Table 1.
Changes in DNMT1, DNMT3A, or DNMT3B expression in AML patients treated with DNMT inhibitors in clinical trials.
| Treatment | Phase and ID | Patients | Regimen | Type of samplesa | Changes in expression | Predictive of response |
|---|---|---|---|---|---|---|
| Decitabine or decitabine + valproic acid (VA)86
Decitabine + bortezomib87 Decitabine89 Decitabine88 Guadecitabine90 |
Phase I ID: NCT 00079378 Phase I ID: NCT 00703300 N/A Phase II ID: NC T00492401 Phase I/II ID: NCT 01261312 |
Adult relapsed AML (n = 13) and older (>60 y/o) untreated AML (n = 12) Untreated poor-risk older (⩾65 y/o) AML patients (n = 19) Young adults or children R/R AML (n = 8) Untreated older (⩾60 y/o) AML patients (n = 53) Adult R/R AML (n = 122) |
Decitabine alone for OBD (days 1-10; n = 14) or decitabine for 10 days + VA for MTD (days 5-21) Decitabine (days 1-10) with cycles repeated every 28 days + bortezomib (days 5 and 8, or days 5, 8, 12, and 15) Decitabine (days 1-10) at ~4-week intervals. Subsequent courses shortened to 5 days in responders Low-dose decitabine (days 1-10) Guadecitabine for 5 (daily ×5) or 10 days (daily ×10) up to 4 cycles followed by daily ×5 cycles. All regimens dosed with a 28-day treatment cycle |
Unselected bone marrow mononuclear cells (n = 14) Serial bone marrow samples (n = 5) Sequential bone marrow samples (n = 3) Unselected diagnostic bone marrow samples (n = 23) Type of samples not stated (n = 122) |
Post-treatment: ↑p15, ER, ER promoter demethylation; ↓DNMT1 protein, global hypomethylation Post-treatment: ↑miR-29b, ESR; ↓DNMT1, DNMT3A, DNMT3B Post-treatment: ↑miR-29b; ↓DNMT1 Responders: ↑miR-29b, a trend for lower DNMT3A. No differences in DNMT1, DNMT3B, or ESR1 N/A |
ER expression N/A N/A miR-29b expression Global DNA demethylation; DNMT3B contributed >5% |
For the primary outcomes (eg, response rate, survival) of the actual clinical trial, readers are directed to the individual reference for each study.
Abbreviaitons: MTD, maximum-tolerated dose; N/A, not available; OBD, optimal biological dose.
a
Denotes the type of samples used to examine the changes in the levels of DNMTs and other genes, and the number of available samples.