[PDF] - Contemporary and Future Approaches in Management of CML Hagop PDF Document

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1 Winship Cancer Institute of Emory University

Contemporary and Future Approaches in Management of CML

Hagop Kantarjian, MD Chairman and Professor, Department of Leukemia University of Texas

M. D. Anderson Cancer Center

Disclosures

Received research funding:

– Ariad, BristolMyers Squibb, Novartis, and Pfizer

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Cure of CML (Almost…). Brief Perspective

IFN – α induced CGCR in

10-30%; CGCR associated with long-term survival; potential cure 5-7% (1983; 1990)

Ph and BCR-ABL molecular events

identified (1980s)

BCR-ABL abnormalities caused

CML in animal models (1990); BCR- ABL legitimate Rx target

Development of TKIs → CGCR 80-

90%; 10-yr survival 80-95%

4

CML. Historical vs. Modern Perspective

Parameter Historical Modern

Course

Fatal Indolent

Prognosis

Poor Excellent

10-yr survival

10% 84 - 90%

Frontline Rx

Allo SCT; IFN- Imatinib; nilotinib; dasatinib

Second line Rx

? New TKIs; allo SCT

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CML Survival by Era

Harrison’s Principles of Internal Medicine. 2014

Population-Based CML Outcome in Sweden

3173 pts Dx in 1973-2008; median age 62 yrs

Bjorkholm, JCO 29: 2514; 2011

21% 23% 37% 54% 80%

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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 Number of Cases

CML - Increasing Prevalence Over Time

Huang. Cancer 118:3123;2012

CML Transformation. Survival by Era

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CML Ph-Associated CG and Molecular Events

10 LTR LTR BCR/ABL

CML

STEM CELL

BCR-ABL Expression Sufficient for CML Induction

(Daley et al., Science 1990)

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11

Do We Need Bone Marrow At Dx?

Assess % of blasts and basos (10-

15% have CML transformation at Dx)

Confirm Ph by CG; detect clonal

evolution

FISH can be falsely positive
QPCR can be falsely positive or

negative

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.

12

Strati. Cancer 120: 373; 2014

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13

Poor Prognostic Factors in CML

Older age
Splenomegaly
Anemia
Thrombocytosis, thrombocytopenia
Blasts, promyelocytes, basophils
Marrow fibrosis
Cytogenetic clonal evolution

Prognostic Models: Sokal, Hasford (Euro), MDACC

Kantarjian. Blood 119:1981;2012

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15

IRIS. PFS Associated With CGCR At

12 Mos, Not With Sokal Risk

n= 179 99% n= 91 95% n= 49 95% Estimated rate at 60 months

p=0.16



p=0.09

p=0.200 (overall)

Low risk Intermediate risk High risk % without PD to AP/BC 10 20 30 40 50 60 70 80 90 100

Months since randomization

6 12 18 24 30 36 42 48 54 60 66

Developmental Therapeutics in CML

FDA Approval Agent Salvage Frontline Interferon 1986 1986 Imatinib 2001 2002 Nilotinib 2007 2010 Dasatinib 2006 2010 Ponatinib 2012 Bosutinib 2012 Omacetaxine 2012

Kantarjian. NEJM 346:645;2002. Kantarjian. NEJM 354:2542;2006. Talpaz. NEJM 354; 2531: 2006. Kantarjian. NEJM

362:2260:2010. Kantarjian. Lancet Oncol 12: 841; 2011. Cortes. NEJM 367: 2075; 2012. Cortes. Blood 120: 2573; 2012.

Cortes. AJH e-Pub 2/2013.

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CML. So Many Choices

Therapy of CML in 2014

Frontline
imatinib 400 mg daily
nilotinib 300 mg BID
dasatinib 100 mg daily
Second / third line
nilotinib, dasatinib, bosutinib, ponatinib,
macetaxine
allogeneic SCT
Other
decitabine, pegasys
hydrea, cytarabine, combos of TKIs and

with TKIs

investigational: hedgehog inhibitors,

JAK2 inhibitors, IL3-DT

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19

CML. The Next Questions
Frontline CML Rx: imatinib vs.

second TKIs

Can we cure CML molecularly? Is

it necessary?

Role and timing of allo SCT
Monitoring of CML
Others: prevalence, pregnancy CG

abn., Rx DC Results with Imatinib in Early CP CML – The IRIS Trial at 8-Years

304 (55%) patients on imatinib on study
Projected results at 8 years:
CCyR 83%
82 (18%) lost CCyR, 15 (3%) progressed to

AP/BP

Event-free survival 81%
Transformation-free survival 92%
If MMR at 12 mo: 100%
Survival 85% (93% CML-related)
Annual rate of transformation: 1.5%,

2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%

Deininger. Blood 114: abst 1126, 2009

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Frontline Rx with Dasatinib or Nilotinib at MDACC

Parallel studies with nilotinib (400 mg BID) or dasatinib

(100 mg QD or 50 mg BID) Nilotinib Dasatinib % Response N=100 N=93 CGCR by 12 mos 93 99 MMR by 12 mos 73 83 3-yr Survival 100 99 3-yr TFS 97 100 3-yr EFS 91 91 3-yr FFS 78 80 Rx discontinuation 11 9

Quintas-Cardama. Blood 118: abst 454, 2011. Pemmaraju. Blood 118; abst 1700; 2011

TKI Frontline Therapy in CML Long-Term Outcome By Response Time

Event-Free Survival Transformation-Free Survival

p<0.001

Jain. Blood 122: abst 2728; 2013

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Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282)

R A N D O M I Z E D *

Nilotinib 400 mg BID (n = 281)

N = 846
217 centers
35 countries

* Stratification by Sokal risk score.

10 years of follow-up are planned

ENEST-nd. Study Design

Kantarjian. Blood 120:abst 1676;2012

Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML

846 pts randomized to nilotinib 300 mg BID (n=282),

nilotinib 400 mg BID (n=281), or imatinib 400 mg QD (n=283)

Minimum follow-up 5 years

Outcome Nil 300 Nil 400 IM 400 % CCyR* 87 85 77 % MMR** 77 77 60 % BCR-ABL ≤0.0032%** 54 52 31 % Transformed AP/BP 3.5 2.1 7.1 % 5-yr EFS 92 95 91 % 5-yr OS 94 96 92

* by 24 months, ** by 60 months (K-M)

Saglio. Blood 122: abst 92; 2013

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ENESTnd. Progression to AP/BC on Core Rx
Saglio. Blood 122: abst 92; 2013

P = .0059 P = .0185 P = .0009 P = .0085

4.2% 0.7% 1.1% 6.0% 1.1% 1.8% Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283)

Nilotinib vs. Imatinib in CML-CP. Adverse Events and Grade 3/4 Myelosuppression

Fluid retention Diarrhea Headache Muscle cramps Nausea Pruritus Rash Vomiting Anemia Neutropenia Thrombocytopenia Any grade Grade 3/4

0.1 0.2 0.3 0.4 0.5

0.1
0.2
0.3
0.4
0.5

Rate difference (imatinib - nilotinib) with 95% CI

Favors imatinib Favors nilotinib (300 mg BID)

Hochhaus. Haematologica. 2010;95(s2):459 [abst 1113]

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ENEST-nd.Cardiac and Vascular Events by 4 Years (All Grades)

Patients With an Event, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD 11 (3.9) 21 (7.6) 5 (1.8) PAOD 4 (1.4) 6 (2.2) 0 (0)

Saglio. Blood 120: abst 92; 2013

Dasatinib Versus Imatinib Study In Treatment- naïve CML (DASISION). Trial Design

Primary endpoint: Confirmed CCyR by 12 months
Secondary/other endpoints: Rates of CCyR and MMR;

times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival

Follow-up 5 years Randomized*

Imatinib 400 mg QD (n=260) Dasatinib 100 mg QD (n=259)

N=519
108 centers
26 countries

*Stratified by Hasford risk score

Kantarjian. NEJM. 362: 2260, 2010

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Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML

519 pts randomized to dasatinib 100 mg QD

(n=259) or imatinib 400 mg QD (n=260)

Minimum follow-up 48 mo

Outcome Das 100 IM 400 % CCyR* 86 82 % MMR** 74 60 % BCR-ABL ≤0.0032%** 34 21 % Transformed AP/BP 5 7 % 4-yr PFS 90 90 % 4-yr OS 93 92

Cortes. Blood 122: abst 653; 2013

* by 24 months, ** by 48 months (K-M)

DASISION. Transformation to AP/BP CML by 4

Years

2 4 6 8 10 12 14 16 18 20

Patients, n On Study Including Follow-up Beyond Discontinuation (ITT) Dasatinib 100 mg QD Imatinib 400 mg QD 8 (3.1%) 14 (5.4%) 12 (4.6%) 18 (6.9%)

Cortes. Blood 122: abst 653; 2013

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DASISION. Forest Plot Comparing Differences

in AE Rates for Dasatinib and Imatinib

Rate Difference (dasatinib-imatinib) with 95% CI Any grade Grade 3/4 Diarrhea Nausea Neutropenia Vomiting Superficial edema Pleural effusion Myalgia Fatigue Headache Rash Thrombocytopenia Anemia Fluid retention Favors dasatinib Favors imatinib             

–40 20 40 –20

Kantarjian. JCO. 29:abst 6510; 2011
CML. Relative Risks of Uncommon Events

Imatinib RR Dasatinib RR Nilotinib RR Marrow/ tumor bleed 14-27 Pleural effusion 17-60 Femoral artery necrosis 409 Conjunct. bleed 9.4 Pericardial effusion 10 PAOD 191 Effusion- ascites 4.5-5.6 PAH 4.0 Coronary stenosis 185 Anginas 7.2 MI 4.9 Arterial ischemia 4.0

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Frontline Rx with Imatinib

vs. Second Generation TKIs

Parameter Imatinib 2nd TKIs

Efficacy

excellent even better

%12-mo CGCR

65-70 80-85 MMR 20-25 40-45 AP- BP 3.5 0.4-2

Tolerances

excellent even better

Follow up (yrs)

10 6-7

Cost ($/yr)

90,000 90,000 – 120,000

CML. What Happens in 2015?

Parameter Imatinib 2nd TKIs

Efficacy

excellent even better

Tolerance

excellent even better

Cost ($/yr)

2-10,000 90-120,000

%5 – 10 yr survival

survival 80 – 90 ? > 90 EFS 50-60 ??? → the difference at 5 yrs in EFS and OS determines frontline Rx

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CML- Possible Future Rxs

Most differences in events in ENEST-nd

and DASISION are in intermediate-high risk Sokal. Most differences in transformation in first 1-2 yrs

Achieving PCR ≤ 10% at 3-6 mos and

CGCR by 6 mos protects against events

Possible strategies

1) imatinib in low-risk Sokal 2) nilotinib-dasatinib in higher risk Sokal for 1 year on until CGCR then change to imatinib

MSD and MUD SCT in CP-CML

Overall Survival Leukemia-Free Survival

Arora. JCO 2009; 27: 1644-52
3514 MDS & 1052 URD SCT from CIBMTR from

1988 to 2003

All in CP1; median age 35-37

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Risk Assessment for SCT in CML

Risk factor Group Score Donor type HLA-identical sibling MUD 1 Stage CP AP 1 BP, ≥2nd CP 2 Age <20 20-40 1 >40 2 Sex match All other M-rec/F-don 1 Time from Dx <12 mo >12 mo 1

Gratwohl. Lancet 1998; 352: 1087-92

Outcome After SCT by EBMT Score

Score % with score % at 5 years LFS OS TRM RI 2 62 76 21 26 1 18 61 73 21 23 2 28 44 59 35 32 3 28 34 49 47 31 4 15 28 38 53 28 5 7 37 39 45 41 6 2 15 19 81 32

Gratwohl. Lancet 1998; 352: 1087-92

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Overall Survival With TKI After Imatinib Failure or With SCT

This image cannot currently be displayed.

Months % alive 100 80 60 40 20

91%

3 6 9 12 15 18 21 24 27 30

Shah. Blood; 2014[E-pub ahead of print]
Kantarjian. Blood 2009; 114: Abs # 1129;

Gratwohl . Lancet 1998; 352: 1087-92

Months Since Start of Treatment 100 90 80 70 60 50 40 30 20 10 % Alive 3 6 9 12 15 18 21 24 27 30 36 33

87%

~55%

Dasatinib Nilotinib

75%

Dasatinib

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CML. Role and Timing of allo SCT

Status TKIs Allo SCT AP-BP Interim Rx to MRD ASAP IM failure in CP, T315I Ponatinib interim Rx to MRD ASAP 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 May forgo allo SCT for many yrs of QOL

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CML Monitoring

Establish confirmed CGCR in first year (BM

at 6-12 mo)

In CGCR
FISH and QPCR every 6 mos
If MMR (QPCR < 0.1%), may monitor with

QPCR only (watch for false results)

If QPCR ↑ by 0.5 – 1 log and/or loss of MMR

(PCR> 0.1%) → monitor more frequently

Mutations studies if resistance / need to

change TKIs

Change TKI only for loss of CGCR, not

based on MMR/QPCR

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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 Loss MMR 4

Soverini. Blood 118:1208 and abst 112, 2011

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43

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
thers (HU, ara-C, HHT, “T315I inhibitors”)
Y253H, E255K/V, F359V/C/I : dasatinib
V299L,T315A, F317L/V/I/C : nilotinib
Kantarjian. Blood 111:1774, 2007. Soverini. Blood 118 : 1208 ,2011

New Criteria for Failure and “Warning”

Baccarani. Blood 2013;122:872-884

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MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS

Kantarjian H. Cancer. 2008;112:837–845.

EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx (Landmark)

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% 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.

The Problem with the 3 Months Response

Transcripts Time

3 mo

10%

Are these the same? Are these the same? Myelosuppression Rash Non-adherence

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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

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%

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Important Response Categories in CML

Response Translates into: CCyR Significantly improved survival MMR Modest improvement in EFS; possible longer duration CCyR; no survival benefit CMR Possibility of Rx discontinuation (clinical trials only)

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My Golden Rules in CML Monitoring

Do not discard a TKI unless there is loss of

CGCR (not MMR) at the maximum tolerated adjusted dose that does not cause grade 3-4

r chronic grade 2 (affecting QOL) toxicities
Dose ranges

–imatinib 300-400mg/D (rarely 200mg/D) –nilotinib

200-400mg BID (rarely 200mg/D)

–dasatinib

20-100mg/D

Mutation studies only if CG or hematologic

relapse

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CGCR, Not “Deep Molecular Response MR 4.5” Associated with Survival in CML (German CML Study IV)

1,551 pts Rx with IM 400, 800mg, with ara-C or IFN
Cumulative CGCR 70%, MMR 80%, MR 4.5 70%, confirmed MR 4.5

54%; 8-yr OS 86%

“Confirmed MR 4.5 at 4 yrs predicted higher 8-yr OS” (p=.047%)
Hehlmann. JCO 32: 415; 2014

Imatinib Treatment Discontinuation STIM1 and STIM2

STIM1 STIM2

100 pts
Median follow-up 55 mo (range, 9-72)
127 pts
Median follow-up 16 mo (range, 0-27)

Mahon et al. ASH 2013; Abstracts #255 & 654

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CG Abnormalities in Ph-negative Metaphases with IM Frontline Therapy

Overall Survival Progression-Free Survival

21/258 (9%) patients developed CG abnormalities in Ph-

metaphases after median 36 mo

Most common abnormalities: -Y (n=9; 43%), +8 (n=9;

43%), -7 (n=5; 17%)

1 (5%; 0.4% overall) developed AML [-7]
Jabbour. Blood 110:2991-5, 2007

Warning? Warning?

Imatinib and Pregnancy

Rare syndrome of fetal malformations

(exomphalos, kidneys, bones) in 3/125

Stop imatinib if pregnancy
Female partners of males on TKIs

→no problems

If pregnancy / children highly desired:

achieve durable CMR on TKIs then hold TKI and proceed with pregnancy / delivery under closer monitoring (e.g. FISH/QPCR every 2-3 mos)

56

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Inhibition of Bcr-Abl

ATP-binding T315I-active Non-kinase Inhibition Bcr-Abl Abl & Src Imatinib Dasatinib Ponatinib Omacetaxine Nilotinib Bosutinib Decitabine INNO-406 AZD 0530

Survival with Dasatinib in CML-CP Post IM Failure

70-76%

Shah. Blood. 123: 2317; 2014

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Ponatinib (AP24534). Pan-BCR-ABL Inhibitor

Rationally designed inhibitor of

BCR-ABL

Active against T315I mutant
Unique approach to

accommodating gatekeeper residue

Potent activity against an array
f BCR-ABL variants
Also targets other

therapeutically relevant kinases:

Inhibits FLT3, FGFR, VEGFR

and PDGFR, and c-KIT

Once-daily oral activity in

murine models

O’Hare T. Cancer Cell. 2009;16:401-412

Avoids T315I

Ile315 Ponatinib Imatinib

Ponatinib

Ponatinib in CML-CP (PACE)

267 pts Rx; 93% failed ≥2 TKI, 58%

failed ≥3 TKI Response Rate % Cytogenetic response 67 MCyR 56 CCyR 46 MMR 34 MR4.5 15

91% MCyR sustained at 12 mos
Cortes. Blood 122: abst 650; 2013

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Months Probability of PFS (%)

6 12 18 24 30 36 10 20 30 40 50 60 70 80 90 100

R/I (N=203) T315I (N=64) Total (N=267)

No. at risk

Total 267 204 170 139 73 3

Months Probability of OS (%)

6 12 18 24 30 36 10 20 30 40 50 60 70 80 90 100

R/I (N=203) T315I (N=64) Total (N=267)

No. at risk

Total 267 242 225 210 162 29

Ponatinib Phase 2 Study. PFS and OS in CP-CML

Cortes. Blood 122: abst 650; 2013
PFS at 2 years: 67%

(median 29 months)

OS at 2 years: 86%

(median not reached)

Ponatinib Toxicities of Concern CML Therapy?

Optimal dose: 30 vs. 45 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%

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Response to Bosutinib 2nd Line Therapy

Dual Src & Abl inhibitor, no effect over c-kit or PDGFR
286 pts with imatinib failure
Median follow-up 24.8 mo (0.2-83.4 mo)

Response, % IM resistant (n = 196) IM intolerant (n = 90) Total (n = 286) CHR 86 84 86 MCyR 59 61 59 CCyR 48 52 49 4-yr MCyR Dur 69 86 75 4-yr Transformation 5 2 4 4-yr Progression/Death 19 22 10

40% remain on therapy

Brumendorf et al. Blood 2013; Asbtract #2723

Bosutinib in CML post imatinib failure PFS and survival

Cortes. Blood 118: 4567;2012