Clinical Trials Assessing Hypomethylating Agents Combined with Other Therapies: Causes for Failure and Potential Solutions

Purpose: Azacitidine and decitabine are hypomethylating agents (HMA), that is, both inhibit and deplete DNA methylapies for myelodysplastic syndromes and acute myelogenous leukemias. Several attempts to improve outcomes by combining HMAs with investigational agents, excepting with the BCL2inhibitor 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 myelosup-pression should prompt dose/frequency reductions of less active investigational agents rather than more active HMA. Adminis-tering 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 processing into DNMT1-depleting nucleotide, and/or inhibit other epige-netic enzymes implicated in oncogenic silencing of lineage differentiation, could be productive, but doses and schedules should adhere to therapeutic index/molecular-targeted princi-ples already learned. Conclusions: More than 40 years of clinical trial history indicates mechanism, pathway, and therapeutic index properties of HMAs that underpin their almost exclusive success and teaches lessons for selection and design of combinations aiming to build on this treatment foundation.