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Randomized Controlled Trial
. 2020 Jan 28;4(2):301-311.
doi: 10.1182/bloodadvances.2019000406.

Early peripheral clearance of leukemia-associated immunophenotypes in AML: centralized analysis of a randomized trial

Giacomo Gianfaldoni  1 , Francesco Mannelli  1   2 , Tamara Intermesoli  3 , Sara Bencini  1   4 , Damiano Giupponi  3 , Giorgio Farina  5 , Ilaria Cutini  1   6 , Maria Ida Bonetti  1 , Arianna Masciulli  3 , Ernesta Audisio  7 , Dario Ferrero  8 , Chiara Pavoni  3 , Anna Maria Scattolin  9 , Alberto Bosi  1 , Alessandro Rambaldi  3 , Renato Bassan  9
Affiliations
Randomized Controlled Trial

Early peripheral clearance of leukemia-associated immunophenotypes in AML: centralized analysis of a randomized trial

Giacomo Gianfaldoni et al. Blood Adv. .

Abstract

Although genetics is a relevant risk factor in acute myeloid leukemia (AML), it can be minimally informative and/or not readily available for the early identification of patients at risk for treatment failure. In a randomized trial comparing standard vs high-dose induction (ClinicalTrials.gov #NCT00495287), we studied early peripheral blast cell clearance (PBC) as a rapid predictive assay of chemotherapy response to determine whether it correlates with the achievement of complete remission (CR), as well as postremission outcome, according to induction intensity. Individual leukemia-associated immunophenotypes (LAIPs) identified pretherapy by flow cytometry were validated and quantified centrally after 3 days of treatment, expressing PBC on a logarithmic scale as the ratio of absolute LAIP+ cells on day 1 and day 4. Of 178 patients, 151 (84.8%) were evaluable. Patients in CR exhibited significantly higher median PBC (2.3 log) compared with chemoresistant patients (1.0 log; P < .0001). PBC < 1.0 predicted the worst outcome (CR, 28%). With 1.5 log established as the most accurate cutoff predicting CR, 87.5% of patients with PBC >1.5 (PBChigh, n = 96) and 43.6% of patients with PBC ≤1.5 (PBClow, n = 55) achieved CR after single-course induction (P < .0001). CR and PBChigh rates were increased in patients randomized to the high-dose induction arm (P = .04) and correlated strongly with genetic/cytogenetic risk. In multivariate analysis, PBC retained significant predictive power for CR, relapse risk, and survival. Thus, PBC analysis can provide a very early prediction of outcome, correlates with treatment intensity and disease subset, and may support studies of customized AML therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Overall design of PBC study and correlation with response to induction. (A) Design of the study of PBC within NILG AML trial 02/06. The trial provided a randomization (R) between standard (ICE) and intensified (HDS) induction chemotherapy. Along treatment, on day 1 and day 4, cells bearing a previously identified aberrant immune-phenotype (LAIP) were quantified by multiparameter flow cytometry, and files were transmitted to the Coordinating Center for central analysis of data and PBC calculation. (B) Box plots show the distribution of PBC values according to response to first cycle. (C) ROC curve methodology allowed setting 1.5 logs as the best cutoff at separating patients with significantly different outcomes. For this threshold, the area under the curve (AUC) was 0.792. (D) Time to achievement of CR according to PBC category (<1.5 log or ≥1.5 log).
Figure 2.
Figure 2.
Distribution of PBC values according to ELN categories and response to first induction cycle. The rate of CR decreased from 91% to 46% in parallel with increasing disease risk according to ELN stratification (P < .0001).
Figure 3.
Figure 3.
Major outcomes according to PBC-related groups (<1.5 log or ≥1.5 log). (A) OS. (B) DFS. (C) EFS. (D) Cumulative incidence of relapse (CIR).
Figure 4.
Figure 4.
Major outcomes according to PBC-related groups (<1.5 log or ≥1.5 log) and treatment arm (ICE or HDS). (A) OS. (B) DFS. (C) EFS. (D) CIR.
See this image and copyright information in PMC

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