Yishai Ofran 2021 The general idea of MRD measurement MRD can be used as a biomarker Sponsors can potentially use MRD status as any of the following types of biomarkers MRD as predictive or monitoring ID: 908684
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Slide1
The new (2021) ELN AML MRD guidelines
Yishai Ofran 2021
Slide2The general idea of MRD measurement
Slide3MRD can be used as a biomarker.
Sponsors
can potentially
use
MRD status as any of the following types of biomarkers:
Slide4MRD as predictive or monitoring
tool that can be used to guide clinical decisions
How we can validate MRD predictive power?
Randomized control trial? –
Are we ready to do nothing while MRD level is rising?
Retrospective observations? –
Different populations, different monitoring protocols
Meta-analysis of observational MRD data from multiple studies that examined a specific question. Statistically proven surrogacy.
Slide5Slide6Pre-transplant
MRD was
associated with worse
LFS
(
hazard
ratio=2.76 [1.90-4.00
]
),
OS
(
hazard
ratio=2.36 [1.73-3.22]
),
and
cumulative incidence of relapse (
hazard ratio=3.65 [2.53-5.27]), but not non-relapse mortality
(
hazard ratio=1.12 [0.81-1.55]
).
Slide7Slide8Limitations of MRD assessments: general
and AML-specific considerations
Faultless discrimination between early progenitors of the leukemia and those who can not be the source of relapse.
Neglected rate of technical errors.
Assuming that:
There is a distinctive 100% specific marker of leukemic blasts (
PML/RARA, BCR/ABL, NPM1?, Inv16? T(8:21)?
). There is minimal false positive and negative results in selected test. BM sample represents the whole body stem cell population Statistically relevant (
enough cells analyzed, TRM, is MRD a yes/no reality?
)
Slide9MRD as prognostic biomarker
Among all AML patients – 1/3 will die despite achieving MRD
neg
, 1/3 will survive despite not achieving
MRD
neg
,…… A prognostic biomarker
informs about the natural history of the disease in a particular patient in the absence of a therapeutic intervention.
Numerous studies – very prominent results
68%
34%
Slide10QUAZAR AML 001 – oral AZA maintenance
20% of patients in the placebo group converted from MRD+ to MRD- during placebo therapy
Slide11MRD as a predictive biomarker in AML –
predicting benefit of alloSCT in CR1
Versulius
et al JCO precision 2017
Relative risk reduction identical for relapse and relapse free survival with allo-SCT in both MRD positive and negative patients????
Absolut risk reduction:
RR: MRD- (40->26%), MRD+ (65%->45%)
Rate of relapse free survival (FU 50m):
MRD
neg
–chemo 55%
MRD neg – alloSCT 58% MRD
pos – chemo 31% MRD pos- alloSCT 44%
Relapse risk
Relapse free survival
Slide12MRD as a predictive biomarker in
AML – predicting benefit of conditioning for
alloSCT
in CR1
Hourigan et al.
Slide13MRD as a predictive biomarker in AML –
predicting benefit of alloSCT in CR1 by MRD test and cutoff
Slide14MRD as a predictive biomarker in AML – predicting benefit of
alloSCT in CR1 by ELN leukemia risk
Slide15MRD as a biomarker for monitoring
How alarming is a conversion from MRD- to MRD+?
Is there a magic cutoff (a Rubicon) that once the leukemia cross it relapse is surly pending?
Slide16Retrospective analysis of PML/RARA level in frozen samples of 519 APL patients
20 cases of molecular relapse identified all eventually relapsed.
Blood
.
1998;92;784-9
Retrospective analysis of T(8:21) level in BM and PB of 155 patients
MRD as a biomarker for monitoring
Slide17MRD as a biomarker for monitoring
PB or BM?
How frequent to monitor?
How long after therapy cessation?
Should protocol be tailored for each marker or method of MRD testing?
Do monitoring protocols for patients who underwent allo-SCT and those who didn’t should be different?
What about maintenance?
What is the optimal cutoff between negative and positive tests?
Slide182021 recommendation
Informative clinical time points for MRD assessment include post chemotherapy cycle 2 (PC), prior to stem cell transplantation, at end of
intensive treatment
, and during follow-up after chemotherapy or
alloHCT
.
Patients tested MRD positive before allo-transplant should be conditioned with MAC.
Slide192021 recommendation
MRD use to monitor patients during CR1 is recommended:
For
patients with
mutant
NPM1, CBF AML
or APL (PML-RARA), we recommend molecular MRD assessment by qPCR or ddPCR in PB AND BM.
AML patients not included in the molecularly defined subgroups should be monitored for MRD by MFC in BM.NGS-based MRD monitoring in PB and BM can be considered in addition to MFC.
Patients with NPM1 or CBF AML who have stable molecular persistence at low copy numbers
(<1% VAF)
do NOT require a change in treatment (at EOT or during follow up).
Slide202021 recommendation
For NPM1 mutated AML and high-risk APL MRD should be assessed by qPCR from BM cells every 3 months for 24 months after the end of treatment. Alternatively, MRD may be assessed by qPCR from PB cells every 4-6
weeks.
In RUNX1-RUNX1T1 and CBFB-MYH11 mutated AML monthly intervals for MRD monitoring in PB are recommended for the first 12-18 months after treatment due to the rapid kinetics of AML relapse.
The optimal MFC-MRD threshold level that best discriminates subsequent relapse risk has not yet been defined for each currently used MFC assay. MFC-MRD positivity is defined as ≥ 0.1% cells with the target phenotype from all CD45+ cells; MRD negativity is defined as <0.1% cells with the target phenotype from all CD45+ cells.
Slide21Thank You