Current challenges in clinical development of “targeted therapies”: the case of acute myeloid leukemia

Abstract

A fundamental difficulty in testing “targeted therapies” in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including “organoids” and combinations of pharmacologic and genetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders.

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

“…However, OS may be an imperfect indicator of a new drug's efficacy because advances in rescue therapies and supportive care have made it possible to keep patients alive after AML has relapsed or failed to enter CR. 262,272 In contrast, EFS includes relapse and failure to enter CR as well as death and thus may better reflect a single treatment's efficacy. [272][273][274][275] Furthermore, less time is required to assess EFS, and use of EFS facilitates crossover designs, that is, patients are randomly assigned to a sequence of treatments.…”

“…Enrollment might include patients with AML and other tumor types provided their cells contain the aberration. 262,263 MTD vs "optimal biologic dose." When a drug's ability to modulate its target appears fundamental to its clinical activity, phase 1 studies might seek to identify the optimal biologic dose (OBD) rather than the MTD.…”

Acute myeloid leukemia: 2016 Update on risk‐stratification and management

“…Although the CR rate was 18%, perhaps similar to what have been seen with more intense therapy, 55% of patients had an increase in absolute neutrophil count of > 1,000 with the increases lasting about 6 months and associated with fewer infections. Of note ANC increases were as common in patients achieving PR as in those achieving CR by conventional criteria with ANC increases seen in 43/52 responders (CR, CRi, marrow CR, PR) vs. 23/57 nonresponders (e.g., stable or progressive disease) Although they will be of undoubted future value in therapy of AML several issues have arisen regarding targeted therapies [89]. For example, since AML cells contain at least several aberrations is it realistic to expect a drug aimed at a single target to be effective?…”

Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia

“…There are several challenges that may hamper the clinical introduction of novel targeted therapies in general. 137 Some of…”