Driving Toward Precision Medicine for Acute Leukemias: Are We There Yet?

Abstract

Despite recent progress in the understanding of the molecular basis of acute leukemias, treatment options for these diseases have not changed significantly over the last few decades. We present a nonexhaustive summary of the current cytogenetic and molecular changes associated with acute leukemias in disease prognostication and potential targeted therapies. An emerging paradigm is that many genetic or molecular alterations target similar signal transduction, transcriptional, and epigenetic pathways. Some of these targets may be used as predictive biomarkers for the development of novel targeted therapies that depart significantly from conventional chemotherapy, the current mainstay for the treatment of acute leukemias. Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia. Evidence indicates that targeted therapy for FLT-ITD gene mutations with small-molecule tyrosine kinase inhibitors can extend its use from relapsed disease to up-front induction therapy. Core-binding factor acute myeloid leukemia in adults predicts benefit with high-dose cytarabine in the absence of KIT mutation. Although risk-adapted therapy based on genetic abnormalities in acute leukemias has allowed the beginning of personalized treatment and selective use of hematopoietic stem cell transplantation, the prognostic and/or predictive value of many novel mutations of the acute leukemic genome is yet to be elucidated. Many challenges lie ahead in targeted therapies due to overlapping of chromosomal and molecular lesions as well as other limiting factors. Future work should focus on the understanding of pathogenetic changes that lead to leukemogenesis, which may guide the rational design of new targeted therapies and make the drive toward precision medicine for acute leukemias one step closer.

The Evolution of Care for Acute Myeloid Leukemia and the Challenges of Defining Value

“…4 The cytogenetic profile (karyotype or chromosomal aberrations) serves as a prognostic indicator in AML by which patients are stratified into favorable, intermediate, and adverse risk groups (Table 1). 2,5 Chromosome alterations and complex karyotype (described as > 3 chromosomal abnormalities) are associated with poor response to therapy and reduced survival. The presence of other cytogenetic abnormalities, such as t (8;21) or inv (16) in core-binding factor AML indicate longer disease remission and survival.…”

“…7 Other disease characteristics of the patient (age, comorbidities, disease status, response to chemotherapy, donor availability for hematopoietic stem cell transplantation (HSCT), and patient/prescriber preference) are also considered when individualizing treatment options. 2 Two staging systems are commonly used for AML. The French-American-British (FAB) classification system 8 is based on morphology to define specific immunotypes.…”

“…Distinct subtypes within each lineage are further defined based on morphology, immunophenotyping, and molecular genetics. 2 New somatic/acquired gene mutations have refined the classification of myeloid neoplasms and have been in-…”

“…4 IDH1/2 gene mutations have been considered a potential predictive marker with hypomethylating agents such as decitabine and azacytidine. 2…”

“…Patients who have mutated NPM1 without the FLT3-ITD genotype have a comparatively better outcome than those with coexisting FLT3-ITD mutations and hence are no longer recommended for transplantation during their first complete remission. 2,4,5…”