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

Abstract

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.

TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients

“…Studies examining samples collected at multiple time points are needed to identify mutations predictive of acquired resistance or relapsed disease. The association between molecular or clinical biomarkers and HMA response may be confounded by the variations in enzymes responsible for the activation and metabolism of AZA and DEC. 11,[29][30][31] Patients who demonstrate significant hypomethylation of blood-cell DNA after treatment with AZA or DEC (indicating sufficient exposure to target DNA methyltransferases) may be more likely to have a clinically significant response. 22,32 It is possible that the predictive value of cell-intrinsic somatic mutations may be enhanced if controlled for cell-extrinsic variables such as effective dose of HMAs received and activated in cells.…”

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation

“…High doses of AZA result in direct cytotoxicity. 20 Response to AZA was seen in adults with high-risk MDS after a median of 2-3 cycles with a maximum efficacy after 4-6 cycles. 21 AZA reduced the percentage of leukemic blasts in the bone marrow and the rate of transformation to MDR-AML, it also prolonged survival and improved quality of life.…”

Biology of DNMT3 and LSD1 inhibition in acute myeloid leukaemia (AML)

“…Moreover, the speculation that the LSD1 inhibition suppress DNMT3A activity is supported by fluorescence polarization and isothermal titration calorimetry experiments [52,65] Work by Petell and coworkers shows that LSD1-facilitated interaction of Dnmt3a with histone tails, which is reduced by LSD1 inhibitor treatment [11]. An innovative approach could interfere effectively without blocking the target enzymatic activity by using peptide against specific region of the two enzymes to provide novel, specific, low-toxicity treatment agents to supplement current reatment protocols [66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84]. …”