For Patients With HMA-Resistant MDS, What Are Their Options?

For patients who are resistant to hypomethylating agent (HMA) treatment, there are no formal treatment recommendations, but several options, spanning from novel HMAs to chemotherapy, have been or are currently being studied in the setting.

Although hypomethylating agents (HMAs) are a cornerstone of treatment for the majority of myelodysplastic syndrome (MDS) cases, there are patients who are resistant to such treatment, representing a need for other treatment options, reports the study in Therapeutic Advances in Hematology.

Both azacitidine (AZA) and decitabine (DEC) are HMAs approved in the United States for all patients with MDS, and most patients who respond to the treatments will do so within the first 6 cycles. With this threshold, it’s recommended to complete 6 cycles of AZA before considering a patient as HMA refractory.

“Since the prognosis of patients failing HMA therapy is dismal except for the small minority of patients eligible for allo-SCT [allogeneic stem cell transplant], there is an urgent need for both prevention of HMA failure by (1) optimization of frontline therapies (eg, adding synergistic agents to HMA therapy) and/or (2) improved salvage therapies for HMA-refractory MDS patients,” explained the researchers.

For these patients who are resistant to HMA treatment, there are no formal recommendations, but several options, spanning from novel HMAs to chemotherapy, have been or are currently being studied in the setting.

Outside of AZA and DEC, which have short half-lives potentially limiting their biologic activity, guadecitabine has emerged as a more effective, easier-to-administer option that has also demonstrated tolerability.

Oral ASTX727, a combination of cedazuridine and DEC, has preliminary data from 50 patients with MDS or chronic myelomonocytic leukemia. The data show an overall response rate (ORR) of 62%, and the most common grade >3 adverse events were hematologic (eg, neutropenia, 48%; thrombocytopenia, 38%; anemia, 22%; leukopenia, 20%), febrile neutropenia (38%), and pneumonia (20%). There is currently an ongoing phase 3 trial comparing the oral option with intravenous DEC.

An oral option of AZA, CC-486, is also being tested in clinical trials.

The review, while highlighting promising treatment options for these patients, also offers rationale for not using certain treatment options. For example, although lenalidomide has proven effective in the first-line setting for patients with del(5q), the treatment has a limited benefit in these patients who are refractory to HMAs, leading researchers to recommend against lenalidomide being used outside of the frontline setting for the subgroup of patients.

Chemotherapy, frequently used for medically fit patients as a bridge to allo-SCT, was tested in an international multicenter retrospective analysis of over 300 patients who were refractory to HMA. The study, which used 3 intensive induction chemotherapy regimens, boasted an ORR of 41% and median overall survival of 10.8 months. Forty percent of patients were bridged to allo-SCT, the only potentially curative options for patients with MDS.

Other research has indicated that “medically fit” should not exclusively qualify patients for chemotherapy treatment, with some data suggesting that the decision should also take into account molecular and cytogenetic features.

Ongoing research is also being targeted at combining HMAs with intensive chemotherapy, other forms of epigenetic therapy, venetoclax, and immune checkpoint inhibitors.

Reference

Bewersdorf J, Carraway H, Prebet T. Emerging treatment options for patients with high-risk myelodysplastic syndrome. Ther Adv Hematol. Published online November 11, 2020. doi:10.1177/2040620720955006