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B. Ball and E.M. Stein et al.
vated T cells. However, none of the targets showed a pro- file comparable with that of CD19 in B-cell malignancies.123 This suggests that combinatorial strategies may be neces- sary for targeting AML with CAR-T cells. An approach for combination includes bispecific T cells that co-express two CAR or a dual-specific CAR (CAR/CAR T cells) allowing T-cell recognition of target cells that express any of two given antigens.123 Alternatively, the combination of a CAR that alone is insufficient to activate a T cell and a chimeric co-stimulatory receptor (CAR/CCR T cells) restricts T-cell recognition to dual antigen-expressing target cells. The lat- ter approach requires pan-expression of CAR targets on AML cells, which was not seen by Perna and colleagues.117 Persistent CAR-T-cell mediated myelotoxicity may neces- sitate incorporation of CAR-T cells with conditioning reg- imens prior to allogeneic SCT. An alternative approach currently in development is the use of genetically modified donor allografts that lack expression of CAR-T-cell targets, such as CD33, followed by administration anti-CD33 CAR-T cells after transplantation.124
Conclusion
Advancements in flow cytometry, quantitative poly- merase chain reaction analysis and more recently next- generation sequencing continue to push the limits of detection of residual disease and open the door to thera- pies aimed at eradicating it. As MRD is a significant nega- tive prognostic factor for relapse and survival in AML fol- lowing allogeneic SCT, therapies capable of eliminating MRD are urgently needed to increase the number of patients cured of their disease. Here, we have reviewed the most promising MRD targets with therapeutic poten- tial based on efficacy in reducing MRD and potential for targeting leukemia repopulating cells mediating relapse. The targets discussed are by no means an exhaustive list and will continue to be refined as single-cell sequencing and xenograft studies better characterize leukemia popu- lations in MRD that mediate relapse. Ultimately, incorpo- ration of MRD into clinical practice will require pivotal tri- als that demonstrate an improvement in survival with MRD-directed approaches. Moving forward with MRD-
targeted therapies will require a standardized method for detecting MRD and rigorous assessment of the safety and efficacy of these therapies.
The European LeukemiaNet MRD working group has recently provided recommendations for assessment of MRD by multiparameter flow cytometry and molecular testing.2 These consensus recommendations aid the stan- dardization of MRD testing should be incorporated into all AML clinical trials. Additional issues that will need to be addressed include the optimal timing of MRD assess- ments. MRD after induction, second induction and con- solidation may have varying prognostic impact. Differences in time to initial response and the duration of response among MRD therapies may also affect the inter- val of MRD assessments. In particular, IDH inhibitors typ- ically take a longer time to produce an initial response and may warrant later MRD assessments at later timepoints than MRD therapies with a faster onset of effect.
The use of MRD as a surrogate endpoint for survival for clinical trials in AML has the potential to accelerate drug development. Although MRD has a significant impact on prognosis, the mortality associated with treating MRD also needs to be considered. The experience with CD33- targeted therapies demonstrates that toxicities associated with treatment may outweigh the potential benefit asso- ciated with eradicating MRD. In addition, MRD as a sur- rogate endpoint would not capture the impact of MRD therapies on transplant outcomes. For example, vadastux- imab and GO were associated with an increased risk of veno-occlusive disease after transplantation. T-cell-acti- vating therapies such as checkpoint inhibitors, dendritic cell vaccines and CAR-T cells have the potential to increase the risk of graft-versus-host disease after trans- plantation. Therefore, initial studies evaluating the safety of MRD-directed therapies should include post-transplant outcomes to identify late toxicities. The development of MRD-directed therapies may be facilitated in other ways. Similar to clinical trials in acute lymphoblastic leukemia and pediatric AML, current and future clinical trials in patients with AML who are fit for allogeneic SCT should include an intensification arm with MRD-directed thera- pies. This has the potential to increase the number of tri- als evaluating MRD therapies.
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