WT1 Expression Levels Combined with Flow Cytometry Blast Counts for Risk Stratification of Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abstract

Wilm’s tumor 1 (WT1), a zinc-finger transcription factor and an epigenetic modifier, is frequently overexpressed in several hematologic disorders and solid tumors, and it has been proposed as diagnostic and prognostic marker of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the exact role of WT1 in leukemogenesis and disease progression remains unclear. In this real-world evidence retrospective study, we investigated prognostic role of WT1-mRNA expression levels in AML and MDS patients and correlations with complete blood counts, flow cytometry counts, and molecular features. A total of 71 patients (AML, n = 46; and MDS, n = 25) were included in this study, and WT1 levels were assessed at diagnosis, during treatment and follow-up. We showed that WT1 expression levels were inversely correlated with normal hemopoiesis in both AML and MDS, and positively associated with blast counts. Flow cytometry was more sensitive and specific in distinguishing normal myeloid cells from neoplastic counterpart even just using linear parameters and CD45 expression. Moreover, we showed that a simple integrated approach combining blast counts by flow cytometry, FLT3 mutational status, and WT1 expression levels might be a useful tool for a better prognostic definition in both AML and MDS patients.

Efficacy of Decitabine and Venetoclax as Salvage and Bridge Therapy to Haploidentical Hematopoietic Stem Cell Transplantation in a Multiresistant Acute Myeloid Leukemia Patient

“…The choice of drugs for adult AML treatment is based on the presence of specific molecular alterations, such as FLT3 mutations, and eligibility of patients for standard induction and consolidation chemotherapy followed by HSCT [ 1 , 2 ]; however, relapse or resistance to induction therapy is common and prognosis varies depending on patient's age, prior allogeneic HSCT, progression-free survival, mutational status, and cytogenetic abnormalities [ 11 ]. Indeed, 25–55% of AML patients relapse after allogeneic HSCT, and primary refractory or relapsed subjects after remission benefit of salvage therapy in 25–50% of cases, while only 11% are alive after 5 years with a substantial CR duration of 4.9–9.8 months and a reported overall survival of 6.2–8.7 months [ 12 ].…”

“…Acute Myeloid Leukemia (AML) is a heterogeneous group of clonal aggressive hematologic malignancies characterized by a block of differentiation and increased proliferation of myeloid neoplastic cells harboring various cytogenetic and/or molecular abnormalities [ 1 ]. The main criterion for AML diagnosis is the presence of at least 20% of leukemic cells with myeloid characteristics in the bone marrow (BM) or peripheral blood, except for AML with specific cytogenetic abnormalities or nucleophosmin 1 ( NPM1 ) mutated forms [ 1 ].…”

“…Acute Myeloid Leukemia (AML) is a heterogeneous group of clonal aggressive hematologic malignancies characterized by a block of differentiation and increased proliferation of myeloid neoplastic cells harboring various cytogenetic and/or molecular abnormalities [ 1 ]. The main criterion for AML diagnosis is the presence of at least 20% of leukemic cells with myeloid characteristics in the bone marrow (BM) or peripheral blood, except for AML with specific cytogenetic abnormalities or nucleophosmin 1 ( NPM1 ) mutated forms [ 1 ]. AML in the elderly (>60 years old) with recurrent genetic abnormalities is not frequent and has a worse prognosis compared to younger subjects, while more often secondary to myelodysplastic syndromes or therapy-related, accounting for 19% and 7% of cases, respectively [ 2 ].…”

“…Despite 40–90% patients achieving a complete remission (CR), persistent and durable response rates are low, especially in older subjects with 10% of long-term overall survival [ 3 , 4 ]. This high incidence of relapse or induction failure in older AML subjects is associated with patient-related factors, such as the presence of several comorbidities and a poor performance status, not allowing high-dose standard chemotherapy regimens and HSCT, and with disease-related features because AML in elderly frequently display adverse cytogenetics abnormalities, including complex karyotype [ 1 , 3 , 5 ]. When certain molecular alterations are present, such as somatic mutations in fms-like tyrosine kinase 3 ( FLT3 ) and isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) genes, specific targeted therapies can be used, such as sorafenib, midostaurin, and gilteritinib [ 6 ].…”

“…When certain molecular alterations are present, such as somatic mutations in fms-like tyrosine kinase 3 ( FLT3 ) and isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) genes, specific targeted therapies can be used, such as sorafenib, midostaurin, and gilteritinib [ 6 ]. Alternatively, hypomethylating agents, including azacytidine and decitabine (5-aza-2′-deoxycytidine), with or without BCL2 inhibitors -venetoclax- can be administered [ 1 , 2 ]. Hypomethylating agents, nucleoside derivatives, incorporate into DNA and inhibit the activities of DNA methyltransferases (DNMT), leading to transcriptional reinduction of silenced genes [ 6 ].…”