update on philadelphia (ph) chromosome positive all - soho

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

Fielding, A. K. et al. Blood 2009;113:4489-4496

UKMRCALLXII/ECOG2993 – Overall survival

Fielding, A. K. et al. Blood 2009;113:4489-4496

Overall survival by availability of sibling donor

Laport, G. G. et al. Blood 2008;112:903-909

City of Hope - Overall survival

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


00.0

0.2

0.4

0.6

0.8

1.0

12n=17

24n=8

36n=2

Total Fail31 92 yr OS = 61%


Ove

rall

Surv

ival

Pro

babi

lity

Survival for Patients Not Undergoing SCT


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


Cohort I – Day 21 MRD by PCR and Flow


% P

ATIE

NTS

Molecular response by time on therapy

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


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

Can we attempt to predict outcome to guide decision for

transplantation in first CR?

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

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


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


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


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


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


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


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


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


Frac

tion

surv

ival


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


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

Overall Survival by p190 vs. p210

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


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


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


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.

Acknowledgments

Leukemia DatabaseRebecca GarrisSherry Pierce

HematopathologyJeffrey JorgensenSa WangRaja Luthra

BiostaticsSijin WenXuelin Huang

LeukemiaLeukemia StaffLeukemia Pas and APNSLeukemia Pharmacy Staff

Patients and Relatives

update on philadelphia (ph) chromosome positive all - soho

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