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MDS, CMML Pipelines Inch Closer to Arrival of Targeted Therapies


The researchers credit wider availability of molecular testing and better understanding of the diseases for the emerging targeted therapies in development.

As ongoing studies continue to investigate which novel therapies can have a positive impact in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), researchers have published a rundown on which of these treatments have shown promise thus far.

Both MDS and CMML have variable symptom burdens and a risk of progression to acute myeloid leukemia.

“Allo-HCT remains the only curative therapy for both MDS and CMML but despite the more frequent use of reduced-intensity conditioning regimens and alternative grafts, as well as advances in supportive care, the majority of patients are not eligible for [allogeneic hematopoietic cell transplant] and are treated with [hypomethylating agents],” wrote the researchers.

With suboptimal response rates to standard of care hypomethylating agents (HMAs), there’s a need for more novel approaches that offer stronger and more durable responses, wrote the researchers. Recently, an oral version of decitabine, a drug typically used in this setting, gained FDA approval.

Concurrently, several targeted therapies are in development, although none have yet been approved. The researchers credit wider availability of molecular testing and better understanding of the diseases for the emerging targeted therapies in development.

“Molecularly driven agents such as IDH1/2 inhibitors, venetoclax, magrolimab, and APR-246 for MDS, as well as tagraxofusp, tipifarnib, and lenzilumab for CMML are being evaluated in various stages of clinical trials but more data are needed prior to their use in routine clinical practice,” wrote the researchers.

Preliminary results from the phase 2 portion of a phase 2/3 IMerge trial of telomerase inhibitor imetlelstat in patients with erythropoiesis-stimulating agent-refractory low-risk MDS showed a 42% 8-week red blood cell-transfusion independence (RBC-TI) rate and a 32% 24-week RBC-TI rate. Data from the phase 3 portion of the study are anticipated.

The oral hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitor roxadustat is being investigated for the treatment of anemia in patients with LR-MDS in a phase 2/3 trial of patients with transfusion-dependent LR-MDS who have serum RPO levels of <400 mIU/L. Early results from the study have showed a 38% 8-week RBC-TI and a 17% 20-week RBC-TI.

In both MDS and CMML, p53-refolding agent APR-246 has showed promise and is currently being evaluated in combination with AZA in a phase 3 trial of patients with TP53-mutant MDS, CMML, or AML.

“Due to the rarity of the disease, dedicated trials in CMML patients have been difficult to conduct,” note the researchers. “However, several novel agents are currently being studied in early phase trials in CMML patients.”

Potential novel treatments in this setting include:

  • Tipifarnib, a farnesyltransferase inhibitor that has been shown to be well-tolerated although with limited efficacy
  • Tagraxofusp, an anti-CD123 antibody, with preliminary results from a phase 1/2 study showing that the treatment elicited a spleen response in all 8 patients with baseline splenomegaly and mCRs in 2 pateints
  • Lenzilumab, an anti-GM-CSF antibody that has demonstrated safety and moderate efficacy in a phase 1 trial of 15 patients with CMML


Bewersdorf J, Zeidan A. Risk-adapted, individualized treatment strategies of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Cancers. 2021;13(7):1610.

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