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W. Xiao et al.
to further reduction in residual disease from remaining therapy.1 Finally, restoration of PDC might also reflect the emergence of normal host mechanisms, such as immune surveillance controlling low-level MRD. Consistent with the latter possibility, we observed regenerating normal hematopoiesis in patients with MRD positivity but a blast/PDC ratio <10, which may play a critical role in clearing residual leukemic blasts. Regardless of the mech- anisms underlying this association, blast/PDC ratio <10 provides additional value in identifying this particular group of potentially lower-risk MRD positive patients at very early time points, which has not been possible with current MRD detection methods. Identifying this subset of patients may benefit critical clinical decision-making with regards to potential MRD-targeted therapy or allo- geneic HSCT. The relatively favorable outcome of this subset of patients (MRD-pos with ratio <10) might also explain the powerful predictive value of blast/PDC ratio on OS and RFS as compared to MRD status, despite the imperfect correlation between blast/PDC ratio and MRD status in this particular subset of patients.
The benefit of PDC recovery on outcome also extends to late time points. In fact, PDC recovery mitigates MRD positivity and predicts better outcome, suggesting that low-level MRD in the presence of normal hematopoiesis recovery portends a larger benefit of HSCT. On the other hand, based on a limited number of patients, our study suggests that lack of PDC recovery prior to HSCT is asso- ciated with extremely poor outcome. If validated by other studies, this would question the benefit of HSCT prior to PDC restoration in this particular subset of patients. Further studies are needed to investigate if these patients would benefit from additional therapies that facilitate PDC recovery.
Plasmacytoid dendritic cell differentiation is regulated by multiple transcription factors including GATA-2, IKAROS, IRF8, TCF4 and ID2.46-48 Although higher levels of peripheral blood PDC was suggested in patients with FLT3-ITD+ AML,33 we did not observe this correlation (data not shown). What mutations in AML regulate PDC differentiation is completely unknown. The decreased PDC differentiation in AML is likely related to overall maturation arrest observed in leukemic blasts. In MRD- pos patients with blast/PDC ratio <10, there were often
two distinct blast populations: one clearly abnormal and the other likely regenerating normal blasts. In this situa- tion, it is reasonable to speculate that the PDC are differ- entiated from normal blasts rather than leukemic blasts. The significance of blocked PDC differentiation has not been well studied in AML. A few studies suggest low-level reconstitution of PDC post-HSCT in AML is associated with higher relapse rate.49-51 It would be interesting to know the MRD status in those patients. As PDC are the major cell type producing type I interferon, the immune regulatory role of PDC in AML also warrants further investigation.
The caveats of this retrospective study include the prob- lems of a single-center study and the relatively small num- ber of patients, which might not have the power to iden- tify moderate but clinically significant differences in sur- vival outcomes. In spite of this, using the blast/PDC ratio, we provide the first objective and quantitative MFC method to risk stratify AML. Increased blast/PDC ratio correlates with residual leukemia, is highly specific for MRD positivity in post-induction patients, and strongly predicts poorer OS and higher likelihood of relapse. Normal PDC proportion predicts MRD clearance in post- induction MRD-pos patients, and is associated with restoration of normal hematopoiesis. Pre-HSCT blast/PDC ratio in combination with MRD status serves as a powerful predictor of post-HSCT outcomes. We pro- pose that using the blast/PDC ratio will facilitate standard- ization of MFC-based MRD approaches and corroborate MRD to risk stratify AML.
Acknowledgments
This study was funded by the Center for Hematologic Malignancies at MSKCC and in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. WX is supported by a startup fund from Department of Pathology at the Memorial Sloan Kettering Cancer Center. ADG is supported by a Young Investigator Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology and a Scholar Award from the American Society of Hematology (ASH). MBG is supported by the Lymphoma Research Foundation and a Scholar Award from ASH. A.D.V. is supported by a National Cancer Institute career development grant K08 CA215317 and an EvansMDS Young Investigator grant from the Edward P. Evans Foundation.
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