Patients with myelodysplastic syndrome (MDS) whose disease progressed during treatment with hypomethylating agents (HMA) demonstrated poor survival outcomes; however, these outcomes were improved compared with historical data, according to the results of a retrospective study presented at Annual Meeting of the Society of Hematologic Oncology (SOHO).

The historical median overall survival (OS) of patients with MDS whose disease progressed during HMA treatment was 6 months. Because these data are from before the availability of venetoclax-based regimens, the aim of this study was to determine if treatment outcomes after progression on HMA therapy has changed.

The retrospective study evaluated data from 71 patients with MDS whose disease progressed during HMA therapy between 2015 and 2021.

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At baseline, the median age was 67 years, 62% of patients were male, and 24% of patients had therapy-related MDS. The R-IPSS score was very high among 46% of patients, followed by high among 27%, intermediate among 18%, and low among 8%. High-risk cytogenetics was present among 56% of patients at diagnosis. Prior HMA therapy included azacitidine for 53% of cases, decitabine for 42%, and azacitidine plus an investigational agent in 4%. There were 7% of patients who had prior allogeneic stem cell transplant.

At progression, 14% of patients had MDS-EB1, 18% had MDS-EB2, and 68% had acute myeloid leukemia (AML). The R-IPSS scores changed at progression to be very high among 65% of patients, high risk among 13%, and intermediate risk among 22%. The most common genes mutated at progression were TP53 among 44%, ASXL1 among 21%, RUNX1 among 14%, and RAS among 13%.

Among patients with TP53-mutated disease, there were 50% with MDS-EB1, 25% with MDS-EB2, and 42% with AML who achieved a complete response (CR), CR with incomplete blood count recovery (CRi), or molecular CR (mCR) with venetoclax-based treatment at progression. Among patients whose disease was wild-type for TP53, none of the patients with MDS-EB1 responded to venetoclax-based therapy, whereas 43% and 71% of patients with MDS-EB2 or AML achieved a CR/CRi/mCR, respectively.

None of the patients with MDS-EB1 or TP53-mutated MDS-EB2 received CPX-351. Of the patients treated with CPX-351, none of the patients with TP53-wild-type MDS-EB2 or TP53-mutated AML responded, whereas 33% of patients with TP53-wild-type AML demonstrate a response.

The CR/CRi/mCR rate with other low-intensity therapy, such as IDH1/IDH2 inhibitors, gemtuzumab ozogamicin, ruxolitinib, or alternating HMAs was 0% and 25% with TP53-mutated or wild-type MDS-EB1, respectively, 0% with TP53-wild-type MDS-EB2, and 50% and 33% with TP53-mutated or wild-type AML, respectively.

The median OS was 5.3, 12.5, and 13.4 months among patients with AML, MDS-EB2, and MDS-EB1, respectively (P =.065). OS was similar regardless of treatment at progression, except for best supportive care, which demonstrated a median OS of 1.37 months (P <.001). Venetoclax-based therapy, CPX-351, and other low-intensity therapies resulted in median OS of 10.8 (P =.40), 3.07 (P =.57), and 7.4 months (P =.37), respectively. For patient with AML, intensive chemotherapy resulted in a median OS that was not reached (P =.63).

Patients with TP53-mutated disease demonstrated a shorter median OS of 2.6 months compared with 14.1 months among patients with wild-type TP53 (P <.001). Among patients with TP53-mutated disease, the median OS after venetoclax or CPX-351on progression was similar at 2.67 and 3.07 months, respectively (P =.90).

Patients who underwent a stem cell transplant demonstrated the longest median OS, which was not reached compared with 8.1 months among patients who did not undergo transplant (P =.002).

The authors concluded that “our report suggests modest improvement in survival of MDS patients progressing on HMA compared to historical data.” They indicated that these data highlight that “more effective therapies are needed to improve outcome of these high-risk patients.”

Disclosures: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


Ghorab A, Al-Kali A, Elliot M, et al. Clinical outcome of myelodysplastic syndrome progressing on hypomethylating agents with evolving frontline therapies: continued challenges and unmet needs. Presented at: Annual Meeting of the Society of Hematologic Oncology (SOHO); September 28-October 1, 2022. Abstract MDS-353.