Abstract
Relapse occurs frequently after treatment of acute myeloid leukemia (AML) patients with the FMS-like tyrosine kinase 3-internal tandem duplication (ITD) mutation. The availability of immunologic biomarkers to predict patients at high risk could allow clinicians to accelerate alternative treatments such as stem cell transplantation, immunotherapy, or novel drugs. We have previously reported that first diagnostic (FD) ITD+ AML showed immunophenotypic and functional characteristics of arrested dendritic cell (DC) precursors. In this study, we show that the high frequency of precursor DCs in 16 FD ITD+ AML samples (Lin−/HLA-DR+/CD11c+/CD123+) was associated with a lack of terminal DCs (myeloid DCs: BDCA-1+ or BDCA-3+; plasmacytoid DC: BDCA-2+). We further evaluated prospectively the peripheral blood complete remission (CR) samples obtained from 11 ITD+ AML patients after chemotherapy regarding the frequency of DCs and their pattern of cytokine production. Whereas the aberrant frequencies of precursor and terminal plasmacytoid DCs resolved during remission, the myeloid DC compartment did not fully recover. For an available cohort of patients (n = 4) who could be monitored over a period of >15 months after FD, we identified IL-10, TNF-α, IL-6, and IL-1β as cytokines produced by the CR samples at high levels a few months prior to relapse. Cell-free supernatant of an FD ITD+ AML sample stimulated monocytes obtained from two healthy donors to secrete IL-10, TNF-α, IL-6, and IL-1β. Thus, we hypothesize that ITD+ AML minimal residual disease can act directly as dysfunctional antigen-presenting cells or indirectly by production of factors that convert monocytes into myeloid-derived suppressor cells secreting cytokines that promote immune evasion. Monitoring these immunologic biomarkers could improve prediction of relapse.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-013-1744-y) contains supplementary material, which is available to authorized users.
Highlights
Acute myeloid leukemia (AML) is a very heterogeneous disease and risk stratification has recently been improved by detection of genetic mutations in samples collected at first diagnosis (FD) and complete remission (CR) [1]
We evaluated if cytokines (IL-10, TNF-α, IL-6, and IL-1β) proposed by several groups as indicators of a broad range of immunopathological conditions affecting cancer [15,16,17,18,19,20] could serve as potential biomarkers to predict internal tandem duplication (ITD)+ leukemia relapse
We provided experimental evidence that soluble factors produced by ITD+ AML stimulated monocytes from healthy donors to produce IL-10, TNF-α, IL-6, and IL-1β
Summary
Acute myeloid leukemia (AML) is a very heterogeneous disease and risk stratification has recently been improved by detection of genetic mutations in samples collected at first diagnosis (FD) and complete remission (CR) [1]. Ann Hematol (2013) 92:1079–1090 duplications (ITD) of the juxtamembrane or tyrosine kinase domain These mutations afflict approximately 30 % of the newly diagnosed AML cases corresponding to a group of patients at high risk [4, 5]. Older patients and patients without suitable donors are not eligible for allo-SCT and conventional chemotherapy is the standard of care. For these patients, novel therapies in clinical development such as immunotherapy or novel drugs are certainly warranted. Kinetic analyses of four ITD+ AML patients who entered CR but relapsed between 16 and 24 months after FD showed a consistent pattern of arrested terminal differentiation of myeloid DCs and upregulation of IL-10 (an anti-inflammatory cytokine), TNF-α, IL-6, and IL-1β (pro-inflammatory cytokines) months prior to leukemia relapse. We provided experimental evidence that soluble factors produced by ITD+ AML stimulated monocytes from healthy donors to produce IL-10, TNF-α, IL-6, and IL-1β
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