Acta haematol: Phase II study of azacitidine, vignitok clarke, and trametinib carrying RAS pathway-activating mutations in relapsed or refractory acute myeloid leukemia

Mutations in the RAS/RAF/MEK/ERK pathway lead to resistance to several treatments for acute myeloid leukemia (AML), including hypomethylating drugs (HMAs) plus intravenous toclax
.
Trametinib is an oral MEK inhibitor that has been studied for the monotherapy of relapsed/refractory (R/R) AML
with KRAS/NRAS mutations.
Preclinical studies have shown that there is a synergistic effect
between vitoclas and tratinib in ras-mutated AML.
Therefore, a research team sought to evaluate azacedin, vignitoclas, and trametinib in combination in patients with R/R AML with R/Ras pathway-activating mutations
.

In this phase II study, adult patients with R/R AML or high-risk R/R MDS or CMML (≥10% high risk) of the International Prognostic Scoring System carrying Ras pathway-activating mutations involving HRAS/NRAS/KRAS, KIT, BRAF, CBL, PTPN11, or NF1 were eligible).

The performance status of PTS was 2 ≤, total bilirubin ≤ was 2.
5 times the upper limit of normal (ULN), ALT/AST ≤ was 3x ULN, and creatinine clearance ≥ was 30 mL/min
.
In cycle 1, patients receive azacitidine 75 mg/m2 SC/IV on days 1-7, vitokla on days 1-28 (1,200 mg on day 1, day 400 mg), and 2 mg
PO on days 1-28.
On day 21, bone marrow examination is performed if the mother is born

Between August 8, 2020 and May 2021, 16 patients were treated
.
The median age was 67 years, and the six patients (38%) were ≥75 years
.
This is a very severe pretreatment population, with a median of 4
for previous treatment.
All patients were treated with HMA, of whom 13 (81%) had previously received HMA Garvitok
.
Eight patients (50%) had previously received a hematopoietic stem cell transplant (HSCT).

Fourteen patients (88%) had adverse risk diseases, of which 6 (38%) had complex karyotypes and 3 (19%) TP53 mutations
.
Excluding Ras pathway mutations, ASXL1 is the most common co-mutation, present in 50% of patients
.

Overall, 4 patients (25%) responded (1 CR, 1 CRi, 2 MLFS).

2 (67%) of 3 patients who did not receive HMA + HMA responded (1 CR and 1 MLFS); In contrast, only 2 (15%) of the 13 patients who received HMA responded (1 CRi and 1 MLFS).

3 of the 4 responders had diploid karyotype and 1 NRAS mutation; The other pt has a complex karyotype and an NF1 mutation
.
Among the 3 patients who responded with NRAS mutations, the frequency of NRAS variant alleles decreased significantly (0.
15~0.
05 and 0.
51~0.
02)
in 2 patients.
In addition to 4 patients who had a formal response, the ≥ of bone marrow explosions was reduced by 50% in 4 (25%) patients, and 1 of them had previously received HMA plus intravenous tokela, and the explosion was reduced from 26% to 6%, and the study continued for 5.
5 months
.

The median follow-up was 7.
4 months
.
One patient who acquired MLFS relapsed
after 2 months of remission.
The other 3 patients remained in remission
.
Two of the patients remained under study and sustained remission for 3 and 8 months, while the others received HSCT and continued to remission for 7 months
.
The median overall survival (OS) for the entire cohort was 2.
7 months, and the overall survival rate at 6 months was 25%.

The median OS for responders and non-responders was not reached, 1.
7 months (P = 0.
02),
respectively.

The most common non-haematological adverse events of any grade were diarrhoea (88%) and nausea (63%)
.
Grade 3 non-haematological adverse events that may be relevant to study treatment include: mucositis (=3), diarrhea (=1), and decreased ejection fraction (EF) (=1).

Six patients (38%) required dose reduction or temporary discontinuation of trametinib
due to mucositis (=2), retinopathy (=1), decreased EF (=1), rash (=1), and diarrhea (=1).

In severely pretreated populations with this Ras pathway-activated myeloid malignancy, the response rate with a triple dose of azacitidine, vevitoclas, and trametinib was 25%.

Two of the three patients who had not been previously exposed to HMA gavitocl responded, and although the response rate in patients with prior HMA gavitocl was moderate (15%), the activity of this population suggested that the addition of trametinib to these patients may be beneficial
.

Original source:

Desikan SP, Ravandi F, Pemmaraju N, Konopleva M, Loghavi S, Jabbour EJ, Daver N, Jain N, Chien KS, Maiti A, Montalban-Bravo G, Kadia TM, Macaron W, DeLumpa R, Kwari M, Borthakur G, Short NJ.
A Phase II Study of Azacitidine, Venetoclax, and Trametinib in Relapsed or Refractory Acute Myeloid Leukemia Harboring RAS Pathway-Activating Mutations.
Acta Haematol.
2022; 145(5):529-536.
doi: 10.
1159/000525566.
Epub 2022 Jun 17.
PMID: 35717939.