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AML Hub Satellite Symposium highlights: How does MRD impact outcome of stem cell transplantation in AML – now and in the future?

Sep 22, 2020

At the 46 th Annual Meeting of the European Society for Blood and Marrow Transplantation, the AML Hub held a virtual Satellite Symposium on the impact of measurable residual disease (MRD) assessment on stem cell transplantation (SCT) outcome in patients with acute myeloid leukemia (AML).

The Satellite Symposium started with presentations focusing on the methodological aspects of MRD assessment. It began with Jaqueline Cloos providing an update on flow cytometry approaches, followed by Christian Thiede, who spoke about the latest advances in molecular MRD techniques. In the subsequent talks, the need for MRD assessment prior to SCT was evaluated by Adriano Venditti, while Charles Craddock highlighted the benefits of posttransplant MRD assessment for treatment decision making.

Methods to detect MRD

Multiparameter flow cytometry

After a brief overview of the techniques used to assess MRD in AML, Jacqueline Cloos focused on multiparameter flow cytometry (MFC)-based MRD measurements. MFC is one of the most commonly used assays for MRD detection, and there are two different approaches for MFC-based MRD assessment:

  • The leukemia-associated immunophenotype (LAIP) approach, which identifies a patient-specific LAIP at diagnosis that can be monitored in subsequent samples.
  • The different-from-normal (DfN) approach, based on the identification of aberrant antigen expression patterns at follow-up. The DfN approach can be useful if information from diagnosis is not available, and also to detect new aberrancies. Because information from diagnosis is not available, it is not possible to assess the efficacy of a novel drug with this approach.

Jacqueline Cloos reinforced the European LeukemiaNet (ELN) Working Party guidelines, which recommend combining both methods for MFC-based MRD assessmentin a “LAIP-based DfN approach.” In addition, these guidelines suggest a cutoff to define MRD-negativity of 0.1%, and the preferential use of bone marrow samples. 1Watch Jacqueline Cloos’s presentation in the video below.

Challenges in MRD measurement by multiparameter flow cytometry in AML

Molecular assessment

The second presentation, delivered by Christian Thiede, outlined the different techniques available for molecular MRD detection, such as quantitative polymerase chain reaction (qPCR), digital PCR, and next-generation sequencing (NGS). He encouraged the audience to follow the European LeukemiaNet (ELN) Working Party guidelines recommending the use of qPCR in patients with RUNX1-RUNX1T1, CBFB-MYH11, and NPM1 mut AML, while using FLT3-ITD, FLT3-TKD, NRAS, KRAS, DNMT3A, ASXL1, IDH1, IDH2, and MLL-PTDonly as secondary markers . 1 The molecular MRD assessment is recommended at diagnosis, after two cycles of treatment, and at the end of treatment both in peripheral blood and bone marrow samples. After the end of treatment, molecular MRD should be assessed every 3 months for 24 months. Monitoring beyond 2 years of follow-up should be based on the relapse risk of the patient. 1

According to Christian Thiede, NGS, with its broader coverage of mutations, can be applied to all leukemia-specific genetic aberrations. However, this method presents limitations, such as technical artefacts produced during the generation of the library, and interpretation of mutations that can appear after treatment although these are not predictor of relapse.

New approaches, such as the combination of NGS with CD34 sorting or single cell sequencing, could represent valid options for future molecular MRD assessment in AML. They will allow better understanding of clonal evolution under therapy and the detection of novel alterations earlier. Watch Christian Thiede’s talk in the video below.

New developments in molecular MRD assessment in AML

MRD assessment in the context of SCT

Importance of MRD assessment pre-SCT

The presence of MRD prior to SCT is a predictor of posttransplant outcomes in AML, with MRD-negative patients performing much better than those who are MRD positive. The determination of MRD prior SCT is of growing interest because it can guide therapeutic decisions.

Professor Adriano Venditti discussed the results of prospective clinical trials using an MRD-guided treatment approaches, with a special focus on the GIMEMA AML 1310trial ( NCT01452646). In this risk-adapted MRD-driven study, patients belonging to the intermediate risk category received autologous (auto-) or allogeneic (allo-)SCT based on the level of MRD as measured by MFC after first consolidation therapy. In patients who were MRD positive before transplant, the delivery of an allo-SCT improved overall survival and disease-free survival to levels comparable to those of patients who were MRD negative and received auto-SCT.

Adriano Venditti highlighted the benefits of allo-SCT in MRD-positive patients in the intermediate risk group. He also pointed out the importance of conditioning intensification in pre-SCT MRD-positive patients. In a recent study by Christopher Hourigan and colleagues, pre-SCT NGS MRD-positive patients receiving a myeloablative conditioningregimen showed a lower incidence of relapse compared with patients receiving a reduced-intensityregimen. 2

In his concluding remarks, he pointed out that MRD-positivity prior to allo-SCT is not a contraindication for delivering allo-HSCT. Watch Adriano Venditti’s presentation in the video below.

Does current evidence support the use of MRD-guided treatment before transplant in AML?

Importance of MRD assessment post-SCT

Relapse represents one of the major causes of transplant failure, and the presence of MRD after allo-SCT in patients with AML is associated with an increased risk of relapse and worse overall survival.

In his presentation, Charles Craddock outlined the strategies to reduce relapse risk post allo-SCT in patients with AML, such as maintenance or preemptive therapies.

He reported the results of a study by Chen-Hua Yan and colleagues, showing that intervention with donor lymphocyte infusion in patients who are MRD-positive after transplantation may improve outcomes. 3In addition, in the RELAZA2trial ( NCT01462578), the use of preemptive azacitidine prevented or delayed relapse in MRD-positive patients with AML or MDS after allo-SCT.

Then, he focused on the role of maintenance therapy in improving transplant outcome. Maintenance therapy might improve outcomes by:

  • Directly targeting leukemic stem progenitor population.
  • Delaying disease relapse, buying time for the graft- versus-leukemia effect.
  • Modulating the alloreactive immune response.

A randomized trial, AMADEUS ( NCT04173533), is evaluating the epigenetic modifier CC-486 as maintenance treatment in patients with AML or MDS who underwent allo-SCT. Watch Charles Craddock’s talk in the video below.

Why should we use MRD assessment post hematopoietic stem cell transplantation?

Conclusion

After an engaged round table discussion, the Chair Gert Ossenkoppele concluded the Satellite Symposium by focusing on the future use of MRD assessment in AML. The combination of different MRD techniques, such as NGS plus MFC, could be useful to detect different populations of leukemia-initiating cells and might represent a solution for decreasing the rate of false-negative MRD results. A large AML project started by HARMONY, a public-private partnership with the aim to harmonize outcome measures and endpoint definitions for hematological malignancies at a European level, will evaluate MRD as surrogate marker for survival in AML. In conclusion, MRD has become a prerequisite for treatment decisions in AML, but standardization and harmonization of MRD techniques is still required.

Watch the video of the round table discussion and Gert Ossenkoppele’s summary and conclusions, below.

AML Hub Satellite Symposium: Round table discussion and conclusions from the Chair

  1. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275-1291. DOI: 1182/blood-2017-09-801498
  2. Hourigan CS, Dillon LW, Gui G, et al. Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With Genomic Evidence of Residual Disease.  J Clin Oncol. 2020;38(12):1273-1283. DOI: 1200/JCO.19.03011
  3. Yan CH, Liu DH, Liu KY, et al. Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation.  Blood. 2012;119(14):3256-3262. DOI: 1182/blood-2011-09-380386