Utility of Immunophenotypic Measurable Residual Disease in Adult Acute Myeloid Leukemia—Real-World Context

Abstract

Introduction: One of the mainstays of chemotherapy in acute myeloid leukemia (AML) is induction with a goal to achieve morphological complete remission (CR). However, not all patients by this remission criterion achieve long-term remission and a subset relapse. This relapse is explained by the presence of measurable residual disease (MRD). Methods: We accrued 451 consecutive patients of adult AML (from March 2012 to December 2017) after informed consent. All patients received standard chemotherapy. MRD testing was done at post-induction and, if feasible, post-consolidation using 8- and later 10-color FCM. Analysis of MRD was done using a combination of difference from normal and leukemia-associated immunophenotype approaches. Conventional karyotyping and FISH were done as per standard recommendations, and patients were classified into favorable, intermediate, and poor cytogenetic risk groups. The presence of FLT3 -ITD, NPM1 , and CEBPA mutations was detected by a fragment length analysis-based assay. Results: As compared to Western data, our cohort of patients was younger with a median age of 35 years. There were 62 induction deaths in this cohort (13.7%), and 77 patients (17.1%) were not in morphological remission. The median follow-up was 26.0 months. Poor-risk cytogenetics and the presence of FLT3 -ITD were significantly associated with inferior outcome. The presence of post-induction MRD assessment was significantly associated with adverse outcome with respect to OS ( p = 0.01) as well as RFS ( p = 0.004). Among established genetic subgroups, detection of MRD in intermediate cytogenetic and NPM1 mutated groups was also highly predictive of inferior outcome. On multivariate analysis, immunophenotypic MRD at the end of induction and FLT3 -ITD emerged as independent prognostic factors predictive for outcome. Conclusion: This is the first data from a resource-constrained real-world setting demonstrating the utility of AML MRD as well as long-term outcome of AML. Our data is in agreement with other studies that determination of MRD is extremely important in predicting outcome. AML MRD is a very useful guide for guiding post-remission strategies in AML and should be incorporated into routine treatment algorithms.

Clinical impact of panel-based error-corrected next generation sequencing versus flow cytometry to detect measurable residual disease (MRD) in acute myeloid leukemia (AML)

“…The monitoring of a patient's response to chemotherapy, called, measurable residual disease (MRD) is one of the most important predictors of outcome in hematological malignancies. Several investigators have demonstrated the clinical utility of flow cytometry based MRD detection (FCM-MRD) in AML at early chemotherapy time points as well as in a pre-transplant setting [6][7][8][9][10][11][12][13][14]. Although universally applicable, FCM-MRD suffers from suboptimal ability to predict relapse in AML compared to precursor B lineage acute lymphoblastic leukemia.…”

Machine learning derived genomics driven prognostication for acute myeloid leukemia with RUNX1-RUNX1T1

“…These patients were accrued over a 7-year period from March 2012 to April 2019. Diagnosis, immunophenotyping and cytogenetic analysis were performed as previously described [3]. [14].…”

Clinical Impact of Panel Based Error Corrected Next Generation Sequencing versus Flow Cytometry to Detect Measurable Residual Disease (MRD) in Acute Myeloid Leukemia (AML)

“…FCM-MRD was detected using a previously described 10 colour two tube MRD assay. 9,20,35,38 This approach uses a combination of leukemia associated immunophenotype and difference from normal approaches to detect MRD in AML. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint…”

“…5 MRD) in AML at early chemotherapy time points as well as in a pre-transplant setting. [6][7][8][9][10][11][12][13][14] Although universally applicable, FCM-MRD suffers from suboptimal ability to predict relapse in AML compared to precursor B lineage acute lymphoblastic leukemia. A diverse array of sensitive molecular methods have been used to detect MRD in AML such as real time PCR 15 and droplet digital PCR.…”