High WT1 expression is an early predictor for relapse in patients with acute promyelocytic leukemia in first remission with negative PML-RARa after anthracycline-based chemotherapy: a single-center cohort study

Abstract

Wilms’ tumor gene 1 (WT1) expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL) and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen) for WT1 monitoring. High WT1 expression (>120 copies/104 ABL1) after consolidation and at early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40) showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001) and inferior disease free survival (62.8 vs. 91.4%, P < 0.001). Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001) and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001) were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention.Trial registrationClinical Research Information Service (CRIS), KCT0002079Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0404-4) contains supplementary material, which is available to authorized users.

Immunotherapy in Myeloproliferative Diseases

“…Moreover, the expression increased during myelofibrotic transformation and high WT1 transcript levels could be linked to splenomegaly and thrombocytopenia and overexpression of WT1 was hypothesized to play an important role in the leukemic transformation of MPN [ 201 , 202 ]. Comparable with the results reported about WT1 expression in MPN, its expression is also higher in leukemia cells and LSCs compared to normal healthy hematopoietic cells and is a possible prognostic factor to predict clinical outcome and to detect MRD [ 203 , 204 , 205 , 206 ]. WT1 is a possible antigen to specifically target in leukemia patients as it was demonstrated that WT1-reactive cytotoxic T-cells mediate a strong anti-tumor immune response in post-transplant patients [ 207 ].…”

Antigen Targets for the Development of Immunotherapies in Leukemia

“…Expression of WT1 on normal hematopoietic progenitor cells was reported as at least 10 times less than in AML cells, confirming the overexpression of the WT1 gene in leukemic cells [114]. Quantification of WT1 gene expression can be used to predict the probability of relapse and to detect minimal residual disease in AML patients [115,116]. Interestingly, WT1 was ranked as the top immunotherapy target in cancer by a national cancer institute pilot project for the prioritization of cancer antigens [117].…”

Post-transplant immunotherapy with WT1-specific CTLs for high-risk acute myelogenous leukemia: a prospective clinical phase I/II trial

“…Wilms’ tumor antigen 1 ( WT1 ) is more abundant in leukemic cells than in normal hematopoietic cells. Quantitative assessment of WT1 gene transcript abundance by real-time quantitative PCR (RQ-PCR) has been shown to be useful for predicting clinical outcome and prognosis in acute myelogenous leukemia (AML), and for detecting minimal residual disease (MRD) [1–3]. In addition, the expansion of WT1 -specific CD8 + T cells was correlated with graft-versus-leukemia (GVL) effect in 10 subjects with acute lymphoblastic leukemia [4].…”