Acute Promyelocytic Leukemia (APL): Genetic Characterization of 78 Argentinian And Uruguayan Patients

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 23 de marzo del 2007

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English

Presenter: Uriarte, M.R.
Presenter's Affiliation: ASESP, Uruguay
Type of Session: Scientific

Background

  • Acute Promyelocytic Leukemia (APL) requires accurate and rapid diagnosis of PML-RAR transcript for implementation of specific therapy, prognostic assessment and molecular relapse of disease (MRD) monitoring.
  • There have been three isoforms of the 15;17 translocation (t(15;17)) identified: long (BCR1), short (BCR2), and variant (BCR3) which are associated with APL.
  • In addition to the t(15;17), mutations in the FLT3 gene, which encodes for a receptor tyrosine kinase, has been detected in 30% of APL patients and was association with aggressive disease.
  • The purpose of this study was the genetic characterization of Argentinean and Uruguayan patients and the prognostic value of Flt3 mutations in patients with APL.

Materials and Methods

Flow-cytometry, cytogenetic and nested-PCR studies were done at presentation to detect the various t(15;17) isoforms as well as the Flt3 mutation. Nested-PCR was used during follow-up. The end point used was risk of relapse.

Results

  • 74 of 78 pts were positive for t(15;17) with an isoform distribution of: BCR1 (59%); BCR2 (36%); and BCR3 (5%). Twelve pts died early and molecular relapse of disease (MRD) monitoring was performed in 54 pts. 93% of patients had a complete clinical response (CCR) and 7% had persistent MRD.
  • After consolidation 98% (53 patients) remained in molecular remission and 2% (1 patient) died during consolidation. Currently, 45 pts (84%) are alive with no evidence of MRD. The remaining 8 patients died of hematologic relapse preceded by conversion to positive t(15;17) on PCR.
  • FLT3 gene status was established in 42 APL patients at presentation. 28.6 % (twelve patients) showed FLT3 mutations: 19% (8) were ITD positive and 9.5% (4) showed D835 mutation. 10 of 12 FLT3 positive patients (83%) had the S-isoform and 2 pts (17%) had the L-isoform.

Author's Conclusions

  • There is not a significant difference in the distribution of t(15;17) isoforms between Latin American and Caucasian populations, contradicting previous studies which have suggested that there is a higher rate of BCR1 in Latin American companies.
  • The BCR2 isoform is the most frequently isoform in children.
  • FLT3 mutations were not seen as frequently as in previous series.
  • FLT3 mutations were associated with the BCR2 isoform (p<0.00032).
  • Conversion to positive t(15;17) on RT-PCR after consolidation predicted risk of relapse, demonstrating the prognostic value of RT-PCR. A larger number of patients are required to fully address the association of FLT3 mutation with poor clinical outcome.

Clinical/Scientific Implications

  • This study examined the distribution of the isoforms of t(15;17) in the Brazilian and Uruguayan population. FLT3 mutations rates were also examined. There was no appreciable difference in t(15;17) isoforms, suggesting that treatment and response in Brazilian and Uruguayan patients is likely not significantly different from their Caucasian counterparts. The BCR2 isoform was demonstrated to be more common in children and it was associated with FLT3. FLT3 has previously been shown to be associated with more aggressive disease, suggesting it is possible that APL may be more aggressive in children. However, as stated by the author, a larger study is needed to determine this. The isoforms present in patients with early relapse, as well as their FLT3 status would have been of interest to see if either of these could predict for early relapse. Further analysis of the various FLT3 isoforms and how they correlated with risk of relapse would further rstrengthen this study, though a larger N would likely be necessary.
  • RT-PCR detection of t(15;17) may be an effective means for the early detection of relapse in APL patients during consolidation, however the N was small in the current study and a larger study could further strengthen the author's conclusions.

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