Characteristics and Outcomes of Acute Myeloid Leukemia in Ethnically Diverse Asians in Singapore

Background

Molecular and cytogenetic classification of AML is standard practice. Most data on mutational frequencies and outcomes with conventional chemotherapy come from large European or American studies. It is unclear if entity-defining and targetable aberrations occur in the same frequency in non-white populations, which has socioeconomic and drug accessibility implications. A large number of FDA-approved targeted therapies for AML remain inaccessible outside the US, either because of local regulatory approval or cost concerns. The aim of this study was to describe the cytomolecular profile and outcomes of AML patients in Singapore, with its Asian population. The only targeted agents approved in Singapore are sorafenib, midostaurin and gilteritinib.

Methods

Pts age ≥18 with newly diagnosed AML treated at our institution were included. All pts had baseline 52-gene next-generation sequencing (NGS) and cytogenetics. FLT3^ITD, FLT3^TKD, IDH1, IDH2 and NPM1 mutations, and t(9;22) or KMT2A rearrangements were considered targetable. Baseline risk was assigned as per the 2022 ELN criteria. Treatments were categorized into anthracycline-based intensive chemotherapy (IC) or low-intensity treatments (LIT). Overall response rate (ORR) was defined as PR or better, CRc as CRi or better. Median time to allogeneic stem cell transplant (SCT) was used for landmark analysis.

Results

100 pts with a median age of 62 (range, 21-91) were included; 58% were ≥60. The ethnic breakdown was 73% Chinese, 17% Malay, 3% Indian, 1% White and 6% others, mirroring the general population in Singapore. 21%, 15% and 64% were classified as favorable, intermediate, and adverse risk, respectively.

The most common mutations were: DNMT3A (26%), NPM1 (22%), FLT3^ITD (20%), IDH2 (20%) and RUNX1 (19%). IDH1^m and FLT3^TKD occurred in 12% and 8% respectively. KMT2Ar and t(9;22) were rare, occurring in 1% each. 58% overall and 68% in ≥60 age group, had targetable aberrations, underscoring the need for access to targeted therapies.

57% were treated with IC and 36% with LIT. 64% of IC and 53% LIT-treated patients achieved CRc. CRc rates were 100%, 67% and 58% for favorable, intermediate, and adverse risk AML, respectively. CRc rates for IC and LIT were 69% and 68%, respectively.

At a median follow-up of 26 months (95% CI, 19-42), the mOS and mEFS were 20 (95% CI, NE) and 10 (95% CI, 6-16) months, respectively. ELN22 favorable and intermediate risk categories were not discriminatory (mOS not reached (NR) for both groups, p=0.79, mEFS 35 vs 14 months for favorable and intermediate respectively, p=0.54). 3-year OS in ELN22 favorable, intermediate, and adverse risk groups was 61% (95% CI, 40-100), 62% (95% CI, 40-100), and 31% (95% CI, 20-50), respectively. When limited to patients treated with IC only, the pair-wise log-rank test showed no difference between any risk groups (3-year OS 71% [95% CI, 68-100], 65% [95% CI, 39-100], and 52% [95% CI, 35-78] for favorable, intermediate and adverse, respectively). This suggests that there may be certain other factors influencing outcomes of such patients in Asia which require exploration.

Pts age ≥ 60 had inferior OS compared with younger patients (mOS 14 months vs NR, p < 0.01). Landmark analysis demonstrated a benefit of SCT in CR1 (mOS NR with SCT vs 28 months without, p=0.03). For pts age ≥60, mOS was not reached with SCT vs 12 months without, p=0.06), with 3-year OS 78% (95% CI, 55-100) vs 17% (95%CI, 4-79) with and without SCT, respectively, reinforcing the concept that age alone should not be a barrier to SCT.

Conclusion

Although an increasing number of targeted therapies for AML are being approved, their accessibility outside the US remains challenging. This study demonstrates that targetable aberrations are highly prevalent in Asians, occurring in 58% overall and 68% in the ≥60 age group. Studies showing similar mutational frequencies in populations traditionally under-represented in large trials or genomic studies are important in determining baseline mutational patterns in different ethnic groups. The prevalence of targetable mutations in Singapore underscores the importance of access to novel and targeted therapies, especially for older patients who require low-intensity treatment options without the toxicity of conventional chemotherapy.

Chan:KITE, norvatis, astrazeneca: Honoraria. OOI:Pfizer: Other: Sponsorship for conference; Abbvie: Other: Sponsorship for conference; BMS: Honoraria; GSK: Honoraria; Antegene: Honoraria; Amgen: Honoraria, Other: Sponsorship for conference; Johnson and Johnson: Honoraria. Chng:Takeda: Honoraria; Hummingbird: Research Funding; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; J&J: Honoraria, Research Funding; Amgen: Honoraria; Abbvie: Honoraria.