Clinical trials assessing hypomethylating agents combined with other therapies: causes for failure and potential solutions.

Abstract

PURPOSE\nAzacitidine and decitabine are hypomethylating agents (HMAs), that is, inhibit and deplete DNA methyltransferase 1 (DNMT1). HMAs are standard single-agent therapies for myelodysplastic syndromes and acute myeloid 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.\n\n\nEXPERIMENTAL DESIGN\nSerial 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.\n\n\nRESULTS\nSingle-agent HMA trial results encourage dose and schedule selection to increase S-phase dependent DNMT1-targeting, and discourage doses that cause indiscriminate anti-metabolite effects/cytotoxicity, since 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 processing into DNMT1-depleting nucleotide, and/or inhibit other epigenetic enzymes implicated in oncogenic silencing of lineage-differentiation, could be productive, but doses and schedules should adhere to therapeutic-index/molecular-targeted principles already learned.\n\n\nCONCLUSION\n>40 years of clinical trials history indicate 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.