Defining goals for molecular remission in Chronic Myeloid Leukemia

SWAMI IYER, MDSWAMI IYER, MDHouston, USAHouston, USA

• Associate Professor, Leader, early drug Associate Professor, Leader, early drug development in Oncology, the Methodist Cancer development in Oncology, the Methodist Cancer CenterCenter

• Dr Iyer is the Leader for Early Drug Development Dr Iyer is the Leader for Early Drug Development Program in Hematology and Oncology at the Methodist Program in Hematology and Oncology at the Methodist Cancer Center, Houston, Texas. He recently served as Cancer Center, Houston, Texas. He recently served as the Director of Hematological Malignancies at CTRC, the Director of Hematological Malignancies at CTRC, and as an Assistant Professor of Medicine at the and as an Assistant Professor of Medicine at the University of Texas Health Science Center University of Texas Health Science Center (UTHSCSA). He is a physician scientist with laboratory (UTHSCSA). He is a physician scientist with laboratory interests in Heat shock proteins and has extensive interests in Heat shock proteins and has extensive expertise in clinical studies.expertise in clinical studies.

Monitoring Responses in CMLMonitoring Responses in CML

Swami Padmanabhan Iyer, MD Swami Padmanabhan Iyer, MD Leader Early Drug Development Program and Leader Early Drug Development Program and

Co-Director of the Malignant Hematology Co-Director of the Malignant Hematology Program, Associate Professor,Program, Associate Professor,

Houston Methodist Cancer Center, Houston Methodist Cancer Center, Weill Cornell Medical College,Weill Cornell Medical College,

Houston, TX Houston, TX

CML Survival 1965 -Present (n=1884)

MDACC 2009

• The remarkable progress made in the treatment of CML over the past decade has been accompanied by steady improvements in our capacity to accurately and sensitively monitor response to therapy.

• After the initial target of therapy, complete cytogenetic response (CCR), is achieved, peripheral blood BCR-ABL transcript levels measured by real-time quantitative reverse transcriptase PCR (RQ-PCR) define the subsequent response targets, major and complete molecular response (MMR and CMR).

• The main purpose of monitoring response with cytogenetics and RQ-PCR is to identify patients likely to achieve better long-term outcome if they are switched early to second-line therapy, either another TKI or an allograft.

Rationale for monitoring Responses in CML

Considerations for TKI Rx in CML

Goals of Rx- achieving CCyR and CMR through Milestones in a predictable timely fashion

Reasons for not reaching the milestones•Clonal evolution- Transformation•TKI Intolerance•TKI Resistance- Mutations•Compliance

Deininger et al; Blood 2009; 114: Abst# 1126

Considerations for TKI Rx in CML

Clinical Value of molecular monitoring in CML

• Early detection of relapse

• Monitoring response of patients treated for relapse

• Evaluation of leukemia cell contamination in stem cell collections

• Monitoring response in complete cytogenetic responders

IRIS 8-Year Update

37%Unacceptable

Outcome

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

–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 et al; Blood 2009; 114: Abst# 1126

Event-Free Survival by Molecular Response at 18 Months

Baccarani et al. Blood, 108 (11): Abstract 2138

Response at 18 months

CCyR with >3 log reduction

CCyR with <3 log reduction

No CCyR

Months since randomization0 12 24 36 48 60 72

Let us look at the Milestones

Decreasing residual leukemia N

umbe r of le ukem

i a cells (log10 )

ne Leukocytosis

Ph-chromosome pos

RQ-PCR <3 log

Cure ?

2.0CCyR

RQ-PCR negative(undetectable)

RQ-PCR >3 log

Ph chromosome and BCR-ABL transcript numbers as measures of ‘residual’ leukemia during treatment

10101212

10101111

10101010

101099

101088

101077

101066

101055

101044

101033

CCyRCCyR

residual disease is assessed at the molecular

Relationship between treatment response Relationship between treatment response level and number of leukaemic cellslevel and number of leukaemic cells

MMRMMR

DiagnosisDiagnosis

Unlike other measurement Unlike other measurement parameters it is difficult to parameters it is difficult to

define a complete molecular define a complete molecular responseresponse

undetectable BCR-undetectable BCR-ABLABL

CMRCMR

CCyCCyRRMMR MMR

10101212

10101111

10101010

101099

101088

101077

101066

101055

101044

101033

Limit of detection will Limit of detection will vary for each samplevary for each sample

Relationship between treatment response Relationship between treatment response level and number of leukaemic cellslevel and number of leukaemic cells

For the IRIS trial CMR was defined as For the IRIS trial CMR was defined as undetectable BCR-ABL with a sensitivity of at undetectable BCR-ABL with a sensitivity of at least 4.5 log below the standardised baselineleast 4.5 log below the standardised baseline

Hughes et al. N Eng J Med. 2003;349(15):1423-32.Hughes et al. N Eng J Med. 2003;349(15):1423-32.

Criteria for Failure and Suboptimal Response to Imatinib

Time (mo)

Response

Failure Suboptimal Optimal

3 No CHR No CG Response < 65% Ph+

6 No CHR>95% Ph+ ≥35% Ph+ ≤35% Ph+

12 ≥35% Ph+ 1-35% Ph+ 0% Ph+

18 ≥5% Ph+ No MMR MMR

Loss of CHRLoss of CCgR

MutationCE

Loss of MMRMutation

Stable or improving

Baccarani. JCO 2009; 27: 6041-51

Criteria for Optimal Response to Imatinib

Time (mo)

Response

Optimal

3 < 65% Ph+

6 ≤35% Ph+ MCyR

12 0% Ph+ CCyR

18 MMR

AnyStable or improving

Baccarani. JCO 2009; 27: 6041-51

Gold Standard- CCyR

Let us look at the Milestones

IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mos

Estimated rate at 60 months

n= 86 93%n= 73 81%

n= 350 97% } p<0.001} p=0.20CCyRPCyRNo MCyR

M o n t h s s i n c e r a n d o m iz a t i o n0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6

Rx aim: major CG response (Ph ≤ 35%)

M o n t h s s i n c e r a n d o m i z a t i o n

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4 6 0 6 6

IRIS. Survival Without AP/BC Worse If No CGCR In Year 2 But Not Related To MMR

n= 139 100%n= 54 98%n= 89 87%

Estimated rate at 60 months

p<0.001 p=0.11

CCyR with >=3 log red.CCyR with <3 log red.No CCyR

Rx aim: CGCR in Year 2+; no need for MMR

MDACC Retrospective Analysis: MCyR at 6 Months Associated With OS

Patients with MCyR have better OS than patients that do not

Landmark analysis at 6 mos

0 12 24 36 48 60 72

Cytogenetic response at 6 mos Total Dead P-value

Complete 201 5

Partial 39 1

Minor 10 3

Othersa 9 3

Months

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

MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS

Patients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos.

Landmark analysis at 12 mos

00 12 24 36 48 60 72

Months

Cytogenetic response at 12 mos Total Failure P-value

Complete 214 7

Partial 19 3

Minor 5 2

Others 8 5

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

EFS and Survival by 12-month Response-CCyR vs Others with TKI Frontline Rx

Jabbour E et al. Blood. 2011.

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

Jabbour E et al. Blood. 2011.

0.010.01

1.01.0

0.0010.001

BCR-ABL International Scale (IS)BCR-ABL International Scale (IS) Absolute valuesAbsolute values

Undetectable by PCRUndetectable by PCR 0 0 ~~101066 leukaemic cells leukaemic cells

major molecular response major molecular response ≤0.10% (MMR)≤0.10% (MMR)

-1 log-1 log

-2 log-2 log

-4 log-4 log

-5 log-5 log

MCRMCR

CCRCCR

-3 log-3 log0.10.1

BaselineBaseline

CMR CMR 66 mo66 mo

CMRCMR

Achieving an MMR may be associated with the most favourable event free survivalAchieving an MMR may be associated with the most favourable event free survival

CCyR 6 moCCyR 6 mo

MMR 15 moMMR 15 mo

1.01.0

0.100.10

0.010.01

Base-Base-lineline

00Months on standard dose imatinibMonths on standard dose imatinib

48482424 36361212 6060 727266

CMR CMR 66 mo66 mo

CMRCMR

Achieving an MMR may be associated with the most favourable event free survivalAchieving an MMR may be associated with the most favourable event free survivalWhat is the additional What is the additional benefit of a further 1 log benefit of a further 1 log

reduction of BCR-ABL for reduction of BCR-ABL for patients with CCyRpatients with CCyR? ?

CCyR 6 moCCyR 6 mo

MMR 15 moMMR 15 mo

00Months on standard dose imatinibMonths on standard dose imatinib

48482424 36361212 6060 727266

1.01.0

0.100.10

0.010.01

Base-Base-lineline

EFS: 6-Month Landmark AnalysisEvents : loss of CHR, MCR, AP/BC or deathEvents : loss of CHR, MCR, AP/BC or death

93%85%85%

P = .25

BCR-ABL % (IS)

<=0.1%>0.1-1%>1-10%>10%

Months Since Start of Treatment0 12 24 36 48 60 72 84

EFS: 12-Month Landmark Analysis

92%91%

P = .25

BCR-ABL % (IS)

<=0.1%>0.1-1%>1-10%>10%

62%58%

P = .01

BCR-ABL % (IS)

<=0.1%>0.1-1%>1-10%>10%

BUT MMR = Progression

Deeper molecular response and lower risk of transformation

Baseline

Intrinsic biology of CML

Good AP/BCPoor

Depth of Molecular response

At 12 M

Good AP/BCPoor

High risk for transformation

High risk for transformationDepth of

Molecular response

At 12 M

Good AP/BCPoor

IRIS trial: Overall estimated log reduction of BCR-ABL transcripts on IM

3 months 6 months 12 months 18 months 24 months

Months since start of treatment

3-<4 log

2-<3 log

<2 log

No CCyR

75% 50% 32% 26% 24%

19% 18% 29%

20% 34%

Clinical Value of molecular monitoring in CML

• Early detection of relapse

• Monitoring response of patients treated for relapse

• Evaluation of leukemia cell contamination in stem cell collections

• Monitoring response in complete cytogenetic responders

Imatinib Failure or Suboptimal Response

CML. Criteria For Failure On Imatinib

• No major CG response at 6 mos (Ph 100%) (Ph > 35%)

• No major CG CR at 12 mos

• No CGCR in Year 2+

• CG relapse or hematologic relapse

• Not failure criteria

- suboptimal CG response

- QPCR ↑ in CGCR

Baccarani. Blood 108:1809-20, 2006

IRIS 8-Year Results: Annual IRIS 8-Year Results: Annual Rate of Events on ImatinibRate of Events on Imatinib

• EFS = 81%• Freedom from progression to AP/BC = 92%

-1 progression to AP/BC and 2 non-CML related deaths in year 8

WithEvent,%

0.80.3

1.4 1.31.5

0.90.5

0 00.4

1 2 3 4 5 6 7 8

EventLoss of CHR,Loss of MCyR,AP/BC,Death during treat

Deininger et al. ASH 2009. Abs # 1126

Phase III Study of Interferon vs Imatinib Mesylate Phase III Study of Interferon vs Imatinib Mesylate in Chronic Phase CML (IRIS): Transformation-Free in Chronic Phase CML (IRIS): Transformation-Free

Survival by Cytogenetic Response*Survival by Cytogenetic Response*%

Months since randomization

0 6 12 18 24 30 36 42 48 54 60 66

Cytogenetic Response at 12 mo

Estimated Rate at 60 mo

Complete (n=350) 97%Partial (n=86) 93%No MCR (n=73) 81%

P<0.001 P=0.20

*Population only includes patients who received first-line imatinib mesylate.

92%91%

P = .25

BCR-ABL % (IS)

<=0.1%>0.1-1%>1-10%>10%

Criteria for Suboptimal Response to Imatinib

Time (mo)

Response

Suboptimal

3 No CG Response

6 ≥35% Ph+

12 1-35% Ph+

18 No MMR

Any Loss of MMRMutation

Baccarani. JCO 2009; 27: 6041-51

Response

Evaluation Time

Optimal Suboptimal Failure Warning

Baseline NA NA NA High risk; CCA/Ph+

3 mos CHR and at least minor

CgR(Ph+ ≤ 65%)

No CgR (Ph+ > 95%)

< CHR NA

6 mos At least partial CgR

(Ph+ ≤ 35%)

< Partial CgR (Ph+ > 35%)

No CgR (Ph+ > 95%)

12 mos CCgR Partial CgR (Ph+ 1% to

< Partial CgR (Ph+ > 35%)

18 mos MMR < MMR < CCgR NA

Any time during treatment

Stable or improving

Loss of MMR; mutations

Loss of CHR, loss of CCgR, mutations,

CCA/Ph+

Increase in transcript levels,

CCA/Ph-Baccarani M, et al. J Clin Oncol. 2009;27:6041-6051.

2009 ELN Recommendations for 2009 ELN Recommendations for Response Assessment Response Assessment

Lack or loss of molecular response is not a

criterion for failure

Failure On Imatinib And Strategies

Imatinib Failure ↑ Imatinib

Second Generation

• Ph 100% at 6 mos _ +

• Ph ≥ 35% at 12 mos

• No CGCR in yr 2 + +

• CG relapse + +

• Hematologic relapse

NIL47%

Comparison of MMR at 12 months

Yeung et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 209.

2nd Generation TKI in CMLParameter Dasatinib Nilotinib Bosutinib

Potency (fold vs IM) 325 30 20-50

Target Src & Abl Abl Src & ABL

BCR-ABL binding Active + Inactive Inactive Intermediate

Resistant mutations T315I T315I T315I

Mutations with intermediate sensitivity

E255K/V, V299L, F317L

E255K/V, Y253F/H, Q252H, F359V

E255V/K,V299L, F317L

Standard dose (CP) 100mg QD 400mg BID 500mg QD

Grade 3-4 neutropenia & thrombocytopenia

33% / 22% 31% / 33% 12% / 21%

Other notable toxicitiesPleural effusion,

bleedingBilirubin, lipase

elevationDiarrhea, rash

C-kit inhibition (vs imatinib) Increased Similar None

PDGFR inhibition (vs imatinib) Increased Similar None

Clinical activity Highly active Highly active Highly active

Conclusions

• MMR is a truly safe haven after 18 months

• Improving MMR response rate does not equate to reducing progression rate

• More potent TKIs improve MMR and may reduce progression

• Selective intensification is another promising approach

Summary• Both molecular and cytogenetic

evaluations should be used to guide treatment decisions until CCyR is achieved, with molecular assessments measured thereafter

• MMR obtained at any time point represents a “safe haven” for patients

SummarySummaryo Dramatic responses are seen in patients treated with CML

with the TKIs

o Resistance to TKI is real and ABL kinase domain point mutations are best studied mechanisms.

o Guidelines for bcr-abl mutation testing must be incorporated to treatment strategies

o Predictable structure- Mutation- Response relationship for 2nd Gen TKIs: P-loop for Nilotinib and Gatekeeper mutations for Dasatinib

o Presence of T315I confers the highest resistance to all approved TKIs and is associated with disease progression and poor survival

谢谢 !!

Follow Blood Cancer Bytes on facebook and Twitter:https://www.facebook.com/pages/Blood-Cancer-Bytes/119732178039292

ENESTnd: Nilotinib vs Imatinib in CML-CP

Study Design and Endpoints

• Primary endpoint: MMR at 12 months

• Key secondary endpoint: Durable MMR at 24 months

• Other endpoints: CCyR, time to MMR and CCyR, EFS, PFS, time to AP/BC, OS

*Stratification by Sokal risk score

Imatinib 400 mg QD (n = 283)

Nilotinib 300 mg BID (n = 282)

RANDOMIZED*

Nilotinib 400 mg BID (n = 281)• N = 846

• 217 centers

• 35 countries

Follow-up 5 years

Hughes TP, et al. ASH Annual Meeting 2010: Oral Presentation 207.

71%, P < .0001

67%, P < .0001

By 24 months

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

Time since randomization (Months)

55%, P < .0001

51%, P < .0001

By 12 months

Δ 24%-28%

Δ 23%-27%

Nilotinib 300 mg BID

Imatinib 400 mg QD

Data cut-off: 20Aug2010

Cumulative incidence of MMR*

*ITT populationReference?

ENESTnd: Nilotinib vs imatinib in CML-CP

*ITT population Data cut-off: 20Aug2010

Kinetics of molecular response*Kinetics of molecular response*

Median BCR-ABLIS % (range)

Time (months)

n = 282

n = 281

Imatinib 400 mg QD

n = 283

0† 48.7 49.2 51.5

3 0.79 0.87 5.41

6 0.19 0.19 1.02

12 0.09 0.10 0.38

18 0.03 0.04 0.17

24 0.02 0.03 0.09

*Only typical BCR-ABL transcript considered†Baseline

Hughes et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 207.

BCR-ABL ≤ 0.01% (CMRBCR-ABL ≤ 0.01% (CMR44) and BCR-ABL) and BCR-ABL≤ 0.0032% (CMR≤ 0.0032% (CMR4.54.5) at any time*) at any time*††

*ITT population†Most sensitive measure of leukemic burden available

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

P < .0001

P = .0004

P < .0001

BCR-ABL (IS) ≤ 0.01%(4-log reduction: CMR4)

BCR-ABL (IS) ≤ 0.0032%(4.5-log reduction: CMR4.5)

n = 282

n = 281 n = 283 n = 282

n = 281 n = 283

Progression to AP/BC on core treatment*†

0.7% 0.7%

Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD

P = .0059

P = .0196

P = .0003

P = .0089

Including Clonal Evolution

*ITT population†Progression to AP/BC or death due to CML while on core treatment

1.1% 4.2% 1.8% 6.0%

Primary endpoint Confirmed CCyR by 12 mos

Other key endpoints Rates of CCyR and MMR, times to CCyR and MMR, time in CCyR (measure of duration), progression-free survival, overall survival

DASISION (DASISION (CA180-056) study design ) study design (ongoing global phase 3 study)(ongoing global phase 3 study)

Follow-up

5 yearsRandomized*

Imatinib 400 mg QD (n=260)

Dasatinib 100 mg QD (n=259) Treatment-

naïve CML-CP patients (N=519)

108 centers

26 countries*Stratified by Hasford risk score

DASISION: First-line Dasatinib vs Imatinib in CML-CP

Shah et al, Blood (ASH Annual Meeting Abstracts), Nov 2010; 116: 206.

BCR-ABL ≤0.0032%

MMR, BCR-ABL ≤0.1%

Based on time-to MMR analysis, likelihood of achieving a MMR was 1.8-fold higher with dasatinib vs imatinib (stratified log-rank P<0.0001; HR=1.8)

Among patients who achieved a MMR, median time to MMR was 8.3 mos for dasatinib and 11.8 mos for imatinib

P<0.0001

P=0.0002

MMR rates (ITT) by month of treatmentDasatinib 100 mg QD

Imatinib 400 mg QD

Mo 3 Mo 6 Mo 9 Mo 12 Any timeAny time

5 patients who achieved a CCyR transformed to AP/BP CML (2 dasatinib, 3 imatinib) No patient who achieved a MMR transformed to AP/BP CML to date Patients were followed for transformation for up to 60 days after the last dose of

study drug; clonal evolution without additional criteria for AP CML was NOT counted as transformation

Transformation to Advanced Phase CML (ITT)Transformation to Advanced Phase CML (ITT)100

n/N 6/259 9/260

Dasatinib 100 mg QD

Imatinib 400 mg QD

What is the best strategy to minimise progression AND maximise MMR?

Imatinib 400 mg/day for all Imatinib 400 mg/day for all NO

Imatinib at higher dose Imatinib at higher dose ????

Imatinib plus interferon Imatinib plus interferon ????

More potent TKI for all (nilotinib, dasatinib)More potent TKI for all (nilotinib, dasatinib)

Selective intensificationSelective intensification

Individualised therapy based on biomarkersIndividualised therapy based on biomarkers

Baseline

Good AP/BCPoor

Defining goals for molecular remission in Chronic Myeloid Leukemia

Documents

Chronic Myeloid Leukemia - Hospital Physician · philic leukemia, myelodysplastic/myeloproliferative neoplasms, such as chronic myelomonocytic leu-kemia, and acute myeloid leukemia

Chronic Myeloid Leukemia Hammad

Treatment adherence in chronic myeloid leukemia: a ...€¦ · Nonadherence in chronic myeloid leukemia Chronic myeloid leukemia (CML) accounts for approximately 15% of all leukemias

Acute Myeloid Leukemia - AACC

Myelodysplasia Acute Myeloid Leukemia Chronic … Acute Myeloid Leukemia Chronic Myelogenous Leukemia Non Hodgkin Lymphoma Chronic Lymphocytic Leukemia Plasma Cell (Multiple) Myeloma

Myeloid Sarcoma of the Skin Derinin Myeloid Sarkomu · isolated or associated with acute myeloid leukemia, chronic myeloid leukemia, primary myelofibrosis, hypereosinophilic syndrome

Leukemia Cutis in Acute Myeloid Leukemia Signifies a Poor

Acute Myeloid Leukemia - Mayo Clinic · Leukemia NCCN. Acute Myeloid Leukemia. 3.2017 American Cancer Society. Key Statistics for Acute Myeloid Leukemia. 2017 American Cancer Society

chronic myeloid leukemia pathway

HOXA9 – Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML)erepo.unud.ac.id/.../1/ceb797062990f1eb607569e953714f4b.pdf · 2020. 7. 21. · Leukemia myeloid akut atau Acute Myeloblastic Leukemia (AML) sering juga

Elderly Acute Myeloid Leukemia

Referat Leukemia Myeloid Akut

ACUTE MYELOID LEUKEMIA (AML) - · PDF fileFACTS AND FIGURES PROGNOSIS & TREATMENT DIAGNOSIS ACUTE MYELOID LEUKEMIA (AML) Acute Myeloid Leukemia is a cancer that begins in

Case Report Complete Remission of Acute Myeloid Leukemia ...downloads.hindawi.com/journals/crihem/2016/8581421.pdfCaseReportsinHematology T : Complete blood count from OSH. WBC HGB

Hematopoietic Cell Transplantation for Acute Myeloid Leukemiamedicalpolicy.bluekc.com/MedPolicyLibrary/Therapy...Acute Myeloid Leukemia Acute myeloid leukemia (AML), also called acute

kasus leukemia myeloid akut

Properties of Chronic Myeloid Leukemia Stem Cells ......ProPerties of ChroniC Myeloid leukeMia steM Cells Chronic Myeloid Leukemia (CML) is a clonal myelo proliferative disorder that

Preleukemic mutations in human acute myeloid leukemia ... · Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission M. Ryan Corces-Zimmermana,

Leukemia --acute myeloid leukemia --- magdi sasi