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Disease-Specific Methods and Strategies for Monitoring Relapse Following Allogeneic
Stem Cell Transplantation
Pediatric Acute Lymphoblastic Leukemia
on behalf of the Sub-Committee
Peter Bader, Wendy Stock,Andre Willasch, Alan Wayne
Surveillance of Remission
Two principle approaches: Chimerism
Characterization of post transplant hematopoiesis MRD
Direct detection of the underlying malignancy
Hematopoietic Chimerismin Children with ALL
Bader et al., J Clin Oncol 33: 1696 (2004)
Studies on Chimerismand Intervention
AuthorNumber
of patients
Diagnosis Interval of investigations
Methods Relapses
FormakovaHaematologica
200354
AL, CML and MDS
children
weekly to +100;
monthlySTR
MC associated with rejection and relapseImmunotherapy was
possible
GorczynskaBMT 2004
14ALL, AMLchildren
weekly to +100;
monthlySTR
In-MC could be converted by immunotherapy to CC
BaderJCO 2004
163ALL
children
weekly to +100;
monthlySTR
MC associated with rejection and relapseImmunotherapy was
possible
HornBMT 2008
20AL
children
1,3,6,12 months;In MC bi-weekly
STRMC associated with
relapseIT was not possible
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?
Retrospective Studies - MRD prior to SCTLiterature
AuthorNumber of patients
Diagnosis Time of investigation
MethodsSurvival
according to MRD status
KnechtliBlood 1998
64 ALLprior to
conditioningIg / TCR
PCR
high level pos. – 0%low level pos. – 36%
negative – 73%
BaderLeukemia 2002
41 ALLprior to
conditioningIg / TCR
PCR
high level pos. – 23%low level pos. – 48%
negative – 78%
UzunelBlood 2001
30 ALLprior to
conditioningIg / TCR
PCR
high level pos. – 47%low level pos. – 50%
negative – 100%
SramkovaPed Blood
Cancer 200725 ALL
prior to conditioning
Ig / TCRPCR
positive – 0%negative – 94%
Prospective Study: MRD Prior SCT ALL REZ BFM Group: CR2
EFS CI
Years after SCT
MRD < 10-4
MRD ≥ 10-4
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Eve
nt-f
ree
Su
rviv
alP
rob
ab
ility
Years after SCT
MRD < 10-4
MRD ≥ 10-4
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Eve
nt-f
ree
Su
rviv
alP
rob
ab
ility
Years after SCT
MRD < 10-4
MRD ≥ 10-4
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Cum
ula
tive
Inci
de
nce
Years after SCT
MRD < 10-4
MRD ≥ 10-4
0 1 2 3 4 5 6
0.0
0.2
0.4
0.6
0.8
1.0
Cum
ula
tive
Inci
de
nce
EFS CIR
MRD < 10-4: n = 46; cens.= 29; pEFS = .60 .08 CI (relapse) = .13 .06≥ 10-4: n = 45; cens.= 14; pEFS = .27 .07 CI (relapse) = .57 .08
p = .0004 p < .001
Bader et al.: JCO 2009
Conclusions II
MRD prior to stem cell transplantation has a profound impact on post transplant outcome!
What adds MRD post transplant?
Retrospective Studies -MRD Post SCTLiterature
AuthorNumber
of patients
DiagnosisTime of
investigationMethods
Survival and MRD status
KnechtliBJH 1998
68 ALLup to 24 months
post SCTIg / TCR
PCRrelapse – 88% pos.
remission – 22% pos.
UzuelBJH 2003
23 ALL 24 monthsIg / TCR
PCRMRD pos. associated with
relapse
SanchezBJH 2002
40 ALLd30, 60, 90,every 2-3 months
Flow cytometry
positive – 33%negative – 74%
Prospective StudyBFM Group
N 92
Diagnosis ALL
Remission ≥ CR2
Transplant Period Jan 1999 May 2006
Evaluation January 15th 2009
Follow up Median Min Max
[Years] 5.13 3.44 6.48
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
MRD in adults with ALL Shown to be useful predictor of DFS in
many studies (non-transplant) Independent prognostic feature Mostly using PCR techniques – IgH/TCR, fusion
genes “Informative” assay available in 60-90% of patients
Early CR time-points predictive of outcome: from 4-22 weeks following initiation of treatment
Fewer studies evaluating role of MRD in setting of alloSCT
PB-04/06tk05.06
AlloSCT improves outcome of MRDpos in CR1 but much room for improvement
0.0
00
.25
0.5
00
.75
1.0
0C
um
ula
tive S
urv
iva
l
0 12 24 36 48 60 72 84Months
Kaplan-Meier survival estimates, by allo_iper2
SCT or H/C (n = 36)
rest )n = 18(
SCT or H/C-auto SCT or H/C-auto vv chemo chemo
Bassan, R. et al. Blood 2009;113:4153-4162
PB-04/06tk05.06
MRD following alloSCT in Adults with ALL
AuthorNumber
of patients
Diagnosis Time of investigation
Methods DFS and MRD status
MortuzaJCO 2002
19ALL
(B-lineage)From 1-20
mos.
Ig / TCRPCR
Semi-quant.
positive – 0%negative – 100% CCR
SpinelliHaematologica
200737 ALL Day +100
Ig/TCR or fusion gene
PCRQuantitativ
e
positive >10-4: 20%negative: 93%
Bassan*Blood 2009
18
ALL*All were
PCR+ prior to
transplant
Not definedIg / TCR
PCRpositive >10-4: 0negative: 50%
PB-04/06tk05.06
Dombret et al: Blood 100:2002
MRD status prior to transplant predicts DFS
Achievement of Molecular Remission Prior to AlloSCT is Important in Ph+ ALL
PB-04/06tk05.06
Combination of ChemoRx + Imatinib
Produces Molecular Remissions Group N Age Time-point % PCR
negative
MDACC 20 <75 After consolidatio
n
60
Korea 20 <67 After 1st consolidatio
n
70
JALSG 77 <63 Day 63 50
GMALL 92 <65 After 2 inductions
52
GRALL 45 <60 After 2 inductions
29 “neg”
64 “low”
PB-04/06tk05.06
Yanada, M. et al. J Clin Oncol; 24:460-466 2006
Is Transplant in CR1 Still Treatment of Choice for Ph+ ALL?
Transplanted patients
No transplant
PB-04/06tk05.06
Wassmann, B. et al. Blood 2005;106:458-463
Imatinib Treatment of Molecular Relapse with Following Allo-SCT for Ph+ ALL
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
Disease-Specific Methods and Strategies for Monitoring Relapse Following Allogeneic
Stem Cell Transplantation
Chronic Lymphocytic Leukemia
Sebastian Böttcher, Issa Khouri, Peter Dreger
Overview
• Techniques
• MRD kinetics
• Clinical significance of MRD
Techniques
ASO IGH qPCR and MRD flow in CLL- Comparative analysis in 530 samples -
10-5 10-4 10-3 10-2 10-1 100 101
10-5
10-4
10-3
10-2
10-1
100
+ < qr0
0
344
140 67
278
7
r = 0.95
ASO IGH qPCR
MR
D f
low
Böttcher, Leukemia, 2009
IgH-consensus PCR - Sensitivity -
Böttcher, Leukemia, 2004
polyclonal monoclonal10-4
10-3
10-2
10-1
100
Consensus primer IGH-PCR
MR
D f
low
le
ve
ln = 43 n = 106
IgH-consensus PCR - Sensitivity -
Böttcher, Leukemia, 2004
polyclonal monoclonal10-4
10-3
10-2
10-1
100
Consensus primer IGH-PCR
MR
D f
low
le
ve
ln = 43 n = 106
Techniques for MRD in CLL
ASO IGHqPCR
MRD flow Consensus IgH PCR
Sensitivity 10-5 10-4 10-2 – 5 x10-4
Quantitative range 10-4 10-4 n.a.
Quantitative reproducibility
high high poor
Standardization
van der Velden,
Leukemia, 2007
Rawstron, Leukemia,
2007poor
iwCLL guidelines accepted accepted Not mentioned
Turn-around time weeks hours days
MRD kinetics
MRD patterns after allogeneic SCT I
SCT↓
CSA red.↓
Ritgen, Leukemia, 2008
1 2 3 4 5 6 7
Landmark
1E-6
1E-5
1E-4
1E-3
1E-2
1E-1
1E+0
1E+1
MR
D l
ev
el
A
MRD patterns after allogeneic SCT II
Ritgen, Leukemia, 2008
1 2 3 4 5 6 7
Landmark
1E-6
1E-5
1E-4
1E-3
1E-2
1E-1
1E+0
1E+1
MR
D l
ev
el
B
SCT↓
CSA red.↓
MRD patterns after allogeneic SCT III
Ritgen, Leukemia, 2008
1 2 3 4 5 6 7
Landmark
1E-6
1E-5
1E-4
1E-3
1E-2
1E-1
1E+0
1E+1
MR
D l
ev
el
C
SCT↓
CSA red.↓
DLI↓
MRD patterns after allogeneic SCT
1 2 3 4 5 6 7
Landmark
1E-6
1E-5
1E-4
1E-3
1E-2
1E-1
1E+0
1E+1
MR
D l
ev
el
C
1 2 3 4 5 6 7
Landmark
1E-6
1E-5
1E-4
1E-3
1E-2
1E-1
1E+0
1E+1
MR
D l
ev
el
B
1 2 3 4 5 6 7
Landmark
1E-6
1E-5
1E-4
1E-3
1E-2
1E-1
1E+0
1E+1
MR
D l
ev
el
A
Prognostic significance
Prognostic significance MRD +12 months after alloSCT
Dreger, ms. in prep.
12 24 36 48 60 72 84 960
50
100
+12 MRD- (27)+12 MRD+ (11)
HR 0.047 (0.007-0.3); p 0.0011
Months from SCT
Perc
en
t re
lap
sed
MRD –ve (1/27)
MRD +ve (5/11)
Prognostic significance MRD +6 months after alloSCT
Farina, Haematologica, 2009
MRD –ve (1/16)
MRD +ve (8/13)
MRD kinetics after RIC alloSCT
Ritgen et al., 2008
Farina et al., 2009
Moreno
et al., 2006*
Caballero et al., 2005
n 28 29 20 21
MRD kinetics– neg / mixed
– pos79 %
21 %
55 %
45 %
70 %
30 %
94 %
6 %
Relapse by MRD– neg / mixed
– pos4 %
83 %
6 %
62 % n.d. n.d.
Evidence for delayed clearance
YES YES YES YES
* and Moreno personal communication 2009
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
Relapse Monitoring after Allogeneic Stem Cell Transplantation for Lymphomas
Issa Khouri, Julie Vose
Response Definitions in LymphomaResponse Definitions in Lymphoma
ResponseResponse DefinitionDefinition Nodal MassesNodal Masses Spleen, LiverSpleen, Liver Bone MarrowBone Marrow
SDSD Failure to attain CR/PR Failure to attain CR/PR
or PDor PD(a) FDG-avid or PET positive prior to (a) FDG-avid or PET positive prior to
therapy; PET positive at prior sites of therapy; PET positive at prior sites of
disease and no new sites on CT or disease and no new sites on CT or
PETPET
(b) Variably FDG-avid or PET (b) Variably FDG-avid or PET
negative; no change in size of negative; no change in size of
previous lesions on CTprevious lesions on CT
Relapsed Relapsed
disease or PDdisease or PDAny new lesion or Any new lesion or
increase by 50% of increase by 50% of
previously involved previously involved
sites from nadirsites from 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 SPD of any
previous lesionsprevious lesions
New or recurrent New or recurrent
involvementinvolvement
Abbreviations: CR, complete remission; FDG, [Abbreviations: CR, complete remission; FDG, [1818F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial
remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease.remission; SPD, sum of the product of the diameters; SD, stable disease; PD, progressive disease.
Cheson, JCO 2007
““False Positive” PET Scans in Therapy False Positive” PET Scans in Therapy of Lymphomasof Lymphomas
996 PET scans in 706 patients with lymphoma996 PET scans in 706 patients with lymphoma PET to evaluate recurrence after treatmentPET to evaluate recurrence after treatment 31/134 scans (23.1%) were False Positive31/134 scans (23.1%) were False Positive
7 brown fat7 brown fat 5 thymic hyperplasia5 thymic hyperplasia 4 muscle contraction4 muscle contraction 4 non-specific inflammation of the colon4 non-specific inflammation of the colon 4 pulmonary/mediastinal inflammation4 pulmonary/mediastinal inflammation 4 intestinal: gastritis (2), colitis (2)4 intestinal: gastritis (2), colitis (2) abscess, lactating breast, abscess, lactating breast, H. zosterH. zoster (1 ea) (1 ea)
Castellucci et al. Nuc Med Commun 26: 689-794, 2005.Castellucci et al. Nuc Med Commun 26: 689-794, 2005.
BM Involvement Present No BM Involvement, GCSF(+)BM Involvement Present No BM Involvement, GCSF(+)
Examples of Bone Marrow Findings on Examples of Bone Marrow Findings on PET in Two Patients with NHLPET in Two Patients with NHL
Message: The films look the same!Message: The films look the same!
0 20 40 60 80 100 120
Months Since Disease Progression
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Cu
mula
tive
Pro
po
rtio
n S
urv
ivin
g
Follicular, 54% (28-74)
T-Cell, 42% (15-66)
MCL, 31% (13-52)
DLCL/Other, 6% (12-17)
Survival in NHL Relapsing post AlloUsing CT Criteria
Khouri et al. unpublished data
Detection Early relapse in Lymphoma
Quantitative PCR
-IgH in b-cell disease
-t(11,14) in MCL and t(14,18) in FL
-t-cell receptor in t-cell lymphoma Chimerism
Chimerism at day 90 and Outcomepost NST
(6)1(6)1No. of relapse, (%)
(69)11(59)10Chronic GVHD, no. (%)
(100)16(100)17Achieved CR, no. (%)
38637129CR: PR at NST,%
1617No. of patients
P valueFull DonorMixed
Chimerism
0.06
0.5
Khouri, Blood 2008
Yes
1. Failure of disease response
2. Responding, but failing to achieve CR at 6 months
No
1. If stable mixed chimera (SMC) in the absence of measurable disease or disease progression
2. SMC definition:
- > 50% donor cells
- No significant decrease of >20% on two consecutive analysis
Donor Lymphocyte Infusion with Rituxan (for b-cell) after Allo
Nicolaus KrögerNicolaus Kröger
Disease specific Monitoring of Relapse after Disease specific Monitoring of Relapse after Allogeneic Hematopoietic Cell TransplantationAllogeneic Hematopoietic Cell Transplantation
Multiple MyelomaMultiple MyelomaNCI Workshop 1./2.-11.2009NCI Workshop 1./2.-11.2009
Conventional techniques for MonitoringConventional techniques for Monitoring
• Bone marrow aspiration: infiltration often Bone marrow aspiration: infiltration often underestimatedunderestimated
• Serum/24h urine electrophoresis (agarose gel or Serum/24h urine electrophoresis (agarose gel or capillary zone): lowest detectable level of M-capillary zone): lowest detectable level of M-component: 0.2 - 0.6 g/Lcomponent: 0.2 - 0.6 g/L
• Immunofixation (serum/urine): lowest detectable level Immunofixation (serum/urine): lowest detectable level of M-component: 0.12 - 0.25 g/Lof M-component: 0.12 - 0.25 g/L
• Free light chain assay (Free light chain assay (κκ//λλ ratio) : useful in light chain ratio) : useful in light chain disease and non-secretory, necessary to determine disease and non-secretory, necessary to determine sCR, early response assessment due to short half time sCR, early response assessment due to short half time (6h)(6h)
Imaging monitoring Imaging monitoring
• More than 80% of the pts develop osteolytic bone lesionsMore than 80% of the pts develop osteolytic bone lesions
• The hallmark of myeloma bone disease is an increased The hallmark of myeloma bone disease is an increased osteoclastic bone resorption and an exhausted osteoblast osteoclastic bone resorption and an exhausted osteoblast function resulting in a reduced bone formation even in patients in function resulting in a reduced bone formation even in patients in complete remissioncomplete remission
• Standard: conventional radiology as skeletal survey involving Standard: conventional radiology as skeletal survey involving cervical, thoracic and lumbar spine, skull, chest, pelvis, humeri cervical, thoracic and lumbar spine, skull, chest, pelvis, humeri and femoraand femora
• Disadvantage: low sensitivity, no exact response assessmentDisadvantage: low sensitivity, no exact response assessment
• CT: high sensitivity, but higher radiation doseCT: high sensitivity, but higher radiation dose
• MRI: high sensitivity, no radiation dose, detect extramedul-lary MRI: high sensitivity, no radiation dose, detect extramedul-lary diseasedisease
• PET-CT: highest sensitivity for extramedullary diseasePET-CT: highest sensitivity for extramedullary disease
Flow-cytometryFlow-cytometry
• Flow cytometry has become an easy applicable method Flow cytometry has become an easy applicable method to detect residual myeloma cells The European Myeloma to detect residual myeloma cells The European Myeloma Network recommends a minimal panel including Network recommends a minimal panel including
• CD19, CD56, CD20, CD117, CD28 and CD27.CD19, CD56, CD20, CD117, CD28 and CD27.
• Plasma cell gating should be based on CD38 vs. CD138 Plasma cell gating should be based on CD38 vs. CD138 expressionexpression
• This method is less sensitive (10This method is less sensitive (10-4-4) than allele-specific ) than allele-specific oligonucleotides PCR (ASO-PCR) oligonucleotides PCR (ASO-PCR)
Rawstron 2008Rawstron 2008
Allele-specific oligonucleotides PCRAllele-specific oligonucleotides PCR(ASO-PCR)(ASO-PCR)
• Patient-specific primers (IgH rearrangement)Patient-specific primers (IgH rearrangement)
• High sensitivity of (10High sensitivity of (10-5 -5 - 10- 10-6-6) and highly specific (100%) ) and highly specific (100%)
• Time-consuming (for each patients), does not detect Time-consuming (for each patients), does not detect extramedullary diseaseextramedullary disease
Rate of molecular remission basedRate of molecular remission basedon rearranged immunoglobulin heavyon rearranged immunoglobulin heavychain geneschain genes
In CR:In CR: after allograft:after allograft: 50% molecular CR50% molecular CRafter autograft:after autograft: 7% molecular CR7% molecular CR
In CR:In CR: after allograft:after allograft: 50% molecular CR50% molecular CRafter autograft:after autograft: 16% molecular CR16% molecular CR
Martinelli et al., JCO 2000Martinelli et al., JCO 2000
Corradini et al., JCO 1999Corradini et al., JCO 1999
No. of ptsNo. of pts 1616 1919 1313
5 year cumulativ5 year cumulativ
risk of relapserisk of relapse 0% 0% 33% 33% 100% 100%
Minimal residual disease after allogeneic stem cell Minimal residual disease after allogeneic stem cell transplantationtransplantation
Multiple Myeloma (EBMT-Studie): Pat with CRMultiple Myeloma (EBMT-Studie): Pat with CR
PCR negPCR neg PCR mixedPCR mixed PCR posPCR pos
Corradini et al., Blood 2003Corradini et al., Blood 2003
ChimerismsChimerisms
• Not specific for relapse, in majority of relapse donor Not specific for relapse, in majority of relapse donor cell chimerism persistedcell chimerism persisted
• Lineage specific chimerism (plasmacell-chimerism: Lineage specific chimerism (plasmacell-chimerism: CD138+ BM cells)CD138+ BM cells)
• By using real-time PCR the sensitivity of the method is By using real-time PCR the sensitivity of the method is 1010-4-4 to 10 to 10-5-5. The disadvantage of the methods is the . The disadvantage of the methods is the lack of specificity.lack of specificity.
Quantitative donor plasma-cell chimerism in Quantitative donor plasma-cell chimerism in patients with negative immunofixationpatients with negative immunofixation
Predictive value of donor-plasma-cell chimerism for Predictive value of donor-plasma-cell chimerism for relapse relapse
• 93% with stable or increasing donor-plasma-cell 93% with stable or increasing donor-plasma-cell chimerism remained immunofixation-negative.chimerism remained immunofixation-negative.
• 83% with a decrease of donor-plasma-cell chimerism 83% with a decrease of donor-plasma-cell chimerism was associated with relapse in the sense of becoming was associated with relapse in the sense of becoming immunofixation-positivity (in 2: 3 and 6 months prior immunofixation-positivity (in 2: 3 and 6 months prior than immunofixation becomes positive)than immunofixation becomes positive)
Kröger et al., 2006
CRCR
non CRnon CR
Depths of remission and survival post allograftingDepths of remission and survival post allografting
p=0.03
According EBMT criteriaAccording EBMT criteria
58%
According Flow cytometry According Flow cytometry
74%CR
Non-CR
p=0.001
According to molecular methodsAccording to molecular methods
81%
CR
p=0.001Kröger et al., 2009Kröger et al., 2009
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