The disparity in clinical outcomes for patients with acute\u00a0myeloid leukemia (AML) illustrates the heterogeneity of this\u00a0disease. Overall survival (OS) in AML is impacted by many\u00a0clinical, cytogenetic, and molecular factors. Although multiple clinical trials in AML have been completed, the standard\u00a0of care for frontline treatment has remained largely unchanged\u00a0since the completion in 1973 of a pilot trial using infusional\u00a0cytarabine with daunorubicin. Since then, new combinations and dosing schedules with these same drugs have resulted in only modest improvements in outcomes.<\/p>\n
Despite the abundance of research, long-term survival in\u00a0AML remains poor, and the search continues for more effective treatments with less toxicity. Genetic profiling is increasingly being used for\u00a0prognostic purposes and treatment decisions. In the therapeutic arena, while targeting of genetic\u00a0alterations with specific therapies could conceivably improve\u00a0outcomes, the presence of multiple genetic \u201cdrivers\u201d in AML\u00a0makes it unlikely that targeting a single molecular anomaly\u00a0will translate into clinical success.\u00a0Trials investigating targeted treatments often involve large\u00a0groups of patients who have been selected without regard to\u00a0the presence or absence of a particular anomaly. The molecular heterogeneity of AML may limit the efficacy of these\u00a0treatments, which are directed at one particular target, thereby\u00a0resulting in low response rates and subsequent lack of new\u00a0drug approval. Although a subset of patients may benefit\u00a0from some of these new treatments, this beneficial effect will\u00a0be obscured when the drug is tested in such a diverse group of\u00a0subjects. By selectively choosing study patients who are\u00a0known to have the targeted aberration, we may begin to\u00a0see the desired response rates. This review will\u00a0discuss some of the novel agents currently being studied\u00a0in AML and will provide insight into what may become\u00a0available in the near future.<\/p>\n
Small Molecule Inhibitors Given the frequency of this mutation as well as its adverse\u00a0prognostic effects, targeting FLT3 is a reasonable therapeutic\u00a0strategy. However, the heterogeneity of AML implies that the\u00a0targeting of FLT3-ITD alone will not be sufficient to result in\u00a0durable remissions. FLT3 mutations are not considered\u00a0founding mutations, but rather driver mutations, bringing into\u00a0question their role in the pathogenesis of AML.\u00a0Furthermore, the appropriate timing of FLT3 inhibitors during\u00a0treatment is not entirely clear. Nonetheless, a number of\u00a0FLT3 inhibitors have been studied in AML, both as single\u00a0agents and in combination. Many of the earlier-generation\u00a0drugs were less selective and potent than the\u00a0newergeneration drugs. Three of the most advanced FLT3\u00a0inhibitors include Sorafenib, Midostaurin<\/a>, and Quizartinib<\/a>\u00a0(formerly known as AC220).<\/p>\n Cell Cycle Inhibitors<\/p>\n Flavopiridol<\/a> Novel Chemotherapeutic Agents Elacytarabine<\/a> Sapacitabine<\/a> CPX-351 Other Novel Anti-CD33 Therapeutics <\/p>\n <\/p>\n Kendra Sweet & Jeffrey E. Lancet. Curr Hematol Malig Rep (2014) 9:109\u2013117<\/p>\n","protected":false},"excerpt":{"rendered":" The disparity in clinical outcomes for patients with acute\u00a0myeloid leukemia (AML) illustrates the heterogeneity of this\u00a0disease. Overall survival (OS) in AML is impacted by many\u00a0clinical, cytogenetic, and molecular factors. Although […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[381,376,385,379,382,380,384,378],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/592"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=592"}],"version-history":[{"count":3,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/592\/revisions"}],"predecessor-version":[{"id":595,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/592\/revisions\/595"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=592"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=592"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=592"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nFLT3 inhibitors<\/a>
\nThe FMS-like tyrosine kinase 3 (FLT3) gene found on chromosome 13 plays a role in early hematopoiesis and development of myeloid precursors. Upregulation of the\u00a0FLT3 ligand and receptor occurs in most leukemia cell lines.\u00a0In the presence of the FLT3 internal tandem duplication (ITD)\u00a0mutation\u00a0– which occurs in nearly 25 % of patients with AML\u00a0– hyperactivity of the FLT3 tyrosine kinase occurs, resulting\u00a0in constitutive activity of FLT3 and dysregulation of cellular\u00a0proliferation. FLT3-ITD mutations commonly\u00a0occur in conjunction with leukocytosis and diploid cytogenetics, resulting in higher relapse rates when compared with\u00a0patients who have wild-type FLT3.<\/p>\n
\nFlavopiridol is a synthetic flavone derivative that inhibits\u00a0multiple serine-threonine cyclin-dependent kinases that result\u00a0in apoptosis in hematopoietic cell lines, including those from\u00a0AML. In vitro data indicate that flavopiridol has direct cytotoxic effects, but when it is administered sequentially with ara-C and mitoxantrone \u2013 both of which are most efficacious\u00a0when cells are in S phase \u2013 it sensitizes the remaining leukemic cells to these drugs as they reenter the cell cycle.<\/p>\n
\nVosaroxin<\/a>
\nVosaroxin (formerly voreloxin, SNS-595) is a first-in-class\u00a0quinolone derivative known to inhibit topoisomerase II by\u00a0DNA intercalation, causing site-selective DNA doublestrand breaks, G2 arrest, and apoptosis. The mechanism of action bears similarities to anthracyclines. However,\u00a0the volume of distribution of vosaroxin is markedly lower\u00a0compared to anthracyclines, suggesting the likelihood that\u00a0off-target organ toxicity is lower. Furthermore, unlike\u00a0anthracycline drugs, vosaroxin is not a P-gp substrate, and it\u00a0has shown activity in anthracycline-resistant models.<\/p>\n
\nElacytarabine is the lipophilic 5\u2019-elaidic acid ester of\u00a0cytarabine (ara-C). Ara-C is a nucleoside analog that incorporates into DNA, thereby inhibiting the activity of DNA polymerase and ultimately resulting in apoptosis. Ara-C serves as\u00a0the backbone for nearly all treatment regimens in AML,\u00a0utilizing the human equilibrative nucleoside transporter\u00a0(hENT1) to enter cells. A large proportion of AML patients,
\nhowever, have hENT1 deficiency which results in ara-C resistance. Elacytarabine was designed to enter\u00a0cells independent of hENT1. Preclinical data indicate activity of\u00a0elacytarabine in AML cell lines with known resistance to\u00a0cytarabine.<\/p>\n
\nSapacitabine is a rationally designed oral cytosine nucleoside\u00a0analog that incorporates into DNA, leading to strand breaks\u00a0and apoptosis after subsequent rounds of DNA replication. The recommended dose from a phase I trial is either\u00a0325 mg PO BID x 7 days or 425 mg PO BID x 3 days weekly\u00a0for two weeks. Sapacitabine was well-tolerated, and 28 % of\u00a0patients had objective responses. In light of the oral\u00a0administration and relatively mild side effect profile, further\u00a0trials have been carried out with sapacitabine in the elderly\u00a0population, where palliation and quality of life become significant factors.<\/p>\n
\nCPX-351 is a liposomal encapsulation of cytarabine and daunorubicin at a 5:1 molar concentration ratio. Building upon the\u00a0concept that drug combinations may act synergistically, additively, or antagonistically, preclinical studies revealed that a\u00a0liposomally encapsulated combination of cytarabine and daunorubicin produced the best synergy at the 5:1 molar ratio in\u00a0AML cells, maintaining this ratio in vivo for over 24 hours.\u00a0In the first-in-human phase I study with CPX-351 in\u00a0patients with primarily advanced AML, the compound was\u00a0well tolerated, with very infrequent grade 3\/4 toxicities that\u00a0included mucositis, maculopapular rash, decreased ejection\u00a0fraction, and increased liver enzymes, with a recommended\u00a0phase II dose of 101 units\/m2. Amongst the 43 AML patients\u00a0treated in this study, an overall response rate of 23 % (CR+\u00a0CRi) and median remission duration of 6.9 months were\u00a0observed. Importantly, pharmacokinetic studies confirmed that the 5:1 molar ratio was maintained for up to\u00a024\u00a0hours on both days 1 and 5, while the half-lives of the\u00a0cytarabine and daunorubicin were observed to be much longer\u00a0than with free drugs.<\/p>\n
\nThe attractiveness of CD33 as a biologically important and\u00a0accessible therapeutic target has led to continued pursuit of\u00a0novel anti-CD33 strategies in the clinic. One such example is\u00a0lintuzumab (SGN-33; HuM195), a humanized monoclonal\u00a0antibody directed against CD33 with effector function through\u00a0multiple mechanisms. This agent recently underwent testing\u00a0in a large randomized trial against low-dose cytarabine as\u00a0initial therapy for elderly patients with CD33-positive AML,\u00a0but conferred no overall survival advantage.\u00a0Perhaps more promising is the compound SGN33a, which\u00a0is currently in phase I testing. This agent is an ADC consisting\u00a0of an anti-CD33 monoclonal antibody conjugated to a novel\u00a0synthetic pyrrolobenzodiazepine dimer, leading to DNA\u00a0crosslinking and cell death. In preclinical studies, this\u00a0compound demonstrated greater cytotoxic potency against\u00a0AML cell lines and primary cells than gemtuzumab\u00a0ozogamicin, including in AML cells demonstrating multidrug\u00a0resistance phenotype. In light of the above-stated recent\u00a0evidence of the efficacy of gemtuzumab ozogamicin, the\u00a0appeal of second-generation ADCs appears justified.<\/p>\nRelated Products:<\/h4>\n
<\/th> <\/th> <\/th> <\/th> <\/th><\/tr><\/thead> CAS Number <\/td> Product Name <\/td> Molecular Formula <\/td> Molecular Weight <\/td> Description <\/td><\/tr> 120685-11-2 <\/td> Midostaurin<\/a><\/td> C35H30N4O4 <\/td> 570.64 <\/td> Midostaurin is a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). <\/td><\/tr> 950769-58-1 <\/td> Quizartinib<\/a><\/td> C29H32N6O4S <\/td> 560.67 <\/td> Quizartinib is an orally available small molecule with potential antineoplastic activity. Class III receptor tyrosine kinase inhibitor AC220 selectively inhibits class III receptor tyrosine kinases, including FMS-related tyrosine kinase 3 (FLT3\/STK1), colony-stimulating factor 1 receptor (CSF1R\/FMS), stem cell factor receptor (SCFR\/KIT), and platelet derived growth factor receptors (PDGFRs), resulting in inhibition of ligand-independent leukemic cell proliferation and apoptosis. <\/td><\/tr> 131740-09-5 <\/td> Flavopiridol Hydrochloride<\/a><\/td> C21H20ClNO5.HCl <\/td> 438.3 <\/td> Flavopiridol hydrochloride competes with ATP to inhibit CDKs including CDK1, CDK2, CDK4 and CDK6 with IC50 of ~ 40 nM. <\/td><\/tr> 175414-77-4 <\/td> Voreloxin<\/a><\/td> C18H19N5O4S <\/td> 401.44 <\/td> Voreloxin(SNS-595; AG 7352) is a small molecule and a naphthyridine analogue with antineoplastic activity; inhibitor of Topo II. <\/td><\/tr> 188181-42-2 <\/td> Elacytarabine<\/a><\/td> C27H45N3O6 <\/td> 507.33 <\/td> Elacytarabine (CP-4055) is the lipophilic 5'-elaidic acid ester of the deoxycytidine analog cytosine arabinoside (cytarabine; Ara-C) with potential antineoplastic activity. <\/td><\/tr> 151823-14-2 <\/td> Sapacitabine<\/a><\/td> C26H42N4O5 <\/td> 490.64 <\/td> Sapacitabine is an orally bioavailable pyrimidine analogue prodrug with potential antineoplastic activity. <\/td><\/tr><\/tbody><\/table><\/div>\n Reference:<\/h4>\n