High Frequency of ASXL1 and IDH Mutations in Young Acute Myeloid Leukemia Egyptian Patients.

BACKGROUND: Prognostication of AML patients depends on association of genetic and epigenetic abnormalities. We aimed to evaluate the frequency and prognostic significance of Additional Sex comb's Like1 (ASXL1), Isocitrate Dehydrogenase (IDH) and Casitas B- lineage Lymphoma (CBL) mutations in AML assessing their association with different cytogenetic risk category. METHODS: We used High Resolution Melting (HRM) technology that detects small differences in PCR amplified sequences by direct melting using EvaGreen saturating dye to analyze epigenetic mutations in 70 denovo AML patients. RESULTS: Median age of AML patients was 39.5 years (18-75). ASXL1, IDH and CBL mutations were detected in 14 (20%), 10 (14%) and 5 (7%) patients, respectively. Mean age of ASXL1 and IDH mutants vs. wild type was 35.9±14.6 years and 42.9±14.4 years (p=0.114) and 46.7±15.2 years vs. 40.6±14.5 years (p=0.290), respectively. AML cytogenetic risk groups included low (25/70, 36%), intermediate (33/70, 47%) and high-risk (12/70, 17%). Nine/14 (64%) ASXL1 and 8/10 (80%) IDH mutants were classified as intermediate risk and 9 ASXL1 positive (64%) were adolescent and young adults (AYA). Overall survival (OS) of mutant ASXL1 vs. wild type was 1.1 years (95% CI 0.83-1.4) vs. 1.9 years (95% CI 0.71-7.51), respectively (p=0.056). OS of mutant IDH vs. wild type was 1.25 years (95% CI 0.85-1.6) vs. 1.8 years (95% CI 1.2-6.7), respectively (p=0.020). In intermediate risk cytogenetic group, ASXL1 and IDH mutants had shorter OS than wild type; 1.1 years (95% CI 0.97-1.2) vs. 2.1 years (95% CI 0.14-10.8) (p=0.002) and 1.8 years (95% CI 0.69-3.15) vs. 2.3 years (95% CI 1.1-5.5) (p=0.05), respectively. CONCLUSION: ASXL1 and IDH mutations occur at a high incidence among young Egyptian AML patients with intermediate risk cytogenetics and confer a poorer outcome. Integration of mutations into risk profiling may predict outcome and impact therapeutic approach of young AML patient with uncertain prognosis.

Predictive Value of Pretreatment BCR-ABL(IS) Transcript level on Response to Imatinib Therapy in Egyptian Patients with Chronic Phase Chronic Myeloid Leukemia (CPCML).

BACKGROUND: A wide range of responses of patients with CPCML to IM has been reported. Several factors were proposed to predict response including molecular response at 3 and 6 months. PURPOSE: To study the impact of pretreatment BCR-ABL transcript level on molecular response to IM, and to assess the value of the milestone ; ≤10% transcript at 3 months on PFS and OS. PATIENTS AND METHODS: Fifty five adult CP-CML patients receiving daily dose of 400 mg IM were subjected to molecular and cytogenetic analysis at diagnosis and at regular time intervals. Median follow up period was 36 months (15-48). Hematologic, cytogenetic, and molecular responses were rated according to ELN. RESULTS: Two Patient groups were distinguished regarding response to IM therapy. A group of 22/55 patients (40%) having pretreatment BCR-ABL(IS) level ≤200% and a second patient group 33/55 (60%) having transcript level >200%. The ≤10% milestone was achieved by 15/22 patients (68%) versus 7/33 patients (21%), p=0.04 in favor of the first group. Optimal responders in first group were 14/22 (64%) compared to 13/33 (39%) in second group, p=0.02. Achievement of 10% transcript level significantly correlated with longer PFS. The median BCR-ABL(IS) transcripts levels in optimal responders at 3, 6 and 18 months was 10%, 2% and 0.1%, respectively compared to 100%, 65% and 10%, in suboptimal/resistant patients p=0.001. Resistance in 11 patients was correlated with identifiable ABL Kinase mutations. CONCLUSIONS: The Pretreatment 200% cutoff and the 3 month BCR-ABL(IS) ≤10% transcript levels proved strong predictors of response to IM and significantly correlated with probability of CCyR, MMR and PFS.