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

Kantarjian, Hagop M.

doi:10.1002/ajh.24246

Cited by 105 publications

(98 citation statements)

References 152 publications

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“…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]. …”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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]. …”

Section: Introductionmentioning

confidence: 99%

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Spontaneous Remission in an Older Patient with RelapsedFLT3ITD Mutant AML

Vachhani

Mendler

Evans

et al. 2016

Case Reports in Hematology

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Spontaneous remission (SR) of acute myeloid leukemia (AML) is a very rare phenomenon. AML characterized by FLT3 internal tandem duplication (FLT3 ITD) is typically associated with an aggressive clinical course with rapid progression, relapse, and short overall survival in the absence of transplantation. We report here the first case of SR of FLT3 ITD mutant AML in the literature. Our patient was an elderly woman with relapsed NPM1 and FLT3 ITD mutant AML whose disease underwent SR for a brief duration without precipitating cause. We review the potential immune mechanisms underlying SR in AML and discuss the implications for novel immunotherapeutic approaches for FLT3 mutant AML.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Spontaneous Remission in an Older Patient with RelapsedFLT3ITD Mutant AML

Vachhani

Mendler

Evans

et al. 2016

Case Reports in Hematology

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Leipold¹,

Figueroa²,

Masih³

et al. 2018

mAbs

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Few treatment options are available for acute myeloid leukemia (AML) patients. DCLL9718A is an antibody-drug conjugate that targets C-type lectin-like molecule-1 (CLL-1). This receptor is prevalent on monocytes, neutrophils, and AML blast cells, and unlike CD33, is not expressed on hematopoietic stem cells, thus providing possible hematopoietic recovery. DCLL9718A comprises an anti-CLL-1 IgG1 antibody (MCLL0517A) linked to a pyrrolobenzodiazepine (PBD) dimer payload, via a cleavable disulfide-labile linker. Here, we characterize the in vitro and in vivo stability, the pharmacokinetics (PK) and pharmacodynamics (PD) of DCLL9718A and MCLL0517A in rodents and cynomolgus monkeys. Three key PK analytes were measured in these studies: total antibody, antibody-conjugated PBD dimer and unconjugated PBD dimer. In vitro, DCLL9718A, was stable with most (> 80%) of the PBD dimer payload remaining conjugated to the antibody over 96 hours. This was recapitulated in vivo with antibody-conjugated PBD dimer clearance estimates similar to DCLL9718A total antibody clearance. Both DCLL9718A and MCLL0517A showed linear PK in the non-binding rodent species, and non-linear PK in cynomolgus monkeys, a binding species. The PK data indicated minimal impact of conjugation on the disposition of DCLL9718A total antibody. Finally, in cynomolgus monkey, MCLL0517A showed target engagement at all doses tested (0.5 and 20 mg/kg) as measured by receptor occupancy, and DCLL9718A (at doses of 0.05, 0.1 and 0.2 mg/kg) showed strong PD activity as evidenced by notable reduction in monocytes and neutrophils.

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“…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].…”

Section: • Targeted Epigenetic Therapy: Bromodomain and Idh Inhibitorsmentioning

confidence: 99%

Future prospects of therapeutic clinical trials in acute myeloid leukemia

2017

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Acute myeloid leukemia (AML) is a markedly heterogeneous hematological malignancy that is most commonly seen in elderly adults. The response to current therapies to AML is quite variable, and very few new drugs have been recently approved for use in AML. This review aims to discuss the issues with current trial design for AML therapies, including trial end points, patient enrollment, cost of drug discovery and patient heterogeneity. We also discuss the future directions in AML therapeutics, including intensification of conventional therapy and new drug delivery mechanisms; targeted agents, including epigenetic therapies, cell cycle regulators, hypomethylating agents and chimeric antigen receptor T-cell therapy; and detail of the possible agents that may be incorporated into the treatment of AML in the future.

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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.

Cited by 105 publications

References 152 publications

Spontaneous Remission in an Older Patient with RelapsedFLT3ITD Mutant AML

Spontaneous Remission in an Older Patient with RelapsedFLT3ITD Mutant AML

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

Future prospects of therapeutic clinical trials in acute myeloid leukemia

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