International perspective| progress in the treatment of high-risk myelodysplastic syndrome

In SWOG S1117, a phase II/III trial in the North American Intergroup, patients randomized to single-agent azacitidine or azacitididine + lenalidomide or azacitidomidine + vorinostat had an improvement in response rates, and there was no significant difference
in OS between groups.

Pevonedistat is a selective NEDD8-activated enzyme inhibitor, which in combination with azacitidine has achieved good efficacy
in myeloid tumors.
The results of a phase II clinical trial of Pevonedistat combined with azacitidine showed that the CR rate and EFS rate of patients with high-risk MDS in the combination group were significantly improved compared with single-agent azacitidine, and the CR rate reached 52%; In the phase III PANTHER trial, Pevonedistat plus azacitidine failed to improve the primary endpoint event-free survival (EFS) and CR rates
in patients with high-risk MDS.
Professor David A.
Sallman explained that the above study is an open-label clinical trial, which may lead to differences in efficacy between groups and ultimately affect potential drug synergies
.

Magrolimab is an anti-CD47 antibody that blocks CD47 interactions with SIRPα; It has been shown to promote phagocytosis
of tumor cells in human cell lines and xenograft models of primary AML.
The 2020 EHA Congress updated the results of
the Phase Ib trial of magrolimab in azacitidine in patients with treatment-naïve high-risk MDS.
In this study, 13% of patients had TP53 mutations, the combination regimen was well tolerated, and no patients were discontinued due to treatment-related adverse events; For efficacy outcomes, the objective response rate (ORR) was 91%, including a CR rate of 42% and a complete bone marrow response rate of 24%, in addition to 58% of patients freed from transfusion dependence, median OS was not achieved, and 6-month OS rate was 100%.

These results prompted a phase III randomized, double-blind clinical trial (ENHANCE-1 study; NCT04313881), comparing magrolimab + azacitidine and azacitidine + placebo in patients with low-risk MDS (n=520), with CR and OS as common primary endpoints
.

Sabatolimab is a novel myeloid immune drug targeting TIM-3, an immunomodulatory protein expressed in immune cells and myeloid leukemia progenitor cells, but not in normal hematopoietic stem cells
.
The 2021 ASH Congress presented updated data
on sabatolimab in combination with demethylating drugs (HMAs) for patients with high-risk MDS and AML.
Compared with single-agent HMA, the ORR and CR rates in the combination group were 57% and 20%, respectively, with no significant improvement, but there were good results in duration of response (DOR), objective response and CR duration were 17 and 19 months, respectively, and patients with high-risk MDS, including TP53 mutations, also achieved good efficacy, with a DOR of 21.
5 months
.

Venetoxalo is an orally potent BCL-2 inhibitor with good synergistic effects with azacitidine, which is the standard regimen
for elderly patients with AML.
Due to safety concerns for high-risk MDS patients, it is necessary to shorten the administration time of venetoclax combined with azacitidine (eg, 14 days), but the synergistic effect of this regimen is still very strong, and the ORR and CR rates of patients reach 80% and 40%, respectively, and even achieve deep molecular remission
.
These data drove the phase III VERONA trial (NCT04401748), which included 500 patients with CR and OS as common primary endpoints
.

Professor David A.
Sallman said that previous studies have confirmed that TP53 mutations are associated with poor prognosis in MDS patients, and the median OS of MDS patients with TP53 mutations is only 6-12 months
.
In addition, TP53 mutations are a predictor of poor OS in patients receiving HMA and allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is currently the only recognized intervention that improves MDS
.
Recent studies have shown that patients with TP53 mutation MDS have an increase in blast and are homogeneous with AML with TP53 mutation, and the prognosis is poor
.

APR-246 (Eprenetapopt) is a novel small molecule anti-cancer drug that kills cancer cells
by restoring mutated non-functioning p53 activity and disturbing cellular redox balance.
Recent studies have shown that APR-246 has anticancer activity independent of p53 due to its ability to increase reactive oxygen components, and can induce early cell death
through ferrozoosis.
Results from a phase Ib/II clinical trial showed that azacitidine in combination with APR-246 was well tolerated with no dose-limiting toxic events
.
A clinical trial (NCT03588078) reported similar data and also showed good response rates
.
These trial results have driven the Phase III clinical trial of APR-246 plus azacitidine versus single-agent azacitidine in patients with TP53-mutated MDS (NCT03745716).

However, the CR rates of the control group and the combination group were 22.
4% and 33.
3%, respectively, and the difference was not significant (P=0.
13).
Survival follow-up is still ongoing, and it is hoped that it will provide some assistance
in the analysis of differences in efficacy.

Magrolimab in combination with azacitidine has significant activity in TP53-mutated diseases, although the mechanism is unclear
.
The 2020 ASH Congress presented cohort data for patients with TP53-mutant AML, with a CR/CRi rate of 59%
in the evaluable cohort of patients with TP53-mutant AML (n=29).
Although the median follow-up was only 4.
7 months, the median OS was 12.
9 months
.
This data supports the ongoing Phase III open-label ENHANCE-2 clinical trial (NCT04778397), which explored the efficacy of azacitidine + magrolimab versus azacitidine + venetoclax in patients with unfit AML and compared the efficacy of induction chemotherapy in patients with fit AML; OS in the non-intensive chemotherapy group was the primary endpoint
.

Professor David A.
Sallman concluded that although the combination of azacitidine combined with veneclax can increase the CR/CRi rate of patients with TP53 mutation AML by 47%, the median duration of response in these patients is shorter, only 5.
6 months, and the median OS is 7.
2 months, similar to the survival data of single-agent HMA
.
Recent studies have shown that TP53 mutations are the main driver of venekla's resistance
.
Despite the homogeneity with TP53-mutated AML, it remains unclear how well the venetoclax combination regimen is effective
in patients with MDS with TP53 mutation.