Revisiting the role of cladribine in acute myeloid leukemia: An improvement on past accomplishments or more old news?

Freyer, Craig W.; Gupta, Neha; Wetzler, Meir; Wang, Eunice S.

doi:10.1002/ajh.23862

Cited by 41 publications

(25 citation statements)

References 74 publications

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“…Initial studies on cladribine have been done in pediatric acute myeloid leukemia (AML) (141)(142)(143). Further studies in different cancers, including acute and chronic leukemias, mantle cell lymphoma, hairy cell leukemia, mucosa associated lymphoid tissue (MALT)-type lymphoma, and Langerhans cell histiocytosis have been done with combination therapies in both pediatric and adult populations (144)(145)(146)(147)(148). Cladribine's main adverse effects documented from the cancer studies, included significant immunosuppression associated with opportunistic infections such as herpes simplex, paresthesias, and possible secondary malignancy (149).…”

Section: Cladribine (Mavenclad)mentioning

confidence: 99%

Multiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies

Melamed

Lee

2020

Front. Immunol.

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Over the past two decades, the field of multiple sclerosis (MS) has been transformed by the rapidly expanding arsenal of new disease modifying therapies (DMTs). Current DMTs for MS aim to modulate innate and adaptive immune responses toward a less inflammatory phenotype. Since the immune system is also critical for identifying and eliminating malignant cells, immunosuppression from DMTs may predictably increase the risk of cancer development in MS patients. Compared with healthy controls, patients with autoimmune conditions, such as MS, may already have a higher risk of developing certain malignancies and this risk may further be magnified by DMT treatments. For those patients who develop both MS and cancer, these comorbid presentations create a challenge for clinicians on how to therapeutically address management of cancer in the context of MS autoimmunity. As there are currently no accepted guidelines for managing MS patients with prior history of or newly developed malignancy, we undertook this review to evaluate the molecular mechanisms of current DMTs and their potential for instigating and treating cancer in patients living with MS.

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Section: Cladribine (Mavenclad)mentioning

confidence: 99%

Multiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies

Melamed

Lee

2020

Front. Immunol.

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“…Hence, a lack of activity might be explained by human kinases not efficiently phosphorylating dihalogenated nucleosides. Intracellular targets of cladribine have been recently well summarized by Freyer and colleagues [29]. Ribonucleotide reductase is one of the main targets of cladribine.…”

Section: Discussionmentioning

confidence: 99%

Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations

et al. 2020

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The enzymatic synthesis of nucleoside analogues has been shown to be a sustainable and efficient alternative to chemical synthesis routes. In this study, dihalogenated nucleoside analogues were produced by thermostable nucleoside phosphorylases in transglycosylation reactions using uridine or thymidine as sugar donors. Prior to the enzymatic process, ideal maximum product yields were calculated after the determination of equilibrium constants through monitoring the equilibrium conversion in analytical-scale reactions. Equilibrium constants for dihalogenated nucleosides were comparable to known purine nucleosides, ranging between 0.071 and 0.081. To achieve 90% product yield in the enzymatic process, an approximately five-fold excess of sugar donor was needed. Nucleoside analogues were purified by semi-preparative HPLC, and yields of purified product were approximately 50% for all target compounds. To evaluate the impact of halogen atoms in positions 2 and 6 on the antiproliferative activity in leukemic cell lines, the cytotoxic potential of dihalogenated nucleoside analogues was studied in the leukemic cell line HL-60. Interestingly, the inhibition of HL-60 cells with dihalogenated nucleoside analogues was substantially lower than with monohalogenated cladribine, which is known to show high antiproliferative activity. Taken together, we demonstrate that thermodynamic calculations and small-scale experiments can be used to produce nucleoside analogues with high yields and purity on larger scales. The procedure can be used for the generation of new libraries of nucleoside analogues for screening experiments or to replace the chemical synthesis routes of marketed nucleoside drugs by enzymatic processes.

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“…This knowledge resulted in the production of drugs mimicking an ADA-deficient state in order to target lymphocytes, which could be useful in patients suffering from lymphoproliferative disorders. Later, the function of ADA was investigated in more detail, and it was discovered that ADA conducted the conversion of deoxyadenosine to deoxyinosine, changing a lymphotoxic substance into a non-toxic metabolite [ 24 ].…”

Section: Oral Immunosuppressants In the Treat- Ment Of Msmentioning

confidence: 99%

From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis

Aly

Hemmer

Korn

2017

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Background: Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, orally available second generation immunosuppressive agents have been approved or are filed for licensing as MS therapeutics. Due to semi-selective targeting of cellular processes, these second-generation immunosuppressive compounds might rather be immunomodulatory. For example, Teriflunomide inhibits the de novo pyrimidine synthesis and thus only targets rapidly proliferating cells, including lymphocytes. It is used as first line disease modifying therapy (DMT) in relapsing-remitting MS (RRMS).Methods: Review of online content related to oral immunosuppressants in MS with an emphasis on Teriflunomide.Results: Teriflunomide and Cladribine are second-generation immunosuppressants that are efficient in the treatment of MS patients. For Teriflunomide, a daily dose of 14 mg reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo. Cladribine reduces the ARR by about 50% compared to placebo but has not yet been licensed due to unresolved safety concerns. We also discuss the significance of older immunosuppressive compounds including Azathioprine, Mycophenolate mofetile, and Cyclophosphamide in current MS therapy.Conclusion: Teriflunomide has shown a favorable safety and efficacy profile in RRMS and is a therapeutic option for a distinct group of adult patients with RRMS.

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Revisiting the role of cladribine in acute myeloid leukemia: An improvement on past accomplishments or more old news?

Cited by 41 publications

References 74 publications

Multiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies

Multiple Sclerosis and Cancer: The Ying-Yang Effect of Disease Modifying Therapies

Efficient Biocatalytic Synthesis of Dihalogenated Purine Nucleoside Analogues Applying Thermodynamic Calculations

From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis

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