High Prognostic Impact of Flow Cytometric Minimal Residual Disease Detection in Acute Myeloid Leukemia: Data From the HOVON/SAKK AML 42A Study

Abstract

A B S T R A C T PurposeHalf the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers. Patients and MethodsIn adults (younger than age 60 years) with AML enrolled onto the Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy). ResultsAfter all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (Ͼ 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment timedependent covariate risk score and early or later CR. ConclusionIn future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.

Leukemic stem cells: identification and clinical application

“…MRD frequency measurement has been shown to have independent prognostic impact across different cytogenetic and molecular subgroups [42][43][44][45], and is currently used to refine risk group classifications after induction therapy. In particular, MRD is implemented in the HOVON/SAKK H132 study to guide decisions for transplantation type in intermediate risk patients.…”

Minimal residual disease as biomarker for optimal biologic dosing of ARA‐C in patients with acute myeloid leukemia

“…One plausible explanation for conflicting evidence is that the efficacy of a given regimen, as reflected by survival estimates, may be influenced by the nature of post-consolidation strategies. In addition, evaluation of BM morphology, although still accepted as the standard index of therapeutic response, may fail to detect clinically relevant amounts of persistent leukemia [16][17][18][19]21]. In this regard, MRD assessment promises to be a valid alternative.…”

“…Once morphologic CR (m-CR) is achieved, MRD testing offers a novel and individualized means of gauging chemotherapeutic efficacy and risk of relapse, providing a very realistic and accurate representation of the quality of response. Indeed, prior reports indicate that low-level MRD (as detected at post-consolidation time points) is significantly associated with OS and RFS prolongations, and with low rates of relapse [16][17][18][19]. Hence, the primary objective of the present retrospective analysis was to compare the impact of SDAC and HDAC induction regimens on MRD, as a plausible biomarker for AC-OBD.…”

Ringsideroblaster

“…Målinger etter avsluttet behandling kan påvise et residiv tidligere enn med morfologisk undersøkelse og evt gi grunnlag for preemptiv behandling. Påvisning av MRD er nå undersøkt i flere prospektive studier, bla HOVON/SAKK AML 42A studien (HOVON 42A), og er vist å ha uavhengig prognostisk betydning (14). Ved AML, unntatt ved akutt promyelocyttleukemi, er MRD målinger foreløpig ikke etablert i Norge som rutinemetode med tanke på behandlingsmessige konsekvenser.…”