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ICKSH 2018
BMS Satellite Symposium
“ Emerging Trends in CML Management ”
CHAIRMAN
• The Head of Catholic Hematology Hospital
• The Director of the Catholic Leukemia Research Institute at the Catholic University of Korea
• Prof. Kim's research interests focus on the biology and treatment of chronic myeloid leukemia. He is the author or co-author of more than 200 peer-reviewed publications in prestigious journals. His work has been carried out by grants from numerous governments and pharmaceutic
Dong-Wook Kim MD Ph.D
SPEAKER
Elias Jabbour MD
• Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center • Section Chief, Acute Lymphocytic Leukemia, Department of Leukemia, The University of Texas MD Anderson Cancer Center • Dr. Jabbour is actively involved in research in both acute and chronic forms of leukemia. He was actively involved in clinical trials that lead to the approval of several drugs in chronic myeloid leukemia (CML) and myelodysplastic syndromes. • His research on resistance to imatinib and mutations of the protein kinase domain were presented in several international; meetings and published in peer-reviewed journals. • He is also developing tailored therapies to CML.
Elias Jabbour, M.D.
Seoul 2018
4
Emerging Trends in CML
Management
CML. The Past and Today Parameter Before 2000 Today
•Course Fatal Indolent
•Prognosis Poor Excellent
•10-yr survival 10% 84 - 90%
•Frontline Rx Allo SCT;
IFN-
Imatinib; dasatinib;
nilotinib;
bosutinib
•Second line Rx ? Bosutinib, ponatinib
; allo SCT
5
CML Survival by Era
Harrison’s Principles of Internal Medicine. 2014
Patients at risk
Final Results CML-IV Molecular Response with Imatinib
92%
89%
81%
72%
59%
Kalmanti L, et al. Leukemia. 2015;29(5):1123-1132. Hehlmann R, et al. Blood. 2017;130(suppl): Abstract 897.
• 1538 pts newly diagnosed CML-CP randomized to imatinib 400, imatinib 800, imatinib + IFN, imatinib + ara-C, or imatinib after IFN
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
• Incidence 4700 per year
• Age-matched mortality ratio vs
normal population = 1.50
• Accounts for increased US
population to 410 million in 2050
Year
Nu
mb
er
of
Cases
CML - Increasing Prevalence Over Time
Wang. Blood 127: 2742; 2016
70,000
112,000
144,000
167,000
181,000
Therapy of CML in 2018
•Frontline
- imatinib 400 mg daily
- dasatinib 100 mg daily
- nilotinib 300 mg BID
- bosutinib 400mg daily
•Second / third line
- nilotinib, dasatinib, bosutinib, ponatinib,
omacetaxine
- allogeneic SCT
•Other
- decitabine, pegasys
- hydrea, cytarabine, combos of TKIs and
with TKIs
CML. Questions
• Best frontline TKI therapy
• Generic imatinib vs Gleevec and second
generation TKIs
• Endpoint of Rx: CGCR vs CMR
• Aim of Rx: survival vs Rx-free remission
• Long-term side effects; costs
• Role and timing of allo SCT
• TKIs vs allo SCT– cost considerations
• Optimal monitoring of CML
• TKI Rx discontinuation
Survival with Imatinib vs IFN + ara-C in Newly Dx CML (IRIS; 10 yr)
• 553 pts randomized to imatinib
• 10 yr survival 83.3%
• Cumulative CGCR rate 83%
• 10-Yr CGCR rate 22%
• 10-Yr MMR rate 93%
• 10-Yr MR 4.5 rate 23%
• 10 yr survival by Sokal: low 90%; intermediate 80%; high 69%
• Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%
Hochhaus. NEJM 2017; 376: 917
CML. Incidence of blast CML-BP Over Time
Hehlmann et al, Leukemia 2017
Survival with Imatinib vs IFN + ara-C in Newly
Dx CML (IRIS; 10 yr)
13
Hochhaus. NEJM 2017; 376: 917
CML Frontline Therapy • 8 main studies compared new generation
TKIs to imatinib frontline: ENEST-nd
(nilotinib), DASISION (dasatinib), BFORE
(bosutinib), EPIC (ponatinib), others
• All showed higher rates of favorable early
surrogate endpoints: CG CR, MMR, MR4.5,
↓ AP/BP
• Increased uncommon toxicities with newer
TKIs: PAOD-MI-TIA, pancreatitis, pleural
effusions; HT and pulmonary HT, ↑BS,
vasospastic reactions, ↑non-CML deaths
CML. Long-term Results of TKIs at
MDACC • 478 pts Rx with imatinib 400 (n=71) or 800 mg/D
(n=204), nilotinib (n=105), or dasatinib (n=98) as
frontline Rx; median FU 106 mos
• 5-yr OS 93%, TFS 86%, EFS 81%, FFS 69%
• In pts in CGCR, no differences in outcomes if
MR4.5 or not Falchi, Cortes-unpublished 2015.
% IM400 IM800 Nilo Dasa
CGCR 85 90 99 97
MR4.5 56 74 80 78
Propensity Score-Matched Comparison of Dasatinib and Nilotinib as Frontline CML Therapy
•Pts treated with dasatinib (N=102) or nilotinib (N=104) matched by propensity score
3-year Survival Endpoints
Percentage P
value Dasatinib N=87
Nilotinib N=87
Overall 99 93 0.95
Event-free 89 87 0.99
Failure-free 74 63 0.71
Transformation-free 95 89 0.28
DASISION – The Final Report •519 pts randomized to dasatinib (n=259) or imatinib
(n=260) •Minimum follow-up 5 yrs
Outcome (%) Dasatinib Imatinib P value or HR
Discontinued 39 37
12m cCCyR 77 66 P=0.007
5y MMR 76 64 P=0.0022
5y MR4.5 42 33 P=0.025
3m <10% 84 64
5y AP/BP 4.6 7.3
5y OS 91 90 HR 1.01
5y PFS 85 86 HR 1.06
Cortes. JCO. 34: 2333; 2016
DASISION—Cumulative MMR Rates Over Time
Months Since Randomization
% W
ith
MM
R
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 = .0022
Cortes J, et al. Blood. 2014;124: Abstract 152.
ENESTnd – The 6-Year Update
•846 pts: nilotinib 600 (n=282), nilotinib 800 (n=281) or imatinib (n=283)
•Minimum follow-up 6 yrs
Outcome (%) Nil 600 Nil 800 Imatinib P value or HR
Discontinued* 40 38 50
5y MMR* 77 77 60 P<0.0001
6y MR4.5 56 55 33 P<0.0001
3m <10% 91 89 67
6y AP/BP 3.9 2.1 7.4 P=0.06/0.003
6y OS 92 96 92 HR 0.9/0.46
Hochhaus. Leukemia 30: 1044; 2016 * 5-yr data from Larson et al ASCO 2014; Abstract #7073
.
ENEST-nd-CV Events
Hochhaus et al., Leukemia 2016
BFORE: First-line Bosutinib vs Imatinib in CML Molecular Response at 12 and 18 Months
Month: 12 18 12 18 12 18 12 18
MMR (ITT) MMR (mITT) MR4 (mITT) MR4.5 (mITT)
P=0.01
P=0.02
P=0.02
P=0.04
P=0.01 P=0.11
P=0.02 P=0.11
MR4.5 (ITT), %
Bosutinib Imatinib P
12 mo 7.5 3.0 0.02
18 mo 11.9 8.2 0.16
MR4 (ITT), %
Bosutinib Imatinib P
12 mo 20.5 11.6 <0.01
18 mo 24.6 18.3 0.08
Bosutinib ITT: n=268 mITT: n=246 12 months 18 months
Imatinib ITT: n=268 mITT: n=241 12 months 18 months
Gambacorti-Passerini et al. ASH 2017; abstract #896
• Randomized frontline pivotal study of bosutinib 400 mg (n=268) v imatinib 400 mg (n=268)
• Stratified by Sokal and geographic area
Radotinib v Imatinib in Frontline CML Molecular Response
Pa
tie
nts
wit
h M
MR
, %
Months since randomization
52%, P = .0044
30%
By 12 months
Δ 22%
66%, P = .0536
51%
By 24 months
Δ 15%
75%, P = .0076
54%
By 36 months
Δ 21%
Radotinib 300mg BID
Imatinib 400mg QD
Pa
tie
nts
wit
h M
R4
.5, %
Months since randomization
15%, P = .2012
9%
By 12 months
Δ 6%
33%, P = .1331
22%
By 24 months
Δ 11%
43%, P = .0538
28%
By 36 months
Δ 13%
• 2nd generation TKI approved in Korea
• Active against BCR-ABL and most mutants (not T315I)
• 3 mo EMR: radotinib 86%, imatinib 71%
• 6 mo EMR: radotinib 77%, imatinib 58%
Do et al. ASH 2017; abstract #317
Radotinib v Imatinib in Frontline CML Cardiovascular Events (All Grades)
Adverse Event, n (%)
Radotinib
300mg BID
(n=79)
Imatinib
400mg QD
(n=81)
Ischemic Heart Disease 0 (0) 0 (0)
Acute MI 1 (1) 0 (0)
Unstable Angina 1 (1) 0 (0)
Angina Pectoris 2 (3) 0 (0)
PAODa 0 (0) 0 (0)
a PAOD: Peripheral Arterial Occlusive Disease
Regardless of causalities Do et al. ASH 2017; abstract #317
Generic Imatinib in India: Survival of the Cheapest
• 1367 pts newly diagnosed CML: 1193 “innovator”, 174 generic
• CP 90% & 83%; AP 7% & 10%; BP 4% & 7%
Innovator Generic
CCyR 67 64
MMR 22 14
MR4 17 24
AP/BP 8 7
AEs
Edema, any grade 12 6
Myalgia, any grade 15 10
Rash, grade 3 <1 3
Thrombocytopenia, any grade 6 9
Neutropenia, any grade 5 3
Anemia, any grade 9 6
Madhav et al. ASH 2016; abstract #630
Significance of Dose Adjustments of 2nd Generation TKI in Frontline Therapy
• 98 pts treated with nilotinib 400mg BID (n=50) or dasatinib 50 mg BID or 100 mg QD (n=48) as initial therapy fro CML CP
• Dose reductions in 50 (51%) (nilotinib 42%, dasatinib 60%)
Percentage
Dose reduction No dose reduction
MCyR 94 88
CCyR 92 88
2-yr FFS 72 83
2-yr OS 100 100
Santos et al. Br. J Haematol 2010; 150: 303-12
Lower-Dose Dasatinib Newly Diagnosed CML-CP
• 56 pts, median age 46 y (range, 22-80 y) • Dasatinib 50 mg/d
Response, n/N (%)
3 mo 6 mo 9 mo 12 mo
BCR-ABL/ABL <10% IS
40/43 (93) 26/27 (96) 19/20 (95) 9/9 (100)
CCyR 23/43 (51) 25/27 (93) 18/20 (90) 9/9 (100)
MMR 12/43 (28) 19/27 (70) 16/20 (80) 9/9/ (100)
MR4 1/43 (2) 8/27 (30) 14/20 (70) 9/9 (100)
MR4.5 0/43 (0) 2/27 (7) 4/20 (20) 3/9 (33)
• Treatment interruption 14 (25); no dose modifications
Naqvi et al. ASH 2017; abstract #1611
Frontline CML Therapy in 2018+
• Dasatinib 50mg* daily produces similar
efficacy and significantly less toxicity than
100mg daily
• Current frontline: dasatinib 50mg
daily+venetoclax 400mg daily. Aim to
achieve high rates of durable CMRs and Rx
discontinuation=molecular cures
* Off-label use
CML. What Happens in 2018?
Parameter Imatinib 2nd TKIs
•Efficacy excellent even better
• Tolerance excellent even better
•Cost ($/yr) 2-10,000 > 120,000
•%5 – 10 yr
survival 80 – 90 ? > 90
EFS 50-60 ???
→ difference at 5-10 yrs in EFS and OS determines
frontline Rx
→ new long-term side-effects of 2nd TKIs; Rx value
CML Therapy in 2018
• Imatinib for low-risk Sokal and older
pts (≥ 65-70 yrs)
• Second TKIs for higher-risk Sokal
–until CGCR, then back to imatinib
–second TKI indefinitely
• Second TKIs for younger pts (< 50 yrs)
in whom Rx DC important
Rx Endpoints When Comparing
Second TKIs to Imatinib in Frontline
Rx
• Lower incidence of early
transformation to AP-BP
• Survival
• Molecular cure
• Long-term safety
• Cost; cost-effectiveness = “Rx
value”
EURO-Ski: The Effect of Duration of TKI Treatment and MR4
Duration of TKI Therapy Duration of MR4
• 755 pts with sustained MR4 for ≥1 yr
• Molecular relapse = loss MMR
• Overall MRFS 47% at 36 months
• Predictors of outcome: Sokal, depth of response, history of resistance,
prior IFN, treatment duration, molecular response duration
Outcome of CML Patients After TKI Discontinuation - MDACC
Month to molecular relapse
Cu
mu
lati
ve
su
rv
iva
l
0 10 20 30 400.00
0.25
0.50
0.75
1.00
p = 0.02
< 64 months
CMR before TKI discontinuation
64 months
Initial Report
Benjamini et al. Leuk & Lymphoma 2014; 55(12):2879-86; Chamoun et al. ASH 2016; abstract #1923
Updated Report
• No patients lost CCyR or CHR, transformed or died
• All evaluable pts regained MMR a median of 1.9 mo after restarting dasatinib
• Factprs associated with RFS: age (p = 0.04), 1st line (p = 0.07)
• 8 withdrawal events
DASFREE - Molecular Relapse-Free Survival
MRFS, %
(95% CI)
Pts on 1st-line dasatinib
(n = 37) 54 (38.0, 70.1)
Pts on subsequent
lines of dasatinib
(n = 47)
Resistant (n = 25)
Intolerant (n = 18)
45 (30.2, 58.7)
44 (24.5, 63.5)
50 (26.9, 73.1)
Patients at risk
15 15 22 27 31 39 61 84 5 44
0 32 28 24 20 16 12 4 36 8
Months Since Dasatinib Discontinuation
Mo
lec
ula
r R
ela
ps
e-f
ree
Su
rviv
al
(%)
100
80
60
40
0
20
Estimated survival
95% confidence band
49% (38.0, 59.4)
Shah et al. ASH 2017; abstract #314
• 84 pts with sustained MR4.5 for ≥1 yr (confirmed in central lab)
• Relapse = loss of MMR
• Frontline 44%, subsequent 56% (resistant 53%, intolerant 38%)
TKIs Rx DC in Clinical Practice--Requirements
Parameter Yes No
Sokal risk low-intermediate high
BCR-ABL transcripts quantifiable-B2A2, B3A2
(e13a2 or e14a2)
not quantifiable
CML past Hx chronic AP-BP
Response to first TKI optimal failure
Duration of all TKIs Rx > 8 yrs < 3 yrs
Depth of molecular
response
CMR (MR 4.5) less than MR 4.0
Duration of molecular
response
> 2-3 yrs < 2 yrs
Monitoring
availability/center-pt
ideal (q2 mo in yrs 1-2) poor; non-compliant
CML Rx Discontinuation • Ready for community practice
• If CMR ≥ 2-3 yrs and Rx DC—50% molecular
cures; monitor BCR-ABL transcript levels Q2
mos in Yr 1-2, then Q3-6 mos. If molecular
relapse, then restart TKIs
• Accidental pregnancy—DC TKIs; 1-2% risk of
fetal malformations (ex. omphalos, kidneys,
bone--- n =3/125)
• Males with CML—no risk to female partners
pregnancies
• Wilful pregnancy—ideally DC TKI ≈ 2 weeks
before pregnancy attempt and only if CMR;
monitor until delivery then resume TKI
CML. Role and Timing of allo SCT
36
Status TKIs Allo SCT
AP-BP Interim Rx to MRD ASAP
IM failure in CP,
T315I
Ponatinib interim
Rx to MRD
If no/loss response
to ponatinib
IM failure in CP –
no CE, no
mutations, good
initial response
Long-term second
line TKIs
Third line post
second TKI failure
IM failure in CP –
CE, bad mutations,
no CG response
Interim Rx to MRD Second line
Older ≥65 – 70 post
IM failure
Long-term; even if
no CGCR?
May forgo allo SCT
for many yrs of
QOL
Monitoring CML Course
• Cytogenetics
• Fluorescent in situ hybridization
(FISH)
• Quantitative PCR (QPCR):real time,
competitive
• Abl mutations
• Must do FISH and PCR pre-Rx for FU 37
When to Look For Mutations? •Mutation analysis in 1301 pts receiving imatinib or 2nd
generation TKI (GIMEMA) Clinical condition % Positive Failure 27 No CHR at 3 mo 19 No CyR at 6 mo 11 No PCyR at 12 mo 17 No CCyR at 18 mo 17 Loss CCyR 31 Loss CHR 50 Suboptimal 5 No CyR at 3 mo 7 No PCyR at 6 mo 5 No CCyR at 12 mo 8 No MMR at 18 mo 0 Loss MMR 4
Soverini. Blood 118:1208 and abst 112, 2011
39
Impact of Mutations and TKI choice
on Health Care System.
Jabbour. Am J Clin Oncol. Nov 2015.
Mutation Percentage of Patients
with Mutation
Mutation Class for 2nd Generation Tyrosine Kinase
Inhibitor (2G-TKI) Response*
Dasatinib Nilotinib
T315I 3.3% D D
M351T 7.3% A A
G250E 5.3% A A
F359V 4.3% A C
M244V 5.0% A A
Y253H 3.0% A C
E255K 3.1% B C
H396R 3.3% A A
F317L 2.7% C A
E355G 2.3% A A
Q252H 1.7% B B
E255V 1.6% B C
E459K 1.6% A A
F486S 1.5% A A
L248V 1.2% A A
D276G 1.2% A A
E279K 1.2% A A
Y253F 0.7% A B
F359C 0.7% A C
F359I 0.7% A B
*Class A: mutation may have same response as no mutation to 2G-TKI. Class B: mutation may confer intermediate
insensitivity/resistance to the 2G-TKI. Class C: mutation may confer substantial insensitivity/resistance to the 2G-TKI. Class
D: mutation may not respond to the 2G-TKI therapy3
40
Impact of Mutations and TKI choice
on Health Care System.
Jabbour. Am J Clin Oncol. Nov 2015.
$120,706
$198,284
$126,753
$209,259
$169,990
$241,515
$0
$50,000
$100,000
$150,000
$200,000
$250,000
$300,000
Total Cost per CHR Total Cost per MCyR
Open Access to Both 2G-TKIs Access to Only Dasatinib Access to Only Nilotinib
To
tal D
rug C
ost ($
) p
er
Eve
nt Δ vs. Open
Access
= 5%
Δ vs. Open
Access
= 41%
Δ vs. Open
Access
= 6%
Δ vs. Open
Access
= 22%
Analysis of Mutations in CML
• If CG or hematologic relapse, mutations studies help
• No role for mutation studies pre-Rx or in imatinib responding patients
• T315I: no role for new TKIs; allo SCT or others (HU, ara-C, HHT, “T315I inhibitors”)
• Y253H, E255K/V, F359V/C/I : dasatinib
• V299L,T315A, F317L/V/I/C : nilotinib
41
Kantarjian. Blood 111:1774, 2007. Soverini. Blood 118 : 1208 ,2011
% Survival/TFS by Early Molecular
Response
Study QPCR < 10% QPCR > 10%
Marin ( 8-yr) 93 54
MD Anderson
(10-yr)
98 94
ENEST-nd 97 87
DASISION 97 86
BELA 98 88
Marin JCO 30: 232; 2012. Jain. Blood 120: abst 70,2012; Hochhaus. Blood 120:abst
167; 2012; Saglio. Blood 120: abst 1675; 2012;Brummendorf. Blood 120: abst 69;
2012.
BCR-ABL Transcripts < 10% at 6 mos
Associated with Better Outcome
Response
3 Mo 6 Mo No. %
Survival
% PFS % FFS
≤ 10 ≤1 342 97 97 87
≤ 10 1-10 42 100 97 79
≤ 10 > 10 10 89 90 51
> 10 ≤ 1 18 100 100 76
> 10 1-10 36 100 94 79
> 10 > 10 35 74 69 11
Brandford. Blood 122: abst 254; 213
CML. Survival by > or ≤ 1% BCR-ABL Transcript Levels at 6
Months
Hehlmann et al, Leukemia 2017
Patients at risk
≤ 1% 594 531 335 161 53
> 1% 385 302 218 146 69
Criteria for Response/Failure and
Change of Rx
Time (mo) Imatinib Second TKIs
3-6 Major CG;
QPCR ≤ 10%
CG CR;
QPCR ≤ 1%
12 CG CR CG CR
Later CG CR CG CR
• CG ≤ 35% ≈ QPCR ≤ 10%
• CGCR ≈ QPCR ≤ 1%
CML. Criteria for Failure and Suboptimal Response to Imatinib –
ELN 2013 Time (mo)
Response
Failure Warning Optimal
3 No CHR, And/or
Ph+ >95%
BCR-ABL >10%, and/or
Ph+ 36-95%
BCR-ABL ≤10%, and/or
Ph+ <35%
6 BCR-ABL >10%
and/or Ph+ >35%
BCR-ABL 1-10%, and/or
Ph+ 1-35%
BCR-ABL <1%, and/or
Ph+ ≤35%
12 BCR-ABL >1%
and/or Ph+ >0%
BCR-ABL >0.1-1% BCR-ABL <0.1%
Any
Loss of CHR Loss of CCyR
Confirmed loss of MMR
Mutations CCA/Ph+
CCA/Ph- (-7, or 7q-)
BCR-ABL <0.1%
Baccarani. Blood 2013; 122: 872-84
and beyond
Important Response
Categories in CML Response Translates into:
BCR-ABL ≤ 10%
at 6 mos; CCyR
later
Significantly improved survival
MMR
Modest improvement in EFS;
possible longer duration
CCyR; no survival benefit
CMR
Possibility of Rx
discontinuation
(clinical trials only)
Therapy of CML Post Frontline Failure
•
Dasatinib in CML CP After Imatinib Failure
• 670 pts randomized to 4 dasatinib schedules
• 6-year follow-up
Outcome (100 mg/d) Percent
MCyR / CCyR (within 2 yr) 63 / 50
MMR 46
IM Resistant 43
IM Intolerant 55
7-yr OS 65
7-yr PFS 42
Discontinued treatment 78
• Reason for discontinuation: AE 30% (related 24%, unrelated 6%), progression 21%, other 47%.
• Pleural effusion 28%, pulmonary hypertension 2%. Shah . Am J Hematol 2016; 91: 869-74
OS by Dasatinib Dose After Imatinib Failure
100
90
80
70
60
50
40
30
20
10
0
% A
live
100 mg QD
140 mg QD
50 mg BID
70 mg BID
Months
65%
73%
68% 70%
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84
Imatinib-resistant Imatinib-intolerant Overall
OS, % (95% CI) 63 (53–71) 70 (52–82) 65 (56–72)
PFS, % (95% CI) 39 (29–49) 51 (32–67) 42 (33–51)
Shah . AJM 91: 896; 2016
Better Outcome on Dasatinib with
Earlier Intervention • Patients on dasatinib studies analyzed by
failure status on imatinib: loss of MCyR vs
loss of CHR
• Status at IM Failure No.
Percentage
CCyR MMR
Loss of MCyR 151 72 60
Loss of CHR & MCyR 33 42 29
Loss of CHR (never MCyR) 109 26 26
Quintás-Cardama. Cancer 115: 2912-21, 2009
Dasatinib Early Intervention EFS & OS
Quintás-Cardama. Cancer 115: 2912-21, 2009
Event-Free Survival Overall Survival
Time to intervene:
Loss of MCyR
2nd Line TKI in CML CP
• 621 pts treated with 2nd TKI: dasatinib 55%, nilotinib 31%, bosutinib 6%, other (7%)
• 1st TKI: imatinib (85%), ponatinib (7%), nilotinib (5%), dasatinib (3%) or bosutinib (<1%)
• Reason to switch: resistance 55%, intolerance 45%
• Median F/U: 50 mo (0.1-139 mo)
• Response: CCyR 50%; Best molecular: MMR 13%, MR4.5 38%
• MVA: specific TKI no impact in OS or TFS; nilotinib or other inferior EFS and FFS
Chamoun et al. ASH 2017; abstract #1594
2nd Line TKI in CML CP MR4.5 Overall Survival
Transformation-Free Survival Event-Free Survival
Chamoun et al. ASH 2017; abstract #1594
N Events
342 61
195 58
39 16
44 9
N Events
342 24
195 17
39 9
44 3
N Events
342 72
195 44
39 10
44 9
Predictors of Outcome to 2nd Line TKI in CML •123 pts treated with dasatinib (n=78) or nilotinib (n=45)
after imatinib failure
•Median follow-up 76 months (range, 25-109)
•MCyR 63%, CCyR 59%, 3-yr EFS 53%, 3-yr OS 84%
•3-mo CCyR33%
•MVA: 3-mo CCyR only factor independently associated with EFS (p<0.001) and OS (p=0.03)
Jabbour et al. Blood. 2010;116: Abstract 2289. Jabbour et al. Clin Lymphoma Myeloma Leuk. 2013 Jan 11. [Epub ahead of print]
How Do You Choose The Second
Generation TKIs • Disease characteristics - AP/BP: favor Dasatinib/ponatinib and combinations
- chronic: see below
• Mutations
-T315I → ponatinib
- nilotinib IC50 > 150nM → avoid
- dasatinib IC50 > 3nM → avoid
• Patient Hx
- Hypertension, CHF, lung problems, COPD → avoid dasatinib
- Severe diabetes, pancreatitis Hx, atherosclerosis → avoid nilotinib
- QTc problems → Bosutinib
Ponatinib Phase 2 Study Responses to Therapy
• Ponatinib 45 mg daily
• 93% ≥2 prior TKI, 58% ≥3 prior TKI
• Median follow-up 38.4 mo (0.1-48.6 mo)
Percentage
CP-CML AP BP Ph+ ALL
MCyR CCyR MMR MR4.5 MaHR MaHR MaHR
R/I 55 48 33 19 62 32 50
T315I 72 70 58 34 61 29 36
Total** 59 53 39 22 61 31 41
Median mo to response 2.8 2.8 5.5 NR 0.7 1.0 0.7
Cortes et al. ASH 2014; Abstract #3135; Kantarjian et al. ASCO 2014; Abstract #7081
5-Year Outcome with Ponatinib in CML-CP by Prior TKI
• 270 pts CML-CP Rx with ponatinib 45 mg/d post-TKI failure
• Median F/U 56.8 mo (0.1-73.1 mo)
Percent 5-yr Probability
MCyR MMR MR4.5 MCyR MMR PFS OS
1 TKI 79 58 32 75 NA 62 89
2 TKI 71 45 25 88 65 68 78
3 TKI 50 37 24 84 54 45 73
4 TKI 58 8 8 NA NA NA
Hochhaus A, et al. Blood. 2017;130(suppl): Abstract 1617.
3rd Line TKI in CML • 185 pts Rx with 3rd TKI: nilotinib 36%, dasatinib
35%, ponatinib 12%, imatinib 10%, bosutinib 7%
• Median time from Dx: 58 mo (3 – 199 mo)
• 1st TKI: intolerance 44%, resistance 67%; 2nd TKI: intolerance 60%, resistance 49%
Response %
CCyR 38
MMR 41
MR4 33
MR4.5 29
• MVA predictors of CCyR and MMR: ponatinib, Hgb, intolerance
Khan M, et al. Blood. 2017;130(suppl): Abstract 2882.
3rd Line TKI in CML OS TFS
• MVA for survival: ponatinib, bosutinib; age; female; intolerance (v
resistance)
Khan M, et al. Blood. 2017;130(suppl): Abstract 2882.
Ponatinib or SCT for T315I CML
•Pts ≥18 yrs with CML T315I in any stage enrolled in PACE (n=449) or EBMT (1999-2010; n=222)
•Median age (yr): CP 53 vs 48; AP 55 vs 46; BP 47 vs 44; Ph+ ALL 55 vs 36
Disease group
Median survival (mo)
PACE EBMT
CP NR 103
AP NR 56
BP 7 11
Ph+ ALL 7 32
CP
AP
BP
Nicolini et al et al, Blood 2014: Abstract #480
0%
20%
40%
60%
80%
100%
0 12 24 36 48
Su
rviv
al (%
)
Months from treatment initiation
Ponatinib
SCT
0%
20%
40%
60%
80%
100%
0 12 24 36 48
Su
rviv
al (%
)
Months from treatment initiation
Ponatinib
SCT
0%
20%
40%
60%
80%
100%
0 12 24 36 48
Su
rviv
al (%
)
Months from treatment initiation
SCT
Ponatinib
Ponatinib Toxicities of Concern CML Therapy?
• Optimal dose: 30 vs. 45 mg daily?
– I use 30 mg daily
• Incidence of toxicities of concern
–Pancreatitis 7%
–Skin rashes 40%; severe 4-7%
–Vasoocclusive disorders (cardiac,
CNS, PAOD) 12%
–Hypertension 67%; severe 20%
Therapy of CML Transformation
• Accelerated--TKI alone or combo
with low intensity Rx (DAC, AZA,
LD ara C, HU, etc)
• Lymphoid BP--TKI + ALL Rx (e.g.
HCVAD)
• Non-lymphoid BP--TKI + AML Rx
or DAC/AZA
Survival in Advanced Phase CML
4A 5A
Accelerated Phase Blast Phase
Kantarjian. Blood 2012; 119: 1981
CMLBP-MDACC Experience (1997-2016)
• 477 pts Rx: lymphoid BP 28%; TKI
alone 35%, TKI + ChemoRx 48%; allo
SCT 22%
• MHR 50%; CGCR 21%; MHR with TKI
alone 43%; TKI + chemo 64%
• Median OS 12 mos
• MVA for OS: TKI combo, allo SCT,
lymphoid BP favorable
Hyper CVAD + TKIs in CML Lymphoid BP
• 42 pts; HCVAD and imatinib (n=27) or dasatinib (n=15)
• CR 90%, CGCR 58%, CMR 25%, FCM-MRD negative 42%
• Median remission 14 mos; median survival 17 mos; 18
(47%) had allo SCT.
66
Strati et al. Cancer 2014; 120: 373
Summary – CML 2018
•Excellent therapy for CML : imatinib, dasatinib, nilotinib, bosutinib, ponatinib, omacetaxine
•CGCR is endpoint of Rx = improves survival
•Early response (3-6 mos) predictive--Do not change at 3 mos, monitor at 6 mos and decide
•Aim for PCR<10% by 6 mos, and for CG CR by 12+mos—these are only indications to change Rx
•Deeper molecular responses (MMR) improve EFS; no impact on transformation or survival
• No clear benefit for CMR (except DC Rx?)
Summary – CML 2018
• Frontline therapy is good (and getting better, safer and cheaper?)
• 2nd line options grossly equivalent; 3rd line ponatinib better (new ones safer?)
• Dose reductions safe in most instances
• Treatment discontinuation feasible if done right (better to wait for long MR4.5)
• Minimal intervention during pregnancy
• CML more molecularly complex than we thought
