Syed Khizer Hasan

Impact of FLT3 internal tandem duplications on Indian acute promyelocytic leukemia patients: prognostic implications.

Abstract Despite recent advances in the treatment of acute promyelocytic leukemia (APL), early mortality and relapses still occur. With the view to evaluate the role of FLT3 mutation in APL, 54 patients (median age 28 years, range 11–57 years, male to female ratio 1.2:1, median TLC 8.4 × 109/l, range 1–170 × 109/l) were studied by reverse transcriptase-PCR. Forty-two patients (77%) achieved first remission (CR1). Ten (18.5%) of the 54 patients had internal tandem duplication of exons 11 and 12 of the FLT3 gene. The median TLC count was significantly higher in FLT3 positive cases (Median TLC 55.0 × 109/l) as compared to FLT3 negative cases (Median TLC 6.8 × 109/l) (p = 0.001). Induction CR was much lower (40%) in FLT3/ITD positive cases as compared to 86% of FLT3/ITD negative cases (p = 0.005). Early deaths too were significantly associated with FLT3/ITD positive cases (50 vs. 16% p = 0.033). The difference in the occurrence of bcrl and bcr3 isoforms was not statistically significant between the two groups. The data suggest that the presence of FLT3/ITD in APL patients confers a poor prognosis.

Two Novel Methods for Rapid Detection and Quantification of DNMT3A R882 Mutations in Acute Myeloid Leukemia

DNMT3A mutations represent one of the most frequent gene alterations detectable in acute myeloid leukemia with normal karyotype. Although various recurrent somatic mutations of DNMT3A have been described, the most common mutation is located at amino acid R882 in the methyltransferase domain of the gene. DNMT3A mutations have been reported to be stable during disease progression and are associated with unfavorable outcome in acute myeloid leukemia patients with normal karyotype. Because of their prognostic significance and high stability during disease evolution, DNMT3A mutations might represent highly informative biomarkers for minimal residual disease monitoring. We describe a new rapid diagnostic RT-PCR assay based on TauI restriction enzyme reaction to identify DNMT3A R882 mutations at diagnosis. In addition, we developed a sensitive and specific test based on peptide nucleic acid real-time PCR technology to monitor DNMT3A R882H mutation. We identified 24 DNMT3A R882H mutated patients out of 134 acute myeloid leukemia screened samples and we analyzed in these patients the kinetics of minimal residual disease after induction and consolidation therapy. This assay may be useful to better assess response to therapy in patients with acute myeloid leukemia bearing the DNMT3A R882H mutation.

Over-representation of bcr3 subtype of PML/RARα fusion gene in APL in indian patients

Thirty six patients with acute promyelocytic leukemia were studied by reverse transcriptase–polymerase chain reaction (RT-PCR) and real-time PCR. There was concordance between the results achieved by both the methods except in one case, which was negative by RT-PCR but positive by real-time PCR. The prevalence of bcr3 (short isoform) was found to be significantly higher than that of bcr1 (long isoform ) (64 vs. 36%, P=0.03). No correlation was found between age, sex, and white blood cell (WBC) count at diagnosis. Molecular remission was achieved in 66.6% of patients with bcr3 isoform. Median WBC count at presentation was found to be higher than that in the West.

Genomic analysis of therapy-related acute promyelocytic leukemias arising after malignant and non-malignant disorders

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