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Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) harboring TP53 mutations have poor prognosis. Response to treatment is generally short, and the risk of relapse following allogeneic stem cell transplantation (allo-SCT) is heightened in this subset of patients.
APR-246 reactivates mutant p53 via a number of mechanisms and has exhibited synergy with azacitidine (AZA) both in-vitro and in-vivo. Preclinical data have provided the rationale for clinical evaluation of the combination, and a phase II study conducted by the Groupe Francophone des Myélodysplasies (GFM) is currently underway. The GFM-APR trial (NCT03931291) is investigating the safety and efficacy of APR-246 plus AZA as maintenance therapy for patients with TP53 mutant AML or MDS following allo-SCT. Results were presented at this year’s virtual European Hematology Association (EHA) Annual Congress by Thomas Cluzeau.
*Patients who received ≥ 3 cycles and underwent bone marrow (BM) evaluation
Table 1. Baseline patient characteristics
AML, acute myeloid leukemia; IPSS-R, revised International Prognostic Scoring System; MDS, myelodysplastic syndromes, WHO, World Health Organization |
||
Total patients (N = 52) |
MDS (% of patients) (n = 34) |
AML (% of patients) (n = 18) |
Median age, years (range) |
74 (46–87) |
72 (44–83) |
Male/Female |
15/19 |
12/6 |
WHO 2016 classification, % |
|
|
MDS IPSS-R |
|
|
Intermediate |
12 |
– |
High |
15 |
– |
Very high |
74 |
– |
AML |
|
|
20–30% blasts |
– |
61 |
> 30% blasts |
– |
39 |
Cytogenetic risk, % |
|
|
Complex karyotype |
85 |
89 |
Monosomal karyotype |
79 |
50 |
del(5q) |
53 |
67 |
Figure 1. ORRs at A varying analysis timepoints and B according to WHO disease classification
CR, complete response; CRi, CR with incomplete count recovery; HI, hematologic improvement; PR, partial response; SD, stable disease; WHO, World Health Organization
Table 2. Patient OS rates
AML, acute myeloid leukemia; ITT, intention to treat; MDS, myelodysplastic syndrome; OS, overall survival |
|||
OS |
Median OS, months |
95% CI |
P |
ITT cohort |
12.1 |
8.9–15.3 |
|
Disease |
|
|
0.34 |
MDS |
12.1 |
8.9–15.3 |
|
AML 20–30% blasts |
13.9 |
5.4–22.5 |
|
AML > 30% blasts |
3.0 |
0.0–6.5 |
|
Treatment duration |
|
|
<0.0001 |
≥ 3 cycles |
13.7 |
11.7–15.7 |
|
< 3 cycles |
2.8 |
1.2–4.4 |
|
Table 3. Grade 3–4 AEs
Grade 3–4 AE |
% of global cohort (N = 52) |
Febrile neutropenia |
37 |
Neurological |
6 |
Ataxia |
4 |
Acute confusion |
2 |
AE, adverse event |
Results from this trial indicate that the combination of APR-246 and AZA possesses encouraging safety and efficacy profiles in patients with TP53-mutated MDS and AML. The study highlighted subgroups of patients (elderly and those with renal failure) who may be particularly susceptible to neurologic side effects. Nonetheless, all AEs were manageable and reversible, and therefore close monitoring of these patients is recommended.
These data could contribute towards a more efficacious treatment route for patients with TP53 mutant disease whose options are currently limited.
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