Patterns of Relapse Following Venetoclax-Based Therapies of Differing Intensity in Acute Myeloid Leukemia
Authors: Arani Naszrin , Jen Wei-Ying , Bataller Alex , Bazinet Alexandre , Ravandi Farhad , Daver Naval , Takahashi Koichi , Loghavi Sanam , Abbas Hussein A. , Almanza Emmanuel , Montalban-Bravo Guillermo , Garcia-Manero Guillermo , DiNardo Courtney D. , Kantarjian Hagop M. , Kadia Tapan M. 
Published: December 2024

Background:
The approval of venetoclax (VEN) has transformed the treatment of AML. However, the patterns of relapse following VEN-based therapies of differing intensity are unclear. We sought to characterize the genomic aberrations at relapse in VEN-treated pts and determine if treatment intensity impacted patterns of relapse.
Methods:
This was a retrospective review of patients (pts) with newly diagnosed AML treated on prospective clinical trials of VEN-based regimens. Treatments were classified based on intensity into intensive (FLAG-IDA+VEN or CLIA+VEN [IV]), intermediate (cladribine, low-dose cytarabine +VEN [CV]) and low-intensity (hypomethylating agents + VEN [HV]).
Data on cytogenetic and mutational profiles at diagnosis and relapse were collected, and baseline risk was assigned per ELN22 guidelines. Cytomolecular aberrations were classified as persistent (present at identified at diagnosis and relapse), emergent (identified at relapse only) or cleared (identified at diagnosis only). Mutations were grouped into signaling (CBL, KIT, FLT3, NRAS, KRAS, HRAS, PTPN11, NF1), epigenetic (DNMT3A, IDH1, IDH2, TET2) or splicing (SF3B1, SRSF2, U2AF1, ZRSR2). Pts whose cytomolecular data was missing at relapse were excluded from the relapse characterization analysis.
Results:
447 pts were included, 172 (38%) IV, 141 (32%) CV and 134 (30%) HV. The median age was 66 years (range, 18-89), with 290 (65%) aged ≥60. Median age differed significantly across treatment groups (IV 48, CV 69, and HV 73 years, p &lt;0.01). The HV group had more adverse (IV 44%, CV 59%, HV 66%) and less favorable risk (IV 22%, CV 21%, HV 13%) AML (p &lt;0.01). Adverse risk assignment was driven by higher proportion of complex cytogenetics (IV 12%, CV 16%, HV 35%, p &lt;0.01) and adverse risk mutations (IV 38%, CV 62%, HV 65%, p &lt;0.01). Frequencies of specific mutations at diagnosis for IV, CV and HV, respectively, were: NPM1mut 22%, 23%, 15%; FLT3ITD 12%, 4%, 4%; IDH1/2mut 22%, 23%, 11%; TP53mut 6%, 16%, 34%; signaling 45%, 38%, 18%; epigenetic 47%, 54%, 27%; and splicing 19%, 32%, 16%.
The CRc rate was 95% for IV, 85% for CV and 75% for HV with 3%, 8% and 19% non-responders (NR), respectively (p &lt;0.01). At a median follow-up of 33 months (95% CI, 27 - 39), relapses occurred in 15%, 19% and 45% of the IV, CV and HV groups, respectively. The 3-year CIR was 20% (95% CI, 13-27) for IV, 26% (95% CI, 16-35) for CV and 57% (95% CI, 46-67) for HV. The 3-year OS was 71% (95% CI, 63-79), 55% (95% CI, 47-65) and 27% (95% CI, 21-36), with a 3-year EFS of 67% (95% CI, 60-76), 49% (95% CI, 41-59) and 24% (95% CI, 18-32) for IV, CV and HV, respectively. Landmark analysis demonstrated the benefit of stem cell transplant (SCT) in intermediate and adverse risk pts treated with IV (73% SCT, 3-year OS 79% [95% CI, 70-89] vs 41% [95% CI, 25-67] for no SCT) and CV+HV (62% SCT, 3-year OS 62% [95% CI, 48-81] vs 35% [95% CI, 26-47] for no SCT).
Cytomolecular data was available for 22 (88%), 25 (93%) and 53 (88%) relapses in the IV, CV and HV groups. The most common mutations at relapse were TP53 (36%), DNMT3A (23%), TET2 (23%), RUNX1 (14%) and NRAS (14%) for IV; RUNX1 (20%), TP53 (16%), TET2 (16%), SRSF2 (12%) and DNMT3A (8%) for CV; and TP53 (42%), DNMT3A (28%), TET2 (25%), NRAS (21%) and RUNX1 (17%) for HV.
Persistent TP53mut was observed across all treatment groups (18% IV, 16% CV, 38% HV). Interestingly, there was no emergent TP53mut in the CV group, in contrast with 18% post-IV. 8% of CV achieved TP53 clearance.
Signaling mutations were seen in 36% of pts relapsing after IV, compared with 16% of CV and 26% of HV. While such mutations were largely persistent or emergent after IV or HV, they were cleared in 40% of CV pts at relapse. FLT3mut at relapse was rare, occurring in only 1 patient in each treatment arm.
Epigenetic mutations were detected in 51% of HV pts at relapse; 25% were emergent mutations. In contrast, they were seen in 41% of IV (all persistent except 1) and 32% of CV (all persistent). Splicing mutations were less frequent (18%) in intensively treated pts compared with CV (32%) and HV (30%). There were no emergent splicing mutations in the IV group; these were emergent in 8% of CV and 17% of HV.
Conclusion:
CIR, OS and EFS improve with intensity of VEN-based regimens, with high proportions of pts undergoing consolidative SCT. Patterns of relapse differed slightly between regimens, suggesting that backbones may be personalized, even in the presence of conventionally non-targetable mutations.