2. Definition of CML
1. Clonal
2. Myeloproliferative disorder
3. Involves early progenitor hematopoietic stem cell.
4. Characterized by presence of Ph chromosome
5. And BCR-ABL fusion gene
A small subset (<5%) of CML is Ph -ve and BCR-ABL –ve
3. Epidemiology
• Incidence 1.5 cases per 100,000
• M:F - 1.6:1
• Median age 55-65 years
• Prevalence increasing every year (plateau at 20
years)
4.
5. CML in India
• M:F - 1:08 to 3:1
• Median age: 32-42 years
6.
7. Etiology
• Ionizing radiation- increased risk (5-10 years)
• No known familial associations
• No known common etiologic agent
• Not related to immuno-deficiency diseases
• Not a frequent secondary leukemia
8. Philadelphia Chromosome Translocation in CML
Results in BCR-ABL Oncogene
Gene Transcription
Inhibits Apoptosis
Excessive proliferation
Cytoskeletal organization
Degradation of inhibitory
proteins
9 9q+
22
Ph
22q-
BCR
ABL
BCR
ABL
Translocation
Transcription and translation
Inhibition by
TKI
BCR-ABL fusion
protein
CML
Constitutive tyrosine kinase
Phosphorylation of multiple substrates
Mitogenic signaling and genomic instability increased
Apoptosis and stromal regulation decreased
t(9;22)(q34;q11.2)
9. CML stem cell hypothesis
• STIM and TWISTER trial
• Immunophenotype: Lin-ve, CD 34+ve, CD 38-ve, CD
90+ve
• Phonotypically and functionally similar to normal
HSCs.
12. Cell lines affected
1. Erythroid
2. Myeloid
3. Monocytic
4. Megakaryocytic
– Less commonly- B cells
– Rarely- T cells and marrow fibroblasts
13. Natural History of CML
Chronic Phase Accelerated Phase Blast Phase
Duration If untreated, 3-5 yrs Varies Median survival of
several mos
Prognosis Responsive to treatment Decreased
responsiveness
Resistant to treatment
Symptoms Asymptomatic
OR
Fatigue
Weight loss
Abdominal pain or
discomfort
Night sweats
Progressive
splenomegaly
Myelofibrosis
Bleeding complications
Infection complications
Accumulation of immature myeloid cells
New cytogenetic changes
14. Diagnosis of CML
Hematologic
Bone marrow
(with myeloid
hyperplasia)
Karyotype
(Ph chromosome)
FISH
Chromosomal translocation
t(9;22)(q34;q11)
Cytogenetic Molecular
(BCR-ABL fusion)
PCR
Abnormal BCR-ABL
Lane 1: BCR-ABL+
Lane 2: BCR-ABL-
Sensitivity
Peripheral blood
(with myeloid
cells)
Abnormal BCR-ABL
Red: BCR
Green: ABL
Yellow: fusion
15. Work up
– History and physical exam, determine spleen size by
palpation
– CBC with differential, platelets
– Blood chemistry profile
– BM aspirate and biopsy
– Conventional cytogenetics
– FISH
– PCR
– Determine risk score
26. Leitner AA, et al. Internist (Berl). 2011;52:209-217.
Yrs After Diagnosis
SurvivalProbability
(AllPh+CMLDiseasePhases)
0 2 64 8 10 16 18 20 2212 14
0
0.2
0.1
0.5
0.6
0.7
0.8
0.9
1.0
0.3
0.4 1995-2008, IFN- or SCT‡
1986-2003, IFN-
1983-1994, busulfan
1983-1994, hydroxyurea
1997-2008, IFN- or SCT
plus second-line imatinib†
2002-2008, imatinib*
Best available therapy 5-Yr OS, %
Imatinib* 93
IFN- or SCT +
second-line imatinib† 71
IFN- or SCT‡ 63
IFN- 53
Hydroxyurea 46
Busulfan 38
1970
2000
1990
1980
1960
2010
Imatinib Changed the Therapeutic
Landscape for Patients With Ph+ CML
*CML IV. †CML IIIA. ‡CML III.
27. IRIS 8-Yr Update: OS (ITT) With Imatinib
Treatment in CML
Estimated OS at 8 yrs: 85%
(93% considering only CML-related deaths)
Deininger M, et al. ASH 2009. Abstract 1126.
100
80
60
40
20
0
OS(%)
0 12 24 36 48 60 72 84 96 108
Mos Since Randomization
28.
29.
30. 55%
Intolerance/Resistance Occurs in Some Patients
With Ph+ CP CML on Imatinib
13.3%
6.7%
6.6%
37.8%
35.6%
Deininger M, et al. ASH 2009. Abstract 1126.
Disposition of Patients After
8 Yrs of Follow-up
(IRIS Trial)
Discontinued
frontline imatinib
Continued frontline
imatinib
55%
Discontinuation of Frontline Imatinib
Adverse effects
Unsatisfactory therapeutic effect
Death
SCT
Other reason cited
45%
31. IRIS 8-Yr Update: Most Events in First
3 Yrs
• Estimated EFS at 8 yrs: 81%
• Estimated rate of freedom from progression to AP/BC at 8 yrs: 92%
0
1
2
3
4
5
6
7
8
1 2 3 4 5 6 7 8
3.3
1.5
7.5
2.8
4.8
1.8 1.7
0.9 0.8
0.5 0.3
0 0
1.4 1.3
0.4
Yr
ProbabilityofEvent
Event
Loss of CHR
Loss of MCyR
AP/BC
Death during treatment
AP/BC
Deininger M, et al. ASH 2009. Abstract 1126.
32. ENESTnd: Comparison of Nilotinib and Imatinib
in Newly Diagnosed CP CML
• Primary endpoint: MMR at 12 mos
• Secondary endpoint: durable MMR at 24 mos
Patients
diagnosed with
Ph+ CP CML
within 6 mos
(N = 846)
Nilotinib 300 mg BID
(n = 282)
Imatinib 400 mg QD
(n = 283)
Nilotinib 400 mg BID
(n = 281)
5-yr follow-up
Saglio G, et al. N Engl J Med. 2010;362:2251-2259. Larson RA, et al. Leukemia. 2012;26:2197-2203. Kantarjian
HM, et al. ASH 2012. Abstract 1676.
Stratified by Sokal risk
33. Kantarjian HM, et al. ASH 2012. Abstract 1676.
ENESTnd 4-Yr Update: Cumulative
Incidence of MMR in CP CML
100
80
60
40
20
0
0 126 2418 30 4236 48 6054
Mos Since Randomization
PatientsWithMMR(%)
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
By 1 yr:
55% (P < .0001)
By 4 yrs:
76% (P < .0001)
51% (P < .0001)
∆24% to 28%
73% (P < .0001)
∆17% to 20%
56%
27%
MMR = BCR-ABL ≤ 0.1%.
34. Progression to AP/BC on Study (Including
After Treatment Discontinuation)
• Rates of progression to AP/BC were lower with nilotinib vs imatinib when including all
progressions occurring on study
Nilotinib 300 mg BID
Nilotinib 400 mg BID
Imatinib 400 mg QD
Kantarjian HM, et al. ASH 2012. Abstract 1676.
20
15
10
5
0
Patients(n)
Including Clonal Evolution
3.2% 2.1% 6.7%
9
6
19
P = .0497
P = .0074
HR: 0.5 (0.2-1.0)
HR: 0.3 (0.1-0.8)
35. Patients newly
diagnosed with
CP CML
(N = 519)
Dasatinib 100 mg QD
(n = 259)
Imatinib 400 mg QD
(n = 260)
DASISION: Comparison of Dasatinib and
Imatinib in Newly Diagnosed CP CML
• Primary endpoint: confirmed CCyR at 12 mos
• Key secondary endpoints: MMR, time in confirmed CCyR, time to confirmed CCyR
and MMR, PFS, OS
5-yr follow-up
Stratified by Hasford risk score
Kantarjian HM, et al. Blood. 2012;119:1123-1129. Jabbour E, et al. Blood. 2014;123:494-500.
36. Which TKI to be used in 1st line?
• All 3 recommended.
• FOR and AGAINST
• Factors which might help:
– Toxicity profile
– Kinase domain mutation status
38. Treatment Options Based on BCR-ABL
Kinase Domain Mutation Status
Mutation Treatment Options
T315I Ponatinib (preferred), omacetaxine, HSCT,
or clinical trial
V299L Consider ponatinib, nilotinib, or omacetaxine*
T315A Consider ponatinib, nilotinib, imatinib,† bosutinib, or
omacetaxine*
F317L/V/I/C Consider ponatinib, nilotinib, bosutinib, or omacetaxine*
Y253H, E255K/V, F359V/C/I Consider ponatinib, dasatinib, bosutinib, or
omacetaxine*
Any other mutation Consider ponatinib, high-dose imatinib,‡ dasatinib,
nilotinib, bosutinib, or omacetaxine*
NCCN. Clinical practice guidelines in oncology: chronic myelogenous leukemia. v.4.2013.
Ponatinib: Restriction on marketing by FDA in Dec 2013
39. Advanced Phase CML
• TKIs can achieve initial good response (second
chronic phase).
– Talpaz M, et alBlood 2002.
• But such responses are usually short lived.
• Allogeneic HSCT is the treatment of choice.
• However, it is prudent to start the patient on a TKI.
• Cure rates - better if transplanted in second chronic
phase.
– Visani G, et al. Br J Haematol 2000.
40. Kantarjian H, et al. Cancer 2005.
Outcome of drug therapy in CML-AP
41. Probability of Survival after HLA-identical Sibling
Donor Transplants for CML, 1998-2010
- By Disease Status and Transplant Year -
Years
0 2 61 3 4 5
0
20
40
60
80
100
10
30
50
70
90
0
20
40
60
80
100
10
30
50
70
90
ProbabilityofSurvival,%
P < 0.0001
CP, 1998-2000 (N=2,239)
AP, 1998-2000 (N=291)
CP, 2001-2010 (N=2,498)
AP, 2001-2010 (N=360)
CIBMTR
42. 710 patients, 1981 and 2010
Hammersmith Hospital, London
Impact of disease phase on transplant
outcome in CML
Jirí Pavlu, et al. Blood October, 2010
43. Imatinib vs HSCT in CML-AP
Jiang Q, et al. Blood, 2011.
Peking University Institute of Hematology, Beijing, China.
44. Current indications for transplant in
CML
• Advanced phase disease (accelerated phase
and blast crises)
• Failure of TKI’s
(Resistance/Intolerance/Relapse)
48. Chronic Myeloid Leukemia
Chronic Phase Accelerated phase
or Blast crisis
(Newly diagnosed)
Accelerated phase or
Blast crisis
(Progressed from
Chronic phase)
1st line TKI
(Imatinib/ Dasatinib/
Nilotinib)
Intolerance
to 1st line TKI
Failure of 1st
line TKI
Anyone of
the other TKI
HLA typing of
patient and
siblings & 2nd
line TKI
Intolerance
to 2nd line
TKI
Failure of 2nd
line TKI
Accelerated
phase with
suboptimal
response to
TKI
Blast
crisis
Allogeneic HSCT for all
eligible patients
1st line TKI (Imatinib/
Dasatinib)
& HLA typing of patient
and siblings
HLA typing of
patient and
siblings & 2nd
line TKI