Abstract
The association of FLT3 mutations with white blood cell (WBC) counts at diagnosis and early death was studied in patients with acute promyelocytic leukemia (APL). Publications indexed in databases of biomedical literature were analyzed. Potential publication bias was evaluated by analyzing the standard error in funnel plots using the estimated relative risk (RR). Mixed-effect models were used to obtain the consolidated RR. All analyses were conducted using the R statistical software package. We used 24 publications in the final meta-analysis. Of 1005 males and 1376 females included in these 24 publications, 645 had FLT3-ITD (internal tandem duplication) mutations. Information on FLT3-D835 mutations was available in 10 publications for 175 patients. Concurrent occurrence of the two mutations was rare. WBC count at diagnosis was ≥10 × 109/L in 351 patients. For patients with the FLT3-ITD mutation, RR was 0.59 for overall survival (OS) and 1.62 for death during induction. For those with FLT3-D835 mutations, the RR was 0.50 for OS and 1.77 for death during induction. RR for WBC count ≥10 × 109/L was 3.29 and 1.48 for patients with FLT3-ITD and FLT3-D835, respectively. APL patients with FLT3-ITD or FLT3-D835 are more likely to present with elevated WBC counts and poorer prognosis than those without these mutations.
Highlights
Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML)characterized by coagulopathy and the accumulation of morphologically aberrant promyelocytes carrying one of the rearrangements involving the RARAα gene, which encodes the retinoic acid receptor alpha located at 17q21
We identified 832 articles after duplicates removal that were screened by titles and abstracts
Studies were included when assessing patients of any age or gender diagnosed with acute promyelocytic leukemia (APL), referred to as acute myeloid leukemia (AML) FAB M3; exposure reported as acquired mutations, secondary mutations, or somatic mutations (FLT3-internal tandem duplication (ITD) or FLT3-D835); and outcomes/events of interest reported as mortality, early death, survival, or prognosis
Summary
Characterized by coagulopathy and the accumulation of morphologically aberrant promyelocytes carrying one of the rearrangements involving the RARAα gene, which encodes the retinoic acid receptor alpha located at 17q21. The rearrangement of RARAα with the promyelocytic leukemia (PML) gene in the translocation t(15;17)(q22;q12) occurs in approximately 95% of APL patients [1]. RARAα fusion proteins are required for APL leukemogenesis, additional genetic aberrations such as mutations in FLT3, which encodes FMS-like tyrosine kinase 3, are frequently found in APL and Cancers 2019, 11, 1311; doi:10.3390/cancers11091311 www.mdpi.com/journal/cancers. The other FLT3 aberration is a point mutation in the region encoding the activation loop, usually in the codon for aspartic acid 835 (D835), which occurs in approximately 8% of APL patients. Worse outcomes have been reported for patients harboring either of these mutation types [6]
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