Exploring Targeted Therapies in Myelodysplastic Syndromes

Lionel Adès, MD, PhD, discussed emerging targeted therapies for myelodysplastic syndromes during a presentation at the 10th Annual Meeting of the Society of Hematologic Oncology.

Ongoing research to identify agents to treat myelodysplastic syndromes (MDS) has taken a keen focus on the emergence of targeted therapies, specifically spliceosome modulators, TP53 modulators, and IDH1/IDH2 modulators. The hypomethylating agents, azacitidine (Vidaza®; Bristol Myers Squibb) and decitabine, are standard of care for MDS but with a response rate of about 50% and a median survival that is limited to 1 to 2 years, the need for novel strategies and drugs continues, said Lionel Adès, MD, PhD, during a presentation at the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022).

“The most frequently mutated spliceosome-associated genes in MDS are SF3B1, SRSF2, U2AF1, and ZRSR2 and these appeared to be the most promising target for novel therapies,” said Adès, professor of hematology at the Hôpital Saint-Louis, and Paris Diderot University, Paris, France.

Spliceosome Modulators

Adès noted 2 studies that investigated the compounds E7107 and H3B-8800 in Nature Medicine.1,2 Although preclinical data for E7107 were encouraging, a phase 1 trial revealed unacceptable toxicity. Investigators who evaluated H3B-8800 noted that the agent potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. They attributed this action to the agent’s interaction with the SF3b complex.

In a phase 1 trial evaluating H3B-8800 in 84 patients, Steensma, et al3 reported limited efficacy for the agent. The investigators reported more than 56 days of red-blood cell transfusion free intervals in 9 patients who were transfusion dependent at study entry (15%). Further, of 15 patients with MDS who harbored missense SF3B1 mutations, 5 experienced RBC transfusion independence.


“The other promising target is TP53,” Adès said. “The presence of TP53 mutation is usually associated with poor prognosis, whether you treat with a hypomethylating agent or stem cell transplant,” he continued.

A phase 2 analysis (NCT03072043) of eprenetapopt and azacitidine showed that the combination was well-tolerated with high response rates in 100 patients with MDS or acute myelocytic leukemia (AML) and who harbored a TP53 mutation.4

Investigators reported an overall response rate of 69% with 43 patients reporting a complete response (CR) and 1 patient with a partial response (PR). They noted that the quality of response and next-generation sequencing negativity strongly predicted overall survival (OS). In the intent-to-treat cohort, the median OS was 11.8 months (95% CI, 9.4-14.3).

After long-term follow-up, however, results were disappointing, Adès said. The investigators reported that the trial failed to meet its primary end point of complete remission rate (33.3%) vs 22.4% in the azacitadine-alone arm and failed to reach statistical significance (P = .13).

IDH Mutations

Adès noted 2 studies evaluating IDH mutations. In a phase 3 study (NCT02677922), patients were randomized 1:1 to receive ivosidenib (Tibsovo®; Servier) at 500 mg once daily and azacitidine at 75 mg/m 2 subcutaneously or intravenously for 7 days in 28-day cycles, or placebo + azacitidine. Median OS was 24.0 months in the treatment arm compared with 7.9 months in the control arm (HR, 0.44; 95% CI, 0.27-0.73; P = .0005).5 The investigators reported that the combination arm significantly improved event-free survival, OS, and clinical response compared with the placebo arm in patients who were ineligible for intensive chemotherapy. Further, the safety profile of the combination arm was favorable and consistent with previous studies.

Another study, NCT02677922, evaluated the safety and activity of enasidenib (Idhifa®; Bristol Myers Squibb; Servier), an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins.6 In the trial, enasidenib plus azacitidine versus azacitidine alone was investigated in patients with newly diagnosed, mutant-IDH2 acute myeloid leukemia who were ineligible for intensive chemotherapy.

Investigators reported that the combination regimen was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukemia.

The ongoing IDIOME study (NCT03503409)7 demonstrated that ivosidenib was well tolerated in patients with MDS. Responses were significant across all 3 of the patient cohorts evaluated. With a response rate of 91%, the agent was particularly effective in treatment naïve higher risk patients with IDH1 mutations (cohort B). Patients had overall response rates of 54%, 92%, and 50% in cohorts A, B, and C, respectively. These encouraging preliminary results must be confirmed in more patients, noted Adès.

“These are some encouraging findings in targeted therapies, and it is only a matter of time that we have some effective drugs for patients with MDS,” concluded Adès.


1. Lee SC, Dvinge H, Kim E, et al. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat Med. 2016;22(6):672-678. doi:10.1038/nm.4097

2. Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497-504. doi:10.1038/nm.4493

3. Steensma DP, Wermke M, Klimek VM, et al. Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms. Leukemia. 2021;35(12):3542-3550. doi:10.1038/s41375-021-01328-9

4. Sallman DA, Komrokji RS, DeZern AE, et al. Long term follow-up and combined phase 2 results of eprenetapopt (APR-246) and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2021;138 (suppl 1): 246. doi: 10.1182/blood-2021-153286

5. Montesinos P, Recher C, Vives S, et al. AGILE: a global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation. Blood. 2021;138(suppl 1):697. doi:10.1182/blood-2021-147805

6. DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22(11):1597-1608. doi:10.1016/S1470-2045(21)00494-0

7. Sebert M, Cluzeau T, Rauzy OB, et al. Ivosidenib monotherapy is effective in patients with idh1 mutated myelodysplastic syndrome (MDS): the IDIOME phase 2 study by the GFM Group. Blood. 2021;138(suppl 1):62. doi:10.1182/blood-2021-146932