cml

1. UPDATES IN CML
DR. R. RAJKUMAR D.M.
MEDICAL ONCOLOGIST VELAMMAL SPECIALITY HOSPITALS

2. Introduction
CML is a myeloproliferative neoplasm
 Dysregulated production and uncontrolled proliferation of mature and maturing
granulocyte with normal differentiation
Fusion of 2 genes: BCR (or chromosome 22) and ABL1 (on chromosome 9), resulting in
BCR-ABL1 fusion gene, a dysregulated tyrosine kinase
Abnormal chromosome 22 called Philadelphia (Ph) chromosome

4. Epidemiology of CML
Annual incidence: 1 to 2 cases per 100,000 population.
15% – 20% of all adult leukemias
 Incidence increases significantly with age, Median age ~ 55 years
Most patients (85%) present in Chronic Phase
 Majority of CML-related deaths due to progression to AP/BC
 50% of CML patients are asymptomatic at diagnosis

5. CML has three clinical phases

6. Clinical Presentation in Chronic Phase CML

7. Diagnosis of CML
Typical findings in the blood and bone marrow
Requires the detection of the Ph chromosome, BCR-ABL1 gene
- Conventional cytogenetic analysis (karyotyping)
-FISH- Cytogenetics
-RT-PCR (The BEST)
-Southern blot techniques – rarely used
-Western Blotting – low sensitivity and labor intensive

8. •Hematologic Tests:
A. Complete hematologic response
B. Partial hematologic response
•Cytogenetic Tests
•Molecular Tests
-

9. Goals of treatment of CML
•Hematologic remission (normal CBC and physical examination [ie, no organomegaly])
•Cytogenetic remission (normal chromosome returns with 0% Ph1-positive cells)
•Molecular remission (negative polymerase chain reaction [PCR] result for BCR/ABL)

10. Therapeutic Options for CML
Tyrosine kinase inhibitor therapy
Chemotherapy
Biologic therapy i.e Interferon
Stem cell transplant
•Ponatinib
•Radotinib*
•Asciminib (ABL001)*
*not FDA-approved
Treatment Advances for CML: TKIs

12. 2nd generation TKI’s
 Dasatinib, Nilotinib , and Bosutinib
 more potent inhibitors of BCR/ABL than imatinib.
 exhibit significant activity against all resistant mutations except BCR/ABL/T315I .
 All three have been approved by the USFDA
Indications: adult patients with newly diagnosed Philadelphia chromosome, chronic-phase(CP) CML, CP-CML
resistant or intolerant to prior therapy that included imatinib.
The goal of TKI therapy is to achieve a CCyR (≤1% BCR-ABL1 IS) within 12 months after first-line TKI therapy
and to prevent disease progression to accelerated or blast phases.

13. Need for 2nd generation TKI’s
•Imatinib has relatively low potency and inhibits its target at micromolecular rather than
nanomolar concentrations.
•Imatinib has increased susceptibility to resistance (20-30% patients) through a number of
mutations in the BCR-ABL target.
 2nd generation TKIs induced higher rates of early complete cytogenic response (CCyR) and major
molecular response than imatinib.
Jabbour E, Kantarjian H, O'Brien S, et al. The achievement of an early complete cytogenetic response is a major determinant for outcome in
patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors. Blood. 2011 Oct 27. 118(17):4541-6; quiz
4759.

16. Efficacy parameters of bosutinib, nilotinib and dasatinib in first-
and second-line treatment
Isfort S, Brümmendorf TH. Bosutinib in chronic myeloid leukemia: patient selection and perspectives. Journal of Blood Medicine 2018:9
Pages 43—50

17. Most frequent side effects of all approved TKI
Isfort S, Brümmendorf TH. Bosutinib in chronic myeloid leukemia: patient selection and perspectives. Journal of Blood
Medicine 2018:9 Pages 43—50

18. Recommendations for
TKI treatment with
regard to comorbidity
status.
Isfort S, Brümmendorf TH. Bosutinib in chronic myeloid
leukemia: patient selection and perspectives. Journal of
Blood Medicine 2018:9 Pages 43—50

19. Dasatinib in the treatment of CML
Dasatinib was first approved for the second-line treatment of CML
patients Post-Imatinib failure.
 As per the DASISION and other trials, Dasatinib can be used in
frontline treatment of CML/treatment naïve patients .
In phase of Blast crisis, Dasatinib can be the choice of TKI treatment
over imatinib and nilotinib, since CNS involvement may be observed in
Blast crisis and dasatinib can penetrate through the blood–brain barrier.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066856/#!po=25.0000

20. Clinical Data on Dasatinib

21.  DASISION Trial
Objective:
To assess efficacy and safety of Dasatinib, as compared with Imatinib, for the
first-line treatment of chronic-phase CML.

22. METHODS
• In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly
assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose
of 400 mg once daily (260 patients).
•The primary end point was CCyR by 12 months, confirmed on two consecutive assessments at
least 28 days apart.
• Secondary end points, including MMR, were tested at a significance level of 0.0001 to adjust for
multiple comparisons.

24. Figure 1. Response Rates over Time. The rates of complete cytogenetic response are shown in Panel A. A total of 10 patients (5 in each group) in whom the assessment of complete
cytogenetic response was based on bone marrow samples containing fewer than 20 cells in metaphase per sample were categorized as not having a response. The rates of major molecular
response are shown in Panel B. A total of 8 patients (5 in the dasatinib group and 3 in the imatinib group) with atypical transcripts at baseline were categorized as not having a response. I
bars indicate 95% confidence intervals.

25. CONCLUSIONS
• Dasatinib, administered once daily, as compared with imatinib, administered once daily,
induced significantly higher and faster rates of CCyR and MMR.
• Since achieving CCyR within 12 months has been associated with better long-term, PFS,
dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-
phase CML.

26. The second-generation TKI dasatinib is a standard first-line therapy for patients with CML-CP1
Patients with newly diagnosed CML-CP treated with dasatinib at 100 mg QD in
DASISION (compared with imatinib) demonstrated1-4
◦ Improved rates of confirmed complete
cytogenetic response
◦ Faster rates of molecular response
◦ An acceptable safety profile

27. Final analysis from DASISION evaluating long-term efficacy and safety outcomes are
presented
◦ Minimum of 5 years of follow-up since randomization
◦ Last patient first visit: 24-Nov-2008
CML-CP, chronic phase chronic myeloid leukemia; DASISION (CA180-056): NCT00481247.
1. Sprycel India Prescribing Information, Version 16, dated 23-May-2016 2. Kantarjian H et al. N Engl J Med 2010;362:2260–70; 3. Kantarjian H et al. Blood 2012;119: 1123–9; 4.
Jabbour E et al. Blood 2014;123:494–500.

28. Imatinib 400 mg QD (N=260)
Dasatinib 100 mg QD (N=259)
 Newly diagnosed
Ph+ CML-CP
patients
 N=519
 108 Centers
 26 Countries
 Enrollment:
Sept 2007–Dec
2008
Follow-up
5 years
Phase 3, randomized, open-label, multicenter study
Randomized1:1*
*Stratified by Hasford risk score
DASISION (1st-Line): Trial Design1,2
 Database lock of 24-Mar-2014
 Primary end point: confirmed CCyR by 12 months
– 77% dasatinib vs. 66% imatinib (P=0.007)1
1Protocol for: Kantarjian H, et al. N Engl J Med. 2010;362:2260-70; 2Kantarjian H, et al. N Engl J Med. 2010;362:2260-70.

29.  Primary endpoint:
- Confirmed CCyR by 12 months
 Secondary endpoints:
- Rates of CCyR and MMR
- Times to CCyR and MMR
- Time in CCyR
- Progression-free survival
- Overall survival
†Proportion of patients who have achieved MMR by 12 months and also maintain continuous MMR until the 24-month time
point; ‡Advanced phase/blastic phase.
Protocol for: Kantarjian H, et al. N Engl J Med. 2010;362:2260-70.
DASISION1st-Line: Overview of Trial Primary and Secondary Endpoints

30. 77
83
46
66
72
28
0
20
40
60
80
100
Patients(%)
Confirmed CCyR CCyR
P=.001b
P=.007a
P<.0001b
MMR
Dasatinib 100 mg QD
Imatinib 400 mg QD
aThis was a prespecified analysis; P-value has been adjusted for multiple comparisons; bThe P-value provided is based on a post-hoc analysis and has not been adjusted for multiplicity.
Kantarjian H, et al. N Engl J Med. 2010;362:2260-70.
DASISION: CCyR and MMR Rates by 12 Months (ITT) in Newly Diagnosed
CP Ph+ CML

31. Patient Disposition at 5 Years
At 5 years (study end), patients were transitioned to off-study therapy or remained on study therapy until local drug
access was available
Treated Patients, n (%)
Dasatinib 100 mg QD
(n=258)
Imatinib 400 mg QD
(n=258)
On initial therapy at study end 158 (61) 162 (63)
Discontinued
Progression or treatment failure 28 (11) 36 (14)
AE related to study treatmenta
42 (16) 17 (7)
AE unrelated to study treatmenta
12 (5) 4 (2)
Poor/nonadherence 1 (<1) 7 (3)
Other 17 (7)b 31 (12)c
J. Cortes,G. Saglio, M. Baccarani et al. Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial
(DASISION, CA180-056) presented at ASH 2014

32. DASISION: Cumulative MMR Rates Over Time
Months Since Randomization
%WithMMR
Dasatinib 100 mg QD
N
Imatinib 400 mg QD 260
259
By 1 year
By 2 years
By 3 years
By 4 years
By 5 years
28%
46%
55%
60%
64%
46%
64%
67%
73%
76%
0 6 12 18 24 30 36 42 48 54 60
100
90
80
70
60
50
40
30
20
10
0
p=0.0022
MMR = BCR-ABL1 (IS) ≤0.1%
.

33. DASISION: Rate of MR4
• The rates of MR4 at any time were 54% and 45% in the dasatinib and imatinib arms,
respectively
Dasatinib 100 mg
QD (n=259)
Imatinib 400 mg
QD (n=260) P-value
MR4 rate, % (95% CI)
By 1 year 14 (10–18) 5 (3–9) .0015
By 2 years 29 (24–35) 19 (14–24) .0035
By 3 years 34 (29–41) 23 (18–29) .0041
By 4 years 48 (42–54) 35 (30–42) .0036
By 5 years 54 (47–60) 44 (38–50) .0241

34. 0 6 12 18 24 30 36 42 48 54 60
100
90
80
70
60
50
40
30
20
10
0
DASISION: Cumulative MR4.5 Rates Over Time
By 1 year
By 2 years
By 3 years
By 4 years
By 5 years
3%
8%
13%
23%
33%
5%
19%
24%
34%
42%
p=0.0251
Months Since Randomization
%WithMR4.5
Dasatinib 100 mg QD
N
Imatinib 400 mg QD 260
259
MR4.5, BCR-ABL (IS) ≤0.0032% (for subjects with B2a2 and B3A2 transcripts).

35. Dasatinib 100 mg QD
(n=259)
Imatinib 400 mg QD
(n=260)
BCR-ABL at 3 Monthsa ≤10%
n=198
>10%
n=37
≤10%
n=154
>10%
n=85
Transformation to AP/BPb, n (%) 6 (3) 5 (14) 5 (3) 13 (15)
Patients,n
Overall transformations to AP/BP
4.6%
7.3%
Dasatinib
n=259
Imatinib
n=260
On study During follow-up beyond discontinuation
Transformation to AP/BP CML by 5 Years
One imatinib patient and no dasatinib patients transformed between 4 and 5 years
aOne dasatinib and one imatinib patient transformed but did not have 3-month molecular assessments.
bIncluding follow-up beyond discontinuation (intent to treat).

36. DASISION: Estimated 5-Year OS and PFS
aOn study treatment and in follow-up after discontinuation of randomized treatment.
bProgression was defined as doubling of white blood cell count, loss of complete hematologic response, increase in Ph+ metaphases to >35%, transformation to AP/BP, or death from any cause.
Cortes J, et al. Presented at ASH Annual Meeting; December 6-9, 2014; San Francisco, CA.
Dasatinib
100 mg QD
(n=259)
Imatinib
400 mg QD
(n=260)
Hazard
Ratio
(95% CI)
Total number of deaths,a n 26 26 –
Estimated 5-year OS,a %
(95% CI)
91
(87–94)
90
(85–93)
1.01
(0.58–1.73)
Estimated 5-year PFS,a,b %
(95% CI)
85
(80–89)
86
(80–89)
1.06
(0.68–1.66)
• Causes of death were cardiovascular disease (2 dasatinib, 1 imatinib); disease progression (9 dasatinib, 17 imatinib); infection (11
dasatinib, 1 imatinib); other malignancy, septic shock and cardiac failure, multiorgan failure, and whole body swelling (1 each dasatinib);
stem cell transplantation complications and unknown
(2 each imatinib); severe chest pain, clinical deterioration and decrease in performance status, and fatal bleeding (1 each imatinib)

37. DASISION: 5-Year Responses and Outcomes by Molecular Response at 3
Months
aOn study treatment and in follow-up after discontinuation of randomized treatment.
bProgression was defined as doubling of white blood cell count, loss of complete hematologic response, increase in Ph-positive metaphases to >35%, transformation to AP/BP, or
death from any cause.
=
Dasatinib 100 mg QD
(n=259)
Imatinib 400 mg QD
(n=260)
BCR-ABL1 at 3 Months
≤10%
(84%)
>10%
(16%)
P-value
≤10%
(64%)
>10%
(36%)
P-value
CCyR, % 94 41 - 92 59 -
MMR, % 87 38 - 81 41 -
MR4.5, % 54 5 - 48 12 -
Estimated 5-year OS,a % 94 81 .0028 95 81 .0003
Estimated 5-year PFS,a,b % 89 72 .0014 93 72 <.0001
Estimated 5-year TFS,a % 97 83 .0004 97 80 <.0001

38. Dasatinib
n=215
MR4MMR MR4.5
Imatinib
n=183
Dasatinib
n=215
Imatinib
n=183
Dasatinib
n=215
Imatinib
n=183
Achieved response
Did not achieve response
Not evaluated for molecular response at 5 years
[off treatment: dasatinib n=62 (29%), imatinib n=48 (26%);
not evaluateda: dasatinib n=9 (4%), imatinib n=6 (3%)
60%
MMR
61%
MMR
47%
MR4
37%
MR4
31%
MR4.5
23%
MR4.5
Molecular Responses at 5 Years for Patients With BCR-ABL ≤10% at 3 Months
5 years ± 3 months.
aPatients on treatment with no sample analyzed at 5 years ± 3 months.

39. Conclusion:
These final results from the DASISION trial continue to support dasatinib 100 mg
once daily as a safe and effective first-line therapy for the long-term treatment
of CML-CP.

40.  253 patients with newly diagnosed CP-CML were randomized to IM 400 mg/day
or DAS 100 mg/day.
 The proportion of patients achieving a complete cytogenetic remission rate
was superior with DAS (84% vs 69%), as was the 12-month molecular response
by the proportions of patients achieving > 3-log, > 4-log, and > 4.5-log reduction
in BCR-ABL transcript levels.
 Overall and progression-free survival was similar in the 2 arms.

41.  Among patients who achieved hematologic CR, 3-year relapse-free survival was 91% with DAS
and 88% with IM 400 mg.
Grade 3 and 4 toxicities were most commonly hematologic, including thrombocytopenia in 18%
and 8% of DAS and IM patients, respectively.
DAS induced more complete cytogenetic response and deeper molecular responses after 12
months, compared with IM 400 mg, and with a median follow-up of 3.0 years there have been
very few deaths, relapses, or progressions in the 2 arms.
Conclusion:
DAS compared with IM appeared to have more short-term cytogenetic and molecular response,
more hematologic toxicity, and similar overall survival.
Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly
diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):3898‐3905. doi:10.1182/blood-2012-02-
410688

42. •Chronic, low-grade adverse events are common in patients with CML who are treated with
imatinib.
•These events may decrease patient quality of life and adherence, and may ultimately contribute
to a suboptimal response.
•Alternative, second-generation tyrosine kinase inhibitors, such as Dasatinib, are available with
the potential to reduce adverse events, improve tolerability, and support long-term treatment
goals.
DASPERSE Study - open-label, multicenter, phase IV study designed to determine whether
chronic, low-grade nonhematologic adverse events in imatinib-treated patients improve after
switching to dasatinib, without affecting efficacy.

43. Methods
•Of the 121 chronic, grade 1/2, imatinib-related adverse events identified at baseline in 39
patients, 77% resolved or improved within 3 months after switching to dasatinib.
•Dasatinib maintained a consistent safety profile; headache (33%), pleural effusion (26%), fatigue
(23%), and rash (23%) were the most common treatment-related adverse events after the
switch.
•Patients either maintained (56%) or improved (44%) their molecular response on dasatinib.
•Patients who switched to dasatinib also experienced improved patient-reported symptom
burden from baseline as assessed by the MD Anderson Symptom Inventory for CML.

44. The status of imatinib-related AEs within 3 months after patients had switched to dasatinib. Resolved AEs are those that are no longer present, improved
AEs reduced from grade 2 to grade 1, unchanged AEs did not improve or worsen, and worsened AEs had a grade increase

45. Molecular response of patients at baseline and at 12 months. The number of patients with each molecular response level at baseline
and at 12 months is listed by color: MR4.5 (blue), MMR (green), BCR-ABL1 0.1–≤ 1.0% (red), BCR-ABL1 1–10% (purple), and BCR-
ABL1 > 10% (yellow). All patients either maintained or improved their response, and no patients ended the study with BCR-
ABL1 > 1%

46. Symptom burden in patients at baseline; weeks 2, 4, and 8; and months 3, 6, and 12 via MD Anderson Symptom Inventory (MDASI) and
MDASI for chronic myeloid leukemia (MDASI-CML) scores. The mean change in patient score at each time point is shown, with a
negative value indicating an improvement in the symptom being assessed

47. Conclusion
• Overall, the efficacy and quality of life/symptom burden improved in many patients, despite the
onset of dasatinib-related adverse events in most patients.
•This suggests that imatinib-treated patients with chronic, low-grade adverse events could
benefit from switching to treatment with dasatinib.

48. Objective: To assess the efficacy and safety of a lower dose of dasatinib (50 mg
daily) in patients with newly diagnosed CML-CP.
Methods: Seventy-five patients with newly diagnosed CML-CP received dasatinib 50
mg daily. The eligibility and response criteria were standards used in previous
protocols.

49. A. CCyR rates compared to historical data (DASISION trial) 2,8

50. B. MMR rates compared to historical data (DASISION trial) 2,8

51. Conclusion:
 Dasatinib 50 mg daily is active and well tolerated in patients with newly diagnosed CML-CP.
 It should be further explored as a new potential standard-of-care option for CML

52.  Objective: To update the long‐term follow‐up results of dasatinib at 50 mg daily
as frontline therapy for CML‐CP.
 Methods:
83 patients with newly diagnosed CML‐CP received dasatinib at 50 mg daily.
Eligibility and response criteria were standards used in previous protocols.

55. Results
•After a minimum follow‐up of 12 months, 81 patients were evaluable.
•The rates of BCR‐ABL1 transcript levels (IS) at ≤10% and ≤1% at 3 months were 96% and 77%, respectively.
•The cumulative rates for a CCyR by 6 and 12 months were 77% and 95%, respectively.
• The cumulative rates for a MMR, a molecular response with a 4.0‐log reduction, and a molecular response
with a 4.5‐log reduction by 12 months were 81%, 55%, and 49%, respectively.
•25% patients had treatment interruptions for a median of 13 days (range, 4‐64 days).
•6% developed pleural effusions; 80% required a dose reduction. 2% failed to achieve any cytogenetic or
molecular response and were taken off the study.
•At a median follow‐up of 24 months, none of the patients had disease transformation to an accelerated or
blastic phase.
•The 2‐year event‐free and overall survival rates were 100%.

56. Conclusions
•These updated results continue to support 50 mg of dasatinib daily as an effective and safe dose
for early CML‐CP.

57. Purpose
Safe, effective treatments are needed for pediatric patients with chronic myeloid leukemia in
chronic phase (CML-CP). Dasatinib is approved for treatment of adults and children with CML-CP.
A phase I study determined suitable dosing for children with Philadelphia chromosome-positive
(Ph+) leukemias.

58. Methods
Phase II, open-label, nonrandomized prospective trial of patients < 18 years of age receiving
dasatinib.
There are three cohorts:
(1) imatinib-resistant/intolerant CML-CP,
(2) imatinib-resistant/intolerant CML in accelerated/blast phase or Ph+ ALL (n = 17), and
(3) newly diagnosed CML-CP treated with tablets or powder for oral suspension.
Major cytogenetic response > 30% for imatinib-resistant/intolerant patients and complete
cytogenetic response (CCyR) > 55% for newly diagnosed patients were of clinical interest.

59. Results
•Of 113 patients with CML-CP, 48% who were imatinib-resistant/intolerant and 73% who were newly
diagnosed remained on treatment at time of analysis.
•Major cytogenetic response > 30% was reached by 3 months in the imatinib-resistant/intolerant group
and CCyR > 55% was reached by 6 months in the newly diagnosed CML-CP group.
• CCyR and major molecular response by 12 months, respectively, were 76% and 41% in the imatinib-
resistant/intolerant group and 92% and 52% in newly diagnosed CML-CP group.
•PFS by 48 months was 78% and 93% in the imatinib-resistant/intolerant and newly diagnosed CML-CP
groups, respectively.
•No dasatinib-related pleural or pericardial effusion, pulmonary edema, or pulmonary arterial
hypertension were reported.
•Bone growth and development events were reported in 4% of patients

60. Cytogenetic responses over time for all treated patients. (A) Cumulative rates of MCyR and (B) cumulative rates of CCyR. CCyR, complete cytogenetic
response;

61. Cumulative rates of molecular responses over time for all treated patients. (A, B) MMR for (A) patients with CML-CP resistant to or intolerant of imatinib and (B) patients with
newly diagnosed CML-CP. (C, D) CMR for (C) patients with CML-CP resistant to or intolerant of imatinib and (D) patients with newly diagnosed CML-CP. Cohorts were not
designed to be comparative. There are numerical differences between MMR and CMR in newly diagnosed patients with CML-CP treated with dasatinib tablets or PFOS, but CIs
overlap.

62. Conclusion
•In the largest prospective trial to date in children with CML-CP, Dasatinib ws found a safe,
effective treatment of pediatric CML-CP.
•Target responses to first- or second-line dasatinib were met early, and deep molecular responses
were observed.
• Safety of dasatinib in pediatric patients was similar to that observed in adults; however, no
cases of pleural or pericardial effusion or pulmonary arterial hypertension were reported.

69. � Treatment Free Remission is the goal
� This is irrespective of the age
� Younger the patient, stronger should be the reason
� To assess risk status : EUTOS long-term survival (ELTS)- score is recommended
� Move to 2G-TKI as and when there is intolerance which cannot be ameliorated
or if the milestones are not reached
� A sixth TKI, radotinib (Supect®, Dae Wong Pharmaceuticals) has been approved
in South Korea only
ELN 2020 RECOMMENDATIONS

70. � BCR-ABL1 at 3 months of >10%, if reconfirmed, indicates treatment failure
� Avoid the term CMR & substitute it with “molecularly undetectable
leukemia” & specify the number of the control-gene transcripts
� Once MMR is achieved, consider reducing TKI doseIf there are no Bcr-abl1 KD
mutations, selection of 2nd line TKI - should be based on host profile
� First line 2G-TKI may be considered for younger pts, pts in whom TFR is the
top priority & in women who wish to become pregnant
ELN 2020 RECOMMENDATIONS

71. Key Take aways
 Dasatinib can be used in frontline treatment of CML/treatment naïve patients (DASISION
trial) .
Dasatinib, administered once daily, as compared with imatinib, administered once daily,
induced significantly higher and faster rates of CCyR and MMR.
 Dasatinib can be the choice of TKI treatment over imatinib and nilotinib, since CNS
involvement may be observed in Blast crisis and Dasatinib can penetrate through the blood–
brain barrier.
Dasatinib is a choice of TKI in Cardiovascular, liver and Metabolic comorbidities and not
associated with VAEs in CML.
 Long term follow up of Dasatinib continues to show excellent safety profile and produces
rapid cytogenetic and molecular responses, durable deep molecular responses and excellent
long-term survival outcomes in CML patients.