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Somatic mutations in components of the RNA spliceosome are highly recurrent in myeloid neoplasia, representing the most common class of acquired mutations in patients with myelodysplastic syndromes MDS , chronic myelomonocytic leukemia CMML , and secondary acute myeloid leukemia AML arising from MDS [ 1 , 2 , 3 ].
The precise mechanisms by which these mutations confer a clonal advantage to mutant hematopoietic stem and progenitor cells are not completely understood, but collectively such mutations result in diverse alternative and aberrant mRNA splicing changes [ 9 , 10 , 11 , 12 ]. Altered splicing is an attractive target for novel therapies, given the high frequency with which spliceosome-associated mutations are seen in myeloid neoplasms [ 17 , 18 , 19 ].
H3B is an orally bioavailable macrocyclic lactone small molecule that binds to the SF3b complex and modulates splicing [ 20 ]. In preclinical models, including xenograft leukemia models with or without core spliceosome mutations, H3B has broad antitumor activity [ 21 , 22 ]. The eligibility criteria were disease-specific and are summarized in Table S1.
MDS patients were enrolled independently of risk category [ 23 ]. Patients were also not required to have a splicing mutation to be eligible. In addition, a second schedule schedule II of 21 days on therapy and a rest of 7 days without therapy was explored. The protocol was originally designed to evaluate schedule I based on preclinical data suggesting the activity of H3B when administered intermittently. However, when limited clinical activity was observed on schedule I, schedule II was introduced to test whether more prolonged spliceosome modulation would lead to higher clinical activity.
