Toward Individualized Therapy in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease in its clinical presentation, response to therapy, and overall prognosis. For decades, pretreatment karyotype evaluation has served to identify subgroups for risk-adapted postremission therapy, but the initial treatment approach has been largely unchanged. With continued advances in the genetic and epigenetic characterization of AML, we have discovered even more diversity and are starting to understand the biological underpinnings of these multiple disease entities. Newer therapies are being developed to address the pathophysiology within these individual AML subsets. This review categorizes AML into biologically defined groups based on currently available data and describes the evolving treatment approaches within these groups. Identifying the genetic abnormalities and biological drivers prior to AML treatment will be important as we work to individualize therapy and improve outcomes.

A Phase 1 Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute Myeloid Leukemia

“…The clinical outcome for acute myeloid leukemia (AML) in adults continues to improve but remains a challenge, particularly for older adults and for those with AMLs characterized by genetic complexity and/or evolution from an antecedent hematologic disorder (1). Multiple genetic, epigenetic, and microenvironmental factors contribute to resistant leukemia in these patients (1, 2).…”

“…Multiple genetic, epigenetic, and microenvironmental factors contribute to resistant leukemia in these patients (1, 2). Among the mechanisms contributing to drug resistance is the activation of various DNA-damage response (DDR) pathways (3).…”

Toward the potential cure of leukemias in the next decade

“…[133][134][135][136][137] Some AML experts state that the 3+7 regimen remains a standard of care and has not been improved upon in more than 4 decades. Subsequent randomized studies refined the regimen.…”

“…This is referred to as the 3+7 regimen and results in cure rates of 30% in unselected younger patients and of 10% to 15% in unselected older patients. [133][134][135][136][137] Some AML experts state that the 3+7 regimen remains a standard of care and has not been improved upon in more than 4 decades. However, this ignores that the regimen was improved by several adjustments: 1) adding high-dose cytarabine as consolidation therapy for 4 courses [138][139][140] ; 2) establishing daunorubicin 60 mg/m 2 (perhaps 90 mg/m 2 in the subset with FLT3-internal tandem duplication AML) as superior to 45 mg/m 2 , 141 as well as intravenous idarubicin 12 mg/m 2 daily × 3 as superior or equivalent to daunorubicin [142][143][144][145] ; 3) the benefit of GO in favorable-risk and intermediate-risk AML when given at a lower dose during induction and consolidation (eg, 3 mg/m 2 1 during induction and 1 consolidation) [146][147][148][149][150] ; 4) the development of epigenetic therapy with hypomethylating agents (azacitidine, decitabine) as an alternative and effective therapy for older patients with AML (age >70 years) and those not fit for intensive chemotherapy 151,152 ; and 5) the more recent development of targeted therapies for FLT3-mutated AML, isocitrate dehydrogenase 1 (IDH1)/IDH2-mutated AML, and against BCL2.…”

MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6

“…The identification of patients who might benefit from chemotherapy is important because the individualized selection of therapeutic agents could maximize the benefits and minimize the side-effects of ineffective therapies [25]. MiRNA expression analyses are effective tools for predicting therapeutic responses to clinical treatments, especially when used in conjunction with well-established gene expression array-based profiling technology.…”