Tag: Acute Myeloid Leukemia

Effect of NPM1 and FLT3 Mutations on the Outcomes of Elderly Patients With Acute Myeloid Leukemia Receiving Standard Chemotherapy

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SUMMARY: Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, cytogenetics stratify patients based on risk and helps manage them accordingly. Even though normal karyotype is the most common cytogenetic finding, approximately 10%-15% of AML patients have a monosomal karyotype (presence of at least 2 autosomal monosomies or a single autosomal monosomy in combination with at least one structural abnormality). These patients have a poor prognosis and alterations in the TP53 gene has been implicated in majority of these patients. AML patients with a normal karyotype should be tested for NPM1 (Nucleophosmin), FLT3 (Fms-related tyrosine kinase 3) and CEBPA (CCAAT/Enhancer Binding Protein Alpha) mutations, in addition to cytogenetics, as this may have therapeutic implications. CEBPA is a transcription factor and plays an important role in myeloid differentiation. Mutations in the CEBPA gene have been described in approximately 10% of patients with AML. Patients can have one or two mutations in this gene. It appears that favorable outcomes may be limited to those patients who have double CEBPA mutations rather than those with single CEBPA mutations. AML patients without FLT3 mutations or NPM1 mutation with CEBPA-double mutations have a favorable outcome. In this retrospective review, the authors analyzed the clinical impact of NPM1 and FLT3 mutations in AML patients, 65 years of age or older, treated with cytotoxic chemotherapy. A total of 557 patients were retrospectively reviewed. They noted that the outcomes were significantly better amongst patients with NPM1-mut/FLT3-wild type genotype compared to any other NPM1/FLT3 genotypes. The median survival was 21.5 months vs. 9.0 months and estimated 2-year survival rates were 51% vs. 38%, respectively (P = .003). The authors concluded that elderly AML patients with NPM1-mut/FLT3-wild type genotype have significantly improved outcomes when treated with cytotoxic chemotherapy. This subset of patients have a good prognosis with outcomes similar to those with favorable cytogenetics such as Inversion 16 and t(8:21). The discovery of molecular mutations is providing valuable information to facilitate risk-adapted therapy. Daver N, Liu Dumlao T, Ravandi F, et al. Clinical Lymphoma Myeloma and Leukemia 2013;13:435-440

 

Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation

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SUMMARY: FLT3-ITD (FMS-like tyrosine kinase 3 – Internal Tandem Duplications) mutations are seen in approximately a third of the patients with AML and are associated with early relapse and poor survival. Quizartinib is an oral tyrosine kinase inhibitor, which has demonstrated activity in patients with both wild type FLT3 as well as those with FLT3 mutations. In this phase II trial, 333 patients were enrolled and divided into 2 cohorts – patients older than 60 years and those between 18 and 60 years of age. The data presented here relates to cohort 2 (younger cohort) which included 137 patients with AML, who either relapsed or were refractory to second line chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT). Of these patients, 99 were FLT3 -ITD mutation positive and 38 were FLT3 wild type. The dose of Quizartinib was 90 mg/day for women and 135 mg/day for men and was given continuously in 28-day cycles. This dosing schedule was chosen because of the risk for QT interval prolongation, based on gender. The primary end point was a composite complete remission rate (CRc), which included complete remission, complete remission with incomplete platelet recovery (CRp) and complete remission with incomplete hematologic recovery (CRi). Patients with FLT3 mutations had a CRc of 44% with 4% CR and 40% CRi. The median duration of response was 11.3 weeks and the median overall survival was 23.1 weeks. This compared to a CRc of 34% for those with wild type FLT3. Thirty four percent (34%) of the patients were able to undergo HSCT following response to Quizartinib. The most common side effects included nausea, vomiting, QT prolongation, cytopenia, diarrhea and fatigue. The authors concluded that Quizartinib has significant activity in patients with resistant and refractory AML and can facilitate HCST in about a third of the treated patients. Levis MJ, Perl AE, Dombret H, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 673

Oncoprescribe Blog Prognosis in AML based on gene signature

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Outcomes in Acute Myeloid Leukemia (AML) is dependent on age, FLT3 mutations and cytogenetics, that is, until now. A study published in the JAMA this month concluded that high expression of Leukemic Stem Cell (LSC) gene expression signature was independently associated with lower remission rates following induction chemotherapy, as well as inferior relapse free, event free and overall survival in patients with normal as well as abnormal karyotypic findings and was also independent of age and FLT3 mutations.

The LSC score will soon become a very important component for risk stratification in patients with AML