Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions
Abstract
PURPOSE: Azacitidine and decitabine are hypomethylating agents (HMA), that is, both inhibit and deplete DNA methyltransferase 1 (DNMT1). HMAs are standard single-agent therapies for myelodysplastic syndromes and acute myelogenous leukemias. Several attempts to improve outcomes by combining HMAs with investigational agents, excepting with the BCL2-inhibitor venetoclax, have failed in randomized clinical trial (RCT) evaluations. We extract lessons from decades of clinical trials to thereby inform future work.
EXPERIMENTAL DESIGN: Serial single-agent clinical trials were analyzed for mechanism and pathway properties of HMAs underpinning their success, and for rules for dose and schedule selection. RCTs were studied for principles, dos and don'ts for productive combination therapy.
RESULTS: Single-agent HMA trial results encourage dose and schedule selection to increase S-phase-dependent DNMT1 targeting, and discourage doses that cause indiscriminate antimetabolite effects/cytotoxicity, because these attrit myelopoiesis reserves needed for clinical response. Treatment-related myelosuppression should prompt dose/frequency reductions of less active investigational agents rather than more active HMA. Administering cytostatic agents concurrently with HMA can antagonize S-phase-dependent DNMT1 targeting. Supportive care that enables on-time administration of S-phase (exposure-time)-dependent HMA could be useful. Agents that manipulate pyrimidine metabolism to increase HMA pro-drug…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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