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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)
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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-
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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
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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
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?
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
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
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Molecular Aberrations as New MRD Markers in ALL?
Inaba H, et al. Lancet 2013; 381:1943-1955
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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
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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
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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
Clonal Heterogeneity in Times of Targeted Treatment NUP214-ABL1 positive T-ALL
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
Clonal Heterogeneity in Times of Targeted Treatment NUP214-ABL1 positive T-ALL
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