Sabatolimab for the treatment of poor prognosis myelodysplastic syndromes and acute myeloid leukemia

High-risk and very high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) carry poor prognosis for patients despite advances in treatment options. Sabatolimab is a novel antibody that targets T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), a putative checkpoint receptor involved in regulating both innate and adaptive immune responses. TIM-3 is expressed on leukemic stem cells, but not normal hematopoietic stem cells. Sabatolimab binds directly to leukemic cells, driving the immune-mediated killing of tumor cells, and blocking replication.¹

At the 26th Congress of the European Hematology Association (EHA2021), Andrew Wei and colleagues¹ presented findings from a phase Ib clinical trial (NCT03066648), which characterized the safety and tolerability of sabatolimab with hypomethylating agents (HMAs) in patients with poor prognosis MDS and AML. The findings are summarized below.

Study design

A phase Ib clinical trial, with the study design shown in Figure 1.

*Adapted from Wei et al.¹

Inclusion criteria

Revised International Prognostic Scoring System (IPSS-R) high-risk or very high-risk MDS or newly diagnosed unfit AML patients, ineligible for standard chemotherapy.

Endpoints were as follows:

• Primary endpoints: maximum tolerated dose; recommended dose; safety and tolerability.
• Secondary endpoints: preliminary efficacy; response rates; duration of response.

Results

A total of 101 patients were recruited. Table 1 shows basic demographic and diagnostic data.

Table 1. Demographic and diagnostic data*

AML, acute myeloid leukemia; HR, high-risk; MDS, myelodysplastic syndromes; vHR, very high-risk. *Adapted from Wei et al.1
Characteristic	HR/vHR MDS (n = 53)	AML (n = 48)
Sabatolimab + decitabine patients, n	19	22
Sabatolimab + azacitidine patients, n	34	26
Median age, years	70 (range, 23−90)	75 (range, 59−89)
Male, n (%)	29 (54.7)	26 (54.2)
Risk category, n (%)
High	32 (60.4)	—
Very high	21 (39.6)	—
Intermediate	—	19 (39.6)
Adverse	—	29 (60.4)

Secondary endpoints: Safety and tolerability

Of the 101 patients, one patient in the AML group discontinued treatment due to a sabatolimab-related adverse event, and there was one sabatolimab-related death in the MDS group (neutropenic colitis with shock). Only one patient discontinued treatment due to sabatolimab dose-limiting toxicity (hepatitis) (Table 2). Overall, treatments were well tolerated with median treatments in the MDS and AML groups of 8.01 and 6.8 months, respectively.

Table 2. Tolerability and continuation data for treatment groups by condition*

AE, adverse event; AML, acute myeloid leukemia; HR, high-risk; MDS, myelodysplastic syndromes; SCT, stem cell transplantation; vHR, very high-risk. *Adapted from Wei et al.1
Tolerability	HR/vHR MDS (n = 53)	AML (n = 48)
Sabatolimab + decitabine, median treatment (months)	8.02 (range, 0.9−33.5)	6.8 (range, 0.8−30.9)
Sabatolimab + azacitidine, median treatment (months)	3.84 (range, 0.8−17.2)	5.98 (range, 1.1−16.7)
Patients discontinuing therapy, n (%)	39 (74)	42 (87.5)
Reasons for discontinuation, n (%)
SCT	12 (23)	0
AE related to sabatolimab	0	1 (2)
Death, related to sabatolimab	1 (2)	0
Dose-limiting toxicity	0	1 (3)

Most of the adverse events were attributable to HMAs alone, not sabatolimab, with 35% of patients requiring a dose interruption, and 1% requiring a dose reduction. The most common events were either hematopoietic-related (thrombocytopenia, neutropenia, anemia) or gastrointestinal (nausea, constipation, diarrhea).

In terms of immune-mediated adverse events, only four patients experienced possible treatment-related (sabatolimab) events, leading to dose delay, reduction, or discontinuation.

In terms of clinical outcomes, the overall risk rate was 58% for MDS patients, and 42.5% for AML patients. Further data relating to efficacy and duration of response can be seen in Table 3, including data on duration of response in patients with adverse risk disease (e.g., TP53 mutations, cytogenetic poor risk, and at least one of the TP53/RUNX1/ASXL1 mutations).

Table 3. Clinical outcomes and survival data for both MDS and AML patients*

AML, acute myeloid leukemia; CR, complete response; DOR, duration of response; HR, high-risk; MDS, myelodysplastic syndromes; NE, not evaluable; ORR, overall response rate; PFS, progression-free survival; vHR, very high-risk. *Adapted from Wei et al.1
Outcome	HR/vHR MDS		AML
Overall DOR, months (95% CI)	16.1 (6.7−NE)		12.6 (5.2−NE)
Estimated 12-month PFS, % (95% CI)	50.1 (27.3−69.2)		27.4 (14.5−42.0)
Patients in CR in the intention-to-treat population, %	20		25
DOR in CR, months (95% CI)	21.5 (12.1−NE)		23.0 (1.3−NE)
Mutation	ORR, %	DOR, months	ORR, %	DOR, months
TP53	71.4	14.7 (95% CI, 6.7−NE)	40	4.2 (95% CI, NE−NE)
Cytogenetic poor risk	60	12.1 (95% CI, NE−NE)	—	—
At least one of the following: TP53/RUNX1/ASXL1	67.7	16.1 months (95% CI, 3.0−NE)	53.8	12.6 months (95% CI, 1.3−NE)

Conclusion

Overall, the data from this phase Ib trial of sabatolimab with HMAs demonstrate that the combination is well tolerated in patients with poor prognosis MDS and AML. It also demonstrates that complete remission, and durable disease responses can be achieved in both patient groups, including those with adverse risk disease, such as TP53 mutations. Further phase II and phase III clinical trials are needed, and currently underway, to determine what benefit patients with poor prognosis MDS and AML could derive from this treatment combinations.