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Treatment of Chronic Myeloid Leukemia with Bcr-Abl Kinase Inhibitors
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Michael J. Mauro, Michael C. Heinrich
For CML currently, we now have very highly active and durable primary therapy (imatinib) and two approved and convincingly proven salvage options, dasatinib and nilotinib. Other developments expanding the roster of novel therapies in Ph(+) leukemias include additional multikinase (Abl, Src, Lyn, etc) inhibitors such as SKI-606 and INNO-406, and the aurora kinase inhibitor MK0457, which is specifically active against the T315I mutant Abl kinase variant. In this revolutionary decade of development in CML, therapy has universally shifted away from the primary immunotherapy-based options of interferon (IFN) and allografting and adopted use of kinase inhibitor therapy as primary therapy and beyond.
Precision medicine for pediatric central nervous system tumors
Published in Expert Review of Precision Medicine and Drug Development, 2019
Daniel C. Moreira, Amar Gajjar
New biologic platforms facilitating high-throughput analyses of pediatric CNS tumors have identified dysregulated proteins that promote tumorigenesis and novel compounds to target these proteins. In cancers where oncogenesis is not heavily dependent on a single pathway, this strategy leverages nononcogenic mutations and cellular adaptations in cancer cells to identify new therapeutic approaches. In a high-throughput, cell-based assay in medulloblastoma, gemcitabine and pemetrexed synergistically inhibited Myc-driven medulloblastoma proliferation [8]. These drugs are now being used in first-line treatment for medulloblastoma (SJMB12). Additional candidate agents for medulloblastoma, such as inhibitors of cell cycle kinases, PARP, and tyrosine kinases, have been identified [9,10]. Atypical teratoid rhabdoid tumor (AT/RT) is a rare embryonal tumor defined by inactivation of the INI-1 locus, with poor prognosis despite multiagent cytotoxic chemotherapy. Insights into the molecular mechanisms driving AT/RT tumorigenesis have also identified candidate agents. Alisertib, an aurora kinase inhibitor, is currently undergoing investigation in a phase 2 trial for AT/RT (NCT02114229).
Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy
Published in Expert Review of Hematology, 2018
Fulvio Massaro, Gioia Colafigli, Matteo Molica, Massimo Breccia
Aurora kinase family has a main role in mitotic spindle formation and centrosome maturation. Danusertib, a pan-Aurora kinase inhibitor, has demonstrated activity also against ABL1 (IC50 = 25 nM) including T315I and other mutations. Particularly, this drug inhibits proliferation of CD34+ cells both from BP-CML patients with (IC50 = 25 nM) or without (IC50 = 9 nM) T315I mutation [18]. A phase I, dose escalation trial was conducted among 37 patients, 22 in advanced phase CML (7 in AP, 15 in BP) and 15 with Ph+ ALL. T315I mutation was detected in 54% of patients. Almost 90% of patients had developed resistance to one or more TKIs, 32% had received an alloSCT. Between evaluable patients, 20% of cases (4/20) achieved a result: a complete hematologic response (CHR) and a CCyR were reported in CML patients. Toxicity profile was characterized by grade 3–4 AEs such as febrile neutropenia (17.2%), diarrhea (14%), mucosal inflammation and stomatitis (7% each), hypotension, hyponatremia, AST increased, mental status changes (3.4%) and vomiting (3%) [19]. Despite an interesting profile of efficacy, the most limiting feature of danusertib is represented by its intravenous schedule of administration, consistent of 7 days of continuous treatment in a 14-day cycle.
Management of chronic myeloid leukemia in myeloid blastic phase with novel therapies: a systematic literature review
Published in Expert Review of Hematology, 2022
Umut Yılmaz, Batuhan Bulan, Çağrı Belli, Ahmet Emre Eşkazan
Danusertib, an Aurora kinase inhibitor, was studied in a phase-1 trial for advanced-phase CML [15]. The trial recruited nine CML-MBP patients, all previously treated. The study investigated the aftermath of different doses. Only one CML-MBP patient (11%) responded to danusertib, and overall, only four of 20 evaluable patients had responses, all carrying the T315I ABL mutation. An interesting observation in this trial was that danusertib reduced the blast volume during treatment in most patients, only to have a rebound increase in the off days of each cycle. The trial concluded that danusertib dose at 180 mg/m2 for seven consecutive days at 14-day cycles should be used for the phase-2 part of its clinical development.