Sub-Committee on Disease-Specific Methods And Sub-Committee on Disease-Specific Methods And Strategies For Monitoring Relapse Following Strategies For Monitoring Relapse Following
Allogeneic Stem Cell TransplantationAllogeneic Stem Cell Transplantation
Co-Chairs: Co-Chairs: Nicolaus Kröger, MD, Alan Wayne, MDNicolaus Kröger, MD, Alan Wayne, MD
Ulrike Bacher, MDUlrike Bacher, MD
Peter Bader, MDPeter Bader, MD
Sebastian Böttcher, MDSebastian Böttcher, MD
Michael Borowitz, MD, PhDMichael Borowitz, MD, PhD
Peter Dreger, MDPeter Dreger, MD
Issa Khouri, MDIssa Khouri, MD
Eduardo Olavarria, MDEduardo Olavarria, MD
Jerald Radich, MDJerald Radich, MD
Wendy Stock, MDWendy Stock, MD
Daniel Weisdorf, MDDaniel Weisdorf, MD
Andre Willasch, MDAndre Willasch, MD
Julie Vose, MDJulie Vose, MD
How can studies using different methods be compared, especially if we are going to change definitions of response?
How do we deal with patients with uninformative markers in clinical trials?
How do we deal with moving target of increasing sensitivity as techniques improve?
CML SUMMARYCML SUMMARY
• MRD monitoring is well established with Q-PCR for BCR-ABL
• PCR positivity predicts for relapse (all types) and disease progression
• PCR monitoring can be used for assessing response to treatment of relapse (DLI +/- Imatinib)
• Treatment of early relapse (molecular-cytogenetic) results in superior response rates and survival
• There is a need for standardization of PCR methodology
• Future clinical trials should focus on MRD monitoring after treatment with TKIs post allogeneic SCT
THE FUTURE
Why do some CP cases relapse? Why don’t all BC? mRNA signature of aggressive disease?
What is PCR negativity? Sensitive detection of low abundance mRNA.
What is the variation of BCR-ABL between cells? Single cell PCR of BCR-ABL mRNA.
Reciprocal rearrangements:
MRD diagnostic with RQ-PCR well established
„favorable“ rearrangements >>
minor role for allo-SCT
Other suitable markers for the SCT setting?
NPM1: 55%?
FLT-ITD: 35%?
NRAS: 10%
FLT3-TKD: 55%
MLL-PTD: 10%
Parameters for post-transplant molecular MRD monitoring in AML?
RUNX1: 10%
Normal karyotype: 45% of all cases
Post-transplant MRD monitoring?
Haferlach et al., Curr Opin Hemat, 2006
Conclusions: Post-transplant monitoring in AML and MDS
• So far, only very few studies focused on MRD monitoring in AML and MDS
specifically in the post-transplant period.
• In AML, post-transplant MRD monitoring with RQ-PCR for patients with NPM1 or
FLT3 mutations should be further evaluated. In MDS, the RUNX1/AML1 mutations
might represent a utile molecular MRD parameter.
• First studies suggest that immunophenotyping with MFC contributes to post-
transplant early detection of relapse in AML. The definition of thresholds of LAIP-
positive cells for immunotherapeutic intervention, however, requiries further studies.
• Monitoring of chimerism offers the possibility of post-transplant monitoring
irrespective of the individual subgroup in myeloid malignancies. Interpretation of the
results should always consider the kinetics of mixed chimerism. The potential of
CD34+ lineage specific chimerism should be further investigated for both entities.
• The combination of chimerism and MRD techniques will improve safety of post-
transplant monitoring. It remains to evaluated whether novel mutations - e.g. of TET2
- might contribute to post-transplant MRD strategies in the future.
Conclusions I
Immunotherapy (WD of immunosuppression, DLI) is principally effective as pre-emptive treatment
Chimerism can be used as surrogate marker for identifying patients at risk for impending relapse However:
Not in all patients! Additional role for MRD?
Conclusions II
MRD prior to stem cell transplantation has a profound impact on post transplant outcome!
What adds MRD post transplant?
MRD - Highest Level post SCTAll Patients
pEFS pRFS
< 10-6: n = 46; cens.= 26; pEFS = .55 .08 n = 46; cens.= 37; pRFS = .77 .07
≥ 10-6- <10-4 n = 25; cens.= 12; pEFS = .48 .10 n = 25; cens.= 17; pRFS = .62 .11≥ 10-4: n = 21; cens.= 03; pEFS = .09 .06 n = 21; cens.= 03; pRFS = .11 .07
P=0.002 P=0.000
Event free survival [years]
1086420
Cu
m E
FS
1,0
0,8
0,6
0,4
0,2
0,0
Relapse free survival [years]
1086420C
um
RF
S
1,0
0,8
0,6
0,4
0,2
0,0
MRD ≥ 10E-4MRD ≥ 10E-4
MRD < 10E-6
MRD < 10E-6
MRD <10E-4 - 10E-6
MRD <10E-4 - 10E-6
Conclusions III and Summary
MRD assessment in BM post transplant is predictive for relapse Serial BM investigations are warranted. Current working recommendations of the BFM: days
30, 60, 100, 200, 300, 365, at 18 months and 24 months.
Summary: Patients with mixed chimerism have a high risk for
relapse Patients, who become/remain MRD positive >10-4,
have a very high risk to develop relapse Additional treatment in these patients is warranted
PB-04/06tk05.06
Summary MRD detection both prior to and following alloSCT for
adults with ALL is associated with poor DFS
Clinical interventions based on MRD measurements suggest utility but data are very limited:
Allocation to alloSCT in CR1 Post-transplant intervention to prevent relapse
Targeted therapy (e.g. imatinib) following transplant
Challenge: implementation of standardized MRD assays that can be done in “real-time”
IgH/TCR qPCR assays are laborious Data on flow cytometric measurements of MRD in adults with
ALL are lacking
Summary: MRD after alloSCT• Techniques: have to be quantitative & sensitive ( 10-4)
• MRD flow • ASO IgH qPCR
• Retrospective analyses show that:• delayed, likely GVL-mediated MRD clearance occurs• MRD clearance:
• predicts of very low relapse risk• is durable• might serve as surrogate marker for cure
• MRD persistence after CsA tapering can be used as trigger for preemptive immun-therapy (DLI)
Treatment aim to be tested prospectively : MRD negativity (< 10-4) 12 months after alloSCT
Perspective: MRD after alloSCT
• Test MRD negativity (< 10-4) 12 months after alloSCT prospectively
• Treat MRD after alloSCT using • DLI• alternative treatment options (e.g. Rituximab)
• Delineate mechanisms of MRD clearance
Nicolaus Kröger Nicolaus Kröger
Dept. of Stem Cell Transplantation, University Hospital HamburgDept. of Stem Cell Transplantation, University Hospital Hamburg
Hamburg, GermanyHamburg, Germany
Relapse DefinitionRelapse DefinitionNCI Workshop 1./2.11.2009NCI Workshop 1./2.11.2009
CML Standard DefinitionCML Standard Definition
Molecular relapse Molecular relapse (The date of molecular relapse is the date of the first positive RT-PCR assay.)(The date of molecular relapse is the date of the first positive RT-PCR assay.)
Is said to be present in a CML patient lacking any other evidence of the disease (i.e. patient in hematological remission Is said to be present in a CML patient lacking any other evidence of the disease (i.e. patient in hematological remission
and cytogenetic remission) at least 4 months after SCT when any of the following apply:and cytogenetic remission) at least 4 months after SCT when any of the following apply:
Three samples over a minimum of 4 weeks show a BCR-ABL/ABL ratio higher than 0.02% as measured by Three samples over a minimum of 4 weeks show a BCR-ABL/ABL ratio higher than 0.02% as measured by
quantitative RT-PCR tests. quantitative RT-PCR tests. Three samples over a minimum of 4 weeks show clearly rising levels of BCR-ABL/ABL ratio with the last two Three samples over a minimum of 4 weeks show clearly rising levels of BCR-ABL/ABL ratio with the last two
higher than 0.02% as measured by quantitative RT-PCR tests.higher than 0.02% as measured by quantitative RT-PCR tests. Two samples over a minimum of 4 weeks show a BCR-ABL/ABL ratio higher than 0.05% as measured by Two samples over a minimum of 4 weeks show a BCR-ABL/ABL ratio higher than 0.05% as measured by
quantitative RT-PCR tests.quantitative RT-PCR tests.
Cytogenetic relapseCytogenetic relapse
Any of the following in a patient lacking any clinical or hematological evidence of the disease (i.e. patient in Any of the following in a patient lacking any clinical or hematological evidence of the disease (i.e. patient in
hematological remission):hematological remission):
Presence of one or more Ph-positive metaphases with standard cytogenetics or hypermetaphase FISH;Presence of one or more Ph-positive metaphases with standard cytogenetics or hypermetaphase FISH; >2% cells with the BCR-ABL fusion gene by interphase FISH>2% cells with the BCR-ABL fusion gene by interphase FISH
Hematological relapseHematological relapse
All of the following:All of the following:
Abnormal blood or marrow counts or morphology consistent with CML.Abnormal blood or marrow counts or morphology consistent with CML. Cytogenetic and/or molecular confirmation of the presence of the disease.Cytogenetic and/or molecular confirmation of the presence of the disease.
Hematological relapse is sub-classified into chronic phase, accelerated phase or blastic phase according to WHO Hematological relapse is sub-classified into chronic phase, accelerated phase or blastic phase according to WHO
criteriacriteria
CML CML ProposalProposal
DiseaseDisease Definition of Definition of
CRCRDefinition of Definition of
RelapseRelapseMolecular Molecular
markermarkerChromosomeChromosome ChimerismChimerism ImagingImaging Flow cytometryFlow cytometry
CMLCML
applicableapplicable
Comment:Comment:
HematologicHematologic
CytogeneticCytogenetic
MolecularMolecular
All patientsAll patients
HematologicHematologic
CytogeneticCytogenetic
MolecularMolecular
All patientsAll patients
BCR-ABL RT-PCRBCR-ABL RT-PCR
All patientsAll patients
qPCR identifies qPCR identifies
relapse risk groupsrelapse risk groups
CytogeneticCytogenetic
(incl FISH )(incl FISH )
All patientsAll patients
Not as sensitive as Not as sensitive as
qPCR for MRD qPCR for MRD
detectiondetection
PCR or PCR or
VNTR/STRVNTR/STR
All patientsAll patients Not Not
applicableapplicable
4-6 color flow4-6 color flow
subgroupssubgroups
Only helpful in Only helpful in
identifying aberrant identifying aberrant
blasts in advanced blasts in advanced
phase diseasephase disease
Myelofibrosis Standard DefinitionMyelofibrosis Standard Definition
Progressive Disease: Progressive Disease: Requires one of the following:Requires one of the following:
•Progressive splenomegaly that is defined by the appearance of a Progressive splenomegaly that is defined by the appearance of a previous absent splenomegaly that is palpable at greater than 5 cm previous absent splenomegaly that is palpable at greater than 5 cm below the left costal margin or a minimum of 100% increase in below the left costal margin or a minimum of 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a palpable distance for baseline splenomegaly of 5-10 cm or a minimum of 50% increase in palpable distance for baseline minimum of 50% increase in palpable distance for baseline splenomegaly of greater than 10 cm.splenomegaly of greater than 10 cm.
•Leukemic transformation confirmed by bone marrow blast count of Leukemic transformation confirmed by bone marrow blast count of at least 20%at least 20%
•Increase in peripheral blood blast percentage of at least 20% that Increase in peripheral blood blast percentage of at least 20% that lasts for 8 weekslasts for 8 weeks
•RelapseRelapse: : Changes from CR to PR or CR/PR to Clinical improvement Changes from CR to PR or CR/PR to Clinical improvement
DiseaseDisease Definition of Definition of
CRCRDefinition of Definition of
RelapseRelapseMolecular markerMolecular marker ChromosomeChromosome ChimerismChimerism ImagingImaging Flow cytometryFlow cytometry
MyelofibrosisMyelofibrosis
applicableapplicable
Comment:Comment:
IWG-MRTIWG-MRT
All ptsAll pts
Not fully Not fully
applicable applicable
IWG-MRTIWG-MRT
All ptsAll pts
Not fully Not fully
applicableapplicable
JAK2/MPLJAK2/MPL
SubgroupsSubgroups
High sensitivity and High sensitivity and
predictive for predictive for
relapserelapse
CytogeneticCytogenetic
(incl FISH)(incl FISH)
SubgroupsSubgroups
Not investigatedNot investigated
PCR/VNTRPCR/VNTR
All ptsAll pts
Correlates with Correlates with
molecular marker, molecular marker,
but less specificbut less specific
MRTMRT
All ptsAll pts
Correlates with Correlates with
fibrosis fibrosis
regressionregression
Flow-cytometryFlow-cytometry
All ptsAll pts
Circulating CD34+ Circulating CD34+
cells may be usefulcells may be useful
Myelofibrosis Myelofibrosis ProposalProposal
AML Standard Definition AML Standard Definition (Cheson et al., 2003)(Cheson et al., 2003)
ParametersParameters Complete remissionComplete remission RelapseRelapse
Morphological/Morphological/
hematological criteriahematological criteria
BM blasts < 5%;BM blasts < 5%;
thrombocytes ≥ 100 x 10thrombocytes ≥ 100 x 1099/L; /L; neutrophils ≥ 1.0 x 10neutrophils ≥ 1.0 x 1099/L/L
Reappearance of blasts post CR Reappearance of blasts post CR (BM: > 5%; PB) (BM: > 5%; PB)
Cytogenetic criteriaCytogenetic criteria Major cytogenetic remission: Major cytogenetic remission: Disappearance of cytogenetic Disappearance of cytogenetic alterationalteration
Minor cytogenetic remission: > 50% Minor cytogenetic remission: > 50% reduction of abnormal metaphasesreduction of abnormal metaphases
Reappearance of cytogenetic Reappearance of cytogenetic alteration alteration
Molecular remissionMolecular remission Disappearance of molecular mutationDisappearance of molecular mutation Reappearance of molecular Reappearance of molecular mutationmutation
Flow cytometryFlow cytometry Disappearance of cells with previously Disappearance of cells with previously determined LAIPdetermined LAIP
Reappearance of cells with LAIPReappearance of cells with LAIP
Criteria of remissionCriteria of remission ParametersParameters
Morphologic and Morphologic and
hematological responsehematological responseComplete remission (CR): bone marrow blasts <5% Complete remission (CR): bone marrow blasts <5%
without dysplasia, hemoglobin ≥11 g/dL, platelets without dysplasia, hemoglobin ≥11 g/dL, platelets
≥ 100 x 10≥ 100 x 1099/L, neutrophils ≥ 1.5 x 10/L, neutrophils ≥ 1.5 x 1099/L/L
Partial remission (PR): reduction of blasts by at least 50% Partial remission (PR): reduction of blasts by at least 50%
or achievement of lower risk category than prior to or achievement of lower risk category than prior to
treatmenttreatment
Cytogenetic responseCytogenetic response Major cytogenetic response: disappearance of a Major cytogenetic response: disappearance of a
cytogenetic abnomalitycytogenetic abnomality
Minor cytogenetic response: ≥50% reduction of abnormal Minor cytogenetic response: ≥50% reduction of abnormal
metaphasesmetaphases
MDS Standard Definition MDS Standard Definition (Cheson et al., 2006)(Cheson et al., 2006)
AML / MDS ProposalAML / MDS Proposal
DiseaseDisease Definition of Definition of
CRCRDefinition of Definition of
RelapseRelapseMolecular Molecular
markermarkerChromo-Chromo-
somesomeChimerismChimerism ImagingImaging Flow cytometryFlow cytometry
AML/MDSAML/MDS
applicableapplicable
Comment:Comment:
IWGIWG
All ptsAll pts
Well Well
establishedestablished
IWGIWG
All ptsAll pts
Well Well
established, established,
but less but less
sensitivesensitive
Mol. MarkerMol. Marker
SubgroupsSubgroups
Expansion of Expansion of
MRD marker MRD marker
panel for post-panel for post-
transplant transplant
monitoring in monitoring in
AML (e.g. AML (e.g. NPM1NPM1
–mutations) or –mutations) or
MDS (e.g. MDS (e.g.
RUNX1RUNX1//AML1AML1
mutations) mutations)
CytogeneticCytogenetic
(incl FISH )(incl FISH )
SubgroupsSubgroups
No No
standardization standardization
for MRD for MRD
monitoring, monitoring,
useful for useful for
specific specific
aberrationsaberrations
PCR or VNTR/STRPCR or VNTR/STR
All ptsAll pts
Well established, lack Well established, lack of specificity: of specificity: investigation of lineage investigation of lineage specific chimerism specific chimerism (e.g. CD34(e.g. CD34+ + cells); and cells); and standardization of standardization of techniques techniques
Not Not
applicableapplicable
4-8 color flow4-8 color flow
All ptsAll pts
Few studiesFew studies
Progressive Disease: Progressive Disease:
An increase of at least 25% in the absolute number of circulating or bone marrow An increase of at least 25% in the absolute number of circulating or bone marrow
leukemic blasts or extramedullary disease burden; leukemic blasts or extramedullary disease burden; oror Development of new extramedullary disease.Development of new extramedullary disease.
Relapsed Disease: Relapsed Disease:
The reappearance of leukemia blast cells in the blood or the bone marrow (≥ 25%) The reappearance of leukemia blast cells in the blood or the bone marrow (≥ 25%)
or in any other extramedullary site after a CR with confirmation of lymphoid blasts or in any other extramedullary site after a CR with confirmation of lymphoid blasts
by morphology and flow cytometry, PCR for antigen receptor loci or fusion genes, by morphology and flow cytometry, PCR for antigen receptor loci or fusion genes,
or cytogenetics/FISH; or cytogenetics/FISH; oror Progression to > 25% leukemia blasts in the marrow after a PR. Progression to > 25% leukemia blasts in the marrow after a PR. Importantly, isolated extramedullary relapses (e.g., CNS) are considered relapse Importantly, isolated extramedullary relapses (e.g., CNS) are considered relapse
from a diagnostic standpoint, although these are commonly approached from a diagnostic standpoint, although these are commonly approached
differently in terms of therapy.differently in terms of therapy.
ALL Standard DefinitionALL Standard Definition
ALL ProposalALL Proposal
DiseaseDisease Definition Definition
of CRof CRDefinition of Definition of
RelapseRelapseMolecular markerMolecular marker ChromosomeChromosome ChimerismChimerism ImagingImaging Flow cytometryFlow cytometry
ALLALL
applicableapplicable
Comment:Comment:
Less than Less than
5% blasts 5% blasts
in BMin BM
All ptsAll pts
More thanMore than
5% blasts in 5% blasts in
BMBM
All ptsAll pts
TCR- and Ig- Gene TCR- and Ig- Gene
rearrangement rearrangement
90% of all patients 90% of all patients
- ASO primer- ASO primer
80-90% of patients80-90% of patients
- Ig VDJ for most - Ig VDJ for most
patients patients
- BCR-ABL for all - BCR-ABL for all
Ph+ ALLPh+ ALL
CytogeneticCytogenetic
(incl .FISH)(incl .FISH)
subgroupssubgroups
clinical not clinical not
important for MRD important for MRD
assessmentassessment
PCR or VNTR/STRPCR or VNTR/STR
All ptsAll pts
Gold standard: Singleplex Gold standard: Singleplex
PCR with fluorescent PCR with fluorescent
labelled STR primers. labelled STR primers.
importantly: product importantly: product
resolution using capillary resolution using capillary
electrophoresiselectrophoresis
Limited data on utilityLimited data on utility
Not Not
applicableapplicable
4-6 color flow4-6 color flow
>95% of patients>95% of patients
Sensitivity in B-ALL Sensitivity in B-ALL
limited after SCT limited after SCT
because of large because of large
numbers of numbers of
hematogoneshematogones
• Relapse: Relapse: progression occurring 6 months or later after having achieved CR or PR progression occurring 6 months or later after having achieved CR or PR
• ProgressionProgression: : IW-CLL/NCI-WG criteria for CLL progression (at least one must apply)IW-CLL/NCI-WG criteria for CLL progression (at least one must apply)•• Appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), splenomegaly, Appearance of any new lesion such as enlarged lymph nodes (> 1.5 cm), splenomegaly, hepatomegaly or other organ infiltrates;hepatomegaly or other organ infiltrates;
•• increase of lymphadenopathy by 50% or more in greatest determined diameter of any increase of lymphadenopathy by 50% or more in greatest determined diameter of any previous site, or an increase of 50% or more in the sum of the product of diameters of previous site, or an increase of 50% or more in the sum of the product of diameters of multiple multiple nodes;nodes;
•• increase in the liver or spleen size by 50% or more or the de novo appearance of increase in the liver or spleen size by 50% or more or the de novo appearance of hepatomegaly or splenomegaly;hepatomegaly or splenomegaly;
•• increase in the number of blood lymphocytes by 50% or more with at least 5/nL B cells;increase in the number of blood lymphocytes by 50% or more with at least 5/nL B cells;
•• transformation to a more aggressive histology (e.g. Richter's syndrome).transformation to a more aggressive histology (e.g. Richter's syndrome).
•• occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL.occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL.
• Complete MRD response: Complete MRD response: clinical remission in the absence of one CLL cell per clinical remission in the absence of one CLL cell per 10,000 leukocytes in the peripheral blood or bone marrow 10,000 leukocytes in the peripheral blood or bone marrow
• MRD relapse: MRD relapse: Tumor cell recurrence or increases at the MRD level that does not Tumor cell recurrence or increases at the MRD level that does not exceed 5 B cells/nL in the peripheral blood.exceed 5 B cells/nL in the peripheral blood.
CLL Standard DefinitionCLL Standard Definition
CLL CLL ProposalProposal
DiseaseDisease Definition of Definition of
CRCRDefinition of Definition of
RelapseRelapseMolecularMolecular
markermarkerChromo-Chromo-
somesomeChimerismChimerism ImagingImaging Flow cytometryFlow cytometry
CLLCLL
applicableapplicable
Comment:Comment:
iwCLL/NCIiwCLL/NCI
All ptsAll pts
iwCLL iwCLL
definition of definition of
MRD MRD
negativity: negativity:
MRD < 10MRD < 10-4 -4 by by
qPCR or MRD qPCR or MRD
FlowFlow
iwCLL/NCiwCLL/NC
All ptsAll pts
ASO-primer ASO-primer IGHIGH
qPCRqPCR
~90%~90%
predictive for predictive for
sustained remission sustained remission
if < 10if < 10-4 -4 1 year post 1 year post
SCT.SCT.
More sensitive than More sensitive than
MRD flow belowMRD flow below
1010-4 -4
CytogeneticCytogenetic
(incl FISH)(incl FISH)
subgroupsubgroup
No role in No role in
relapse relapse
monitoringmonitoring
PCR/VNTRPCR/VNTR
All ptsAll pts
Complete donor Complete donor
chimerism usually chimerism usually
prerequisite for MRD prerequisite for MRD
negativity, but not negativity, but not
suitable as MRD suitable as MRD
markermarker
CTCT
All ptsAll pts
Only to be used if Only to be used if
CR by clinical CR by clinical
methods or in methods or in
clinical trialsclinical trials
MRD flowMRD flow
> 95% > 95%
predictive for predictive for
sustained sustained
remission if < 10remission if < 10-4 -4 1 1
year post SCT.year post SCT.
Equally sensitive Equally sensitive
and specific as and specific as
qPCR up to10qPCR up to10-4-4
ResponseResponse DefinitionDefinition Nodal MassesNodal Masses Spleen, LiverSpleen, Liver Bone MarrowBone Marrow
CR Disappearance of all evidence of disease
(a) FDG-avid or PET positive prior to therapy; mass of any size permitted if PET negative
(b) Variably FDG-avid or PET negative; regression to normal size on CT
Not palpable, nodules disappeared
Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative
Relapsed Relapsed disease disease
or PDor PD
Any new lesion Any new lesion or increase by ≥ or increase by ≥ 50 % of 50 % of previously previously involved sites involved sites from nadirfrom nadir
Appearance of a new lesion(s) > 1.5 Appearance of a new lesion(s) > 1.5 cm in any axis, ≥ 50 % increase in SPD cm in any axis, ≥ 50 % increase in SPD of more than one node, or ≥ 50 % of more than one node, or ≥ 50 % increase in longest diameter of a increase in longest diameter of a previously identified node > 1 cm in previously identified node > 1 cm in short axisshort axis
Lesions PET positive if FDG-avid Lesions PET positive if FDG-avid lymphoma or PET positive prior to lymphoma or PET positive prior to therapytherapy
> 50 % increase > 50 % increase from nadir in the from nadir in the SPD of any previous SPD of any previous lesionslesions
New or recurrent New or recurrent involvementinvolvement
Lymphoma Standard Definition Lymphoma Standard Definition (Cheson et al., 2007)(Cheson et al., 2007)
Lymphoma ProposalLymphoma Proposal
DiseaseDisease Definition of CRDefinition of CR Definition of Definition of
RelapseRelapseMolecularMolecular
markermarkerChromosomeChromosome ChimerismChimerism ImagingImaging FlowFlow
cytometrycytometry
LymphomaLymphoma
applicableapplicable
Comment:Comment:
Cheson criteriaCheson criteria
All patientAll patient
Well established Well established
for all for all
lymphomaslymphomas
ChesonCheson criteriacriteria
All patientAll patient
Well Well
established for established for
all lymphomasall lymphomas
ASO-primer (IgH ) for ASO-primer (IgH ) for
B-cell NHLB-cell NHL
subgroupssubgroups
Bcl-2 for FLBcl-2 for FL
Bcl-1for about 30% of Bcl-1for about 30% of
MCLMCL
T cell receptor for T-T cell receptor for T-
NHLNHL
CytogeneticCytogenetic
(incl FISH)(incl FISH)
subgroupssubgroups
t(14;18) for FLt(14;18) for FL
t(11,14) for MCLt(11,14) for MCL
PCR or VNTR/STRPCR or VNTR/STR
All patientAll patient
Monitoring T-cell Monitoring T-cell
by PCR useful in by PCR useful in
NHL. Role not NHL. Role not
established in HDestablished in HD
CT/PETCT/PET
All patientAll patient
Well Well
establishedestablished
in all in all
lymphomaslymphomas
4-6 color flow4-6 color flow
SubgroupsSubgroups
Could be helpful Could be helpful
for FL and MCLfor FL and MCL
Multiple Myeloma Standard DefinitionMultiple Myeloma Standard Definition
RelapseRelapse: : EBMT criteria (Bladè et al) requires at least one of the following:EBMT criteria (Bladè et al) requires at least one of the following:
• Reappearance of serum or urinary paraprotein on immunofixation or routine Reappearance of serum or urinary paraprotein on immunofixation or routine electrophoresis, confirmed by at least on further investigation and excluding oligoclonal electrophoresis, confirmed by at least on further investigation and excluding oligoclonal immune reconstitution.immune reconstitution.
• ≥ ≥ 5 % plasma cells in a bone marrow aspirate or on trephine bone biopsy.5 % plasma cells in a bone marrow aspirate or on trephine bone biopsy.
• Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase Development of new lytic bone lesions or soft tissue plasmacytomas or definite increase in the size of residual bone lesions (development of a compression fracture does not in the size of residual bone lesions (development of a compression fracture does not exclude continued response and may not indicate progression).\exclude continued response and may not indicate progression).\
• Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dl or 2.8 mmol/l) not Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dl or 2.8 mmol/l) not attributable to any other cause.attributable to any other cause.
IWG Criteria (Durie et al):IWG Criteria (Durie et al): Relapse from CR requires at least one of the following:Relapse from CR requires at least one of the following:
•• Reappearance of serum or urinary M-protein by immunofixation or electrophoresisReappearance of serum or urinary M-protein by immunofixation or electrophoresis
•• ≥ ≥ 5 % plasma cells in a bone marrow.5 % plasma cells in a bone marrow.
•• Appearance of any other sign of progression (i.e new lytic bone lesions or soft tissue Appearance of any other sign of progression (i.e new lytic bone lesions or soft tissue plasmacytomas or hypercalcemia).plasmacytomas or hypercalcemia).
Multiple Myeloma Multiple Myeloma ProposalProposal
DiseaseDisease Definition of Definition of
CRCRDefinition Definition
of Relapseof RelapseMolecular Molecular
markermarkerChromosomeChromosome ChimerismChimerism ImagingImaging Flow Flow
cytometrycytometryOther Other
methodsmethods
MultipleMultiple
MyelomaMyeloma
applicableapplicable
Comment:Comment:
1) EBMT1) EBMT
2) IWG2) IWG
All ptsAll pts
Accepted Accepted
but less but less
sensitivesensitive
1) EBMT1) EBMT
2) IWG2) IWG
All ptsAll pts
Accepted Accepted
but less but less
sensitivesensitive
ASO-primerASO-primer
(IgH)(IgH)
40-80%40-80%
Important, but Important, but
not included in not included in
EBMT and IWG EBMT and IWG
definitiondefinition
CytogeneticCytogenetic
(incl FISH)(incl FISH)
subgroupssubgroups
May be useful* May be useful*
PCR or VNTR/STRPCR or VNTR/STR
All ptsAll pts
MNC-donor MNC-donor
chimerism not chimerism not
useful, lineage useful, lineage
specific donor specific donor
chimerism (CD138+ chimerism (CD138+
plasma cells) plasma cells)
predicts relapsepredicts relapse
MRIMRI
PET-CTPET-CT
All ptsAll pts
Not Not
established, established,
but useful but useful
for for
extramedullextramedull
aryary
diseasedisease
4-8 color flow4-8 color flow
All ptsAll pts
More sensitive More sensitive
than than
EBMT/IWG in EBMT/IWG in
predicting predicting
relapserelapse
Free lightFree light
chainchain
assayassay
subgroupssubgroups
Proposed by Proposed by
IWG: no valid IWG: no valid
datadata
Sub-Committee on Disease-Specific Methods And Sub-Committee on Disease-Specific Methods And Strategies For Monitoring Relapse Following Strategies For Monitoring Relapse Following
Allogeneic Stem Cell TransplantationAllogeneic Stem Cell Transplantation
Panel Discussion
Relapse and Response Definitions After SCTRelapse and Response Definitions After SCTStandard diagnostic criteria used to define response and relapse Standard diagnostic criteria used to define response and relapse
Well validated in upfront clinical trialsWell validated in upfront clinical trials
Utility after allogeneic SCT is limited for most hematologic malignanciesUtility after allogeneic SCT is limited for most hematologic malignancies
Sensitive disease-specific detection methodsSensitive disease-specific detection methods
Methodologic standardization and validationMethodologic standardization and validation
Highly sensitive monitoring possibleHighly sensitive monitoring possible
Prognostic value in predicting continuous remission Prognostic value in predicting continuous remission vs.vs. relapse relapse
Facilitate early intervention Facilitate early intervention
Utility “pre-emptive” initiation of therapy prior to overt relapseUtility “pre-emptive” initiation of therapy prior to overt relapse
Proposed incorporation of sensitive detection methods to augment Proposed incorporation of sensitive detection methods to augment standard response/relapse definitions for use in allogeneic SCT trialsstandard response/relapse definitions for use in allogeneic SCT trials
Response endpoints Response endpoints
Relapse predictionRelapse prediction
Relapse prevention Relapse prevention
Relapse treatmentRelapse treatment
Discussion PointsDiscussion Points1. Are the standard diagnostic criteria for relapse and response
adequate for use after allogeneic SCT?
2.2. Proposed incorporation of sensitive detection methods to Proposed incorporation of sensitive detection methods to augment disease-specific definitions after allogeneic SCTaugment disease-specific definitions after allogeneic SCT
A. Methods included for specific diseases
B. Value of chimerism
C. Discordant results
D. Frequency of monitoring
3. Should achievement of molecular remission be the goal of allogeneic SCT?
4. When does molecular relapse or residual disease justify therapeutic intervention?
Research PrioritiesResearch Priorities1. Harmonization and standardization of molecular
monitoring and flow cytometry
2. Define the kinetics of molecular remission and molecular relapse after allogeneic SCT
3. Determine the predictive value of MRD and chimerism (incl lineage-specific) for clinical relapse
4. Apply and assess proposed definitions in studies designed to change the natural history of relapse after SCT
5. Apply and assess proposed definitions in trials of new treatments for prevention and treatment of relapse after SCT