Acute myeloid leukemia—Major progress over four decades and glimpses into the future

Abstract

In this Review, the progress in research and therapy of acute myeloid leukemia is detailed. Am. J. Hematol. 91:131–145, 2016. © 2015 Wiley Periodicals, Inc.

Spontaneous Remission in an Older Patient with RelapsedFLT3ITD Mutant AML

“…In the subset of patients with FLT3 ITD, only age, white blood cell count, and 4-log reduction in peripheral blood MRD, but not FLT3 ITD allelic ratio, were significantly associated with a higher cumulative incidence of relapse. Indeed, MRD may eventually be incorporated into routine practice as an important determinant of therapy response, modification, and need for transplant, similar to our current usage of AML cytogenetics and mutation information [13, 26]. …”

“…The majority of these mutations involve internal tandem duplications (ITD) of the juxtamembrane domain-coding sequence of FLT3 , leading to constitutive activation of FLT3 receptors and triggering of multiple downstream signaling pathways (such as JAK/STAT, Raf/MEK/ERK, and PI3K/Akt), which promote tumor growth [10–12]. In general, the presence of FLT3 ITD mutation in AML connotes worse outcomes [13, 14]. Indeed, despite achieving complete remission following induction chemotherapy, the majority of patients with normal cytogenetics and FLT3 ITD mutant AML experience significantly shortened remission duration, lower salvage rate in first remission, and decreased overall survival [14–17].…”

“…Indeed, despite achieving complete remission following induction chemotherapy, the majority of patients with normal cytogenetics and FLT3 ITD mutant AML experience significantly shortened remission duration, lower salvage rate in first remission, and decreased overall survival [14–17]. While the advent of FLT3 inhibitors may change these outcomes for the better, the only current curative modality for FLT3 ITD mutant AML patients remains allogeneic stem cell transplantation [11, 13, 14]. …”

Preclinical pharmacokinetics and pharmacodynamics of DCLL9718A: An antibody-drug conjugate for the treatment of acute myeloid leukemia

“…1 Over the past few decades, increased knowledge around AML biology has led to the development of new targeted agents (e.g., mutated FLT3, IDH inhibitors). 2 However, these advances have been limited to subpopulations, with the majority of AML patients relying on modifications to doses and schedules of the standard of care cytarabine and anthracycline chemotherapy induction regimens (7 + 3) or improvements in hematopoietic stem cell transplantation methodologies. 3 AML has been a target for the therapeutic use of monoclonal antibodies or antibody-drug conjugates (ADCs), partly due the accessibility of the malignant cells and expression of well-defined cell surface antigens.…”

Future Prospects of Therapeutic Clinical Trials in Acute Myeloid Leukemia

“…Two isoforms of IDH exist [58], and both have been targeted for investigation as potential therapy for AML. Unlike conventional chemotherapy, these therapies do not induce rapid cell death and tumor clearance, but a more gradual response that persists over a longer period [59]. AG-221, an IDH2 inhibitor, demonstrated a 41% overall response rate and a 17% CR rate in adults with relapsed IDH2-mutated AML in a Phase II trial with 181 patients [60].…”