Download Current Treatment Strategies for Chronic Myelogenous Leukemia

A
CME-certified
Oncology
Exchange
Activity
METHOD OF PARTICIPATION
Prior to the start of the program, please check
your syllabus to ensure you have the following
printed program materials:
• Pre-activity Survey
– Located at the front of your syllabus
• CME Evaluation with Post-activity Survey
–
Located at the back of your syllabus
Disclosures
All relevant financial relationships with commercial interests reported by
faculty speakers, steering committee members, non-faculty content
contributors and/or reviewers, or their spouses/partners have been listed
on page 5 of your program syllabus.
Off-label Discussion Disclosure
This educational activity may contain discussion of published and/or
investigational uses of agents that are not indicated by the Food and Drug
Administration. PCME does not recommend the use of any agent outside of
the labeled indications. Please refer to the official prescribing information
for each product for discussion of approved indications, contraindications
and warnings. The opinions expressed are those of the presenters and are
not to be construed as those of the publisher or grantors.
Educational Objectives
At the conclusion of this activity, participants should be able to
demonstrate the ability to:
• Identify changes in therapeutic indications and clinical practice
guideline for CML
• Understand practical aspects of monitoring responses in patients
with CML
• Identify the role of BCR-ABL mutations in making treatment
decisions in CML
• Review emerging data from ongoing studies of novel treatment
regimens and evaluate ongoing clinical trials of investigational
agents
Pre-activity Survey
• Please remove the Pre-activity Survey from the front of your packet
• Your answers are vital to our understanding of the effectiveness of
this CME program, and will help shape future educational activities
and topics
• Please fill in the most appropriate answer(s) for the questions below:
– Degree:
 MD/DO
 Nursing Professional
 PharmD
 Other: _____________________________
– Specialty:
 Oncology/Hematology
 Internal Medicine
 Transplant specialist
 Other: ___________
Pre-activity Survey Question 1
Please rate your level of confidence in treating and
managing patients with chronic myelogenous leukemia
(CML):
1
Not confident
2
3
4
5
Expert
Pre-activity Survey Question 2
Please rate your level of competence in individualizing
treatment options for patients with CML based on patient
and disease characteristics:
1
Not competent
2
3
4
5
Expert
Pre-activity Survey Question 3
Six years after starting imatinib, a 53-year-old patient’s BCR-ABL/ABL
has increased to 27.3%. After performing a bone marrow biopsy, the
patient is still in chronic phase, has 75% Ph+ metaphases and an
F317L mutation. The patient receives nilotinib at 400 mg for 12 months
after which there is no cytogenetic response. The most suitable option
for this patient would be to:
a) Continue therapy unchanged
b) Consider ponatinib, omacetaxine, or SCT
c)
Consider bosutinib or dasatinib
d) None of the above, enroll in a clinical trial
Pre-activity Survey Question 4
A 37-year-old male was diagnosed with CML and treated with imatinib
400 mg for 12 months. He was re-evaluated and found to be in
hematologic and partial cytogenetic response. Which of the following
options would NOT be appropriate at this point:
a)
Repeat mutational analysis
b)
Switch therapy
c)
Check patient’s compliance with medications
d)
Continue treatment
e)
None of the above
Pre-activity Survey Question 5
Cytogenetic analysis at 6 months of a 45-year-old female patient, who
received prior imatinib, shows Philadelphia chromosome in 45% of
metaphases and a BCR-ABL/ABL of 0.15. According to the 2013
European LeukemiaNet recommendations for the management of
CML, how would you characterize this response.
a) Failure
b) Warning
c)
Suboptimal response
d) Optimal response
Pre-activity Survey Question 6
Which of the following treatment options can be considered for a
patient who has failed imatinib and dasatinib or nilotinib:
a) Omacetaxine
b) Bosutinib
c)
Ponatinib
d) Any of the above
Evolution of CML Therapy
Signal Transduction Inhibition in CML
The Beginning
All seven individuals
showed a similar
minute chromosome.
The findings suggest
a causal relationship
between the
chromosome
abnormality observed
and chronic
granulocytic leukemia.
Nowell PC & Hungerford DA. Science 1960, 132: 1497
The Evolution of CML Therapy
Chemotherapy 
SCT 
IFN 
TKI
History Lesson #1: SCT is Curative
(For Some)
Leukemia-Free Survival
Overall Survival
58%
50%
Reprinted with permission. © (2013) American Society of Clinical Oncology. All rights reserved. Arora, M et al: J Clin Oncol 27(10): 1644-1652.
History Lesson #2: CCyR Correlates with
Improved Survival
SURVIVAL BY CG RESPONSE
1.0
78 %
0.9
PROPORTION ALIVE
0.8
0.7
0.6
39 %
0.5
0.4
Total
0.3
0.2
0.1
Dead
140
38
CR
72
40
PR
110
86
Minor
180
138
Others
(P < 0.0001)
25 %
0.0
0
24
48
72
96
120
144
168
MONTHS (LANDMARK AT 12 MONTHS)
Kantarjian et al. Cancer 2003; 97: 1033
192
History Lesson #3: SCT is NOT the Only
DURATION OF for
MAJOR
CG RESPONSE BY RT-PCR
Curative Treatment
CML
PROPORTION IN MAJOR CYTOGENETIC RESPONSE
1.0
P < 0.001
0.8
0.6
0.4
RT-PCR
0.2
Total
Lost response
Persistent negative
20
0
Transient negative
18
4
Positive
32
15
0.0
0
24
48
72
96
120
144
MONTHS FROM FIRST CR
Kantarjian et al. Cancer 2003; 97: 1033
168
192
216
Survival in Early Chronic Phase CML
TKI
Interferon
Chemotherapy
Kantarjian et al. Blood 2012; 119: 1981-7. Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.
Is The Outcome Really That Good?
MDACC event: progression to AP/ BP; loss of MCyR; loss of CHR; no response (ELN criteria); intolerance; or death (any cause,
any time)
Kantarjian et al. ASH 2010; Abstract 672.
Or Is It Really That Bad?
• 281 pts Rx with imatinib as initial therapy (73 SD, 208 HD)
• CCyR 88%  75 stopped IM
– 41 events  23 received subsequent TKI  14 (67%) CCyR
1.0
CEFS at 7 yrs = 88%
Probability (%)
0.8
EFS at 7 yrs = 81%
0.6
0.4
0.2
0.0
0
12
Al-Kali et al. Cancer 2011; 117: 327-35
24
36
48
60
72
84
CEFS = Current event free survival; EFS = Event free survival
Good Outcome: Just in Clinical Trials?
• 65 pts treated off protocol & 71 on protocols
• Imatinib 400 mg; Median f/u 51 mo
Age, y
High-risk Sokal
3-mo MCyR
12- mo CCyR
12-mo MMR
5-yr EFS
5-yr TFS
5-yr OS
Median income, $
Education HS or less
Uninsured
Yilmaz et al. ASH 2012; Abstract #1693
Median [range], or Percentage
On protocol
Off protocol
US Population
49 [15-79]
49 [15-84]
6
5
71
69
84
83
30
24
86
84
96
94
90
96
45,735
44,606
42,148
42
43
48
10
8
14
Clinical Case Discussions
Case 1: Frontline Therapy in
Newly Diagnosed Setting
Case 1: History & Presentation
• 37 year old male, manufacturing employee at a mechanical
shop. Married with two children.
• Presented with noted weight loss of 22 pounds in the last
12 months, with simultaneous onset of night sweats and
fullness in the left side of his abdomen.
• This patient did not have a PCP and had not been seen by
a physician since his childhood days for routine checkups.
Case 1: Work-up
• The major clinical finding was splenomegaly at 14 cm
below the costal margin.
• Laboratory tests revealed:
– WBC of 317,000/ml with 47% immature myeloid cells (meta
myelocytes, myelocytes, promyelocytes)
– 3% blast cells and 7% basophils in the peripherial blood
– Blood chemistries were abnormal with elevated lactated
dehydrogenase of 842 u/L
– Platelet count was 916,000
– Hemoglobin was 9.3
– Other blood chemistries were WNL.
Case 1 (continued)
• CML is suspected and a test for bcr-abl revealed that the
disease was bcr-abl positive leukemia with b3 a2 transcript
consistent with CML.
• A bone marrow test followed and revealed bone marrow with
high cellularity of 100% with predominant but well matured
myeloid series. The bone marrow had 4% myeloblasts
• Bone marrow cytogenetic test revealed 20/20 cells with Ph+
and no evidence of additional chromosomal abnormalities was
noted.
• With the diagnosis of CML in the chronic phase the patient was
placed on imatinib 400 mg daily.
Case 1: Question 1
Is this the correct treatment decision?
1. Imatinib is approved as first line treatment for CML and it
is the correct choice
2. The patient has high risk CML and he would have
benefited from starting nilotinib or dasatinib
3. With high-risk disease the patient should have been
placed on ponatinib
4. All are correct
5. Only 1 & 2 are correct
6. Only 2 & 3 are correct
Case 1: Answer
Is this the correct treatment decision?
1. Imatinib is approved as first line treatment for CML and it is
the correct choice
2. The patient has high risk CML and he would have benefited
from starting nilotinib or dasatinib
3. With high-risk disease the patient should have been placed
on ponatinib
4. All are correct
5. Only 1 & 2 are correct
6. Only 2 & 3 are correct
IRIS 8-Year Update
No CCyR
17%
Safety
5%
Sustained
CCyR on
study
53%
Lost CCyR
15%
Lostregained
CCyR
3%
At least
37%
Unacceptable
Outcome
CCyR
Other
7%
• EFS = 81%; Freedom from progression to AP/BC = 92%; OS = 85%
Deininger M, et al. Blood . 2009;114(22): 1126.
Imatinib Toxicities
Imatinib: Common or Frequent Complaints
Neutropenia
Musculoskeletal complaints
Thrombocytopenia – mainly during yr 1
Hypophosphatemia
GI disturbances / Diarrhea
Rash
Edema and fluid retention
Pediatrics: growth retardation
Occasional bone mineral metabolism problem
Long Term Toxicities of Imatinib
Liver, kidney, cardiac toxicity and immunosuppression.
CHF:
• 1276 patients at MDACC were studied with median follow up at 47 mos
• 22 patients, or 1.7% have CHF, however 13/22 had received cardio toxic
drugs in the past.
Management of Acute Toxicities
Management of anemia and neutropenia includes use of erythropoietin and filgrastim
Atallah et al, Blood 2007; 110: 1233–1237; Gleevec prescribing information, 2013.; NCCN Guidelines v4.2013.
ENESTnd 3-year update: OS and PFS
OS
3-yr OS, %
HR (95% CI) vs imatinib
P value vs imatinib
PFS
3-yr PFS, %
HR (95% CI) vs imatinib
P value vs imatinib
Nilotinib 300 mg
BID
(n = 282)
Nilotinib 400 mg
BID
(n = 281)
Imatinib 400 mg
QD
(n = 283)
95.1
97.0
94.0
0.75 (0.37-1.55)
0.46 (0.20-1.07)
--
.4413
.0639
--
Nilotinib 300 mg
BID
(n = 282)
Nilotinib 400 mg
BID
(n = 281)
Imatinib 400 mg
QD
(n = 283)
96.9
98.3
94.7
0.44 (0.17–1.15)
0.30 (0.10–0.92)
--
. 0.0842
0.0260
--
BID, twice daily; CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progressionfree survival; QD, once daily.
Larson RA, et al. Leukemia 2012; 26: 2197-2203.; Kantarjian et al , ASH 2012 Abstract 1676.
ENESTnd 3-yr Update
Nilotinib
300 mg BID
(n = 282)
Nilotinib
400 mg BID
(n = 281)
Imatinib
400 mg QD
(n = 283)
MMR
73; P < .0001
70; P < .0001
53
MR4
50; P < .0001
44; P < .0001
26
MR4.5
32; P < .0001
28; P = .0003
15
(Larson et al 2012, Leukemia 2197-2203.)
Response by 3 yrs, %
3-mo landmark analysis: BCR-ABL transcript levels*, % MMR by 1 yr/2 yrs, %
≤ 1% (n = 120, 123, 41)
76/89
72/91
> 1 to ≤ 10% (n = 89, 95, 133)
40/67
38/54
> 10% (n = 24, 28, 88)
4/29
14/29
Freedom from progression to AP/BC, %
71/78
31/52
2/20
Estimated 3-yr rate on core treatment
99.3; P = .0059
98.7; P = .0185
95.2
Including events after discontinuation
OS, %
96.7; P = .0496
98.1; P = .0076
93.5
95.1; P = .4413
97.0; P = .0639
94.0
98.1; P = .0356
98.5; P = .0159
95.2
11
3
11
2
21
3
Estimated 3-yr OS rate
Only CML-related deaths
Patients with BCR-ABL mutation, n
Any mutation
T315I
ENESTnd 3-Yr Update
Hematologic AEs and Biochemical Abnormalities
Grade 3/4 AEs, %
Nilotinib 300 mg BID Nilotinib 400 mg BID
(n = 279)
(n = 277)
Imatinib 400 mg QD
(n = 280)
Neutropenia
11.8
10.8
21.4
Thrombocytopenia
10.4
12.3
8.9
Anemia
3.9
4.7
5.7
Lipase increase
7.5
7.9
3.9
ALT increase
4.3
9.4
2.5
Total bilirubin increase
3.9
7.9
0.4
Hyperglycemia
6.1
5.4
0
Nilotinib Toxicities
• Prolongation of QTC and vascular adverse events
• Coronary events
• Peripheral Arterial Occlusive Disease – PAOD
Larson RA, et al. Leukemia 2012;26; Tasigna prescribing information, 2013; NCCN Guidelines v4.2013.
DASISION 3-Yr Update
Cumulative Molecular Responses
Outcome, %
Dasatinib 100 mg QD
(n = 259)
Imatinib 400 mg QD
(n = 260)
1 yr
46*
23
2 yrs
64*
46
3 yrs
68*
55
Cumulative MR4
3 yrs
35†
22
Cumulative MR4.5
3 yrs
22‡
12
Cumulative MMR
*P < .0001 vs imatinib. †P = .00635 vs imatinib. ‡P = .00069 vs imatinib.
OS and PFS
3-Yr Survival Outcome Dasatinib (n = 259)
Imatinib (n = 260)
HR (95% CI)
PFS, %
91.0
90.9
1.00 (0.55-1.80)
OS, %
93.7
93.2
0.86 (0.45-1.65)
17
20
-
Deaths, n
Hochhaus A, et al. ASCO 2012. Abstract 6504.
DASISION 3-Yr Update
Hematologic AEs and
Biochemical Abnormalities
Grade 3/4 AEs, %
Toxicities
Dasatinib 100
mg BID (n = 281)
Imatinib 400 mg
QD (n = 283)
Neutropenia
24.0
20.9
Thrombocytopenia
19.4
11.2
Anemia
11.6
8.5
Decreased phosphorus
7.0
28.3
Decreased calcium
3.1
1.9
Elevated creatinine
1.2
0.8
Elevated total bilirubin
1.2
0
Elevated ALT
0.4
1.6
Elevated AST
0.4
1.2
0
2.3
Decreased potassium
• Impaired platelet
aggregation and bleeding
• Pleural effusion
(up to 29% of pts)
• Reversible pulmonary
arterial HTN
• Dose interruption in 83%
of pts
• Dose reduction in 71% of
pts
Hochhaus A, et al. ASCO 2012. Abstract 6504; Sprycel Prescribing information 2013; NCCN Guidelines v4.2013.
Case 1 (continued)
• The patient responded rapidly to imatinib with resolution of
his symptoms: weight gain and splenomegaly.
• The WBC returned to normal as did the platelet count, and
the anemia resolved.
• Repeat quantitative bcr-abl test after 3 months of treatment
revealed bcr-abl/abl ratio by international scale of 11%.
• A FISH test for bcr-abl was 22% positive.
• With these improved results the physician elected to
continue imatinib at 400 mg daily.
NCCN Guidelines v4.2013
Case 1: Question 2
Is continuation of imatinib an appropriate option?
1.
No, the patient failed to achieve a bcr-abl/abl ratio of <10% and
should be a candidate for allogeneic bone marrow transplant.
2.
It is the correct treatment. The patient has achieved a
hematologic response and a partial cytogenetic response
3.
The response is inadequate and the patient should have been
switched to a 2nd generation TKI inhibitor, either nilotinib or
dasatinib
4.
A mutation analysis should have been performed first and if there
was no bcr-abl mutation, then the decision to continue with the
same treatment could have been made
NCCN Guidelines v4.2013
Case 1: Answer
Is continuation of imatinib an appropriate option?
1.
No, the patient failed to achieve a bcr-abl/abl ratio of <10% and
should be a candidate for allogeneic bone marrow transplant.
2.
It is the correct treatment. The patient has achieved a
hematologic response and a partial cytogenetic response
3.
The response is inadequate and the patient should have been
switched to a 2nd generation TKI inhibitor, either nilotinib or
dasatinib
4.
A mutation analysis should have been performed first and if there
was no bcr-abl mutation, then the decision to continue with the
same treatment could have been made
NCCN Guidelines v4.2013
Case 1 (continued)
• After six months of therapy the patient started to complain
of worsening diarrhea – up to 6x daily, poorly controlled
with Imodium.
• The patient states that it has been embarrassing at times
because of an inability to control it and that it is interfering
with his work and social activities.
• At this juncture the hematologist lowered the imatinib to
200 mg daily
Adverse Event Management: Diarrhea
• Imatinib’s most frequently reported drug-related adverse events
were edema, nausea and vomiting, muscle cramps,
musculoskeletal pain, diarrhea and rash
• Important to listen to patients and acknowledge that diarrhea
can be debilitating and may seriously affect their daily activities.
• Physicians should discuss diet and explain to patients that
certain foods, like spicy ones, can worsen diarrhea.
• Patients should be prescribed anti-diarrheal medications as
needed.
• TKI dosage should be adjusted accordingly.
Gleevec prescribing information 2013; DeAngelo, 2012; Kurtin, 2010.
NCCN Guidelines for CML Treatment
Continuation or Change
Time
3 mo.
Response
Recommendation
Bcr/abl: ≤ 10 %
Continue treatment
Bcr/abl: > 10%
Evaluate compliance ; Mutation Analysis; Change
Therapy
12 mo.
CCYR
≤ PCYR
18 mo.
CCYR
≤ PCYR
NCCN Guidelines v4.2013
Continue Treatment
Evaluate compliance ; Mutation Analysis; Change
Therapy /Evaluate for HSCT
Continue Treatment
Evaluate compliance ; Mutation Analysis; Change
Therapy /Evaluate for HSCT
Case 1: Outcome
• The patient continued on imatinib 200 mg daily for an
additional 9 months.
• At 12 months was found to be in hematologic response
and partial cytogenetic response.
• Overall, he tolerated this change in treatment reasonably
well and his diarrhea was moderately well controlled.
Clinical Case Discussions
Case 2: Relapsed/Refractory Setting
Case Study 2
A 54-year old man has been receiving therapy with imatinib
400 mg daily for 6 months. Cytogenetic analysis shows
Philadelphia chromosome in 25% of metaphases.
Question 1
How would you label this response:
1. Failure
2. Secondary resistance
3. Suboptimal response
4. Optimal response
5. Warning
6. None of the above
Case Study 2: Answer
How would you label this response:
1.
2.
3.
4.
5.
6.
Failure
Secondary resistance
Suboptimal response
Optimal response [ELN 2009 criteria]
Warning [ELN 2013 criteria]
None of the above
Criteria for Failure and Suboptimal Response to
Imatinib – ELN 2009
Time (mo)
Failure
Response
Suboptimal
No CgR
>95% Ph+
Optimal
3
No CHR
6
No CgR
>95% Ph+
>35% Ph+
12
>35% Ph+
1-35% Ph+
18
≥5% Ph+
Loss of CHR;
Loss of CCgR;
Mutation;
CCA/Ph+
No MMR
CCgR
0% Ph+
MMR
Loss of MMR;
Mutation
Stable or
improving MMR
Any
≤65% Ph+
≤35% Ph+
Acronyms: Ph = Philadelphia chromosome; CHR = complete hematologic response; CgR = cytogenetic response; MMR = major
molecular response; CCgR = complete cytogenetic response; CCA = clonal chromosome abnormalities.
Baccarani et al. JCO 2009; 27: 6041-51
Criteria for Failure and Suboptimal Response to
Imatinib – ELN 2013
Time
(mo)
3
6
12
Any
Failure
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%
and/or
Ph+ >35%
BCR-ABL1 >1%
and/or
Ph+ >0%
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
Response
Warning
BCR-ABL1 >10%,
and/or
Ph+ 36-95%
BCR-ABL1 1-10%,
and/or
Ph+ 1-35%
Optimal
BCR-ABL ≤10%,
and/or
Ph+ ≤35%
BCR-ABL <1%,
and/or
Ph+ 0%
BCR-ABL1
>0.1-1%
BCR-ABL1
≤0.1%
CCA/Ph(-7, or 7q-)
BCR-ABL1 ≤0.1%
Acronyms: Ph = Philadelphia chromosome; CHR = complete hematologic response; CgR = cytogenetic response; MMR = major
molecular response; CCgR = complete cytogenetic response; CCA = clonal chromosome abnormalities.
Baccarani et al. Blood 2013; 122: 872-84. Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.
Case Study 2: Question 2
The patient has occasional muscle cramps, and no other
toxicity. Your treatment recommendation:
1.
Continue therapy unchanged
2.
Increase the dose of imatinib to 400mg BID
3.
Change therapy to nilotinib 400mg BID
4.
Change therapy to dasatinib 100mg QD
5.
SCT
Case Study 2: Answer
The patient has occasional muscle cramps, and no other
toxicity. Your treatment recommendation:
1.
Continue therapy unchanged
2.
Increase the dose of imatinib to 400mg BID
3.
Change therapy to nilotinib 400mg BID
4.
Change therapy to dasatinib 100mg QD
5.
SCT
Treatment Discontinuation for Frontline TKIs
in CML
Percentage
F/U
IM400 IM800 Nilotinib Dasatinib Bosutinib
(mo)
ENESTnd*¥ >36
38
DASISION
>36
31
BELA
>24
29
MDACC
>36
29
29
30
37
24
18
8
* Nilotinib 300mg BID shown.
¥ Includes patients who discontinued into extension study; rates are 26% imatinib and 22% nilotinib if all excluded
Alattar et al. ASH 2011; Abstract #745; Saglio et al. ASH 2011; Abstract #452; Kantarjian et al. ASCO 2011; Abstract #6510; Cortes et al.
ASH 2011; Abstract #455
Factors Influencing Early Discontinuation of 2nd
Generation TKI
• Adverse events
• Lack of efficacy
• Availability of alternative options
• Decrease tolerance to adverse events
• Unreasonable expectations regarding toxicity
• Suboptimal management of AEs
• Lack of familiarity
Baccarani et al. Blood 2013; 122: 872-84
Case Study 2: Question 3
The patient has been on imatinib therapy now for 48 months. He had
achieved an MMR (BCR-ABL/ABL <0.1% IS) that had been sustained for
the last 18 months, most recently at 0.05 at 36 months and 0.03 at 42
months. A routine follow up assessment shows a normal CBS with a
BCR-ABL/ABL of 0.09.
Question 3
What additional tests would you request:
1.
2.
3.
4.
5.
6.
7.
8.
Obtain FISH
Repeat PCR in 3 months
Assess for mutations
Repeat cytogenetic analysis
Perform a bone marrow aspiration
All of the above
1&3
3&5
Case Study 2: Answer
What additional tests would you request:
1.
Obtain FISH
2.
Repeat PCR in 3 months
3.
Assess for mutations
4.
Repeat cytogenetic analysis
5.
Perform a bone marrow aspiration
6.
All of the above
7.
1&3
8.
3&5
Significance of KD Mutations in Patients
Responding to Imatinib
• 10 of 214 (5%) pts who
achieved CCyR had mutation
– 4 before CCyR
• Median time from mutation to
loss CCyR 20.7 months
• Median time from detection of
mutation to 2-fold  PCR 12 mo
• KD mutation predictive of loss
of CCyR
PFS by Mutation at 2 Yrs
Reprinted with permission. © (2013) American Society of Clinical Oncology. All rights reserved. Khorashad, JS et al: J Clin Oncol 26(29):
4806-4813.
When to Look For Mutations?
Mutation analysis in 1301 pts receiving imatinib or
2nd generation TKI (GIMEMA)
Clinical condition
Failure
No CHR @ 3 mo
No CyR @ 6 mo
No PCyR @ 12 mo
No CCyR @ 18 mo
Loss CCyR
Loss CHR
Suboptimal
No CyR @ 3 mo
No PCyR @ 6 mo
No CCyR @ 12 mo
No MMR @ 18 mo
Loss MMR
Soverini et al. ASH 2011; Abstract #112
% Positive
27
19
11
17
17
31
50
5
7
5
8
0
4
Molecular Response in CML
TFS and OS by MR at 24 months
Survival (%)
TFS
OS
p=.50
Response
p=.52
Total AP/BP P-value (vs.
UND)
66
113
37
72
25
1
0
0
0
0
Response
n/a
.25
.38
.33
.56
Time (months)
Falchi et al. Am J Hematol 2013: (In press)
Total
Died
P-value (vs.
UND)
66
113
37
72
25
3
4
2
2
3
n/a
.89
.94
.70
.22
Criteria for Failure and Suboptimal Response to
Imatinib – ELN 2013
Time
(mo)
Response
Failure
Warning
Optimal
3
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%,
and/or
Ph+ 36-95%
BCR-ABL ≤10%,
and/or
Ph+ ≤35%
6
BCR-ABL1 >10%
and/or
Ph+ >35%
BCR-ABL1 1-10%,
and/or
Ph+ 1-35%
BCR-ABL <1%,
and/or
Ph+ 0%
12
BCR-ABL1 >1%
and/or
Ph+ >0%
BCR-ABL1
>0.1-1%
BCR-ABL1
≤0.1%
Any
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
CCA/Ph(-7, or 7q-)
BCR-ABL1 ≤0.1%
Baccarani et al. Blood 2013; 122: 872-84
Criteria for Failure and Suboptimal Response to
Imatinib – ELN 2013
Time
(mo)
Response
Failure
Warning
Optimal
3
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%,
and/or
Ph+ 36-95%
BCR-ABL ≤10%,
and/or
Ph+ ≤35%
6
BCR-ABL1 >10%
and/or
Ph+ >35%
BCR-ABL1 1-10%,
and/or
Ph+ 1-35%
BCR-ABL <1%,
and/or
Ph+ 0%
12
BCR-ABL1 >1%
and/or
Ph+ >0%
Any
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
CCA/Ph(-7, or 7q-)
BCR-ABL1 ≤0.1%
Baccarani et al. Blood 2013; 122: 872-84
Lack of MMR is not
a criterionBCR-ABL1
for
BCR-ABL1
>0.1-1%
≤0.1%
failure; confirmed
loss of MMR is
Criteria for Failure and Suboptimal Response to
Imatinib – ELN 2013
Time
(mo)
Response
Failure
Warning
Optimal
3
No CHR,
and/or
Ph+ >95%
BCR-ABL1 >10%,
and/or
Ph+ 36-95%
BCR-ABL ≤10%,
and/or
Ph+ ≤35%
6
BCR-ABL1 >10%
and/or
Ph+ >35%
BCR-ABL1 1-10%,
and/or
Ph+ 1-35%
BCR-ABL <1%,
and/or
Ph+ 0%
12
BCR-ABL1 >1%
and/or
Ph+ >0%
BCR-ABL1
>0.1-1%
BCR-ABL1
≤0.1%
Any
Loss of CHR
Loss of CCgR
Confirmed loss of MMR
Mutations
CCA/Ph+
CCA/Ph(-7, or 7q-)
BCR-ABL1 ≤0.1%
Baccarani et al. Blood 2013; 122: 872-84
Case Study 2: Question 4
Six years after the start of therapy, on a routine follow-up assessment
you find the BCR-ABL/ABL has increased to 27.3% (IS). You perform
a bone marrow and confirm that the patient is still in chronic phase
but has 75% Ph+ metaphases. A mutation analysis shows a mutation
F317L.
Question 4
Your choice now is:
1. Increase the dose of imatinib to 400mg BID
2. Change therapy to nilotinib 400mg BID
3. Change therapy to dasatinib 100mg QD
4. Change to bosutinib 500 mg BID
5. Change to ponatinib 45 mg daily
6. Proceed to SCT
Case Study 2: Answer
Your choice now is:
1.
2.
3.
4.
5.
6.
Increase the dose of imatinib to 400mg BID
Change therapy to nilotinib 400mg BID
Change therapy to dasatinib 100mg QD
Change to bosutinib 500 mg BID
Change to ponatinib 45 mg daily
Proceed to SCT
2nd Generation TKI in CML
Parameter
Potency (fold vs IM)
Target
BCR-ABL binding
Resistant mutations
Mutations with intermediate
sensitivity
Standard dose (CP)
Grade 3-4 neutropenia &
thrombocytopenia
Dasatinib
325
Src & Abl
Active + Inactive
T315I
E255K/V, V299L,
F317L
100mg QD
Nilotinib
30
Abl
Inactive
T315I
E255K/V, Y253F/H,
Q252H, F359V
400mg BID
Bosutinib
20-50
Src & ABL
Intermediate
T315I
E255V/K,
V299L, F317L
500mg QD
33% / 22%
31% / 33%
12% / 21%
Pleural effusion,
bleeding
Bilirubin, lipase
elevation
Diarrhea, rash
C-kit inhibition (vs imatinib)
Increased
Similar
None
PDGFR inhibition (vs imatinib)
Increased
Similar
None
Highly active
Highly active
Highly active
Other notable toxicities
Clinical activity
Sprycel®, Tasigna®, Bosulif® prescribing information (2013).
2nd Generation TKI in CML CP Post-Imatinib
Resistance
Response
Percentage
Dasatinib
Nilotinib
Bosutinib
FU (mo)
>24
>24
24*
CHR
89
77
86
MCyR
59
56
54
CCyR
44
41
41
24 mo PFS**
80%
64%
79%
24 mo OS**
91%
87%
92%
* Median
** All patients
Shah et al. Haematologica 2010; 95: 232-40; Kantarjian et al. Blood 2011; 117: 1141-45; Cortes et al. Blood 2011; 118; 4567-76
2nd Generation TKI in CML CP Post-Imatinib
Intolerance
Percentage
Response
Dasatinib
Nilotinib
Bosutinib
CHR
100
NR
85
MCyR
77
66
49
CCyR
67
51
41
Shah et al. Haematologica 2010; 95: 232-40; Kantarjian et al. Blood 2011; 117: 1141-45; Cortes et al. Blood 2011; 118; 4567-76
2nd-Generation TKI in CML CP
Post- Imatinib Failure
Toxicity
Pleural effusion
Liver
Dasatinib
++
+
Nilotinib
+
Bosutinib
+
+
+
++
+
++
+
++
Diarrhea
Lipase
Glucose
- (+)
-
++
++
++
-
Hypophosphatemia
++
++
+
Bleeding
QTc
+
++
++
-
Transaminases
Bilirubin
Rash
2nd-Generation TKI in CML CP
Post- Imatinib Failure
Toxicity
Dasatinib Nilotinib Bosutinib
Anemia
13
11
13
Neutropenia
35
31
18
Thrombocytopenia
23
30
24
Shah et al. Haematologica 2010; 95: 232-40; Kantarjian et al. Blood 2011; 117: 1141-45; Cortes et al. Blood 2011; 118; 4567-76
Sensitivity of Mutations
to
TKI
IC50-fold increase (WT=1)
WT
L248V
G250E
Q252H
Y253F
E255K
E255V
D276G
E279K
V299L
T315I
F317L
M351T
F359V
L384M
H396P
H396R
G398R
F486S
Imatinib
1
3.54
6.86
1.39
3.58
6.02
16.99
2.18
3.55
1.54
17.50
2.60
1.76
2.86
1.28
2.43
3.91
0.35
8.10
Highly Resistant / Resistant / Sensitive
Bosutinib
1
2.97
4.31
0.31
0.96
9.47
5.53
0.60
0.95
26.10
45.42
2.42
0.70
0.93
0.47
0.43
0.81
1.16
2.31
Dasatinib
1
5.11
4.45
3.05
1.58
5.61
3.44
1.44
1.64
8.65
75.03
4.46
0.88
1.49
2.21
1.07
1.63
0.69
3.04
Nilotinib
1
2.80
4.56
2.64
3.23
6.69
10.31
2.00
2.05
1.34
39.41
2.22
0.44
5.16
2.33
2.41
3.10
0.49
1.85
Redaelli et al. JCO 2009; 27: 469-71
CCyR by Mutations in CML Treated with 2nd
Generation TKI after IM Failure
• 86/169 (51%) pts treated had mutation
– CP 30/59 (51%), AP 41/71 (58%), BP 15/39 (38%)
• IC50 for mutation with dasatinib, nilotinib predictive for response in CP and AP
Chronic Phase
Accelerated Phase
Jabbour et al, Blood 2009; 114: 2037-43. . Reproduced with permission of AMERICAN SOCIETY OF HEMATOLOGY.
Case Study 2: Question 5
The patient has received nilotinib for 12 months with no
cytogenetic response. You elect now to:
1.
2.
3.
4.
5.
6.
Continue therapy unchanged
Change therapy to dasatinib 100mg QD
Change therapy to bosutinib 500 mg QD
Change therapy to ponatinib 45 mg QD
Change to omacetaxine
SCT
Case Study 2: Answer
The patient has received nilotinib for 12 months with no
cytogenetic response. You elect now to:
1.
2.
3.
4.
5.
6.
Continue therapy unchanged
Change therapy to dasatinib 100mg QD
Change therapy to bosutinib 500 mg QD
Change therapy to ponatinib 45 mg QD
Change to omacetaxine
SCT
Are Responses Less Than CCyR Clinically
Meaningful in 2nd Line Therapy for CML?
• 165 pts treated with ≥2nd line TKI after imatinib failure
• Best response: CCyR 52%, PCyR 7%, mCyR 14%, CHR 14%, no
response 17%
Survival
Survival free from transformation
Overall
responses
%
95% C.I.
%
95% C.I.
CCyR
98
94-100
95
90-100
PCyR
89
71-100
73
47-100
MinCyR
85
71-100
84
69-100
CHR only
72
52-100
88
67-100
No response
67
45-100
0
NA
• Responses inferior to CCyR still confer a long-term clinical benefit to
patients treated with ≥2nd line TKI in CML CP compared to no response
Cortes et al. Clin Lymphoma Myeloma Leuk 2011; 11: 421-6
Response to Bosutinib 3rd Line Therapy
• 114 pts who failed imatinib (600mg) & dasatinib or nilotinib
• Minimum 24 mo F/U
Response, %
CHR
MCyR
CCyR
PCyR
MMR
2-yr progression or
death
IM, imatinib; D, dasatinib; NI, nilotinib.
Khoury et al. ASH 2012; Abstract #3785
IM + D
resistant
(n = 37)
62
33
19
14
3
IM + D
intolerant
(n = 49)
80
48
43
5
25
IM + NI
resistant
(n = 27)
76
39
27
12
11
21
12
49
Ponatinib Phase 2 Study - PACE
Response Characteristics CP-CML
• 93% failed ≥2 TKI, 58% failed ≥3 TKI
Response Rate, n (%)
Any Cytogenetic Response
MCyR
CCyR
MMR
MR4.5
BCR-ABL ≤10% at 3 months, n/N(%)
1 prior approved TKI
Median Time to Response*, months [range]
MCyR
MMR
• 91% MCyR sustained at 12 months (K-M)
Cortes et al. ASH 2012; Abstract #163
N=267
180 (67)
149 (56)
124 (46)
91 (34)
39 (15)
142/240 (59)
14/16 (88)
2.8 [1.6 – 11.3]
5.5 [1.8 – 19.2]
Omacetaxine for CML CP After Failure
to ≥2 TKI
• 122 pts with CML CP (n=81) or AP (n=41) with ≥2 prior TKI
• Omacetaxine 1.25 mg/m2 BID x14d, then x7d
CP
N=81
Primary endpoint
MCyR 20%
CCyR 10%
Median duration, mo
17.7
Median PFS, mo
9.6
Median OS, mo
33.9
• 11 pts (9 CP, 2 AP) ongoing response
• Median 35 cycles over median 39 months
• Median response duration: 14 mo CP, 24 mo AP
Response, %
Cortes et al. Clin Lymphoma Myeloma Leuk 2013 [Epub ahead of print]
AP
N=41
MaHR 27%
CHR 24%
9
4.7
16
Management of Failure After TKI
• Close monitoring per standard recommendations (ELN)
required
• Indication to change therapy when failure (not
warning/suboptimal)
• Mutation analysis when failure; informative in some patients
• Avoid rapid succession of TKI
• Manage adverse events effectively
• Consider all your options
Participant Post-activity Survey
• Please remove the Participant Post-survey & CME
Evaluation from the end of your packet
• By completing both the Pre- and Post-survey forms, you
will help provide benchmarks and feedback that are vital to
our understanding of the effectiveness of this CME
program, and will help shape future educational activities
and topics
Post-activity Survey
• Please fill in the most appropriate answer(s) for the questions below:
– Degree:
 MD/DO  Nursing Professional  PharmD
 Other: _____________________________
– Specialty:  Oncology/Hematology  Transplant specialist
 Internal Medicine
 Other: ___________
– Approximately, how many patients with CML do you treat/diagnose
every month? _________
Post-activity Survey Question 1
As a result of attending the educational activity, please rate
your level of confidence in treating and managing patients
with CML:
1
Not confident
2
3
4
5
Expert
Post-activity Survey Question 2
As a result of attending the educational activity, please rate
your level of competence in individualizing treatment options
for patients with CML based on patient and disease
characteristics:
1
Not competent
2
3
4
5
Expert
Post-activity Survey Question 3
Six years after starting imatinib, a 53-year-old patient’s BCR-ABL/ABL
has increased to 27.3%. After performing a bone marrow biopsy, the
patient is still in chronic phase, has 75% Ph+ metaphases and an
F317L mutation. The patient receives nilotinib at 400mg for 12 months
after which there is no cytogenetic response. The most suitable option
for this patient would be to:
a) Continue therapy unchanged
b) Consider ponatinib, omacetaxine, or SCT
c)
Consider bosutinib or dasatinib
d) None of the above, enroll in a clinical trial
Post-activity Survey Question 4
A 37-year-old male was diagnosed with CML and treated with imatinib
400 mg for 12 months. He was re-evaluated and found to be in
hematologic and partial cytogenetic response. Which of the following
options would NOT be appropriate at this point:
a)
Repeat mutational analysis
b)
Switch therapy
c)
Check patient’s compliance with medications
d)
Continue treatment
e)
None of the above
Post-activity Survey Question 5
Cytogenetic analysis at 6 months of a 45-year-old female patient, who
received prior imatinib, shows Philadelphia chromosome in 45% of
metaphases and a BCR-ABL/ABL of 0.15. According to the 2013
European LeukemiaNet recommendations for the management of
CML, how would you characterize this response.
a) Failure
b) Warning
c)
Suboptimal response
d) Optimal response
Post-activity Survey Question 6
Which of the following treatment options can be considered for a
patient who has failed imatinib and dasatinib or nilotinib:
a) Omacetaxine
b) Bosutinib
c)
Ponatinib
d) Any of the above
Thank you for joining us today!
Please remember to turn in your evaluation form.
Your participation will help shape future CME activities.