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Key MDS Studies
My Thoughts on Key Studies in MDS From ASH 2021

Released: February 16, 2022

Expiration: February 15, 2023

Amy E. DeZern
Amy E. DeZern, MD, MHS
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The 2021 American Society of Hematology (ASH) conference produced exciting presentations of clinical interest for healthcare professionals treating patients with myelodysplastic syndromes (MDS). In this commentary, Amy E. DeZern, MD, MHS, discusses a selection of the most clinically relevant studies for MDS.

A Molecular IPSS for MDS Risk Stratification
We have long used the International Prognostic Scoring System (IPSS) and the more recent revised version (IPSS-R) for risk stratification in MDS. With the increasing prognostic importance of molecular factors for patient risk, Bernard and colleagues in the International Working Group for the Prognosis of MDS presented data on the development of the Molecular International Prognostic Scoring System (IPSS‑M).

To develop this system, researchers integrated molecular features into previous data from an International Working Group discovery cohort of 2957 patients with MDS and then validated it in a Japanese cohort of 754 patients with MDS. The group molecularly characterized these patients with conventional cytogenetics, as well as oncogenic mutations in 152 genes, all of which had variant allele frequencies of >2%. Researchers found 48 genes mutated in ≥1% of patients, with ≥1 oncogenic mutation in 94% of patients.

Adjusting for age, sex, and MDS type, multiple genes were associated with adverse survival outcomes, particularly TP53 multihit, MLL partial tandem duplication, and FLT3 mutations. SF3B1 mutations were associated with favorable outcomes. The group used leukemia‑free survival as the primary endpoint, using other conventional parameters combined with mutations in 31 key genes to improve MDS risk stratification and prognostication. They then validated the system with the Japanese cohort, seeing the same restratification patterns from IPSS-R to IPSS-M in both cohorts.

Conclusion
IPSS-M is a risk score that can be personalized as a continuous score with 6 risk categories (from very low to very high) for an individual patient, and the group is working on a strategy to allow for missing data and develop an online risk calculator, which will be available to healthcare professionals treating these patients to provide better prognostic indicators for improved outcomes.

CPX‑351 in Patients With Higher‑Risk MDS
Patients with higher‑risk MDS (≥10%-19% blasts) are on a continuum for acute myeloid leukemia (≥20% blasts). CPX‑351 (a liposomal combination of cytarabine and daunorubicin) is approved by the FDA for patients with secondary acute myeloid leukemia (AML), including patients with myelodysplasia-related changes, so given the biologic similarities between higher‑risk MDS and AML, it may have efficacy in patients with higher‑risk MDS, as well.

To examine this, Peterlin and colleagues investigated CPX-351 for efficacy and safety in a phase II study in 31 adult patients 70 years of age or younger with previously untreated intermediate-2 or high‑risk MDS. Primary endpoints were dose-limiting toxicity and recommended phase II dose, and secondary endpoints were overall survival (OS), event‑free survival, measurable residual disease, and overall response rate (ORR).

Results showed no dose-limiting toxicities, and ORR was 87%, with 23% complete response (CR) and 45% marrow CR (16% with hematologic improvement). Response was seen across the subtypes of MDS. Hematologic recovery was not significantly prolonged compared with AML data, and adverse events were as expected in this group with mucositis and alopecia. No deaths were reported within 30 days of induction, and no ICU management was required. In total, 29 patients (94%) received a stem cell transplant.

Conclusion
Overall, this first look at CPX‑351 as first‑line treatment in higher‑risk MDS suggests efficacy and safety. It clears the blasts and can be a bridge to allogeneic transplant, and the safety profile compares favorably with other options. The trial was small, with a lower‑risk high‑risk cohort—in that many patients did not have adverse conventional karyotypes—but it shows promise as a reasonable therapeutic option for this patient group.

Retrospective Analysis of Venetoclax Plus HMAs for Higher‑Risk MDS
Hypomethylating agents (HMAs) are the standard of care for patients with higher‑risk MDS. Unfortunately, however, HMAs are associated with a CR of <20% and median OS of only 12-18 months in this group. Early-phase studies have suggested a role for the combination of venetoclax with an HMA in higher‑risk disease, and an ongoing phase III trial is examining this treatment strategy in patients with untreated MDS.

This current study by Komrokji and colleagues is a retrospective analysis from a single institution analyzing clinical outcomes in patients with higher‑risk MDS receiving first‑line HMA (n = 1158), first‑line HMA in combination with venetoclax (n = 35), or the addition of venetoclax to HMAs after HMA failure (n = 31). ORR and median OS were assessed.

The ORR for the upfront combination cohort vs HMAs alone was 77% vs 40% (P <.005), with CRs of 34% vs 13%, respectively. The response rate was significantly higher in the combination arm with ASXL1-mutated MDS, as well as higher for TP53‑mutated MDS. Median OS between the 2 groups was 19.4 months and 17.2 months, respectively, from start of treatment. The rates of AML transformation were higher, although not statistically significant, for HMA alone compared with HMA plus venetoclax. In patients who went on to transplant, 2-year OS was 91% for HMA plus venetoclax (n = 13) vs 51% for HMA alone (n = 256).

In the relapsed/refractory MDS arm, the addition of venetoclax to an HMA after single‑agent HMAs had an ORR of 61%, but most of those were marrow CR. However, the median OS from diagnosis for this cohort was 33 months, with 9 proceeding to autologous stem cell transplant (ASCT), but there was no difference in OS between patients with ASCT vs no ASCT in this group.

Conclusion
This retrospective analysis shows that treatment with first‑line HMA with venetoclax has higher response rates than HMA alone, and this may help salvage the impact of a poor‑risk molecular phenotype such as an ASXL1 mutation. The combination populations were small, however, so I look forward to the phase III data to see if this particular cohort data hold up in the larger trial.

Summary
These are just a few of the promising studies for MDS treatment presented at ASH 2021. For further discussion of these and other investigational treatments for MDS, including eltrombopag plus lenalidomide, sabatolimab, and more, please see CCO’s ASH 2021 MDS/myeloproliferative neoplasms conference coverage.

Your Thoughts?
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