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Sub-Committee on Disease-Specific Methods And Strategies For Monitoring Relapse Following Allogeneic Stem Cell Transplantation. Co-Chairs: Nicolaus Kröger, MD, Alan Wayne, MD. Eduardo Olavarria, MD Jerald Radich, MD Wendy Stock, MD Daniel Weisdorf, MD Andre Willasch, MD Julie Vose, MD.

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Sub-Committee on Disease-Specific Methods And Strategies For Monitoring Relapse Following Allogeneic Stem Cell Transplantation

Co-Chairs: Nicolaus Kröger, MD, Alan Wayne, MD

Eduardo Olavarria, MD

Jerald Radich, MD

Wendy Stock, MD

Daniel Weisdorf, MD

Andre Willasch, MD

Julie Vose, MD

Ulrike Bacher, MD

Peter Bader, MD

Sebastian Böttcher, MD

Michael Borowitz, MD, PhD

Peter Dreger, MD

Issa Khouri, MD

points to consider
  • 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 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.

Parameters for post-transplant molecular MRD monitoring in AML?

Reciprocal rearrangements:

MRD diagnostic with RQ-PCR well established

„favorable“ rearrangements >>

minor role for allo-SCT

Other suitable markers for the SCT setting?

Normal karyotype:

45% of all cases

Haferlach et al., Curr Opin Hemat, 2006

NPM1: 55%?

FLT-ITD: 35%?

Post-transplant MRD monitoring?

NRAS: 10%

FLT3-TKD: 55%

MLL-PTD: 10%

RUNX1: 10%


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 withNPM1 or FLT3mutations 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
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
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 sct all patients
MRD - Highest Level post SCTAll Patients


MRD < 10E-6

MRD < 10E-6

MRD <10E-4 - 10E-6

MRD <10E-4 - 10E-6

MRD ≥ 10E-4

MRD ≥ 10E-4

< 10-6: n = 46; cens.= 26; pEFS = .55  .08 n = 46; cens.= 37; pRFS = .77  .07

≥ 10-6- <10-4n = 25; cens.= 12; pEFS = .48  .10 n = 25; cens.= 17; pRFS = .62  .11

≥ 10-4: n = 21; cens.= 03; pEFS = .09  .06n = 21; cens.= 03; pRFS = .11  .07


conclusions iii and summary
Conclusions III andSummary
  • 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
  • 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
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
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 Definition

NCI Workshop 1./2.11.2009

Nicolaus Kröger

Dept. of Stem Cell Transplantation, University Hospital HamburgHamburg, Germany


Myelofibrosis Standard Definition

  • Progressive Disease: Requires one of the following:
  • Progressive splenomegaly that is defined by the appearance of a previous absent splenomegaly that is palpable at greater than 5 cm below the left costal margin or a minimum of 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a minimum of 50% increase in palpable distance for baseline splenomegaly of greater than 10 cm.
  • Leukemic transformation confirmed by bone marrow blast count of at least 20%
  • Increase in peripheral blood blast percentage of at least 20% that lasts for 8 weeks
  • Relapse: Changes from CR to PR or CR/PR to Clinical improvement

AML Standard Definition

(Cheson et al., 2003)


MDS Standard Definition

(Cheson et al., 2006)


CLL Standard Definition

  • Relapse: progression occurring 6 months or later after having achieved CR or PR
  • Progression: 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, hepatomegaly or other organ infiltrates;
  • • 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 multiple nodes;
  • • increase in the liver or spleen size by 50% or more or the de novo appearance of hepatomegaly or splenomegaly;
  • • 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).
  • • occurrence of cytopenia (neutropenia, anemia or thrombocytopenia) attributable to CLL.
  • Complete MRD response: clinical remission in the absence of one CLL cell per 10,000 leukocytes in the peripheral blood or bone marrow
  • MRD relapse: Tumor cell recurrence or increases at the MRD level that does not exceed 5 B cells/nL in the peripheral blood.

Lymphoma Standard Definition

(Cheson et al., 2007)


Multiple Myeloma Standard Definition

  • Relapse: EBMT criteria (Bladè et al) requires at least one of the following:
  • Reappearance of serum or urinary paraprotein on immunofixation or routine electrophoresis, confirmed by at least on further investigation and excluding oligoclonal immune reconstitution.
  • ≥ 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 in the size of residual bone lesions (development of a compression fracture does not exclude continued response and may not indicate progression).\
  • Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dl or 2.8 mmol/l) not attributable to any other cause.
  • IWG Criteria (Durie et al):Relapse from CR requires at least one of the following:
  • • Reappearance of serum or urinary M-protein by immunofixation or electrophoresis
  • • ≥ 5 % plasma cells in a bone marrow.
  • • Appearance of any other sign of progression (i.e new lytic bone lesions or soft tissue plasmacytomas or hypercalcemia).
Sub-Committee on Disease-Specific Methods And Strategies For Monitoring Relapse Following Allogeneic Stem Cell Transplantation

Panel Discussion

relapse and response definitions after sct
Relapse and Response Definitions After SCT

Standard diagnostic criteria used to define response and relapse

Well validated in upfront clinical trials

Utility after allogeneic SCT is limited for most hematologic malignancies

Sensitive disease-specific detection methods

Methodologic standardization and validation

Highly sensitive monitoring possible

Prognostic value in predicting continuous remission vs. relapse

Facilitate early intervention

Utility “pre-emptive” initiation of therapy prior to overt relapse

Proposed incorporation of sensitive detection methods to augment standard response/relapse definitions for use in allogeneic SCT trials

Response endpoints

Relapse prediction

Relapse prevention

Relapse treatment

discussion points
Discussion Points

Are the standard diagnostic criteria for relapse and response adequate for use after allogeneic SCT?

Proposed incorporation of sensitive detection methods to augment disease-specific definitions after allogeneic SCT

Methods included for specific diseases

Value of chimerism

Discordant results

Frequency of monitoring

Should achievement of molecular remission be the goal of allogeneic SCT?

When does molecular relapse or residual disease justify therapeutic intervention?

research priorities
Research Priorities

Harmonization and standardization of molecular monitoring and flow cytometry

Define the kinetics of molecular remission and molecular relapse after allogeneic SCT

Determine the predictive value of MRD and chimerism (incl lineage-specific) for clinical relapse

Apply and assess proposed definitions in studies designed to change the natural history of relapse after SCT

Apply and assess proposed definitions in trials of new treatments for prevention and treatment of relapse after SCT