Archives

  • 2018-07
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • br Results Fifty seven patients were

    2019-04-29


    Results Fifty-seven patients were enrolled (Table 1). The median number of treatment cycles received was 2 (range 1–26) with similar medians for AML and MDS. The maximum number of cycles received for AML and MDS patients was 26 and 6, respectively, with differences between diseases driven by an increased response rate in AML patients.
    Discussion The lack of response in MDS patients compared with AML patients may point to important clues in alisertib clinical mechanism of action. Failure of hematopoeisis in MDS is principally driven by increased apoptosis in the malignant clone, in contrast to marrow suppression by a proliferative Selumetinib in AML. In-vitro studies have shown that reduction of intracellular AAK results in mitotic inhibition, senescence, and apoptosis in human cell lines [1]. Thus, alisertib may be unable to stimulate an apoptotic clone in MDS but may suppress a proliferative clone in AML. Transfusion independence was achieved in 13 patients and maintained for 2–5 cycles in 11 patients, suggesting that recovery of normal hematopoiesis can occur. Additional studies are needed to identify predictors of response and to understand how AAK inhibition may induce leukemic cell senescence, a property described with preclinical model systems [8], which may complement an antimitotic effect. In conclusion, alisertib demonstrated modest single-agent anti-leukemic activity, mostly limited to AML patients in this study. The toxicity profile was generally acceptable, and consistent with expected effects of Aurora kinase inhibition in proliferative tissues [9,10]. To allow for potentially delayed treatment effects by alisertib, improved clinical outcomes in larger populations will likely require additional strategies to enable early disease control. Results of this study of alisertib in AML/MDS highlight the need to develop predictors of response, combination regimens, and other strategies to enhance the clinical utility of treatment with this novel AAK inhibitor.
    Role of the funding source
    Contributions
    Conflicts of interest
    Acknowledgments The authors would like to thank the patients who participated in this study and their families. The authors would also like to acknowledge the writing assistance of Stephen Mosley, Ph.D., of Knowledge Point 360, in the development of this manuscript, which was funded by Millennium: The Takeda Oncology Company, and Jeff Klko, MD, for providing photomicrographs.
    Introduction Acute promyelocytic leukemia (APL) is an aggressive myeloid malignancy defined by the presence of the PML-RARα fusion gene produced by a translocation between chromosomes 15 and 17. Through risk stratification and incorporation of tretinoin (all-trans-retinoic acid; ATRA) into treatment, patient outcomes have drastically improved with complete response (CR) rates reaching >90% when combined with chemotherapy [1–3]. Most recently, dual differentiation therapy with ATRA and arsenic trioxide (ATO) (Table 1), has become a recommended first-line regimen by the National Comprehensive Cancer Network for the management of patients with low/intermediate risk APL (white blood cell (WBC) count <10×109/L), or patients with high risk disease who are unable to receive anthracycline-based chemotherapy [4]. ATO binds to the PML end of the fusion protein resulting in apoptosis of APL cells [5]. A randomized controlled trial by Lo-Coco et al. [6] demonstrated complete remission rates of 100% with dual differentiation therapy, proving non-inferiority of the ATO-ATRA combination over ATRA plus chemotherapy in the management of low/intermediate risk APL. Pseudotumor cerebri (PTC), also known as idiopathic intracranial hypertension, is a condition characterized by an increase in intracranial pressure, without cerebrospinal fluid (CSF) abnormalities or radiological evidence of other intracranial pathology (hydrocephalus, mass, structural or vascular lesion) [7]. Selumetinib PTC following ATRA administration for APL has been well described [8–26]. However, reports of PTC resulting specifically from dual differentiation therapy are currently lacking, and there is a paucity of evidence describing management of this condition specifically in patients with APL, where continuation of therapy is necessary for optimal clinical outcomes. Although the exact mechanism of ATRA induced PTC is currently unknown, a variety of medications are used in its management including carbonic anhydrase inhibitors, diuretics, corticosteroids, and analgesics. Acetazolamide, a carbonic anhydrase inhibitor, is the most commonly used agent in the management of non-drug induced PTC and is thought to work through reduction of CSF production. More recently, the anticonvulsant topiramate has been viewed as an attractive treatment option for idiopathic PTC given its activity as a carbonic anhydrase inhibitor (mostly at receptor subtypes II and IV) and its efficacy as a migrainolytic [27–29]. The precise mechanism of both migrainolysis and anti-epileptic efficacy is unknown, however the drug is known to antagonize sodium channels, augment the effect of gamma-aminobutyrate (GABA) at receptor subtype A, and antagonize the AMPA/kainate subtypes of the glutamate receptors [30].