Low-dose melphalan in elderly acute myeloid leukaemia: complete remissions but resistant relapse with therapy-related karyotypes

Kerr, Ron; Cunningham, Joan; Bowen, D.

doi:10.1038/sj.leu.2401762

Cited by 9 publications

(2 citation statements)

References 4 publications

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“…Melphalan, an alkylating agent used for the treatment of multiple myeloma, retinoblastoma, melanoma and ovarian cancer, is still under investigation as a potential treatment against AML. In 2000, two cases of elderly AML patients achieved CR when treated, albeit relapsed showing therapy-related chromosomal abnormalities and become resistant to treatment [ 35 ]. Successful results were obtained since using low-doses of melphalan in elderly patients with relapsed/refractory AML.…”

Section: Drug Repurposing In Amlmentioning

confidence: 99%

Has Drug Repurposing Fulfilled Its Promise in Acute Myeloid Leukaemia?

Valli¹,

Gruszka-Westwood²,

Alcalay³

2020

JCM

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Drug repurposing is a method of drug discovery that consists of finding a new therapeutic context for an old drug. Compound identification arises from screening of large libraries of active compounds, through interrogating databases of cell line gene expression response upon treatment or by merging several types of information concerning disease–drug relationships. Although, there is a general consensus on the potential and advantages of this drug discovery modality, at the practical level to-date no non-anti-cancer repurposed compounds have been introduced into standard acute myeloid leukaemia (AML) management, albeit that preclinical validation yielded several candidates. The review presents the state-of-the-art drug repurposing approach in AML and poses the question of what has to be done in order to take a full advantage of it, both at the stage of screening design and later when progressing from the preclinical to the clinical phases of drug development. We argue that improvements are needed to model and read-out systems as well as to screening technologies, but also to more funding and trust in drug repurposing strategies.

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Section: Drug Repurposing In Amlmentioning

confidence: 99%

Has Drug Repurposing Fulfilled Its Promise in Acute Myeloid Leukaemia?

Valli¹,

Gruszka-Westwood²,

Alcalay³

2020

JCM

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“…Interestingly, patients with normal karyotype and low bone marrow cellularity were the most frequent responders. Two cases describing relapses on melphalan demonstrated clonal evolution with appearance of the high-risk loss of 17p including the TP53 gene ( 52 ). Both of these patients were resistant to cytarabine, the standard drug used extensively in AML.…”

Section: Repositioning Of Chemotherapy For Amlmentioning

confidence: 99%

Drug Repurposing for the Treatment of Acute Myeloid Leukemia

Andresen

Gjertsen

2017

Front. Med.

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Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of immature myeloid progenitor cells in the bone marrow, compromising of normal blood cell production and ultimately resulting in bone marrow failure. With a 20% overall survival rate at 5 years and 50% in the 18- to 65-year-old age group, new medicines are needed. It is proposed that development of repurposed drugs may be a part of the new therapy needed. AML is subdivided into recurrent molecular entities based on molecular genetics increasingly accessible for precision medicine. Novel therapy developments form a basis for novel multimodality therapy and include liposomal daunorubicin/cytarabine, broad or FLT3-specific tyrosine kinase inhibitors, Bcl-2 family inhibitors, selective inhibitors of nuclear export, metabolic inhibitors, and demethylating agents. The use of non-transplant immunotherapy is in early development in AML with the exceptional re-approval of a toxin-conjugated anti-CD33. However, the full potential of small molecule inhibitors and modalities like immunological checkpoint inhibitors, immunostimulatory small molecules, and CAR-T cell therapy is unknown. Some novel therapeutics will certainly benefit AML patient subgroups; however, due to high cost, more affordable alternatives are needed globally. Also the heterogeneity of AML will likely demand a broader repertoire of therapeutic molecules. Drug repurposing or repositioning represent a source for potential therapeutics with well-known toxicity profiles and reasonable prices. This implies that biomarkers of response need to accompany the development of antileukemic therapies for sharply defined patient subgroups. We will illustrate repurposing in AML with selected examples and discuss some experimental and regulatory limitations that may obstruct this development.

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