Search

BACKGROUND The prognostic significance of internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 gene (FLT3) for patients with myelodysplastic syndrome (MDS) is not clearly defined. In the current study, the authors sought to assess the value of FLT3/ITD mutation status as a prognostic genetic marker for patients with MDS. METHODS FLT3/ITD mutation status was evaluated by performing DNA polymerase chain reaction assays on 198 bone marrow samples obtained from patients with MDS at initial diagnosis. All aberrant products were sequenced, and GeneScan analysis was performed to measure FLT3/ITD mutant levels. RESULTS Five patients (2.5%)—2 of the 99 patients who had refractory anemia with excess blasts and 3 of the 51 patients who had chronic myelomonocytic leukemia—had FLT3/ITD mutations. FLT3/ITD was not observed in any of the 48 patients who had refractory anemia (with or without ringed sideroblasts). There was no significant difference in clinicohematologic characteristics, cytogenetic characteristics, or International Prognostic Scoring System score between the FLT3/ITD-positive group and the FLT3/ITD-negative group. Four of the 5 patients carrying the FLT3/ITD mutation experienced progression of disease to acute myeloid leukemia (AML), compared with 70 of the 193 patients who did not have FLT3/ITD (P = 0.066). In addition, progression to AML was more rapid in patients with FLT3/ITD-positive disease than in patients with FLT3/ITD-negative disease (mean ± standard error, 3.0 ± 0.5 months vs. 62.8 ± 5.6 months; P < 0.0001). Patients with FLT3/ITD-positive disease also had significantly shorter survival compared with patients who had FLT3/ITD-negative disease (mean ± standard error, 5.2 ± 1.4 months vs. 33.7 ± 3.1 months; P < 0.0001). On multivariate analysis, FLT3/ITD was identified as an independent predictor of reduced time to development of AML (P = 0.0001) and reduced overall survival (P = 0.002). CONCLUSIONS The results of the current study demonstrate that FLT3/ITD is associated with a high risk of transformation to AML, rapid progression of AML, and poor survival in patients with MDS. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND The clinical relevance of mutations of the FMS-like tyrosine kinase 3 (FLT3) gene in specific cytogenetic subgroups is not clear. The authors examined internal tandem duplication (ITD) and Asp835 mutations of FLT3 in patients with acute promyelocytic leukemia (APL) to determine the incidence of these mutations and to analyze the results for correlations with clinicohematologic features and outcome. METHODS Bone marrow samples from 107 patients with APL were analyzed. Isoforms of PML-RARα were identified using a reverse transcription–polymerase chain reaction assay. A standard polymerase chain reaction (PCR) assay was used to detect FLT3/ITD mutations. Asp835 mutations were analyzed by PCR amplification of exon 20 followed by EcoRV digestion. All aberrant PCR products subsequently were sequenced. RESULTS Twenty-two patients had FLT3/ITD mutations: 9 of 63 patients with L-type PML/RARα, 13 of 34 patients with S-type PML/RARα, and 0 of 10 patients with V-type PML/RARα (P = 0.005). The incidence of FLT3/ITD mutations was significantly higher in patients with S-type PML/RARα than in patients with L-type PML/RARα or V-type PML/RARα. Twenty patients had Asp835 mutations (L-type PML/RARα: n = 11; S-type PML/RARα: n = 8; V-type PML/RARα: n = 1). The frequency of Asp835 mutations was not significantly different among patients with different PML/RARα isoforms (P = 0.582). Three patients had both ITD and Asp835 mutations. The microgranular variant (M3v) form of leukemia was found to be associated with a higher frequency of ITD (P = 0.002) but not with a higher frequency of Asp835 mutations (P = 1.000); analysis of clinicohematologic variables revealed no significant differences in FLT3 mutation incidence among other patient subgroups. There was no significant difference in complete remission rate, overall survival, or event-free survival between patients with ITDs and those without ITDs or between patients with Asp835 mutations and those without Asp835 mutations. CONCLUSIONS The current study found that ITD or Asp835 mutations of the FLT3 gene were present in 36.4% of patients with APL; however, these mutations had no prognostic impact. FLT3/ITD frequently was associated with S-type PML/RARα and with the M3v form of leukemia. Cancer 2003;98:1206–16. © 2003 American Cancer Society. DOI 10.1002/cncr.11636

The clinical relevance of mutations of the FMS-like tyrosine kinase 3 (FLT3) gene in specific cytogenetic subgroups is not clear. The authors examined internal tandem duplication (ITD) and Asp835 mutations of FLT3 in patients with acute promyelocytic leukemia (APL) to determine the incidence of these mutations and to analyze the results for correlations with clinicohematologic features and outcome.Bone marrow samples from 107 patients with APL were analyzed. Isoforms of PML-RAR alpha were identified using a reverse transcription-polymerase chain reaction assay. A standard polymerase chain reaction (PCR) assay was used to detect FLT3/ITD mutations. Asp835 mutations were analyzed by PCR amplification of exon 20 followed by EcoRV digestion. All aberrant PCR products subsequently were sequenced.Twenty-two patients had FLT3/ITD mutations: 9 of 63 patients with L-type PML/RAR alpha, 13 of 34 patients with S-type PML/RAR alpha, and 0 of 10 patients with V-type PML/RAR alpha (P = 0.005). The incidence of FLT3/ITD mutations was significantly higher in patients with S-type PML/RAR alpha than in patients with L-type PML/RAR alpha or V-type PML/RAR alpha. Twenty patients had Asp835 mutations (L-type PML/RAR alpha: n = 11; S-type PML/RAR alpha: n = 8; V-type PML/RAR alpha: n = 1). The frequency of Asp835 mutations was not significantly different among patients with different PML/RAR alpha isoforms (P = 0.582). Three patients had both ITD and Asp835 mutations. The microgranular variant (M3v) form of leukemia was found to be associated with a higher frequency of ITD (P = 0.002) but not with a higher frequency of Asp835 mutations (P = 1.000); analysis of clinicohematologic variables revealed no significant differences in FLT3 mutation incidence among other patient subgroups. There was no significant difference in complete remission rate, overall survival, or event-free survival between patients with ITDs and those without ITDs or between patients with Asp835 mutations and those without Asp835 mutations.The current study found that ITD or Asp835 mutations of the FLT3 gene were present in 36.4% of patients with APL; however, these mutations had no prognostic impact. FLT3/ITD frequently was associated with S-type PML/RAR alpha and with the M3v form of leukemia.

Human T-lymphotropic virus-I (HTLV-I) proviral DNA was demonstrated in the leukemic cells of two newly identified cases of adult T-cell leukemia/lymphoma (ATL) in Taiwan by the Southern blot hybridization method. Therefore, the ATL cases diagnosed clinicopathologically in Taiwan were, for the first time, documented to be definitely related to HTLV-I.