Page 107 - 2019_07 resto del Mondo-web

Plasmacytoid dendritic cells in AML
<10 and 6 had ratio >10). MRD-neg patients had a superi- or RFS and OS. MRD-pos patients with blast/PDC <10 had comparable or slightly inferior RFS and OS (Figure 5A and B). Although the number was small, the analysis sug- gested that MRD-pos patients with blast/PDC ratio >10 had significantly worse RFS and OS.
Discussion
Measurable residual disease is an independent prognos- tic indicator in AML that is important for risk stratification and for planning future treatment.1,2,4 However, the major obstacles in interpretation and standardization of the methodology of monitoring MRD by flow cytometry has meant that this has only gradually been applied to risk stratification in AML.4,26,28 LAIP-based DfN approaches are qualitative in principle, highly expertise-dependent, and subject to errors of interpretation.4 An objective, quantita- tive flow cytometry-based approach to identify MRD in AML has yet to be developed. Our study is the first attempt of its kind to establish such an objective and sim- ple approach. We demonstrate that PDC proportion can be reliably quantified and that a blast/PDC ratio >10 has very high specificity and moderate sensitivity for detect- ing MRD positivity. More importantly, blast/PDC ratio following induction chemotherapy has a strong predictive value for relapse, OS and RFS, comparable to DfN MFC- based identification of AML MRD in a uniformly treated AML cohort. Moreover, blast/PDC ratios at late time points, i.e. post consolidation and/or pre-transplant, can also help risk stratification of MRD-pos patients. While we investigated the most common therapy regimen, the study was confined to a single large academic institution. We attempted to evaluate another cohort of AML patients treated with hypomethylating agents, but these patients
rarely enter remission or experience PDC recovery, mak- ing evaluation impossible (data not shown). Nonetheless, the measurement of blast/PDC ratio shows promise for AML risk stratification. This method does not require identification of MRD through specific recognition of DfN myeloid blasts, but rather allows for the calculation of the ratio of total myeloid blasts to PDC. Owing to its objec- tive calculation and simple methodology, potentially, this approach can be widely applied in various laboratories with different levels of expertise. Our results should also encourage investigation into other objective and quantita- tive parameters in flow cytometry-based MRD evalua- tion, in a similar way to how the Ogata scoring system was developed for the diagnosis of myelodysplastic syn- drome.43-45 In this regard, the proportions of other popula- tions including immature progenitors warrant further investigation in AML.
Although our results are limited by small numbers, the suggestion of a higher MRD clearance rate in patients who were post-induction MRD-pos but had a blast/PDC ratio <10 is intriguing. The DfN approach-based MRD positiv- ity in all cases was confirmed by a second review arguing against diagnostic errors. Among post-induction MRD- pos patients with blast/PDC ratio <10 (vs. >10), a larger proportion was converted to MRD negativity and a lower incidence of relapse was observed. Several potential mechanisms may explain this finding. DfN-based MRD positive blasts in AML patients with blast/PDC ratio <10 may have lost leukemic potential, whereby damage to residual leukemic blasts led to delayed cell death. Additionally, leukemic blasts in marrows with a blast/PDC ratio <10 may have been cleared through ther- apeutic selection or differentiation with consolidation therapy. Restoration of PDC might suggest an inherent chemotherapy sensitivity and progression towards normal hematopoiesis in which remaining blasts are susceptible
AB
P<0.001 P<0.001
Figure 5. Kaplan-Meier survival analysis based on pre-hematopoietic stem cell transplantation (HSCT) measurable residual disease (MRD) status and blast/plas- macytoid dendritic cell ratio (PDC). (A) Overall survival (OS) of MRD-negative (neg), MRD-positive (pos) with blast/PDC ratio <10, and MRD-pos with ratio >10 groups. (B) Relapse-free survival (RFS) of MRD-neg, MRD-pos with blast/PDC ratio <10, and MRD-pos with ratio >10 groups.
haematologica | 2019; 104(7)
1385