chronic myelogenous leukemia: applying emerging evidence in practice
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Chronic Myelogenous LeukemiaApplying Emerging Evidence in Practice
Michael J. Mauro, MDProfessor of Medicine
Leader, Myeloproliferative Neoplasms ProgramMemorial Sloan Kettering Cancer Center
Disclosures
Dr. Mauro discloses the following commercial relationships:– Novartis (consultant)– Bristol-Myers Squibb (consultant)– Pfizer (consultant)– Ariad Pharmaceuticals (consultant)
Nursing Learning Objectives Describe clinical challenges associated with the
contemporary management of CML Evaluate patient- and tumor-related factors that
inform evidence-based treatment planning Recognize the clinical application of novel therapies
in the treatment of newly CML lymphoma Assess side-effect profile of novel therapies for CML
The History of CML Is Long, the Kinase Inhibitor Era Short
1845
First description of CML
1865
Fowler’s solution - 1% arsenic trioxide
2001
Imatinib
1879
Staining methods for blood
1903 1953 19831965
RadiotherapyBusulfan
Hydroxyurea
Interferon
1968
Bone Marrow Transplant
2006
Dasatinib, Nilotinib
2012
Bosutinib Ponatinib
1960:Nowell & Hungerford describe the Philadelphia Chromosome
1973:Janet Rowley describes the9:22 translocation
1999: After seminal preclinical work first clinical trials commence with STI571 (imatinib)
1845:John Hughes Bennett reported a “Case of Hypertrophyof the Spleen and Liver in which Death Took Place from Suppuration of the Blood” in the Edinburgh Medical Journal
2016
Generic Imatinib
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 205020000
40000
60000
80000
100000
120000
140000
160000
180000
200000
Incidence 4,700 per year
Age-matched mortality ratio vs normal popula-tion = 1.50
Accounts for increased US population to 410 million in 2050
CML = chronic myelogenous leukemia.Huang et al, 2012.
Year
Num
ber o
f Cas
es 10x greatersteady state number
of CML patients in USby 2050
As Result of Treatment Success the Prevalence of CML Is Increasing Steadily
CML in 2016
qPCR = quantitative polymerase chain reaction.NCCN, 2016.
CML is now highly treatable and “functional cure” appears to be within our grasp
Initial therapy for many is an “embarrassment of riches”– Five approved tyrosine kinase inhibitors (TKIs) overall, three front-line, in the US
Key diagnostic (qPCR): blood-based and widely available Rapidity of response and passing key thresholds improve odds of
deep remission in the short and long term
Success in CML contingent on managing reversible early toxicity, adherence to therapy, achieving landmarks of response, and vigilance for ‘late effects’
CML is a marathon, not a sprint!
Topics to Discuss
1. What should we be looking at upon diagnosis and what is best initial therapy?
2. How to define and manage resistance3. Is stopping therapy going to be appropriate?4. Are we seeing late complications with TKI
therapy?5. What else is new on the horizon for CML?
Making the Diagnosis of CML
History and physical(record spleen size)
Complete blood count/differential Ph+ chromosome determination
(cytogenetics > FISH > PCR) Baseline qPCR for BCR-ABL
(quantitative, International Scale reported)
Required
Bone marrow aspirate/biopsy HLA typing of siblings
Suggested/Implied
Ph = Philadelphia chromosome; FISH = fluorescence in situ hybridization; HLA = human leukocyte antigen. NCCN, 2016.
Risk score calculation– Predicts treatment response
• NCCN guidelines suggest risk-based approach to TKI choice– Predicts “treatment free remission” success
• Independent predictor of relapse with cessation
Baseline Bcr-Abl transcript level– Clarifies determination of “early molecular response”– Patient-specific “kinetics” of transcript reduction
P= 0.0076
Low Sokal risk
High and Intermediate Sokal risk
@ 60 months 73% ( 95 %CI: 61-84)
@ 60 months 47% ( 95 %CI: 34-62)
Mahon et al, 2011.
Why?
What Do NCCN Guidelines Recommend at Diagnosis?
H&P = history and physical exam; CBC = complete blood count; HSCT = hematopoietic stem cell transplant. NCCN, 2016.
Which TKI to Choose?
High dose imatinib (IM) for all?– Randomized trial (TOPS) of 400 mg vs 800 mg did not show difference in major
molecular response (MMR) rates at 12 months; greater toxicity in high-dose arm
High-dose IM for high-risk patients only?– GIMEMA study of 800 mg for high Sokal risk: no difference in cytogenetic response
(CyR)
– Impact of higher dose diluted by inability to deliver (toxicity)
Early dose optimization/600 mg IM (TIDEL, TIDEL II)?– Response very closely approximates second generation TKIs
With all these data, 3 available TKIs for new diagnosis and a generic option coming, how to decide?
NCCN, 2016.
Dasatinib and nilotinib?
– Offer clear advantages but no overall survival (OS) benefit yet; “promise” of treatment-free remission (TFR) not a reality yet
IM + Interferon (IFN)?
– SPIRIT trial showed increase in molecular response (MMR, MR4 and MR4.5) particularly if IFN tolerated for a critical amount of time (>4 mos)
Ponatinib?
– Demonstrates no “ceiling effect” response >> imatinib and likely >nilotinib and dasatinib; toxicity questions and time needed to settle this question
Bosutinib?
– BELA trial (bosutinib 500 vs imatinib 400) showed improvement in molecular response but primary end point complete cytogenetic response (CCyR) failed
– “Repeat” bosutinib 400 vs imatinib 400 trial in progress globally
Which TKI to Choose? (cont.)
NCCN, 2016.
Reality CheckCost matters, generics are here!
Sun Pharma (Mumbai, India) began selling generic imatinib in the US on February 1 with exclusive rights (single generic) for 6 months
CML patients with higher copayments were 1.7x more likely to stop and 42% more likely to be nonadherent with TKI therapy in the first 180 days
Dusetzina, 2014; Kantarjian et al, 2013.
Global Generic Experience: Mixed News….
Indian Experience: 2001-07 (n=719)(Courtesy H. Menon, Tata MH, Mumbai) Gleevec Generic
CP n=618; AP n=55; BC n=46 n=372 n=246
CCyR at 1 year 25% 19%
CCyR at 2 years 47% 45%
MCyR at 2 years 88% 94%
What Is the Standard? Comparative Results:Imatinib 400/600,Nilotinib, Dasatinib
aInferred from MR2.0; bMR4.0 rather than MR4.5.Druker et al, 2006; Kantarjian et al, 2010; Kantarjian, Shah et al, 2012; Hughes et al, 2008; Yeung et al, 2015; Preudhomme et al, 2010.
IRIS(IM400)
IM400ENEST/
DASISION
TIDEL I(IM600)
TIDEL II(IM600)
SPIRIT FRANCE(IM600)
ENESTnd(NIL)
DASISION(DAS)
>10% at 3 mos --- 33%/36% 24% 12% --- 9% 16%
CCyR at 12mos 69% 65%/73% 88% 87%a 65% 80% 85%
MMR at 12mos 40% 27%/28% 47% 64% 49% 55% 46%
MMR at 24 mos 55% 44%/46% 73% 73% 53% 71% 64%
MR4.5 at 12mos --- 4%/--- 18%b 19% 22%b 11% 5%
MR4.5 at 24mos --- 9%/8% --- 34% 26%b 25% 17%
OS at 3 yrs 92% 94%/93% --- 96% --- 95% 94%
Second Generation TKIs Have Improved Response But Not Changed Overall Survival Over Imatinib
ResponseLandmarks
ENESTnd DASISION
Imatinib Nilotinib Gain Imatinib Dasatinib Gain
Complete cytogenetic
response at 12 mos65% 80% +15% 73% 85% +12%
Major molecular response at 12 mos 27% 55% +28% 28% 46% +18%
Major molecular response at 60 mos 60% 77% +17% 64% 76% +12%
Complete molecular response at 60 mos 31% 54% +23% 33% 42% +9%
Overall survival at 60 mos 91.7% 93.7% +2% 90% 91% +1%
Saglio et al, 2010; Kantarjian et al, 2010; Kantarjian, Shah et al, 2012; Larson et al, 2013; Hochhaus et al, 2013.
Green Indicates Statistically Significant DifferenceRed Indicates Nonsignificant DifferenceΔ
The Value of Early Molecular Response on Outcome and Response
Branford, Yeung, Parker, et al, 2014.
Overall Survival Progression-Free Survival Failure-Free Survival
Major Molecular Response Complete Molecular Response
≤ 10%> 10%
≤ 10%> 10%
≤ 10%> 10%
≤ 10%> 10%
≤ 10%> 10%
(BCR-ABL values ≤10% at 3 months)
Pace of Response Matters, Not Just the Milestone
Branford, Yeung, Parker et al, 2014; Branford, Yeung, Ross et al, 2014.
Recent work by the same group:<11 day halving time in first month may be a good judge…
Change in BCR-ABL1 value from the individual patient baseline value according to the halving time at 3 months for patients with >10% BCR-ABL1 (all considered suboptimal by NCCN)
Value of MMR in Prolonging Remission
Response at 12 months n
Loss of CCyR
CCyR without MMR 95 24%
CCyR plus MMR 32 3%
Months Since Start of Imatinib Therapy
Loss
of C
CyR
(%
)
P=0.04
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60
Hughes et al, 2010; Cortes et al, 2005; Marin et al, 2008.
Aside From Being a Launching Point for TFR Trials, Does CMR Add Value?
23 11 5 1 0 0 092 81 60 33 10 3 065 63 53 35 15 3 2
CCvR+MMR-CCvR+MMR+CMR-CCvR+MMR+CMR+
Number at risk
23 11 5 1 0 0 092 81 60 33 10 3 065 63 53 35 15 3 2
CCvR+MMR-CCvR+MMR+CMR-CCvR+MMR+CMR+
Number at risk
P=0.00124
P<0.0001
P<0.0001
1.0
0.8
0.6
0.4
0.2
0.0
0 20 40 60 80 100 120Follow-Up (Months)
Even
t-Fre
e Su
rviv
al
EFS
CCyR+MMR+CMR+
CCyR+MMR+CMR-
CCyR+MMR-
P=0.0335
P<0.0001P<0.0001
1.0
0.8
0.6
0.4
0.2
0.0
0 20 40 60 80 100 120Follow-Up (Months)
Failu
re-F
ree
Surv
ival
FFS
CCyR+MMR+CMR+
CCyR+MMR+CMR-
CCyR+MMR-
Complete molecular response (CMR) defined as undetectable BCR-ABL with a sensitivity of at least 4.7 logs on 2 consecutive analyses at least 2 months apart.
EFS = event-free survival; FFS = failure-free survival.Etienne et al, 2014.
ASH 2015: Peg-INF + Dasatinib
Roy et al, 2015.
81 Pts(Oct 2013 - Jul 2014)
22 Centers
Key Inclusion/Exclusion
Criteria• Ph+ CP-CML 3 Mo• 18-65 years• No prior TKI nor
IFNα• No CI to Peg-IFNα
nor Dasatinib
M3Eligibility for
Peg-IFN
Yes
At M3ANC ≥1.5 x 109/LPlt ≥ 100 x 109/L
Ly ≤4 x 109/L
Dasatinib 100 mg/d
Dasatinib+ Peg-IFN-2b 30 µg/w
(Max 21 Mo)
D1
DasatinibNo
FU 5 Years
61 pts
18 pts
M12: Primary End Point
M3 M6 M9 M120%
10%20%30%40%50%60%70%80%90%
100%
UNKNo MR3MR3MR4MR4,5
8%
10%31%13%
11%
16%
28%
39%34%
n=3
15%
All pts (N=79), MR 4.5: 25% at M12,
≤ MR3: 73%
Roy et al, 2015.
ASH 2015: Peg-INF + Dasatinib
Putting CML Response Into Perspective
Mauro, 2014.
International Standard (IS) qPCR
10%
1%
0.1%
0.01%0.0032%
Early Molecular Response: <10% or 1-log (10x) drop from
starting levelComplete Cytogenetic Response:
<1% or 2-log (100x) drop
Major Molecular Response:<0.1% or 3-log (1000x) drop
4-log drop (<0.01%)
4.5 log drop, MR4.5,Complete Molecular Remission:
<0.0032%; below the level ofdetection for standard labs
Early Molecular Response
Complete Cytogenetic Response
Major Molecular Response
MR4
MR5-6?
MR4.5CMR
The
Future ?
Early Molecular Response
Complete Cytogenetic Response
Major Molecular Response
MR4MR4.5CMR
“Inverted iceberg” schematic of CML response over time
Reality of US/EU Risk Stratification and Monitoring Patient baseline risk and ECOG PS scores Only 32.6% of patients had either Hasford or Sokal scores recorded 68.4% of EU patients had available Hasford or Sokal scores, compared with 14.3% of US patients (P<0.001)
50% or more, no Cy testing 15-20%, no Molecular testing
Cortes et al, 2013.
Topics to Discuss
1. What should we be looking at upon diagnosis and what is best initial therapy?
2. How to define and manage resistance3. Is stopping therapy going to be appropriate?4. Are we seeing late complications with TKI
therapy?5. What else is new on the horizon for CML?
What Do the Guidelines Tell Us at 3 and 6 Months?
NCCN, 2016.
What Do the Guidelines Tell Us at 12 and 18 Months?At 12 months and 18 months
NCCN, 2016.
Practical Approach to a Patient With Resistance (or Intolerance ± Resistance)
First, determine what the disease state requires– Disease phase– Prior TKI exposure– Mutational status
• T315I unique• Select mutations may
support role of specific 2nd generation TKIs
• Predictive potential imprecise• “Iceberg” phenomenon• More detailed assays
forthcoming (like ultra deep sequencing)
Next, balance therapy risk and toxicity potential with known comorbidities– Are there true
contraindications?– Does risk outweigh benefit
expected from therapy?– Can risk be mitigated or
anticipated?– Enlist the patient’s insight,
trust, and awareness
NCCN, 2016.
Mutations Mirror the Degree of Genetic Instability of the Ph+ Clone
gene
tic in
stab
ility
Mutations are not induced by TKI therapy TKI therapy simply results in selection of
mutations independently arisen as a consequence of the genetic instability of the Ph+ clone
Genetic instability is most probably fostered by BCR-ABL itself
The longer BCR-ABL remains active, or the less efficiently it is inhibited, the higher the mutation rate
BCR-ABL is still the key target for therapeutic improvement
mut
atio
n fre
quen
cy
BCR-ABLNCCN, 2016.
P-loop SH2 contact A-loop SH3 contact
M244V
G250E/RQ252R/H
E255K/VY253F/H
V280A
L273M
D276G
E292V/Q
F311L/IT315I
F317L/V/I/C
M343T
L364I
H396P/R/A
M351T
S417F/YF359V/I/C/L
F486S
E459K/V/G/QE453G/K/V/Q
E355D/G/A
L248V E279KT277A
V379IA380T
F382LL384ML387M/F/V
E450K/G/A/V
M237V
I242T
E258D
V299L
Y342H
D363Y
A365VA366G
M388LY393C
A397P
I418S/V
S438C
M472I
P480L
K247R
E275K/Q
L298V
A433T
Y320CV371A
E373KL324Q
W261L
V289A/I
I293VA344V
A350V
L370P
E507G
10 most frequent mutations, accounting for ~70% of resistance, highlighted in redMutations: Many Besides T315I
Soverini et al, 2011.
DASISION ENESTndDasatinib100 mg
QDn=258
Imatinib 400 mg
QDn=258
Nilotinib 300 mg
BIDn=282
Nilotinib400 mg
BIDn=281
Imatinib 400 mg
QDn=283
Patients with any newly detectable mutations on treatment, n
10 11 10 8 20
Mutation category:
T315I, n 7 0 3 2 3Less sensitive to dasatinib (DASISION) or nilotinib (ENESTnd), n 1 0 5 6 4Sensitive to dasatinib (DASISION) or nilotinib (ENESTnd), n 3 11 2 0 13
Mutations clinically less sensitive to dasatinib included V299; less sensitive to nilotinib E255K/V, F359C/V,and Y253H
Mutations sensitive to nilotinib or dasatinib included all mutations other than less-sensitive mutations and T315I
Mutations Identified During Treatment in Frontline Trials
Kantarjian, Shah, et al, 2012; Kantarjian et al, 2011.
Mutations: When to Look
Soverini et al, 2011; NCCN, 2016.
Recommendations on When to Perform Mutational AnalysisELN NCCN
At diagnosis- Only in advanced phase or blast
crisis patients During first-line imatinib therapy
- In case of failure- In case of an increase in BCR-ABL
transcript levels leading to loss of major molecular response
- In any other case of suboptimal response
During second-line dasatinib or nilotinib therapy
- In case of hematologic or cytogenetic failure
BCR-ABL transcript levels >10% by qPCR IS or less than partial cytogenetic response at 3 months
Less than complete cytogenetic response at 12 or 18 months
Any sign of loss of response - Defined as hematologic or
cytogenetic relapse or 1 log increase in BCR-ABL transcript levels and loss of major molecular response
Disease progression to advanced phase
Both the European LeukemiaNet (ELN) and National Comprehensive Cancer Network recommend ABL kinase domain mutational analysis under certain circumstances:
Likelihood Mutation Testing Will Influence TKI Choice
LBC = lymphoid blast crisis; MBC = myeloid blast crisis; AP = acute phase; CP = chronic phase; ALL = acute lymphoblastic leukemia.Branford et al, 2009.
Mutation Spectrum at Time of Switch Is More Complicated When Assessed by Ultra Deep Sequencing
SS = simple sequencing; UDS = ultra deep sequencing.Soverini et al, 2013.
02468
1012141618202224
No Mutations 1 Mutation 2 Mutations ≥3 Mutations
Num
ber o
f Pat
ient
s
SSUDS
What Do the Guidelines Tell Us About Switching Treatment?
Primary Treatment Second-line Therapy and Subsequent Therapy
Imatinib
BosutiniborDasatiniborNilotinib
Dasatinib or Nilotinib or Ponatinib
Bosutinib or Nilotinib or Ponatinib
Bosutinib or Dasatinib or Ponatinib
Clinical trialor
HSCTor
Omacetaxine
Dasatinib
BosutiniborNilotinib
Nilotinib or Ponatinib
Bosutinib or Ponatinib Clinical trialor
HSCTor
Omacetaxine
Nilotinib
BosutiniborDasatinib
Dasatinib or Ponatinib
Bosutinib or Ponatinib
Management of Cytogenetic or Hematologic Resistance to TKIs
NCCN, 2016.
ELN Treatment Recommendations for Switch: Chronic Phase CML
SCT = stem cell transplantation.Baccarani et al, 2013
1st line
2nd line
3rd line
Any line, T315I
mutation
Imatinib, nilotinib, dasatnib
Intolerance to 1st TKI
Failure of 1st line imatinib
Failure of 1st line nilotinib or dasatinib
Nilotinib, dasatinib, bosutinib, ponatinib
Ponatinib
Failure of, and/or intolerance to 2 TKIs
Any of the remaining TKIs
Imatinib, nilotinib, dasatinib
Nilotinib/dasatinib, bosutinib, ponatinib SCT
considerationin many cases
SCT investigation
warranted
Second Generation TKIs, CML Chronic Phase, After Imatinib: Similar Benefits
Shah et al, 2010; Kantarjian, Giles et al, 2011; Cortes et al, 2011.
Dasatinib Bosutinib Nilotinib
Months follow-up >24 Median of 24 >24
Complete Hematologic Response 89% 86% 77%
Major Cytogenetic Response 59% 54% 56%
Complete Cytogenetic Response 44% 41% 41%
2-year Progression Free Survival 80% 79% 64%
2-year Overall Survival 91% 92% 87%
Third-Line Therapy: Response to Bosutinib
Response (n)
Imatinib and Dasatinib Resistant
(n=38)
Imatinib Resistant, Dasatinib Intolerant
(n=50)
Imatinib and Nilotinib
Resistant(n=26)
Complete hematologic response 68 76 76Major cytogenetic response 39 42 36
Complete cytogenetic response 22 40 28
Partial cytogenetic response 17 2 8Major molecular response 3 25 11Transformation (3 yr) 8 0 4
Cortes, Khoury et al, 2013.
Pfizer Study 200 118 patients who failed imatinib and either dasatinib or nilotinib
Switching to Other Second Generation TKI(s) After Imatinib Failure
Study Garg, et al Rossi, et al
Ibrahim, et al
Giles, et al
Khoury, et al
Third-line treatment
Dasatinib or nilotinib
Dasatinib or nilotinib
Dasatinib or nilotinib Nilotinib Bosutinib
N 25 (CP) 66 (91% CP) 26 (CP) 37 (CP) 118 (CP)
Complete cytogenetic response (%)
24 15 35 24 24
Garg et al, 2009; Rossi et al, 2010; Ibrahim et al, 2010; Giles et al, 2010; Khoury et al, 2012.
If a second generation TKI is not successful after imatinib, how successful is switching to other second generation TKI(s)?
Omacetaxine for CML After Failure of ≥2 TKIs
Response, % CPN=81
APN=41
Primary end point(s)
Major cytogenetic response: 20%
Major hematologic response: 27%
Complete cytogenetic response: 10%
Complete hematologic response: 24%
Median duration, months 17.7 9
Median progression-free survival, months 9.6 4.7
Median overall survival, months 33.9 16
11 patients (9 chronic phase, 2 accelerated phase) ongoing response Median 35 cycles over median 39 months Median response duration: 14 months for chronic phase, 24 months for accelerated phase
Cortes et al, 2013.
Ponatinib After Second Generation TKI Failure
Lipton et al, 2013.
In a cross-study comparison, ponatinib consistently achieved higher complete cytogenetic response rates after 2nd generation TKI failure
Ponatinib Response Rates in3rd- and 4th-Line CP-CML
I-N I-D
n=33 n=52
MCyR, % Patients MMR, % Patients CCyR, % Patients
73 58
25%
100%
0%
50%
75%
25%
100%
0%
50%
75%
25%
100%
0%
50%
75%
I-N I-D
n=33 n=52
67
44
I-N I-D
n=33 n=52
4637
Imatinib-nilotinib Imatinib-dasatinib
35
I-D-N
n=68
Imatinib-dasatinib-nilotinib Imatinib-nilotinib-dasatinib
46 44 4033
28
I-D-N I-N-D
n=68 n=46
I-D-N I-N-D
n=68 n=46
I-N-D
n=46
Hochhaus et al, 2013; Kantarjian et al, 2013.
What Is the Role of Allografting in CML?
QOL = quality of life.NCCN, 2016.
Status TKIs TransplantAccelerated or blast transformation has occurred
Interim treatment to best response/minimal residual disease
ASAP
Imatinib failure in chronic phase, T315I (+)
Ponatinib If no response to ponatinib
Imatinib failure in chronic phase without clonal evolution, mutations, good response
Long-term second line TKIs
Third line post second TKI failure or beyond
IM failure in chronic phase with clonal evolution, mutations, poor response
Interim treatment to best response
Second line, taken case by case
Older age (≥65 – 70) post imatinib failure
Long-term second line TKIs
May forgo allo SCT for many yrs of QOL
In CP and AP CML, No Early Gain in OS With SCT vs Ponatinib
*P-value <0.05. OS = overall survival; IQR = interquartile range; NR = not reached.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 12 24 36 48
Surv
ival
Rat
e (%
)
Months from Treatment Initiation
Adjusted OS, CP-CML
PonatinibSCT
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 12 24 36 48
Surv
ival
Rat
e (%
)
Months from Treatment Initiation
Adjusted OS, AP-CML
PonatinibSCT
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 12 24 36 48
Surv
ival
Rat
e (%
)
Months from Treatment Initiation
Adjusted OS, BP-CML
SCTPonatinib
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 12 24 36 48
Surv
ival
Rat
e (%
)
Months from Treatment Initiation
Adjusted OS, Ph+ ALL
SCTPonatinib
Treatment N Median (IQR)Ponatinib 64 NR (45.9 - NR)SCT 26 103.3 (6.6 - 103.3)Log-rank p-value = 0.013*
Treatment N Median (IQR)Ponatinib 18 NR (24.6 - NR)SCT 8 55.6 (11.4 - NR)Log-rank p-value = 0.889
Treatment N Median (IQR)Ponatinib 24 7.0 (3.5 - 11.0)SCT 17 10.5 (5.8 - 49.0)Log-rank p-value = 0.026*
Treatment N Median (IQR)Ponatinib 22 6.7 (4.0 - 15.3)SCT 5 32.4 (7.8 - NR)Log-rank p-value = 0.119
Nicolini et al, 2015.
Topics to Discuss
1. What should we be looking at upon diagnosis and what is best initial therapy?
2. How to define and manage resistance3. Is stopping therapy going to be appropriate?4. Are we seeing late complications with TKI
therapy?5. What else is new on the horizon for CML?
The Promise of 2nd Generation TKIs Regarding TFR: Frontline Imatinib, Dasatinib, or Nilotinib (Postulated)
Hughes & White, 2013.
0102030405060708090
100
Cum
ulat
ive
Inci
denc
e %
0 4 5 6 7Years After Commencing 2nd Gen TKI
1 2 3
60-80%
24-32%
16%
40%
Deep molecularremission (CMR)
TFR
36 mo: 61%
0
20
40
60
80
100
0 6 12 18 24 30 36 42
Sur
viva
l with
out M
MR
loss
%
Months since 2G-TKI discontinuation
12 mo: 61.1%(95% CI: 45.6-76.6)
Survival Without Loss of MMR: Approximately 60% Success
Rousselot et al, 2014; Rea et al, 2012; Ross et al, 2013.
AUSTRALASIAN CML8
STOP 2G TKIA-STIM study
Stable confirmed CMR before stopUnstable cCMR before stop
Mol
ecul
ar
Rel
apse
-Fre
e Su
rviv
al (%
)
100
80
60
40
20
012 24 36 48 60 72 84
Time (months)
A-STIM study
ASH 2015: STIM Trial Long-Term Follow-Up/Molecular recurrence
N=61; median follow-up = 63 mo 4 patients died after molecular recurrence (MR) of CML-unrelated causes MR: 80% within M 1-3, 15% within M 4-7 and 5% (n=3) within M 18 to 22
a(Pleural mesothelioma, metastatic gastric adenocarcinoma, acute renal failure, cerebral hemorrhage; one case of each)Etienne et al, 2015.
Number at risk: 100 44 41 38 38 38 38 37 29 25 19 11 5 1 0
Cum
ulat
ive
Inci
denc
e o
f MR
Months Since Stop of Imatinib
• Median time to MR : 2.5 mo (range,0.8 to 22.2)
• 57 out of the 61 pts restarted TKI (imatinib, n=56; dasatinib , n=1) and 55 achieved 2nd CMR at a median of 4.2 months
• Median follow-up of 63 mo : - None of the MR patients have CML progression
event
Paradise Lost, Regained?
Months
Perc
ent C
MR
4.5
0 12 24 360
20
40
60
80
100
Median time to regain deep molecular remission: 7.3 mo One patient with CML >15 yr experienced lymphoid blast crisis 8.5 mo from regained
MMR after restarting imatinib
Rousselot et al, 2014.
Perc
ent M
R4.
5
Cumulative incidence of regained MR4.5 in A-STIM retreated patients after loss of MMR
With >500 patients reported and very large numbers under investigation, single case of transformation resulting from TFR trial
Relapse defined as BCR-ABL >0.1%(loss of MMR) at one time point
TKI Discontinuation From Detectable Levels of MR (MR4): EURO-SKI Study Design
Inclusion violation n=2,- Restart of TKI without relapse n=4,
Not eligible for interim analysis n=48
n=200Evaluable at 6 mos
n=254
Mahon et al, 2014.
100
80
60
40
20
0
Rel
apse
-Fre
e Su
rviv
al
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Months From Discontinuation of TKI
EURO-SKI: Survival Without Loss of MMR(Molecular Relapse-Free Survival)
9 patients with relapse after 6 months (month 7-16) 4 patients also had loss of CCyR, no loss of complete hematologic response Of 26 patients with relapse, 13 regained MR4
n=200Relapses, n=86Relapses within 6 months , n=77
Molecular relapse-free survival at 6 months: 61% (54-68)
Mahon et al, 2014.
Do Adverse Events Occur With TKI Withdrawal?
PatientsAll Grade
(n)
PatientsGrade 3
(n)
AEsAll Grade
(n)
AEsGrade 3
(n)
Musculoskeletal pain, joint pain, arthralgia23 3 39 6
Other(sweating, skin disorders, folliculitis, depressive episodes, fatigue, urticaria, weight loss)
8 0 18 3
Musculoskeletal pain in CML patients after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?Richter J et al (2014). J Clin Oncol, 32(25):2821-2823.
Tyrosine kinase inhibitor withdrawal syndrome: a matter of c-kit?Response to Richter et al. Rousselot et al.
N=200; 222 AEs in 98 patients were reported 57 AEs in 31 patients were related to treatment stop, no grade 4
Mahon et al, 2014.
What Is Really Happening With TFR?Patients who maintain MR4.5 off imatinib commonly have evidence of BCR-ABL when assessed with a more sensitive genomic DNA (gDNA) based test
Ross et al, 2010.
Ten patients with loss of CMR had rising gDNA PCR levels, whereas a generally stable gDNA level was detectable in 7/8 patients with sustained CMR (follow-up 12-41 months).
Topics to Discuss
1. What should we be looking at upon diagnosis and what is best initial therapy?
2. How to define and manage resistance3. Is stopping therapy going to be appropriate?4. Are we seeing late complications with TKI
therapy?5. What else is new on the horizon for CML?
The Spectrum of CML TKI Toxicities
Myelosupression
Transaminase
Electrolyte ΔQT
prolongation
ImatinibEdema/fluid
retentionMyalgias
Hypophosphatemia
GI effects (diarrhea, nausea)
?Renal changes Bosutinib
Diarrhea/nauseaTransaminitis?Renal effects
DasatinibPleural/pericardial
effusionPulmonary arterial
hypertensionBleeding risk
PonatinibVascular adverse
eventsHypertension
Pancreatic enzyme elevation
Rash
NilotinibVascular adverse
eventsHyperglycemia,
LipidsPancreatic enzyme
elevationIndirect
hyperbilirubinemia
NCCN, 2016.
Kantarjian, O’Brien et al, 2012.
BCR-ABL1 TKI-Associated Cardiovascular Adverse Events
Cerebrovascular Disease
Coronary Heart DiseaseMyocardial Infarction
Pulmonary Arterial Hypertension
Venous ThrombosisPeripheral Arterial Disease
CardiomyopathyCongestive Heart Failure
Morbidity and mortality; effect on OS observations in frontline studies Delay/deferral of advantageous therapy both in frontline and salvage
Cardiomyocyte injury?
Endothelial dysfunction?Atherosclerosis?
Endothelial dysfunction?Atherosclerosis?
Endothelial dysfunction?Atherosclerosis?
Endothelial dysfunction?
Platelet dysfunction?Prothrombotic state?
Fatigue Musculoskeletal symptoms/
cramping Exercise-induced symptoms
Other:
ENESTnd: Select Cardiovascular Events by 5 Years
Patients had longer exposure to nilotinib than imatinib due to treatment discontinuation Approximately 85% of patients with a cardiovascular event had at least 1 risk factor and
were not optimally managed for hyperglycemia and hypercholesterolemia
Patients With an Event, n
Imatinib400 mg QD
n=280
Nilotinib300 mg BID
n=279
Nilotinib400 mg BID
n=277
Total, n
Y1-4, n
Y5, n
Total, n
Y1-4, n
Y5, n
Total, n
Y1-4, n
Y5, n
Ischemic heart disease
5 3 2 11 11 0 21 14 7
Ischemic cerebrovascular disease
1 1 0 4 3 1 8 5 3
Peripheral arterial disease
0 0 0 7 4 0 6 5 1
Larson et al, 2014.
All Cause (Treatment Related or Not), All Grades
Dasatinib (n=259) Imatinib (n=260)
Adverse event (AEs) Grade1/2
Grade 3/4
Grade 5
Totaln (%)
Grade 1/2
Grade 3/4
Grade 5
Totaln (%)
Cardiac ischemia 10(3.9%)
3(1.2%)
Myocardial infarction 1 2 2 5 (1.9%) 0 1 1 2
(0.8%)
Angina 2 1 0 3 (1.2%) 1 0 0 1
(0.4%)Coronary artery disease, myocardial ischemia
2 0 0 2 (0.8%) 1 0 0 1
(0.4%)
Peripheral arterial occlusive disease 0 0 0 0 0 0 0 0
DASISION: Arterial Occlusive Events of Interest (Any Cause)
Patients with a history of cardiac disease were included in DASISION, except those who had angina within 3 months, myocardial infarction within 6 months, congestive heart failure within 3 months, significant arrhythmias, or QTc prolongation
9 of 10 dasatinib and 2 of 3 imatinib patients with cardiac ischemia had at least 1 baseline risk factor for cardiovascular disease (eg, diabetes, hypertension, hyperlipidemia, left ventricular dysfunction, coronary artery disease)
Cortes, Hochhaus, et al 2013.
Pulmonary Hypertension With Dasatinib: Characterization
PH = pulmonary hypertension. Montani et al, 2012.
Pulmonary Hypertension With Dasatinib: Clinical and Functional Evaluation
Montani et al, 2012.
Ponatinib: Arterial and Venous Thrombotic Events (PACE Trial)
aEvents occurring in patients with CP-CML; bMedian follow-up 35.3 months, analysis for ≥3 years does not cover a fourth full year for all patients.Cortes et al, 2015.
Total YearsAE SAE 0-<1 1-<2 2-<3 ≥3a
12 10 14.5 14.1 10.5 7.2
Total YearsAE SAE 0-<1 1-<2 2-<3 ≥3a
2 2 3.5 1.8 1.7 0.9
Exposure-adjusted incidence over time (per 100 patient years):
Vascular occlusive eventsa
Venous thromboembolic events: 5%
Peripheral vascular
Cerebro- vascular
Cardio- vascular
AE 14%
SAE 11%
AE 11%
SAE 9%
AE 11%
SAE 8%
AE 5%
SAE4%
Arterial occlusive events: 28%
Ponatinib Phase II Study (PACE) Multivariate Analysis: Arterial Thrombotic AEs
Factors significantly associated with arterial thrombotic AEs: Older age (P<0.0001) History of diabetes
(P=0.0003) History of ischemia
(P=0.0087) Higher dose intensity to
time of first event (P=0.0009)
Each 15 mg/d reduction in dose intensity results in a predicted reduction of ~40% in the risk of an arterial thrombotic event
Dose Intensity (mg/day)
Estim
ated
Pro
babi
lity
15 30 450.0
0.1
0.2
0.3
fit & 95% CI
Cortes, Kim et al, 2013.
CML IV Study and Comorbidity:No Effect on CML TKI Response or Transformation
Saussele et al, 2015.
CML IV Study and Comorbidity:Significant Effect on Survival, Irrespective of Age
Saussele et al, 2015.
Charlson Comorbidity Index (CCI)calculated including age
Charlson Comorbidity Indexcalculated without age
Charlson Comorbidity Index Scoring System
Charlson et al, 1987.
Prevalence of Comorbidities: EUTOS Data
Hoffman et al, 2015.
56% with comorbidities42% Cardiovascular
Topics to Discuss
1. What should we be looking at upon diagnosis and what is best initial therapy?
2. How to define and manage resistance3. Is stopping therapy going to be appropriate?4. Are we seeing late complications with TKI
therapy?5. What else is new on the horizon for CML?
Y253H
T315I
L248R
F359V
New sequencing techniques, like ultra deep sequencing:
lower detection limit, 1%
Old sequencing (Sanger sequencing): lower detection
limit, 20%
Iceberg Analogy #2:Resistance May Be More Complex Than We Think
T315I + Y253H
Soverini et al 2013.
Resistance to TKIs and Compound Mutations
Hard to differentiate polyclonal mutations (2 different clones)
From compound mutations(>1 mutation in the same clone)
Zabriskie et al, 2014.That may be challenging to treat…
Multiple Mutations Often Hide Complex Mixtures of Single and Compound Mutants
Soverini et al, 2013.
quadrupletripledoublesingle
compound49.6% 38.3%
10.6%1.5%
Frequency of single and compound mutants in 33 patients (CML or Ph+ ALL) who had experienced sequential relapses with selection of one or more TKI-resistant mutations:
SH2
SH3
BCR
ACTIVE
4th Generation TKI ABL001 Allosterically Inhibits BCR-ABL1 Kinase Activity
Developed to gain greater BCR-ABL1 inhibition, with activity against BCR-ABL1 mutations conferring resistance to TKIs
Potential to combine with TKIs for greater pharmacological control of BCR-ABL1
Kinase
ABL001
t(9;22)BCR
SH2SH2
SH3
Kinase
INACTIVE
ABL001
Ottman et al, 2015.
Combination of ABL001 and Nilotinib Prevents Emergence of Resistance
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
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400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
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800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
days post-implant
Tum
or V
olum
e (m
m3 )
0 20 40 60 800
200
400
600
800
1000
180 180
Nilotinib (75 mg/kg) BID
ABL001 (30 mg/kg) BID
Nilotinib (75 mg/kg) BID + ABL001 (30mg/kg) BID
Dosing stopped on day 77, all mice remain disease free >176 days
T315I detected
A337V detected
*Each line represents individual animals.Wylie et al, 2014.
* *
KCL-22 CML Xenograft
ASH 2015: ABL001 Phase I Trial All patients had >1 postbaseline
safety assessment
There were 5 dose-limiting toxicities:
Grade 3 lipase increase (n = 2, 40mg BID, 200 mg QD)
Grade 2 myalgia/arthralgia (80 mg BID)
Grade 3 acute coronary event (150 mg BID)
Grade 3 bronchospasm(200 mg BID)
No deaths occurred on study
Dose escalation is ongoing
Ottman et al, 2015.
0
10
20
30
40
50
60
70
80
90
100
Hematologic Relapse(n=12)
Cytogenetic Relapse(> 50% Ph+; n=12)
Molecular Relapse (no MMR; n =29)
Patie
nts
With
Res
pons
e, %
CHR within 2 months:
100% (12/12)
CCyR:66.7% (8/12)
MMR:34.5% (10/29)
≥1-log reduction:
24.1% (7/29)
<1-log reduction:
31.0% (9/29)
None:33.3% (4/12)
None: 10.3% (3/29)
Hematologic ResponseWithin 2 Months
Cytogenetic ResponseWithin 3-6 Months
Molecular ResponseWithin 6 Months
Status at Baseline
Patients With ≥ 3 Months of Follow-Up on Study (n=29)
How I Follow a Recently Diagnosed CML Patient
Cardiovascular evaluation– Overall approach: at least age- and comorbidity-appropriate studies– If nilotinib to be used, inclusive of peripheral/cerebral/cardiovascular– If dasatinib to be used, echocardiogram to estimate pulmonary pressure– Monitoring of blood pressure, lipids, and glycemic control
Initial studies to include bone marrow and baseline qPCR (IS) Lab studies every 1-2 weeks for at least 6 weeks, then less often/as indicated;
frequency increased again for change in therapy 3-mo assessment: qPCR (IS) If response surpasses CCyR equivalent and blood count “new normal” is
acceptable/stable no imperative for repeat BM Sequential molecular analyses every 3 mo Repeat CV eval if/when indicated (eg, for signs/symptoms)
IS = in situ.
How I Decide/Navigate With My CML Patients
3-mo response: An opportunity to critically appraise therapy choice and response trajectory; change possible, EMR
6-mo, 12-mo response: Change warranted for missed milestone (EMR, CCyR)
18-mo response: Focus on molecular response
Subsequent: Stability of response and progression towards optimization of MRD– CMR > MR4 > MMR– Plateau, fluctuation common
Treatment-free remission: Still the realm of clinical trials– Approximately 3 yrs of therapy in general with approximately 2 yrs of optimal
MRD reduction prior to consideration
MRD = minimal residual disease; EMR = early molecular response.
Key Takeaways
CML is a highly treatable condition Generic imatinib is here; combinations still hold
promise Early response increasingly predictive of long
term success Resistance based in mutations can drive
treatment choice but is likely quite complex; Novel agents in study (ABL001)
Key Takeaways (cont.)
Second-line therapy can be highly effective; third-line therapy needs to be carefully chosen (risk/benefit of ponatinib vs other alternatives)
SCT still needed option
Many TKIsResponseRemission
Cure?
= Long, Happy,
Healthy Life!
Case Discussion 1
45-year-old man New diagnosis of CML No comorbid conditions
Question 1: Which of the following regimens would you select for this patient?
1. Imatinib2. Dasatinib3. Nilotinib4. Bosutinib5. Ponatinib
Question 1: Responses
Imatinib Dasatinib Nilotinib Bosutinib Ponatinib0%
20%
40%
60%
80%
100%
0% 0% 0% 0% 0%
Case Discussion 2
34-year-old manNew diagnosis of CMLNo comorbid conditionsArrives late for appointmentsMissed three appointmentsWorks irregular shifts
Question 2: Which of the following regimens would you select for this patient?
1. Imatinib2. Dasatinib3. Nilotinib4. Bosutinib5. Ponatinib
Question 2: Responses
Imatinib Dasatinib Nilotinib Bosutinib Ponatinib0%
10%20%30%40%50%60%70%80%90%
100%
0% 0% 0% 0% 0%
Case Discussion 3
55-year-old womanNo known comorbid conditionsGlucose consistently 150 rangeHeight 65 inchesWeight 190 poundsBMI 31.6
Question 3: Which of the following regimens would you select for this patient?
1. Imatinib2. Dasatinib3. Nilotinib4. Bosutinib5. Ponatinib
Question 3: Responses
Imatinib Dasatinib Nilotinib Bosutinib Ponatinib0%
10%20%30%40%50%60%70%80%90%
100%
0% 0% 0% 0% 0%
Case Discussion 4
57-year-old man42-pack-year smoking historyNo diagnosed comorbid conditions
Question 4: Which of the following regimens would you select for this patient?
1. Imatinib2. Dasatinib3. Nilotinib4. Bosutinib5. Ponatinib
Question 4: Responses
Imatinib Dasatinib Nilotinib Bosutinib Ponatinib0%
10%20%30%40%50%60%70%80%90%
100%
0% 0% 0% 0% 0%
Thank you to i3 Health and USF Health for the kind invitation to join you, and you for your attention!
Questions?maurom@mskcc.org
212-639-3107
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