use of minimal residual disease to guide therapy in...

Use of minimal residual disease to guide therapy in ALL

Monika Brüggemann Department of Hematology

University Hospital Kiel Kiel, Germany

Disclosures for Monika Brüggemann, MD, PhD

Royalty N/A

Receipt of intellectual property/ Patent holder

N/A

Consulting fee Amgen

Speakers bureau N/A

Fees for non-CME services N/A

Contracted research Amgen

Ownership interest (stocks, stock options)

N/A

Other N/A

N/A = Not Applicable (no conflicts listed) Presentation includes discussion of off-label or unapproved use of a drug or medical device: N/A

Brüggemann M et al. Blood 2012; 120:4470-4481

Quantification of Minimal Residual Disease (MRD)

Copyrighted material

Factors that influence treatment response

Characteristics of the leuKemic cell

E.g.- Cytogenetics, molecular genetics

- Immunophenotype

- In vitro chemosensitivity

- Gene expression profile

“Host” Factors

E.g.- Gastrointestinal absorption

- Pharmacogenetics

- Liver and renal function

- Age

Treatment protocol

E.g.- Type and dosage of therapy

- Type of maintenance

- Targeted therapy

- Stem cell transplantation

Quantification of Minimal Residual Disease (MRD)

MRD:

Integrated

evaluation of

treatment

response

Individualised

treatment

early MRD late MRD

(14/113)

MRD <10-2

(28/113)

MRD > 10-2

(71/113)

MRD neg /<10-4

(110/149)

MRD >10-4

(39/149)

MRD neg /<10-4

years years

Identification of patients with rapid tumor

clearance and excellent prognosis

Identification of patients with MRD persistence

and poor prognosis

RFS 0.92 ± 0.08

RFS 0.52 ± 0.16

RFS 0.33 ± 0.07

RFS 0.66 ± 0.06

RFS 0.12 ± 0.08

Brüggemann M et al., Blood. 2006;107:1116

Impact of MRD During Front-line Treatment on Prognosis -Ph-negative SR ALL-

→ MRD: time-point dependent variable

→ MRD negativity not identical with eradication of disease

MRD for Remission Assessment in ALL Studies -major published trials, focus on Ph neg-

Study Group Age Group No of pts Method COG Pediatric 1971 FCM

St. Jude Pediatric 492 Ig/TCR-RQ-PCR, FCM

MD Anderson Cancer Center

Adult Ph+ 76 FCM, IGH-GS in BCR-ABL positive ALL

AIEOP-BFM Pediatric 3384 Ig/TCR-RQ-PCR, FCM

Swedish Multicenter Study

Pediatric 288 Ig/TCR-RQ-PCR, FCM

DCOG Pediatric 508 Ig/TCR-RQ-PCR, FCM

EORTC-CLG Pediatric 100 Ig/TCR-PCR (GS), Ig/TCR-RQ-PCR

UKALL Pediatric+YA 3092 Ig/TCR-RQ-PCR

GRAALL Adult 423 Ig/TCR-RQ-PCR

GMALL Adult 580 Ig/TCR-RQ-PCR,

NILG-ALL Adult 253 Ig/TCR-RQ-PCR

PETHEMA Adult 234 FCM

UK NCRI Adult ALL Adult 85 IGH-PCR

Ma-Spore Pediatric 420 Ig/TCR-RQ-PCR

Borowitz MJ et al. 2008, Coustan-Smith et al. 2002, Ravandi et al. 2013, Conter et al. 2010, Thörn et al. 2011, Deny et

al. 2013, Cave et al. 1998, Vora et al. 2013, Beldjord et al. 2014, Gökbuget et al. 2012, Bassan et al. 2009, Ribera et

al. 2014, Mortuza et al. 2002, Yeoh et al. 2012

Molecular Aberrations in ALL

-GRAALL: MRD (w+6) and oncogenetics-

MRD negative MRD <10-4

MRD ≥10-4

p<0.001

BCP-ALL: MRD and genetics T-ALL: MRD and genetics

Beldjord K et al. Blood 2014; 123:3739-3749


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Raff T et al. Blood 2007; 109:910-915

n=105

80

60

40

20

0

nu

mb

er

of p

atie

nts

MRD

negative

MRD

positive

CCR 72 11 83

REL 5 17 22

77 28

MRD for Early Detection of Relapse -GMALL: MRD negative SR patients in CR1 after consolidation-


MRD pos: n=28

median RFS 9.5 months

MRD pos within QR: n=15

median RFS 4.1 months

Raff T et al. Blood 2007; 109:910-915

MRD for Early Detection of Relapse -GMALL: MRD negative SR patients in CR1 after consolidation-

MRD-based Treatment

Treatment reduction in MRD-LR

Treatment intensification in MRD-HR

Brüggemann M et al. Blood 2012; 120:4470-4481

Adapted from Spinelli O et al. MJHID 2014,6(1): e2014062

Study MRD+ Estimate allo SCT No allo SCT p

n (%) % n (%) %

GMALL 120 5-y DFS

5-y OS

57

(47%)

44%

54%

63

(53%)

11%

33%

<0.001

0.06

NILG 60 6-y DFS 26

(43%) 42%

34

(57%) 12% 0.000

Gökbuget M et al. Blood.2012;120:1868 Bassan R et al. Blood 2009;113: 4153

CCR DFS

p<0.0001

MRD for Tailoring Treatment - Treatment intensification in MRD-HR ALL: the GMALL and NILG experience -

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Induction Consolidation

N=403 HR-ALL

• 30-60y

• WBC>25x109/L

• 11q23/MLL rearrangement

d+14

Cytomorphology w+17

Flow MRD

S

d+14 >10% a/o

w+17 >0.05% allo SCT

d+14 <10% AND

w+17<0.05% Cons+Maint.

Evaluable for post

consolidation by ITT:

N=179

Allocated to SCT

N=71

SCT received:

N=50

Allocated to chemo

N=108

Chemo received:

N=104

MRD for Tailoring Treatment - Treatment de-escalation in MRD-LR ALL: the PETHEMA experience-

Ribera JM et al. JCO 2014; 32:1595-1604

DFS OS

All

HR

Stringent

HR

MRD for Tailoring Treatment - Treatment de-escalation in MRD-LR ALL: the PETHEMA experience-

©2014 by American Society of Clinical Oncology Ribera JM et al. JCO 2014; 32:1595-1604


Impact of MRD on Outcome after Allo SCT -major published trials, selected-

Study Type of

SCT

No. of pts. Method Estimate MRD neg MRD pos

(low/high)

p

Knechtli

(1998)

Allo 64 (P) PCR 2-y EFS 73% 36% <0.001

Dombret

(2002)

Allo 63 (A) PCR (BCR-ABL)

3-y IOR 41% 75% 0.01

Krejci

(2003)

Allo 140 (P) PCR 5-y EFS 75% 41%/21% <0.001

Spinelli

(2007)

Allo 37 (A) PCR 3-y IOR

3-y OS

0%

80%

46%

49%

0.027

NS

Bader

(2009)

Allo 91 (P) PCR 4-y IOR

4-y EFS

11%

64%

20%/57%

48%/31%

57%

Patel

(2010)

Allo

Auto

36 (A)

25 (A)

PCR 5-y EFS 50%

77%

52%

25%

NS

0.01

Leung

(2011)

Allo 64 (P) Flow 5-y IOR 6% 28% 0.03

Sanchez-

Garcia (2012)

Allo 102

(P+A)

Flow 5-y LFS

5-y OS

66%

52%

43%/0%

29%/0%

<0.001

<0.001

Bachanova

(2012)

UCB 86

(P+A)

Flow 2-y IOR

3-y LFS

16%

55%

30%

30%

0.05

0.02

Zhou

(2014)

Allo 149 Flow 2-y PFS

2-y OS

47%

55%

28%

40%

0.08

0.22

Adapted from Campana D, Leung W, BJH 2013; 162:147-161

100% 80% 60% 40% 20% 20% 40% 60% 80% 100%

day 11

n=113

day 24

n=157

day 44

n=114

week 11

n=153

week 16

n=149

week 22

n=128

week 30

n=133

week 41

n=109

week 52

n=126

% of patients with detectable MRD threshold ( )

(threshold: 10-2 for day 11, 10-4 for all other time-points)

% of patients with detectable MRD < threshold ( )

or without detectable MRD ( )

0% 0%

Treat MRD Prior to Allo SCT?

Brüggemann M et al., Blood. 2006;107:1116

Phase II Study 103-202:

B-cell precursor ALL in CR and:

MRD persistence after consolidation I

(n=16)

MRD relapse (n=5)

Topp MS et al JCO 2011; 29:2493-2498

Blinatumomab to Treat MRD

RFS: patients with SZT

RFS: patients without SZT

n=9

n=11

Topp MS et al Blood 2012; 120:5185-5187




?

Molecular Aberrations

Clonal Immune gene (IG/TR)-

Rearrangements

Marker for MRD Assessment in ALL

Leukemia-

associated

Immunophenotype

Diagnosis of disease MRD

Cell

population

Low throughput

technique BIOMED-II EuroMRD

IG/TR NGS for MRD Assessment in ALL

High throughput

technique

EuroClonality NGS Network

RESULTS III :

Concordance and Discordance Of MRD Results Comparative Analysis IGH-NGS vs IGH-RQ-PCR

268 Samples from 15 BCP-ALL , 30 MCL, 10 Myeloma

Major Qualitative discordance : positive/negative

discordance with positive result >1 E-05

Borderline qualitative discordance : positive/negative

discordance with positive result <1 E-05

Quantitative discordance: presence of two positive

results with a quantitative discrepancy >1 log

Concordance

ALL

MCL

MM

111 samples

concordant

POS

pos<QM

Ladetto M, Brüggemann M, et al. Leukemia 2014;28:1299-1307

//Crick/WINNT/Profiles/brueggemann/Local Settings/Temporary Internet Files/OLKB28/Documents and Settings/Usuario/Configuración local/Application Data/Microsoft/CD Burning/Nueva carpeta/González et al, 2003a.pdf

Frequency of Subclones at Dagnosis in B-precursor ALL. Each Cell Shown Represents a

Distinct Subclone Based on IgH Sequencing.

Zweidler-McKay P A Blood 2012;120:4280-4281


Molecular Aberrations as New MRD Markers in ALL?

Inaba H, et al. Lancet 2013; 381:1943-1955


IKZF1 Deletions as MRD marker

Cayé A et al. Haematologica 2013;98:597-601 Venn NC et al. Leukemia 2012;26:1414-6

n=162 follow-up samples

of BCR-ABL negative childhood ALL

n=88



Graux C et al. Nature Genetics 2004;36:1084-9

Clonal Heterogeneity in Times of Targeted Treatment NUP214-ABL1 positive T-ALL

Extrachromosomal

amplification

GMALL: detection of NUP214-ABL1 transcripts in 11/279

(3.9%) of T-ALL patients

Burmeister T et al. Blood 2006;108:3556-9


1xE-07

1xE-06

1xE-05

1xE-04

1xE-03

1xE-02

1xE-01

1xE+00

diagnosis d+26 d+46 w+16 w+16 d+24 (after

allo SCT)

d+110 d+140 d+200 d+231 d+265

time-point

MR

D

neg

Initial treatment:

Induction chemotherapy

Imatinib

NUP214-ABL relapse

TCRB/TCRG

Salvage treatment:

Nelarabine

Dasatinib

relapse SCT

Dasatinib


Koschmieder S et al. Leukemia 2014; 28:419-422

Graux C et al. Leukemia 2009;23:125-133

Chemotherapy: survival and proliferative advantage for cells with

NUP214-ABL1 fusion gene

→selection of cells with highest number of episomes

TKI: survival and proliferative advantage

for cells without fusion gene

→selection of cells without episomes


Conclusions

MRD: time-dependent parameter

MRD after induction treatment: most important independent

prognostic factor in adult and childhood ALL

Prognostic genetic abnormalities: not fully recapitulated by early

response to treatment

Ongoing postremission MRD monitoring: identification of an

impending relapse

MRD guided treatment is feasible:

Treatment intensification for MRD-HR patients

Treatment de-escalation of MRD-LR patients

NGS based MRD assessment provides new insights into the

clonal diversity of ALL

Usage of predictive molecular aberrations as MRD markers can

identify clonal selection processes in times of targeted treatment