treatment approaches in relapsed cml

Treatment Approaches in Relapsed CML

Jorge Cortes, MDProfessor of Medicine

Deputy Chair, Department of LeukemiaThe University of Texas

MD Anderson Cancer CenterHouston, TX

A 50-year old female presented with LUQ pain and splenomegaly 10 cm/BCM. Her WBC was 105 x 109/L, Plts 800 x 109/L. BM shows 5% blasts, 4% basophils. CG show 100% Ph, no clonal evolution. She has a perfect match brother. Your treatment plan is:

Allogeneic BMT ASAP

Imatinib 400 mg QD

Imatinib 400 mg BID

Dasatinib 100 mg QD

Nilotinib 400 mg BID

Case Study: Question 1

Patient has now received imatinib 400 mg QD for 12 months. CG at 12 months shows Ph+ 10%. You would now proceed to:

Allogeneic BMT

Continue Imatinib 400 mg QD

Imatinib 400 mg BID

Dasatinib 100 mg QD



Patient has now received imatinib for two years, the second year at imatinib 800 mg/D. Repeat CG show Ph+ 0%, QPCR is .15%. You would now proceed with:

Allogeneic BMT ASAP

Send sample for mutation studies and decide accordingly

Continue Imatinib 400 mg BID

Dasatinib 100 mg QD



Patient is now on imatinib 800 mg/D for the past 40 months. Repeat CG shows Ph+ 40%, and a mutation screen identifies the T359C mutation. Your next approach is:

Allogeneic BMT ASAP

Consider MK 0457


Dasatinib 100 mg QD



The patient achieved a compete cytogenetic response. One year later, cytogenetic analysis shows 50% Ph+ metaphases. A T315I mutation is detected. Your approach now is:

Allogeneic SCT

Imatinib 400 mg BID

Increase Dasatinib to 140 mg QD

Change to Nilotinib 400 mg BID

Consider Homoharringtonine


Results with Imatinib in Early CP CML – The IRIS Trial

• 364 (66%) patients on imatinib on study• Projected results at 6 years:

–CCyR 87%–Event-free survival 83%–Transformation-free survival 93%

• If MMR at 12 mos: 100%• If CCyR, no MMR: 98%

–Survival 88%• Annual rate of transformation: 1.5%, 2.8%,

1.6%, 0.9%, 0.6%, and 0%Hochhaus et al; Blood 2007; 110: abst# 25

Criteria for Failure to Imatinib

Time (mo)Response

Failure Suboptimal3 No HR No CHR6 No CHR

100% Ph+≥ 35% Ph+

12 ≥ 35% Ph+ ≥ 5% Ph+18 ≥ 5% Ph+ No MMR (<3-log

BCR-ABL/ABL)Any Loss of CHR

Loss of CCgRMutation

Clonal EvolutionLoss of MMR

Mutation

Baccarani et al. Blood 2006; 108: 1809-20

Survival Post Imatinib Failure by CML Phase

Kantarjian et al. Cancer 2007; 109: 1556-60

Inhibition of Bcr-Abl

ATP-bindingT315I-active

Non-kinase InhibitionBcr-Abl Abl & Src

Imatinib Dasatinib MK-0457 17-AAG

Nilotinib Bosutinib KW-2449 HDAC

INNO-406 XL228 HHT

AZD 0530 PHA-739358 ATO

ON 012380

Outcome After Imatinib Dose Increase • 102 patients with imatinib dose escalation after imatinib

failure (N = 85), suboptimal (N = 9), or other (N = 8)• Dose from 400800 (N = 86) or 300600 (N = 16)• Median follow-up after dose : 50 mo (range 3-83)

% outcome after dose 2-year (%) from dose

CCyR MMR LossCCyR EFS TFS

Failure 39 8 1885 86 Cytogenetic 49 10 17

Hematologic 12 4 33

Suboptimal 0/1 1/9 (11) 0 88 100

Other 4/4** 4/8 (50) 0 100 100

• Median time to cytogenetic response 9 mosJabbour et al. Blood 2007; 110: abst# 1035

Dasatinib in CML Chronic Phase After Imatinib Failure (START-C)

• 387 pts; IM resistance 74%; median CML duration 61 mos; dasatinib 70 mg BID

• Parameter Percent

CHR 91

MCyR / CCyR 62 / 53

MMR 47

24-mos PFS / OS 80 / 94

• Dose reductions 73%; median dose 101 mg/d• Grade 3-4 ↓ plts 49%, neuts 50%; pleural

effusions 26% (grade 3-4 9%)Stone et al. Blood 2007; 110: abst# 734

Duration of MCyR to Dasatinib in CML CP

0 3 6 9 12 15 18 21 24 27 30

Stone et al. Blood 2007; 110: abst# 734

Months

100

80

60

40

20

0

% w

ith

ou

t lo

ss o

f M

CyR

24-month response rates

45%

CCyR

55%

MCyR

37%

MMR

84%

Months

24-month response rates

78%

CCyR

82%

MCyR

78%

MMR

0 3 6 9 12 15 18 21 24 27 30

100

80

60

40

20

0

97%

Imatinib Resistance Imatinib Intolerance

PFS and Overall Survival with Dasatinib in CML CP by Imatinib Failure

Progression was defined as increasing WBC count, loss of CHR / MCyR, AP / BP, or death


100

80

60

40

20

0 0 3 6 9 12 15 18 21 24 27 3033

Months

96%92%

88%

75%

Months

0 3 6 9 12 15 18 21 24 27 3033

100

80

60

40

20

0

100% 100%

98% 94%

Imatinib Resistance Imatinib Intolerance

Overall Survival

Progression-Free Survival

Phase II Studies of Dasatinib After Imatinib Failure

ResponsePercent by Disease Stage

CPN = 387

APN = 174

MyBPN = 109

LyBPN = 48

ALLN = 46

Hematologic 91 64 50 39 49

CHR 91 50 26 29 35

NEL - 14 7 6 7

Cytogenetic 62 40 47 58 62

Complete 53 33 27 46 54

Partial 9 7 7 6 2ASH 2007; abst# 470, 734

100

80

60

40

20

0

PFS with Dasatinib in CML After Imatinib Failure

Months

0 3 6 9 12 15 18 21 24 2730 Months

0 3 6 9 12 15 18 21 24 2730

100

80

60

40

20

0

0 3 6 9 12 15 18 21 24 27 3033 Months

88%

75%

100

80

60

40

20

00 3 6 9 12 15 18 21 24 27 3033 Months

100

80

60

40

20

0

64%

46%

MyBP (Median 5.6 mo)

LyBP (Median 3.1 mo) All (Median 3.3 mo)

Non T315I (Median 5.7 mo)

CP AP

ALLBP

Dasatinib vs HD Imatinib in CML (START-R)• 150 pts post failure of IM 400-600 mg/d• Randomized (2:1) to dasatinib 70 mg BID vs IM 400 mg BID; median FU 15 mos• Endpoint: CG response at 12 weeks crossover

• OutcomePercent Response

Dasatinib HD IM P value

CHR 93 82 0.03

MCyR 53 33 0.017

CCyR 44 18 0.002

MMR 29 12 0.028

• PFS better with dasatinib (HR 0.14; p<0.0001)• More grade 3-4 plts (57% vs 14%) and neuts (63% vs

39%), and pl. effusions (17% vs 0%) with dasatinibKantarjian et al. Blood 2007; 110: abst# 736

PFS with Dasatinib vs HD IM by Prior Imatinib Dose

P=0.0033

Prior imatinib dose: 600 mg

P=0.0562

Per

cen

t P

FS

100

80

60

40

20

0

Dasatinib

Imatinib

Prior imatinib dose: 400 mg

0 3 6 9 12 15 18 21 24 27 30 33Months

Kantarjian et al. Blood 2007; 110: abst# 736

Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib Failure

Parameter100mg

QDN = 166

50mgBID

N = 166

140mgQD

N = 163

70mgBID

N = 167

P-value

MCyR 64 58 62 58 NSCCyR 46 46 47 50 NSAnemia 10 18 19 17 0.105Neutropenia 34 46 43 43 0.123Thrombocytopenia 22 34 40 38 0.003

Pleural effusion 10 16 20 18 NSInterruption 58 66 69 71 0.047

Reduction 33 45 54 57 <0.001

Shah et al. JCO 2007; 25; (Abst # 7004)

Better Outcome on Dasatinib with Earlier Intervention

• Patients on dasatinib studies analyzed by failure status on imatinib: loss of CG response vs loss of CHR

• Status at IM Failure No. % CCyR % 1-yr PFS

Loss of MCyR 15250-83

[69]

87-100

[95]

Loss of CHR 14714-50

[24]

58-93

[84]


Nilotinib in CML Chronic Phase Post Imatinib Failure

• 320 pts with imatinib resistance (71%) or intolerance (29%)

• Median age 58 yrs; median CML duration 58 mo• Nilotinib 400 mg PO BID ≥ 6 mos

• Outcome Percent - CHR 77 - CG response 76

MCyR / CCyR 57 / 41 - 18-month OS / PFS 91 / 64


• Median dose 790 mg/d• Grade 3-4 ↓ plts 28%, neuts 30%; lipase elevation

15% (pancreatitis <1%), bilirubin 8%

Nilotinib in CML-CP Duration of Major CG Response

89% 84%

Months

Wit

ho

ut

Lo

ss o

f M

CyR

, %

Total = 184Failed = 23lll = Censored observations


Response

Percentage

CPN = 321

APN = 129

MyBPN = 105

LyBPN = 31

Ph+ALLN = 39

HR 77 54 22 19 29

CHR 77 26 11 13 26

Cytogenetic

Major 57 31 38 48 51

Complete 41 19 29 32 34

ASH 2007

Phase II Studies of Nilotinib After Imatinib Failure

Time to Progression with Nilotinib in CML After Imatinib Failure

le Coutre et al. Blood 2007; 110: abst# 471

70%

57%

Months

78%

64%

Months

CP AP

Bosutinib (SKI–606) in CML and Ph+ ALL

• Src-Abl inhibitor; 30x more potent than IM– No inhibition of PDGFR, c-kit

• 152 CP pts; median time from Dx 65 mos; 76% IM resistant

• Bosutinib 400-600 mg/d; Phase II 500 mg/d • Response in CP (N=56) %• CHR 89• Cytogenetic 81

– Major 41– Complete 30

• G 3-4 toxicity: rash 7%, thrombocytopenia 14%, neutropenia 9%

Cortes et al. Blood 2007; 110: abst# 733

Phase I INNO-406• Abl/Lyn kinase inhibitor 25-55x more potent

than imatinib• Inhibits 17/18 Bcr-Abl mutants • Not MDR dependent; good CNS penetration;

active against F317C/L/V• 41 pts: 21 CP, 7 AP, 6 BP, 7 ALL• 32 pts received ≥ 2 TKIs• INNO-406 30 mg SD → 480 mg BID• Responses:

–2 CG CR + 1 CG major + 1 CG minor / 7 CP post IM failure

–1 CG CR + 2 HR in ≥ 2 TKI failures• DLT transient LFT ; phase II 240 mg P.O. BID


Survival Post Imatinib Failure in CP by Treatment


Survival Post Imatinib Failure in AP by Treatment


Time to Response to 2nd Generation TKI• 113 pts with CML CP receiving nilotinib (N = 43) or

dasatinib (N = 70) after imatinib failure.

Months

3624120

Event

1.0

.8

.6

.4

.2

0.0

MCyR or CCR (59)

P = 0.003

mCyR or CHR (27)

Response at 12 mo % AP/BP/Death/CHR loss Next Year

MCyR or CCyR 3%

mCyR or CHR 17%

• Failure to achieve mCyR by 3 or 6 mos = 3-7% chance of reaching MCyR at 12 mo (vs > 50% if mCyR at 3-6 mos).

Tam et al. Blood 2007; 110: abst# 1931

Hematologic Response to 2nd Generation TKI in Advanced Stage CML After IM Failure

0 1 2 3 4

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

MCyR, with CHR MCyR, no CHR No MCyR

No.312697

Dead (%)6 (19)

14 (54)55 (57)

p=0.0003

0 1 2 3 4

Years

0.0

0.2

0.4

0.6

0.8

1.0

MCyR, with CHR MCyR, never CHR MCyR, later CHR No MCyR

No.31131397

Dead (%)6 (19)9 (69)5 (38)55 (57)

• 136 pts: CML AP (N = 87), BP (N = 60) or Ph+ ALL (N = 7) treated with dasatinib (N = 73) or nilotinib (N = 81) after imatinib failure

• MCyR 35%; 46% no CHR at time of MCyR • Most common causes of no CHR: thrombocytopenia (88%),

neutropenia (35%), immature cells (31%)

Fava et al, Blood 2007; 110: abst# 1944

Complete CyR

Partial CyR

Complete HR

No response

Response to Dasatinib by BCR-ABL Mutation in CML CP After Imatinib Failure

Cellular IC50 (nM)Dasatinib Imatinib N

M244V 1.3 2000 17

L248V 1500 9

G250E/V 1.8 1350–3900 23

Y253F/H/K 1.3–10 >10000 14

E255K/V 5.6–13 4400–8400 10

D276G 1500 3

T315I >1000 >10000 3

F317L 7.4 1050 4

M351T 1.1 930 15

E355G 400 6

F359C/I/V 2.2 1200 8

L387M 2.0 1000 2

H396P/R 0.6–1.13 850–4200 17

Other 30


Response to Nilotinib in CML CP after Imatinib Failure by Mutation

MutationIC50 (nM)

No.

Percentage

MCyR CCyR MMR Progressed

No Mutation 83 60 42 25 23

IC50 ≤150 nM 45 62 40 29 31

IC50 >150 nM

Y253H 700 8 13 0 0 38

E255K/V 548/791 8 38 0 14 75

F359C/V 258/161 10 10 0 0 90

Others 33 58 42 20 39

Hughes et al. Blood 2007; 110: abst# 320

EFS by Mutations in CML CP Treated with 2nd Generation TKI after IM Failure

Jabbour et al, Blood 2007; 110: abst# 1941

• 87/169 (51%) pts treated had mutation• CP 31, AP 41, BP 15• Mutations classified into high, intermediate, and low

sensitivity to dasatinib or nilotinib based on IC50EFS for Chronic Phase

Months

3624120

1.0

.8

.6

.4

.2

0.0

Low IC50

No Mutation

Intermediate IC50

P = 0.43

P = 0.0004

• No significant difference in AP or BP

Inducible Mutations in Mutagenesis Studies with AMN and BMS

• Mutants induced by saturation, selection, or induced (ENU)

• Mutations: imatinib 20, nilotinib 10, dasatinib 9

DrugConcentration

Low Intermediate

AMN L248V, G250E, F359C, L384M, L387F

Y253H, E255K/(V), T315I

BMS L248V, Q252H, E255K/V, V299L

T315I, F317C/L/V

Bradeen et al. Blood. 2006; 108: 2332-8; Ray et al. Blood. 2007; epub ahead of print; von Bubnoff et al. Blood. 2006; 108: 1328-33. Burgess et al. PNAS. 2005; 102: 3395-400.

35

67% patientsTotal match

H396P/R (2)

E453K (1)

+F359V/C (3)

+F311I/L (2)

D276G (1)

+E255K (1)

+Y253H (3)

+Q252H (1)

M244V (1)

In vitro models*

This series

N=15

NILOTINIB

80% patientsTotal match

T495R (1)

+F317L (5)

+V299L (3)

G250E (1)

In vitro models*

This series

N=10

DASATINIB

Occurrence of Mutations Predicted from In Vitro Models

Cortes et al. Blood 2007 [e-pub ahead of print]

*Burgess et al. PNAS 2005; 102: 3395-400; von Bubnoff et al. Blood 2006; 108: 1328-33; Bradeen et al. Blood 2006; 108: 2332-8.

Impact of Clonal Evolution in Response to Dasatinib or Nilotinib

0 1 2 3 4

Years

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

CP CP + CE AP AP + CE

No.161342324

Died (%)13 (8)8 (24)7 (30)

16 (67)

p<0.0001

p=0.04

p=0.01

• CE in 60/242 pts (25%) with CML AP treated with nilotinib (30) or dasatinib (30) after IM failure

• Double Ph 28%, chr 8 (17%), chr 17 (17%), other 35%)• Response: CHR 80%, CCyR 40%, PCyR 6%

Verma et al, Blood 2007; 110: abst# 2949

2nd Generation TKI in Newly Dx CML

Dasatinib

• 37 pts with previously untreated CML CP

• Dasatinib 100 mg SD or 50mg BID

• Median FU 18 mos

Nilotinib

• 32 pts with CML CP previously untreated

• Nilotinib 400 mg BID

• Median FU 6.5 mosCortes et al. Blood 2007; 110: abst# 29 & 30

38

TKI in Newly Diagnosed CML

ParameterPercent response

IM400N = 50

IM800N = 205

DasatinibN = 39

NilotinibN = 14

CG CR

3 mo 37 62 72 96

6 mo 54 82 94 100

12 mo 65 86 100 100

MMR (12 mos)

24 47 25 45

Cortes et al. Blood 2007; 110: abst# 29 & 30

HHT in CML with Mutation T315 I• 19 pts: 11 CP, 4 AP, 4 BP

• Failure on IM (19), dasatinib (10), nilotinib (8), MK457 (3)

• HHT 1.25 mg SQ BIDx14 Q4 wks until CHR → x 7 Q4 wks

• T315I undetectable in 4 CP and 1 AP

• Responses:

–CP: 5 CHR, 1 mCyR, 2 CCyR

–AP: 1 HI, 2 PHR, 1 mCyRKhoury et al. Blood 2007; 110: abst# 1050


Allogeneic BMT ASAP

Imatinib 400 mg QD

Imatinib 400 mg BID

Dasatinib 100 mg QD




Allogeneic BMT ASAP

Imatinib 400 mg QD

Imatinib 400 mg BID

Dasatinib 100 mg QD


Recommended approach:

• Imatinib 400 mg QD



Allogeneic BMT


Imatinib 400 mg BID

Dasatinib 100 mg QD




Allogeneic BMT


Imatinib 400 mg BID

Dasatinib 100 mg QD



• Imatinib 400 mg BID



Allogeneic BMT ASAP



Dasatinib 100 mg QD




Allogeneic BMT ASAP



Dasatinib 100 mg QD



• Continue imatinib 400 mg BID



Allogeneic BMT ASAP

Consider MK 0457


Dasatinib 100 mg QD




Allogeneic BMT ASAP

Consider MK 0457


Dasatinib 100 mg QD



• Dasatinib 100 mg QD



Allogeneic SCT

Imatinib 400 mg BID






Allogeneic SCT

Imatinib 400 mg BID





• Allogeneic SCT or Homoharringtonine


Take Home Message – CML 2008• Imatinib effective in most patients

– High-dose? • Dose optimization and adequate monitoring

more important then ever• Sub-optimal responses:

dose imatinib (400 mg → 800 mg)– New TKI?

• Failure:– Dasatinib, nilotinib– Others (Bosutinib, INNO 406)

• Frontline use of new TKI?• T315I: HHT, XL-228, PHA-739538

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