Evidence for selective benefit of sequential treatment with azanucleosides in patients with myelodysplastic syndromes (MDS).

Komrokji, Rami S.; Apuri, Susmitha; Ali, Najla Al; Padron, Eric; Pinilla‐Ibarz, Javier; Ho, Viet Q.; List, Alan F.; Lancet, Jeffrey E.

doi:10.1200/jco.2013.31.15_suppl.7113

Cited by 5 publications

(1 citation statement)

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“…Response rates to decitabine after azacitidine are ,30%, [59][60][61] and only 1 study reported a response rate of 40% for patients who received azacitidine after first-line decitabine. 60 Because of the slightly different mechanisms of action of the 2 agents, switching may be partially justified, but recent evidence 33 suggests that azacitidine is clinically active only when incorporated into DNA, with a mechanism overlapping that of decitabine. In any case, the prolonged duration of HMA treatment seems to account for the increased responses observed when the second HMA is sequentially introduced.…”

Section: Management Of Hma Failuresmentioning

confidence: 99%

How I treat MDS after hypomethylating agent failure

Santini

2019

Blood

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Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for myelodysplastic syndrome (MDS). Response to these agents occurs in ∼50% of treated patients, and duration of response, although variable, is transient. Prediction of response to HMAs is possible with clinical and molecular parameters, but alternative approved treatments are not available, and in the case of HMA failure, there are no standard therapeutic opportunities. It is important to develop a reasoned choice of therapy after HMA failure. This choice should be based on evaluation of type of resistance (primary vs secondary, progression of disease [acute leukemia or higher risk MDS] vs absence of hematological improvement) as well as on molecular and cytogenetic characteristics reassessed at the moment of HMA failure. Rescue strategies may include stem-cell transplantation, which remains the only curative option, and chemotherapy, both of which are feasible in only a minority of cases, and experimental agents. Patients experiencing HMA failure should be recruited to clinical experimental trials as often as possible. Several novel agents with different mechanisms of action are currently being tested in this setting. Drugs targeting molecular alterations (IDH2 mutations, spliceosome gene mutations) or altered signaling pathways (BCL2 inhibitors) seem to be the most promising.

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Section: Management Of Hma Failuresmentioning

confidence: 99%

How I treat MDS after hypomethylating agent failure

Santini

2019

Blood

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Guadecitabine (SGI-110): an investigational drug for the treatment of myelodysplastic syndrome and acute myeloid leukemia

Daher-Reyes

Merchán

Yee

2019

Expert Opinion on Investigational Drugs

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Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes

Saunthararajah

2013

Hematology

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Clinical experience with 5-azacytidine and decitabine treatment of myelodysplastic syndromes (MDS), complemented by biological and pharmacological studies, has revealed compelling mechanism of action differences compared with traditional myeloid cancer treatment mainstays such as cytarabine. For example, 5-azacytidine and decitabine produce remissions and better overall survival in MDS with high-risk chromosome abnormalities at a surprisingly high rate, consistent with experimental observations that noncytotoxic DNA methyltransferase depletion by 5-azacytidine/decitabine can trigger cell cycle exit independently of p53, thus circumventing a basis for resistance to apoptosis-based DNAdamaging therapy. That responses cut across the chaotic genomic landscape of MDS highlights common threads in disease, such as high expression in myeloblasts of differentiation-driving transcription factors yet paradoxical epigenetic suppression of proliferation-terminating late-differentiation genes. Less toxic regimens (lower dosages but more frequent administration) of 5-azacytidine/decitabine have been more successful, underscoring the importance of preserving functionally normal stem cells, which are rendered more precious by attrition from age, previous cytotoxic treatments, and the disease process and are needed to relieve cytopenias, the cause of morbidity and mortality. Also emphasized is that there can be no therapeutic benefit, regardless of mutation or cytogenetic subtype, if DNA methyltransferase is not depleted by sufficient overlap between intracellular drug half-lives and S-phase entries of malignant cells. Improved understanding of mechanism-of-action differences demands new approaches, from historic (but not scientific) more-is-better and one-sizefits-all empiricism to pharmacodynamic-based designs and combinations directed not solely at suppressing malignant clones, but at improving therapeutic indices.

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Evidence for selective benefit of sequential treatment with azanucleosides in patients with myelodysplastic syndromes (MDS).

Cited by 5 publications

References 0 publications

How I treat MDS after hypomethylating agent failure

How I treat MDS after hypomethylating agent failure

Guadecitabine (SGI-110): an investigational drug for the treatment of myelodysplastic syndrome and acute myeloid leukemia

Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes

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