Background: The discovery of IDH1/2 mutations in AML has resulted in FDA approving therapies targeting IDH1/2. Similarly, the changes in methylation brought about by IDH mutations in the AML genome have ushered in treatment regimens combining venetoclax (VEN) with hypomethylating agents (HMA). However, due to the absence of direct comparative studies, there is no clear guidance on the optimal frontline therapy and sequential treatment options for pts with IDH mutations. We set out to investigate a real-world cohort of pts with IDH mutations treated with various frontline and second-line treatment regimens.

Methods: We retrospectively analyzed clinical and molecular characteristics, frontline as well as second-line treatments of 939 newly diagnosed older or unfit AML pts with IDH1/2 mutation who were treated with non-intensive therapy (IDH1/2 inhibitor +/- HMA [IDHi-based], VEN/HMA, or HMA monotherapy). IDHi-based consisted of either IDHi alone or 2 drug combination, IDHi and HMA. Of these pts, 360 were treated from 2015 to 2024 at 10 major US and 1 Mexican Cancer Center as part of the Myeloid Malignancy Association on Rapid Research Outcomes Working Group (MARROW) Consortium. Their data underwent central review and analyses. In addition, we analyzed 579 IDH1/2-mutated pts included in the Flatiron Health EHR-derived and de-identified database (2014-2024). This allowed us to assess characteristics and outcomes across both major cancer/academic centers and community practice.

Results: Of the 939 pts, 60% received VEN/HMA as initial therapy, while 26% and 14% received HMA and IDHi-based, respectively. The median age at diagnosis was 75 years (range 27-90) with 44% of pts being female. For the IDH1-mutated subset, composite complete remission (cCR) rates were highest for VEN/HMA treated pts (VEN/HMA, 61%; IDHi-based, 51%; HMA, 25%, p<0.001). Allogeneic hematopoietic cell transplantation (alloHCT) was performed in 23% of pts treated with VEN/HMA, 10% with IDHi-based, and 14% with HMA, with higher alloHCT rates observed among pts in MARROW compared to those in Flatiron.

While disease-free survival (DFS) was not significantly different for pts on any of the regimen, IDH1-mutated pts on HMA had inferior OS (3-year rate, 15%) compared to VEN/HMA (36%) and IDHi-based (36%). For IDH2-mutated pts, cCR rates were highest for VEN/HMA treated pts (VEN/HMA, 69%; IDHi-based, 41%; HMA, 29%, p<0.001). However, only 13% of VEN/HMA, 14% of IDHi-based and 4% of HMA treated pts proceeded to alloHCT. Similarly, there was no difference in DFS between treatment groups. IDH2-mutated pts treated with VEN/HMA had superior OS (3-year rate, 37%) compared to HMA (17%) and IDHi-based (21%). Notably, this significant OS benefit persisted even among pts who did not undergo alloHCT (3-year rate, VEN/HMA, 32% vs 15% for both IDHi-based and HMA).

Next, we assessed treatment response for second-line treatments. For pts who received VEN/HMA as frontline therapy, 65% of pts achieved cCR with IDHi-based as subsequent line of therapy. However, OS did not differ for IDHi-based (n=31) or HMA (n=23) as second-line therapy. For IDH1/2-mutated pts receiving IDHi-based as first-line treatment, VEN/HMA second-line therapy resulted in CR rates of 88% (7/8), and a 3-year OS of 49%.

In multivariable analyses (MVA), VEN/HMA and younger age are associated with higher CR rates (p<0.001). For MVA for DFS, JAK2 mutations conferred inferior survival, after adjustment for alloHCT. In MVA for OS, JAK2 mutations, as well as KRAS and TP53 mutations were associated with shorter OS (JAK2, HR 1.75, p<0.001; KRAS, HR 2.00, p=0.01; TP53, HR 1.65, p<0.001). For pts who received VEN/HMA as first-line therapy, NPM1 mutations were associated with higher CR rates and longer OS (HR 0.55, p=0.01). DNMT3A mutations were associated with shorter DFS (HR 1.56, p=0.01), and both JAK2 (HR 2.1, p=0.003) and TP53 (HR 1.65, p=0.02) were associated with shorter OS.

Conclusion: These large-scale analyses of newly diagnosed older/unfit AML pts suggest that VEN/HMA and IDHi-based (triplet not assessed), are comparable frontline treatment options for IDH1-mutated pts, while favoring VEN/HMA for pts with IDH2. IDHi-based therapy is under-utilized in the real-world. HMA alone is a viable option in the second line setting. JAK2 mutations are associated with inferior responses to VEN/HMA. Prospective studies are needed to better determine the best sequence of available frontline therapies for IDH-mutated AML pts.

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2025
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