A Pharmacokinetic/Pharmacodynamic Model of the Action of Hypomethylating Agents in Chronic Myelomonocytic Leukaemia

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Robert Charles Jackson Tomas Radivoyevitch


Chronic myelomonocytic leukaemia (CMML) is a disease that borders between a myelodyplastic syndrome (MDS) and myeloproliferative neoplasia (MPN). It is a progressive condition: about 20% of CMML patients progress to secondary acute myeloid leukaemia (sAML), which has a very poor prognosis.  In all cases, normal bone marrow function is compromised with resulting depletion of circulating erythrocytes and platelets.  We modelled the dynamics of CMML at two levels: a cytokinetic model was developed that describes bone marrow cell population dynamics for multiple cell lineages, and changes in DNA mutational status that occur in MDS and CMML.  This model, in conjunction with pharmacokinetic (PK) models for cytotoxic drugs and hypomethylating agents, was used to study the pharmacodynamics (PD) of these drugs.   For the subset of CMML with loss of activity of TET2, our models suggest that TET2 activators may restore normal DNA methylation with a resulting antileukaemic effect. Mouse and human data were used to place bounds on the parameters of our model.  Our modelling suggests that both hypomethylation and cytotoxic effects contribute to the antileukaemic activity of decitabine.

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JACKSON, Robert Charles; RADIVOYEVITCH, Tomas. A Pharmacokinetic/Pharmacodynamic Model of the Action of Hypomethylating Agents in Chronic Myelomonocytic Leukaemia. Medical Research Archives, [S.l.], v. 9, n. 10, oct. 2021. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2568>. Date accessed: 28 nov. 2021. doi: https://doi.org/10.18103/mra.v9i10.2568.
Research Articles


1. Ko M, Huang Y, Jankowska AM et al., Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468: 839-843 (2010).
2. Issa JP, The myelodysplastic syndrome as a prototypical epigenetic disease. Blood 121: 3811-3817 (2013).
3. Gerds AT, I walk the other line: myelodysplastic/myeloproliferative neoplasm overlap syndromes. Curr Hematol Malig Rep 9: 400-408 (2014).
4. Cui Y, Tong H, Du X, et al., Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia, Exp Hematol Oncol 4: doi: 10.1186/s40164-015-0009-y (2016).
5. Jin X, Qin T, Bailey N et al. Oncogenic N-ras and Tet2 haploinsufficiency collaborate to dysregulate hematopoietic stem and progenitor cells. Blood Adv 2: 1259-1271 (2018).
6. Kunimoto H, Meydan C, Nazir A, et al. Cooperative epigenetic remodeling by TET2 loss and NRAS mutation drives myeloid transformation and MEK inhibitor sensitivity. Cancer Cell 33: 44-59 (2018).
7. Bartram CR. Molecular genetic aspects of myelodysplastic syndromes. Hematol Oncol Clin North Am 6: 557-570 (1992).
8. Gur HD, Loghavi S, Garcia-Manero G et al. Chronic myelomonocytic leukemia with fibrosis is a distinct disease subset with myeloproliferatice features and frequent JAK2 p.V617F mutations. Am J Surg Pathol 42: 799-806 (2018).
9. Adamson DJ, Dawson AA, Bennett B et al. p53 Mutation in the myelodysplastic syndromes. Brit J Haematol 89: 61-66 (1995).
10. Thomopoulos TP, Bouhla A, Papageorgiou SG, Pappa V. Chronic myelomonocytic leukemia – a review. Expert Rev Hematol 14: 59-77 (2020).
11. Chan O, Renneville A. Padron E. Chronic myelomonocytic leukemia diagnosis and management. Leukemia 35: 1552-1562 (2021).
12. Kwon J, Diagnosis and treatment of chronic myelomonocytic leukemia. Blood Res 56: S5-S16 (2021).
13. Jian J, Qiao Y, Li Y, Guo Y, Ma H, Liu B. Mutations in chronic myelomonocytic leukemia and their prognostic relevance. Clin Transl Oncol 23: 1731-1742 (2021).
14. Patel AB, Deininger MW. Genetic complexity of chronic myelomonocytic leukemia. Leuk Lymphoma 62: 1031-1045 (2021).
15. Mason CC, Khorashad JS, Tantravahi SK et al. Age-related mutations and chronic myelomonocytic leukemia. Leukemia 30: 906-913 (2016).
16. Ricci C, Fermo E, Corti S et al. RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant. Clin Cancer Res 16: 2246-2256 (2010).
17. Zhang L, Singh RR, Patel KP et al. BRAF kinase domain mutations are present in a subset of chronic myelomonocytic leukemia with wild-type RAS. Am J Hematol 89: 499-504 (2014).
18. Carr RM, Patnaik MM. Genetic and epigenetic factors interacting with clonal hematopoiesis resulting in chronic myelomonocytic leukemia. Curr Opin Hematol 27: 2-10 (2020).
19. Patel BJ, Przychodzen B, Thota S et al. Genetic determinants of chronic myelomonocytic leukemia. Leukemia 31:2815-2823 (2017).
20. Gu J, Wang Z, Xiao M et al. Chronic myelomonocytic leukemia with double mutations in DNMT3A and FLT3-ITD treated with decitabine and sorafenib. Cancer Biol Ther 18: 843-849 (2017).
21. Patnaik MM, Tefferi A, Chronic myelomonocytic leukemia: 2016 update on diagnosis, risk stratification and management. Am J Hematol 91: 631-642 (2016)
22. Itzykson R, Kosmider O, Cluzeau T et al., Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 25: 1147-1152 (2011).
23. Jackson RC, Radivoyevitch T, A pharmacodynamic model of Bcr-Abl signalling in chronic myeloid leukaemia. Cancer Chemother Pharmacol (2014) doi:10.1007/s00280-014-2556-z
24. Jackson RC, Radivoyevitch T, Evolutionary dynamics of chronic myeloid leukemia progression: the progression-inhibitory effect of imatinib. AAPSJ (2016). doi:10.1208/s12248-016-9905-2
25. Jackson RC, Seven Equations of Life: The Fundamental Relationships of Biomathematics, p.107. Saarbrücken, Germany, Lambert Academic Publishing (2016).
26. Lavelle D, Vaitkus K, Ling Y et al. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. Blood 119: 1240-1247 (2012).
27. Momparler RL. Pharmacology of 5-aza-2'-deoxycytidine (decitabine). Seminars in Hematology 42(3 suppl 2):S9-S16 (2005).
28. Cashen AF, Shah AK,Todt L et al. Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Cancer Chemother Pharmacol 61: 759-766 (2008).
29. Kantarjian H, Garcia-Manero G, O'Brian S et al. Phase I clinical and pharmacokinetic study of oral sapacitabine in patients with acute leukemia and myelodysplastic syndrome. J Clin Oncol 28: 285-291 (2010).
30. Molokie R, Lavelle D, Gowhari M et al. Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: a randomized phase I study. PloS Med 2017 Sep 7;14(9):e1002382. Doi:10.1371/journal.pmed.1002382. eCollection 2017
31. Terse P, Engelke K, Chan K et al. Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice. Int J Toxicol 33: 75-85 (2014).
32. Alcazar O, Achberger S, Aldrich W et al., Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo. Int J Cancer 131: 18-29 (2012).
33. Uchida N, Hsieh MM, Platner C et al. Decitabine suspends human CH34+ cell differentiation and proliferation during lentiviral transduction. PloS One 2014; 9: e10422. doi:10.1371/journal.pone.010422.
34. Maes K, De Smedt E, Kassambara A et al, In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple myeloma. Oncotarget 6: 3319-3334 (2015).
35. Kalac M, Scotto L, Marchi E et al. HDAC inhibitors and decitabine are highly synergistic and associated with unique gene expression and epigenetic profiles in models of DLBCL. Blood 2011; 118: 5506-5516.
36. Murrell P. R Graphics, Boca Raton, Florida: Chapman and Hall (2006).
37. Jackson RC, DiVeroli GY, Koh,SB, Goldlust I, Richards FM, Jodrell DI (2017) Modelling of the cancer cell cycle as a tool for rational drug development: a systems pharmacology approach to cyclotherapy. PloS Computational Biology 13: e1005529. https://doi.org/10.1371/journal.pcbi.1005529.
38. Hoeksema MA, de Winther MPJ. Epigenetic regulation of monocyte and macrophage function. Antioxidants and Redox Signaling 25: 758-774 (2016).
39. Yamazaki J, Jelinek J, Cesaroni M et al. TET2 mutations affect non-CpG island DNA methylation at enhancers and transcription factor-binding sites in chronic myelomonocytic leukemia. Cancer Res 75: 2833-2843 (2015).
40. Walenda T, Stiehl T, Braun H et al., Feedback signals in myelodysplastic syndromes: increased self-renewal of the malignant clone suppresses normal hematopoiesis. PLOS Computational Biology 10: e1003599 (2014).
41. Jackson RC. What can systems pharmacology contribute to drug development? Disease modelling as a predictive tool. BioDiscovery 2012: 4: 4; doi: 10.7750.2012.4.4
42. Moran-Crusio K, Reavie L, Shih A et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20: 11-24 (2011).