Flt3 Internal Tandem Duplication and D835 Mutations in Patients With Acute Lymphoblastic Leukemia and Its Clinical Significance

Elyamany, Ghaleb; Awad, Mohammed; Alsuhaibani, Omar; Fadalla, Kamal; Sharif, Omer Al; Shahrani, Mohammad Al; Alabbas, Fahad; Al-Abulaaly, Abdulaziz

doi:10.4084/mjhid.2014.038

Cited by 12 publications

(11 citation statements)

References 44 publications

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“…Earlier studies suggest that mutation in FLT3 tyrosine kinase domain (TKD) may affect the FLT3i response (16,18,46). The co-occurrence of FLT3-ITD and TKD mutations was rare in our FLT3-ITD-positive cohort (10.3%), as expected (20,47,48), and was not enriched in any of the FLT3-ITD classes. Together, these analyses suggest that co-occurring point mutations are not differentially associated with typical or atypical FLT3-ITD cases.…”

Section: Resultssupporting

confidence: 63%

Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors

Schwartz

Manning

Zhou

et al. 2019

Clinical Cancer Research

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Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk -ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of-ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of -ITD mutations, we investigated the effects of-ITD structural features on the response of AML patients to treatment. We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in -ITD-positive AML patients. HeatITup accurately identifies and classifies ITDs into newly defined categories of "typical" or "atypical" based on their nucleotide composition. A typical ITD's insert sequence completely matches the wild-type , whereas an atypical ITD's insert contains nucleotides exogenous to the wild-type Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypicalITDs. These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing toward personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software.

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Section: Resultssupporting

confidence: 63%

Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors

Schwartz

Manning

Zhou

et al. 2019

Clinical Cancer Research

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“…These findings concur with previously published international and local reports. [36][37][38] This preliminary study, although limited sample size of our cohort, suggested that the incidence of FLT3 gene mutations most probably is low in Saudi pediatric patients with ALL. A further study with larger number of patient samples is necessary to confirm the findings and assessment of the prognostic value of FLT3 mutations among pediatric patients with ALL.…”

Section: Discussionmentioning

confidence: 96%

Cytogenetic Profile and FLT3 Gene Mutations of Childhood Acute Lymphoblastic Leukemia

Alkhayat

Elborai

Sharif

et al. 2017

Clin Med Insights Oncol

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Background:Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers.Aims:There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results.Materials and methods:Patients—We reviewed all cases from 2007 to 2016 with an established diagnosis of childhood ALL. Of the 110 patients, 98 were B-lineage ALL and 12 T-cell ALL. All the patients were treated by UKALL 2003 protocol and risk stratified according previously published criteria. Cytogenetic analysis—Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Analysis of FLT3 mutations—Bone marrow or blood samples were screened for FLT3 mutations (internal tandem duplications, and point mutations, D835) using polymerase chain reaction methods.Result:Cytogenetic analysis showed chromosomal anomalies in 68 out of 102 cases with an overall incidence 66.7%. The most frequent chromosomal anomalies in ALL were hyperdiploidy, t(9;22), t(12;21), and MLL gene rearrangements. Our data are in accordance with those published previously and showed that FLT3 mutations are not common in patients with ALL (4.7%) and have no prognostic relevance in pediatric patients with ALL. On the contrary, t(9;22), MLL gene rearrangements and hypodiploidy were signs of a bad prognosis in childhood ALL with high rate of relapse and shorter overall survival compared with the standard-risk group (P = .031).The event-free survival was also found to be worse (P = .040).Conclusions:Our data are in accordance with those published previously, confirming the overall frequency of cytogenetic abnormalities and their prognostic relevance.

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“…One Chinese study by Tong et al reported the mean age of 17.4 years at diagnosis (Tong et al, 2010). When compared with earlier study from Saudi Kingdom, findings are more or less similar with the median age of 31.5 years (Elyamany et al, 2014).…”

Section: Discussionmentioning

confidence: 55%

Acute Lymphoblastic Leukemia in Adults - an Analysis of 51 Cases from a Tertiary Care Center in Pakistan

Sultan

Irfan²,

Parveen³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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Background: Acute lymphoblastic leukemia (ALL) is a malignant disease in which early lymphoid precursors proliferate and replace the normal hematopoiesis. It has distinctive clinical and biological features. In respect to adult ALL, available data from Pakistan are limited. Therefore we reviewed the demographical and clinicohematological profiles along with FAB stratification of adult patients with ALL presented at our hospital. Materials and Methods: In this cross sectional study, 51 adults (≥15 years) patients with ALL were enrolled from January 2010 to December 2014. Results: The mean age was 23.8±12.9 years with the median age of 18.0 years. The male to female ratio was 2:1. The major complaints were fever (60.7%), generalized weakness (47.0%), overt bleeding (19.6%) and weight loss (13.7%). Physical examination revealed lymphodenopathy as a predominant finding detected in 43.1% followed by splenomegaly and hepatomegaly in 23.5% and 21.5%, respectively. The mean hemoglobin level was 9.0±2.75g/dl with a mean MCV of 82.2±15.4 fl, a mean total leukocyte count of 31.1±64.0x10 9 /l, a mean ANC of 2.1±3.0 x10 9 /l and a mean platelet count of 71.7±85.7x10 9 /l. According to FAB classification, 47.1% were L1 type, 45.1% L2 and 7.8% L3 variant. Conclusions: Clinico-pathological features appeared comparable to published data. Febrile illness associated with lymphodenopathy was the commonest presentation. FAB classification revealed a predominance of ALL-L1 variant in Pakistani adult patients with ALL.

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Flt3 Internal Tandem Duplication and D835 Mutations in Patients With Acute Lymphoblastic Leukemia and Its Clinical Significance

Cited by 12 publications

References 44 publications

Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors

Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors

Cytogenetic Profile and FLT3 Gene Mutations of Childhood Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia in Adults - an Analysis of 51 Cases from a Tertiary Care Center in Pakistan

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