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Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

ABSTRACT: Acute myeloid leukemia (AML) is a malignancy of immature progenitor cells. AML differentiation therapies trigger leukemia maturation and can induce remission, but relapse is prevalent and its cellular origin is unclear. Here we describe high resolution analysis of differentiation therapy response and relapse in a mouse AML model. Triggering leukemia differentiation in this model invariably produces two phenotypically distinct mature myeloid lineages in vivo. Leukemia-derived neutrophils dominate the initial wave of leukemia differentiation but clear rapidly and do not contribute to residual disease. In contrast, a therapy-induced population of mature AML-derived eosinophil-like cells persists during remission, often in extramedullary organs. Using genetic approaches we show that restricting therapy-induced leukemia maturation to the short-lived neutrophil lineage markedly reduces relapse rates and can yield cure. These results indicate that relapse can originate from therapy-resistant mature AML cells, and suggest differentiation therapy combined with targeted eradication of mature leukemia-derived lineages may improve disease outcome. Differentiation therapy induces the maturation and clearance of acute myeloid leukemia cells. Here, using a mouse model, the authors show that a specific lineage of mature leukemia-derived cells persists during remission and is responsible for disease relapse.

SUBMITTER: Ngo S

PROVIDER: S-EPMC8586014 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We report here the largest study to date of adult patients with acute myeloid leukemia (AML) tested for measurable residual disease (MRD) at the time of autologous hematopoietic cell transplantation (auto-HCT). Seventy-two adult patients who underwent transplantation between 2004 and 2013 at a single academic medical center (University of California San Francisco) were eligible for this retrospective study based on availability of cryopreserved granulocyte colony-stimulating factor (GCSF)-mobilized autologous peripheral blood progenitor cell (PBPC) leukapheresis specimens ("autografts"). Autograft MRD was assessed by molecular methods (real-time quantitative PCR [RQ-PCR] for Wilms tumor 1 (WT1) alone or a multigene panel) and by multiparameter flow cytometry (MPFC). WT1 RQ-PCR testing of the autograft had low sensitivity for relapse prediction (14%) and a negative predictive value of 51%. MPFC failed to identify MRD in any of 34 autografts tested. Combinations of molecular MRD assays, however, improved prediction of post-auto-HCT relapse. In multivariate analysis of clinical variables, including age, gender, race, cytogenetic risk category, and CD34+ cell dose, only autograft multigene MRD as assessed by RQ-PCR was statistically significantly associated with relapse. One year after transplantation, only 28% patients with detectable autograft MRD were relapse free, compared with 67% in the MRD-negative cohort. Multigene MRD, while an improvement on other methods tested, was however suboptimal for relapse prediction in unselected patients, with specificity of 83% and sensitivity of 46%. In patients with known chromosomal abnormalities or mutations, however, better predictive value was observed with no relapses observed in MRD-negative patients in the first year after auto-HCT compared with 83% incidence of relapse in the MRD-positive patients (hazard ratio, 12.45; P?=?.0016). In summary, increased personalization of MRD monitoring by use of a multigene panel improved the ability to risk stratify patients for post-auto-HCT relapse. WT1 RQ-PCR and flow cytometric assessment for AML MRD in autograft samples had limited value for predicting relapse after auto-HCT. We demonstrate that cryopreserved autograft material presents unique challenges for AML MRD testing because of the masking effects of previous GCSF exposure on gene expression and flow cytometry signatures. In the absence of information regarding diagnostic characteristics, sources other than GCSF-stimulated PBSC leukapheresis specimens should be considered as alternatives for MRD testing in AML patients undergoing auto-HCT.

Project description:BACKGROUND:Optimal management of acute myeloid leukemia (AML) requires monitoring of treatment response, but minimal residual disease (MRD) may escape detection. We sought to identify distinctive features of AML cells for universal MRD monitoring. METHODS:We compared genome-wide gene expression of AML cells from 157 patients with that of normal myeloblasts. Markers encoded by aberrantly expressed genes, including some previously associated with leukemia stem cells, were studied by flow cytometry in 240 patients with AML and in nonleukemic myeloblasts from 63 bone marrow samples. RESULTS:Twenty-two (CD9, CD18, CD25, CD32, CD44, CD47, CD52, CD54, CD59, CD64, CD68, CD86, CD93, CD96, CD97, CD99, CD123, CD200, CD300a/c, CD366, CD371, and CX3CR1) markers were aberrantly expressed in AML. Leukemia-associated profiles defined by these markers extended to immature CD34+CD38- AML cells; expression remained stable during treatment. The markers yielded MRD measurements matching those of standard methods in 208 samples from 52 patients undergoing chemotherapy and revealed otherwise undetectable MRD. They allowed MRD monitoring in 129 consecutive patients, yielding prognostically significant results. Using a machine-learning algorithm to reduce high-dimensional data sets to 2-dimensional data, the markers allowed a clear visualization of MRD and could detect 1 leukemic cell among more than 100,000 normal cells. CONCLUSION:The markers uncovered in this study allow universal and sensitive monitoring of MRD in AML. In combination with contemporary analytical tools, the markers improve the discrimination between leukemic and normal cells, thus facilitating data interpretation and, hence, the reliability of MRD results. FUNDING:National Cancer Institute (CA60419 and CA21765); American Lebanese Syrian Associated Charities; National Medical Research Council of Singapore (1299/2011); Viva Foundation for Children with Cancer, Children's Cancer Foundation, Tote Board & Turf Club, and Lee Foundation of Singapore.

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Acute myeloid leukemia maturation lineage influences residual disease and relapse following differentiation therapy

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