survival 92%
 If MMR at 12 months 100%
Annual rate of transformation:
1.5%; 2.8%; 1.8%; 0.9%; 0.5%; 0%; 0%; 0.4%
Deininger M et al, ASH 2009

19. ENESTnd: Nilotinib vs Imatinib in
Newly Diagnosed CML
 Primary endpoint: MMR at 12 mos; secondary endpoint: CCyR by 12 mos
 Other endpoints: time/duration of MMR and CGCR, EFS, PFS, time to AP/BP, OS
 Stratification by Sokal risk; MMR defined as ≤ 0.1% BCR-ABL(/ABL ratio) on international
scale
R
A Nilotinib 300 mg BID (n = 282)
Newly diagnosed N
CML-CP in D
217 centers and O Nilotinib 400 mg BID (n = 281)
35 countries M
I
(N = 846) Z Imatinib 400 mg QD (n = 283)
E
Larson RA, et al. ASCO 2010. Abstract 6501. Saglio G, et al. N Engl J Med. 2010;362:2251-2259.

20. Results from the ENESTnd trial at
12 months of treatment
Saglio G, et al. N Engl J Med. 2010;362:2251-2259. Hughes TP, et al. ASH 2010. Abstract 207.
Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270

21. DASISION (CA180-056): Dasatinib
vs Imatinib in Treatment-Naive
CML Stratified by Hasford risk score
N = 519 Dasatinib 100 mg QD (n = 259)
108 centers Follow-up
26 countries 5 yrs
Imatinib 400 mg QD (n = 260)
 Primary endpoint: confirmed CCyR by 12 mos
 Secondary/other endpoints: rates of CCyR and MMR; times to
confirmed CCyR, CCyR, and MMR; time in confirmed CCyR and
CCyR; PFS; OS
Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.

22. Results from the DASASION study
at 12 months.

23. Meta-analysis: Frontline Imatinib
vs Dasatinib vs Nilotinib for CML
 Bayesian mixed comparison meta-analysis to assess relative
efficacy of BCR-ABL inhibitors across randomized clinical trials
of patients with previously untreated CP-CML[1]
 Imatinib 400 mg QD
 Dasatinib 100 mg QD
 Nilotinib 300 mg BID
 Nilotinib 400 mg BID
 After systemic review, data from 3 published studies used to
construct evidence network for CCyR at 6 mos, CCyR at
12 mos, and MMR at 12 mos[2-4]
1. Mealing S, et al. ASH 2010. Abstract 3436. 2. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.
3. Saglio G, et al. N Engl J Med. 2010;362:2251-2259. 4. Baccarani M, et al. Blood. 2009;113:4497-4504.

24. Meta-analysis of Frontline Imatinib
vs Dasatinib vs Nilotinib for CML:
Summary
 Data suggest CCyR and MMR rates significantly higher
with dasatinib or nilotinib vs imatinib for frontline CP-
CML treatment
 Relative efficacy of dasatinib and nilotinib similar
 Insufficient data at present to distinguish between these
agents by indirect comparison
Mealing S, et al. ASH 2010. Abstract 3436.

26. Comparisons of Imatinib to Nilotinib- side effects
Imatinib 400 Nilotinib 300 Nilotinib 400
P Value/Comments
mg/d mg bid mg bid
Nausea,
Rash, headache, pruritus,
diarrhea, All grades, most being
alopecia, elevations of alanine
vomiting, grade 1/2; adverse events
Adverse events aminotransferase, aspartate
muscle were similar with both
aminotransferase, and
spasms, and doses of nilotinib
bilirubin, increased glucose
edema
Discontinuation for
7% 5% 9%
adverse events
Neutropenia 20% 12% 10% Grade 3/4
Thrombocytopenia 9% 10% 12% Grade 3/4
Anemia 5% 3% 3% Grade 3/4

27. DASISION: Differences in Adverse
Event Rates With Dasatinib vs
Imatinib Patients, n
DAS IM
Fluid retention l 60 111
Superficial edema l 25 92
Pleural effusion l 31 0
Myalgia l 56 99
Nausea l 23 55
Any grade
Vomiting l 12 27
Diarrhea l 47 50
Fatigue l 21 28
Headache l 32 27
Rash l 29 44
Neutropenia l 57 52
Grade 3/4 Thrombocytopenia l 49 27
Anemia l 29 18
-0.4 -0.2 0.0 0.2 0.4
Rate difference (dasatinib-imatinib) with exact 95% CI
Favors dasatinib Favors imatinib
Shah N, et al. ASH 2010. Abstract 206..

28. Frontline Rx With Imatinib vs
Second-Generation TKIs
Parameter Imatinib Second-Generation TKIs
Efficacy Excellent Even better
12-mo outcome, %
 CGCR 65-70 80-85
 MMR 20-25 40-45
 AP-BP 3.5 0.4-2.0
Tolerance Excellent Even better
Follow-up, yrs 10 6-7
Cost, $/yr 54,000 90,000-96,000
Larson RA, et al. ASCO 2010. Abstract 6501. Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.

30. Recommendations for
Monitoring CML Therapy
 Hematologic response: diagnosis, then every 15 days
until CHR confirmed, then at least every 3 mos
 Cytogenetic response: Diagnosis, 3 and 6 mos, then
every 6 mos until CCgR confirmed, then every 12 mos if
regular molecular monitoring cannot be assured; always
for occurrences of treatment failure and for occurrences
of unexplained anemia, leukopenia or thrombocytopenia
 Molecular (RT-PCR): every 3 mos until MMR confirmed
then every 6 mos
 Molecular (mutation assessment): suboptimal response
or failure; always required before changing to other TKIs
Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.

31. Recommendations for Response
Assessment
Response
Evaluation Time Optimal Suboptimal Failure Warning
High risk;
Baseline NA NA NA
CCA/Ph+
CHR and at least
No CgR
3 mos minor CgR < CHR NA
(Ph+ > 95%)
(Ph+ ≤ 65%)
At least partial
< Partial CgR No CgR
6 mos CgR NA
(Ph+ > 35%) (Ph+ > 95%)
(Ph+ ≤ 35%)
Partial CgR < Partial CgR
12 mos CCgR < MMR
(Ph+ 1% to 35%) (Ph+ > 35%)
18 mos MMR < MMR < CCgR NA
Stable or Loss of CHR, loss of Increase in
Any time during Loss of MMR;
improving MMR CCgR, mutations, transcript levels,
treatment mutations
CCA/Ph+ CCA/Ph-
Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.

33. Mechanisms of Resistance to
Imatinib
 BCR-ABL dependent
 Amplification/overexpression
 Mutations in ABL
 Remigration of BCR-ABL to cytoplasm
 BCR-ABL independent
 Increased MDR expression
 Increased alpha-1 acid glycoprotein
 Overexpression of Src-related kinases
 Quiescent stem cells (persistence)
le Coutre P, et al. Blood. 2000;95:1758-1766. Weisberg E, et al. Blood. 2000;95:3498-3505. Mahon FX, et al.
Blood. 2000;96:1070-1079. Gambacorti-Passerini C, et al. J Natl Cancer Inst. 2000;92:1641-1650. Vigneri P, et
al. Nat Med. 2001;7:228-234.

34. Options for Patients who failed Initial
Imatinib
 Increase dose of imatinib
 Second line: Dasatinib, Nilotinib
 Allogeneic Stem Cell Transplant (BMT/PBSCT)
 Classical drugs: Cytarabine, Hydroxyurea, Busulphan,
Intereron-alpha
 Experimental agents, Autografting.
BCSH, 2007

35. When Does Imatinib Dose
Escalation Work?
 Imatinib dose escalation in 84 patients with imatinib
failure
 CG failure (n = 63): imatinib associated with CGCR in
52%
 MCyR durable at 2 yrs in 88% of patients
 Hematologic failure (n = 21): only transient responses;
CGCR in 5%
 However, results of new TKIs better
Jabbour E, et al. Blood. 2009;113:2154-2160.

36. Nilotinib in Chronic-Phase CML
Post-Imatinib: OS and PFS
 Patient population (n = 321)
 70% imatinib resistant
 30% imatinib intolerant
 Median duration of nilotinib: 18.4 mos
 2-yr survival rates
 PFS: 64%
 OS: 87%
Kantarjian HM, et al. Blood 2011;117:1141-1145.

37. PFS and OS With Dasatinib in
Chronic-Phase CML by Imatinib
Failure Imatinib Intolerance
Imatinib Resistance
96% 100% 100%
100 92% 100
98% 94%
80 88% 80
75%
60 60
40 PFS 40 PFS
OS OS
20 20
0 0
0 3 6 9 12 15 18 21 24 28 30 33 0 3 6 9 12 15 18 21 24 28 30 33
Mos Mos
Progression defined as increasing WBC count, loss of CHR/MCyR, AP/BP, or death.
Stone RM, et al. ASH 2007. Abstract 734..

38. Choosing a second generation TKI for patients
intolerant of or resistant to imatinib
1. Efficacy: Little to choose between dasatinib, nilotinib
2. All three agents are ineffective in patients with a T315I kinase domain
mutant subclone
3. If other mutations are present, they may influence choice in favour of
either nilotinib or dasatinib
4. Toxicity:
Myelo- Hepatic Pancreatic Pleural Diarrhoea QTc interval
suppression effusions prolongation
Dasatinib +++ - - ++ - +
Nilotinib + ++ + - - +

39. Imatinib Resistance – Common Mutations Influencing
Therapeutic Decisions
Nilotinib Dasatinib
T 3151 X X
F 317L X
E 255 V/K X
Y 253H X
F 359 V/C X

40. Emerging TKIs in the Newly Diagnosed and
Relapsed/Refractory
 Bosutinib, an experimental TKI, shows modestly
improved efficacy with more toxicity compared
with imatinib as first-line therapy for chronic-phase
CML
 Bosutinib is approximately as active as nilotinib and
dasatinib as second-line treatment, with activity in
some Bcr-Abl mutations resistant to these 2 agents
 Ponatinib, another experimental TKI, produced
high rates of major cytogenetic responses across
subgroups of heavily pretreated patients with CML,
including those with the T315I mutation

42. Transplantation for CML
 Indications :-
 Failure of second-generation TKI (donor search should
be undertaken after failure of imatinib)
 imatinib failure and
 T315I BCR-ABL1 mutation
 Curative Treatment for most patients
 High rate of morbidity and mortality
 Problems of:
 Toxicity of preparative regimen
 Graft-vs-Host disease
 Relapse

43. Survival after BMT for CML by CML-
CP score
Donor type
Matched Sib 0
Matched Unrelated 2
Age
<30 0
30 – 40 1
>40 2
Donor recipient gender
Female Male 1
Other 0
Interval from Diagnosis
< 1 year 0
> 1 year 1
Performance Status
KPS > 85 0
Passweg, J.R. et al. BJH 125:613, 2004
other 1

46. CML Treatment Paradigm
Chronic-phase CML Advanced-phase CML
Complete diagnostic workup
Tumor burden by RQ-PCR CHEMO + TKI vs TKI alone
Imatinib 400 mg daily Imatinib 400 mg BID
Nilotinib 300 mg BID Dasatinib 70 mg BID
Dasatinib 100 mg daily Nilotinib 400 mg BID
Dasatinib
No
Goals Nilotinib
Heme CR in 1-2 mos
Cyto response in 3-6 mos
CCyR in 12-15 mos
MMR in ~ 12 mos
Allogeneic BMT
@ progression

47. THANK YOU