update on philadelphia (ph) chromosome positive all - soho
TRANSCRIPT
Update on Philadelphia (Ph) Chromosome Positive ALL
Farhad Ravandi, MDProfessor of MedicineUniversity of Texas – M. D. AndersonCancer Center
Allogeneic SCT for Ph+ ALL
Study No. %TRM %Survival (X yrs)
Barrett 67 42 31 (2)
Arico* 38 8 72 (5)
Goldstone* 72 37 42 (5)
Dombret* 56 25 37 (3)
* Allogeneic SCT in 1st CR
Survival in Ph-ALL by Regimen (Excluding Primary Refractory)
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168Months
0.0
0.2
0.4
0.6
0.8
1.0
Hyper-CVAD + imatinib Hyper-CVAD
No. No. Fail 48 21 50 45
p<0.001
Median follow-up 77 mos (range, 27 to 101+ mos)
Survival in Ph-ALL after Hyper-CVAD + Imatinib by aSCT in 1st CR(No Age Restrictions Excluding Primary Refractory)
0 12 24 36 48 60 72 84 96 108Months
0.0
0.2
0.4
0.6
0.8
1.0
Y N
No. No. Fail. Median age (range)14 4 37 (17 - 60)33 20 53 (27 - 84)
Median time to SCT 5 mos (range, 1-13)
p=0.12
Survival in Ph-ALL by aSCT in 1st CR after Hyper-CVAD + Imatinib De Novo & CR at Start Groups Age < 40 years
0 12 24 36 48 60 72 84 96 108Months
0.0
0.2
0.4
0.6
0.8
1.0
Y N
No. No. Die No. Rel10 1 0 6 4 3 p=.05
Trials with frontline imatinibReference N Median
age (range)
Imatinib and chemo
schedule
CR %
Relapse %
EFS % (years)
Survival % (years)
Thomas 45 51 (17-84) Concurrent 93 22 68* (3) 55 (3)
Yanada 80 48 (15-63) Concurrent 96 26 51 (2) 58 (20
Lee 20 37 (15-67) Concurrent 95 32 62 (2) 59 (2)
Lee 29 36 (18-55) Alternating 79 4 78 (3) 78 (3)
Wassmann 45
47
41 (19-63)
46 (21-65)
Concurrent
Alternating
*
*
*
*
61 (2)
52 (2)
43 (2)
36 (2)
de Labarthe 45 45 (16-59) Concurrent 96 19 51 (1.5) 65 (1.5)
Delannoy 30 66 (58-78) Alternating 72 60 58 (1) 66 (1)
Vignetti 30 69 (61-83) +Prednisone 100 48 48 (1) 74 (1)
Ottmann 28
27
68 (54-79) ChemoConcurrent
ImatinibConcurent
96
50
41
54
29 (1.5)
57 (1.5)
35 (1.5)
41 (1.5)
Ravandi F, Hematol Oncol Clin North Am, 2009; 23(5), 1043
2 3 1 4 5 6 7 8
100 70
100
24 months
Hyper-CVAD
MTX-cytarabine
Dasatinib 70 mg daily continuously 2nd courseVincristine + prednisone
Maintenance phase
Intensive phase
HyperCVAD + Dasatinib - Amendment
Risk-adapted intrathecal CNS prophylaxis
R R R R
R R
R Rituximab
00.0
0.2
0.4
0.6
0.8
1.0
Total Fail35 92 yr OS = 64%
12n=18
24n=9
36n=2
Months from Start of Treatment
Ove
rall
Surv
ival
Pro
babi
lity
Previously untreated patientsSurvival
Ravandi F, et al. Blood. 2010; 116 (12): 2070
00.0
0.2
0.4
0.6
0.8
1.0
12n=17
24n=8
36n=2
Total Fail33 52 yr CRD = 70%
Months from Response Date
Com
plet
e R
emis
sion
Dur
atio
n Pr
obab
ility
Previously Untreated PatientsCR Duration
Ravandi F, et al. Blood. 2010; 116 (12): 2070
00.0
0.2
0.4
0.6
0.8
1.0
12n=17
24n=8
36n=2
Total Fail31 92 yr OS = 61%
Months from Start of Treatment
Ove
rall
Surv
ival
Pro
babi
lity
Survival for Patients Not Undergoing SCT
Ravandi F, et al. Blood. 2010; 116 (12): 2070
00.0
0.2
0.4
0.6
0.8
1.0
12n=16
24n=7
36n=2
Total Fail29 52 yr CRD = 67%
Months from Response Date
Com
plet
e R
emis
sion
Dur
atio
n Pr
obab
ility
CR Duration for Patients Not Undergoing SCT
Ravandi F, et al. Blood. 2010; 116 (12): 2070
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
# of
Pat
ient
s
PosNeg
MRD by Flow Cytometry
00.0
0.2
0.4
0.6
0.8
1.0
HCVAD+DasatinibHCVAD+Imatinib
12 24 36
Regimen Total Fail42 1254 31
Months from Start of Treatment
Ove
rall
Surv
ival
Pro
babi
lity
HyperCVAD + Dasatinib - OS
P=NS
SCT in 1st CR Dasatinib 4 (10%) Imatinib 16 (20%)
Schultz KR, et al. JCO, 2009, 5175
80.7% ± 17.7%*
70.1% ± 27.1%*
64.2% ± 19.2%*
2-year EFS outcomes in cohort 5 (280 days continuous imatinib) similar to related and unrelated BMT
2-Year EFS for Cohort 5 vs Related BMT vs Unrelated BMT
0 1 2 3Years
EFS
Prob
abili
ty
Cohort 5 chemo (n = 25)Related BMT (n = 21)Unrelated BMT (n = 11) *P = .20
40.0
0.2
0.4
0.6
0.8
1.0
Population studied• April 2001 to March 2011• 122 patients with Ph+ ALL treated on
• HyperCVAD + Imatinib (n=54)• HyperCVAD + Dasatinib (n=68)
• 115 (94%) achieved CR • 101 achieved CR with one course and
had at least 1 MRD assessment• 25 underwent alloSCT in first CR –
excluded• FINAL N=76
MRD Assessment• MRD by Multi-parameter Flow
Cytometry• Initially 4-color• Starting in 3/2009 6-color stains
• MRD by PCR: BCR-ABL/ABLstandardized to the international scale
• MRD by IgH PCR
Patient characteristicsCharacteristics N (%)
HyperCVAD + Dasatinib
HyperCVAD + Imatinib
Overall
Number 48 28 76
Median age in years [range] 55 [21-78] 53 [28 – 84] 54 [21 – 84]
Median WBC(x109/L) [range]
11.4 [0.4 – 658.1]
10.4 [3.7 – 211]
10.8 [0.4 – 658.1]
Performance status0-12
46 (96)2 (4)
24 (86)4 (14)
70 (92)6 (8)
CNS disease at Dx 3 (6) 0 3 (4)
CytogeneticsPh+Ph+ plus otherIM/ND (BCR-ABL+)
9 (19)34 (71)5 (10)
4 (14)16 (57)8 (29)
13 (17)50 (66)13 (17)
Moleculare1a2 or e1a3e13a2 or e14a2
38 (79)10 (21)
20 (71)8 (29)
58 (76)18 (24)
CD 20 expression ≥ 20% 27 (56) 19 (68) 46 (61)
Comparing outcome by the 2 regimens
Overall Survival
0 52 104 156 208 2600.0
0.2
0.4
0.6
0.8
1.0
hyperCVAD+DasatinibhyperCVAD+Imatinibp=.19
Total Fail4828
1617
Weeks from Start of Treatment
Frac
tion
surv
ival
Outcome by MFC at CR
Overall Survival by MFC at CR
0 52 104 156 208 260 312 364 416 4680.0
0.2
0.4
0.6
0.8
1.0
Neg
Pos
Total Fail33 11
24 11p=.2
Weeks from Start of Treatment
Frac
tion
surv
ival
CRD by MFC at CR
0 52 104 156 208 260 312 364 4160.0
0.2
0.4
0.6
0.8
1.0
NegPos
Total Fail33 8
24 7
Weeks from Response Date
Frac
tion
surv
ival
Outcome by MFC at 3 months
Overall Survival by MFC at 3 months
0 52 104 156 208 260 312 364 4160.0
0.2
0.4
0.6
0.8
1.0
Neg FlowPos Flow
Total Fail
46 145 3
p=.04
Weeks from Start of Treatment
Frac
tion
surv
ival
CRD by MFC at 3 months
0 52 104 156 208 260 312 364 416 4680.0
0.2
0.4
0.6
0.8
1.0
NegPos
Total Fail
44 10
6 3p=.001
Weeks from Response Date
Frac
tion
surv
ival
Outcome by MFC at 12 months
CRD by MFC at 12 months
0 52 104 156 208 260 312 364 416 4680.0
0.2
0.4
0.6
0.8
1.0
Neg
Pos
Total Fail
29 7
4 4
p=.0001
Weeks from Response Date
Frac
tion
surv
ival
Overall Survival by MFC at 12 months
0 52 104 156 208 260 312 364 4160.0
0.2
0.4
0.6
0.8
1.0
Neg
Pos
Total Fail
29 4
4 4
p=.001
Weeks from Start of Treatment
Frac
tion
surv
ival
Outcome by BCR-ABL/ABL at CR
Overall Survival by level of BCR/ABL to ABL transcripts at CR
0 52 1041562082603123644164685200.0
0.2
0.4
0.6
0.8
1.0
MMR or CMRNo MMR
Total Fail3626 12
11
Weeks from Start of Treatment
Frac
tion
surv
ival
CRD by level of BCR/ABL to ABL transcripts at CR
0 52 104 156 208 260 312 364 416 468 5200.0
0.2
0.4
0.6
0.8
1.0
MMR or CMRNo MMR
Total Fail3626 10
7
p=.09
Weeks from Response Date
Frac
tion
surv
ival
Overall survival by BCR-ABL/ABL at 3, 9, and 12 months
Overall Survival by level of BCR/ABL to ABL transcripts at 3 months
0 52 104 156 208 260 312 364 416 468 5200.0
0.2
0.4
0.6
0.8
1.0
MMR or CMRNo MMR
Total Fail
526 4
14
p=.02
Weeks from Start of Treatment
Frac
tion
surv
ival
Overall Survival by level of BCR/ABL to ABL transcripts at 9 months
0 52 104 156 208 260 312 364 416 468 5200.0
0.2
0.4
0.6
0.8
1.0MMR or CMRNo MMR
Total Fail434 3
12
p=.05
Time
Frac
tion
surv
ival
Overall Survival by level of BCR/ABL to ABL transcripts at 12 months
0 52 104 156 208 260 312 364 416 468 5200.0
0.2
0.4
0.6
0.8
1.0
M M R o r CM RNo M M R
T o ta l Fa i l
334 3
5
p=.01
W eeks from Start of Treatment
Frac
tion
surv
ival
CIR by MFC status at 3 months (competing risk analysis - death
and relapse)
Time (month)
Cum
mul
ativ
e in
cide
nce
rate
(rel
apse
)
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
NegativePositive
p-value = 0.039
flow
CIR by BCR-ABL/ABL status at 3 months (competing risk analysis -
death and relapse)
Time (month)
Cum
mul
ativ
e in
cide
nce
rate
(rel
apse
)
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
Non-responseResponse
p-value = 0.93
mmr
CIR by IgH PCR status at 3 months (competing risk analysis -
death and relapse)
Time (month)
Cum
mul
ativ
e in
cide
nce
rate
(rel
apse
)
0 20 40 60 80 100 120
0.0
0.2
0.4
0.6
0.8
1.0
NegativePositive
p-value = 0.94
IGH
Multivariate analysis of predictors of long-term outcome
Hazard ratio l95% CI pMMR 0.321 0.159 - 0.648 0.002positive CD20 0.549 0.265 - 1.137 0.107Protein fusion = p210 0.443 0.164 - 1.198 0.109Cyto= FISH and/or PCR Positive 0.877 0.277 - 2.779 0.824Cyto = Philadelphia ± other 0.597 0.225 - 1.583 0.300Plt 0.996 0.990 - 1.003 0.258Blast.BM 0.981 0.959 - 1.003 0.084Age 1.008 0.979 - 1.037 0.600Time.to.hemaCR 0.957 0.886 - 1.034 0.269log.WBC 1.923 1.000 - 3.698 0.049
Multivariate analysis of predictors of long-term outcome
Hazard ratio 95% CI pIGH positive 2.533 1.170 - 5.485 0.018positive CD20 0.658 0.300 - 1.442 0.295Protein fusion = p210 0.493 0.168 - 1.444 0.197Cyto = FISH and/or PCR Positive 0.620 0.185 - 2.071 0.437Cyto = Philadelphia ± other 0.529 0.190 - 1.468 0.221Plt 0.998 0.991 - 1.004 0.491Blast.BM 0.980 0.959 - 1.002 0.067Age 1.013 0.984 - 1.043 0.368Time.to.hemaCR 0.957 0.892 - 1.027 0.219log.WBC 2.635 1.336 - 5.197 0.005
Multivariate analysis of predictors of long-term outcome
Hazard ratio 95% CI pflow positive 2.523 1.107 - 5.750 0.028positive CD20 0.557 0.265 - 1.170 0.122Protein fusion = p210 0.552 0.209 - 1.453 0.229Cyto = FISH and/or PCR Positive 0.623 0.194 - 2.006 0.428Cyto = Philadelphia ± other 0.506 0.191 - 1.342 0.171Plt 0.996 0.989 - 1.002 0.190Blast.BM 0.983 0.962 - 1.005 0.131Age 1.008 0.981 - 1.036 0.572Time.to.hemaCR 0.972 0.904 - 1.046 0.451log.WBC 1.860 1.000 - 3.460 0.050
Multivariate analysis of predictors of long-term outcome
HR 95% CI pMMR 0.248 0.110 - 0.559 0.001MRD positive by IgH 1.651 0.714 - 3.819 0.242MRD positive by flow 1.464 0.583 - 3.679 0.418positive CD20 0.486 0.211 - 1.118 0.090fusion protein = p210 0.532 0.179 - 1.582 0.256Cyto = Ph+ alone or + other 0.665 0.220 - 2.010 0.470Platelet count 0.996 0.989 - 1.002 0.212Blast % BM 0.984 0.962 - 1.007 0.162Age 1.014 0.985 - 1.045 0.347Time to CR 0.971 0.897 - 1.051 0.460log.WBC 2.083 1.050 - 4.133 0.036
Conclusions• MMR or better, or negative MFC at CR not predictive
• 3 months and beyond: negative MFC means better outcome
• MRD by IgH PCR not predictive of outcome
• Multivariate analysis: achieving MMR or better at any time associated with better outcome
• MRD analysis can be used to determine the need for allogeneic SCT in first CR
• Alternative donor SCT should be avoided in patients in MMR or better with negative MFC at 3 months and beyond
Ponatinib (AP24534):A Pan-BCR-ABL Inhibitor
Rationally designed inhibitor of BCR-ABL
Active against T315I mutant– Unique approach to accommodating
gatekeeper residue– Binds inactive (closed) ABL
conformation Broad spectrum of activity against an
array of BCR-ABL variants Multi-targeted kinase inhibitor
– Tyrosine kinases, including VEGF, FGF, and PDGF receptors, c-KIT and SRC kinase
Once-daily oral activity in murine models
Ponatinib cocrystal structure with ABLT315I
Ponatinib
O’Hare T, et al. Cancer Cell. 2009;16:401-412.