Outcomes with HMA Plus Venetoclax Vs Intensive Chemotherapy in AML Patients with Chromosome 5 and 7 Abnormalities
Authors: Boussi Leora , Bewersdorf Jan Philipp , Liu Yiwen , Shallis Rory M. , Aguirre Luis E. , Zucenka Andrius , Garciaz Sylvain , Bystrom Rebecca P. , DeAngelo Daniel J. , Stone Richard M , Luskin Marlise R. , Garcia Jacqueline S. , Winer Eric S. , Chen Evan , Wadleigh Martha , Ling Kelly , Zeidan Amer M. , Goldberg Aaron D. , Stein Eytan M. , Shimony Shai O. , Stahl Maximilian 
Published: December 2024

Background: Deletions in chromosome 7 (del(7)) are the most common individual cytogenetic abnormality conferring adverse risk in acute myeloid leukemia (AML). Adverse risk monosomy 5 and 5q deletions (-5/del(5q)) occur in up to 40% of clinically defined secondary AML. As these alterations are associated with poor outcomes, allogeneic stem cell transplant (alloSCT) is recommended for patients (pts) who achieve post-induction complete remission (CR). However, whether induction with intensive chemotherapy (IC) is superior to hypomethylating agent plus venetoclax (HMA+ven) is unclear. Hence, we performed a retrospective study in a large cohort comparing outcomes in pts with del(7)/del(7q) and/or -5/del(5q) treated with IC vs HMA+ven.
Methods: We included clinicopathological and molecular data from 1125 pts with newly diagnosed AML from 4 academic centers (MSKCC, DFCI, Yale, NCI in Lithuania) treated with 7+3 or CPX-351 (IC) vs HMA+ven. We defined molecular ontogeny as previously described (Lindsley, Blood 2015). The Kaplan-Meier method was used to estimate overall survival (OS). Log-rank test was used to compare OS between groups. Composite CR (cCR) was defined as CR+CR with incomplete count recovery (CRi).
Results: 228 pts (20%) had del(7)/del(7q) (n=140/228, 61%) and/or -5/del(5q) (n=145/228, 64%). Median age was 68 yrs (22, 92). Induction therapy was IC in 38% (86/228) and HMA+ven in 62% (142/228). Clinical and molecular characteristics differed between groups: HMA+ven-treated pts were older (median 72 vs 61 yrs, p&lt;0.001) and more likely to harbor TP53 mutations (70% vs 37%; p&lt;0.001) and complex karyotype (83% vs 64%; p&lt;0.001); IC-treated pts had higher rates of prior MDS (30% vs 22%, p=0.16), HMA exposure (20% vs 10%, p=0.046), and RUNX1 (23% vs 10%; p=0.012), BCOR (10% vs 3%; p=0.048), RAS pathway (63% vs 29%; p&lt;0.001), and secondary ontogeny mutations (56% vs 28%; p&lt;0.001). cCR rates were comparable across IC and HMA+ven groups (40% vs 41%), with morphologic leukemia-free state rate of 5% vs 14%. In pts with minimal residual disease (MRD) assessment, MRD negativity was achieved in 17% (7/42) of IC- and 37% (22/59) of HMA+ven-treated pts. AlloSCT rates were higher after IC than HMA+ven (53% vs 18%, p&lt;0.001). Relapse rates were lower in the IC group (35% vs 76%).
In the entire cohort (n=1125), median OS (mOS) was shorter with del(7)/del(7q) and/or -5/del(5q) than without [7.4 months (mos) (95% CI, 6.2-9.4) vs 27 mos (95% CI 22-32), p&lt;0.001)]. Pts with del(7)/del(7q) and/or -5/del(5q) treated with IC had longer mOS compared to HMA+ven [10 mos (95% CI, 7.6-15) vs 6.1 mos (95% CI, 5.6-7.8), p=0.0032]. As HMA+ven-treated pts were older, subsequent OS comparison was focused on pts age 60-75, wherein IC-treated pts had comparable mOS to HMA+ven [7.6 mos (95% CI, 5.6-11) vs 6.4 mos (95% CI, 5.7-9.4), p=0.67]. The mOS for pts who received alloSCT was significantly longer compared to pts who did not [24 mos (95% CI 18-44) vs 5.5 mos (95% CI 4.4-6.1), p&lt;0.0001]. However, mOS of pts undergoing alloSCT did not differ by pre-transplant IC vs HMA+ven [21 mos (95% CI, 16-51) vs 25 mos (95% CI, 18-NR), p=0.49].
Lastly, we evaluated the differential effect of the ontogeny of co-occurring mutations and treatment strategy on survival. Of all pts with del(7)/del(7q) and/or -5/del(5q), 18%, 25%, and 57% had co-mutations of de novo, secondary, and TP53 mutated ontogeny, respectively. Evaluation of each ontogeny by treatment revealed that with a secondary ontogeny defining co-mutation, mOS was longer in 30 IC- than 24 HMA+ven-treated pts [14 mos (95% CI 6.8-51) vs. 5.7 mos (95% CI 2.9-NR), p=0.045]. Conversely, with de novo ontogeny defining co-mutations, there was no difference in mOS between 24 IC- and 18 HMA+ven-treated pts [13 mos (95% CI 5.7-36) vs. 13 mos (95% CI 5.9-24), p=0.49]. In pts with TP53 co-mutations, mOS was comparable between 32 IC- and 98 HMA+ven-treated pts [8.3 mos (95% CI 6.2-16) vs. 6 mos (95% CI 5.1-8), p=0.11]. A multivariable analysis of predictors of survival will be presented at the ASH meeting.
Conclusions: In this large multicenter cohort, survival outcomes for pts with del(7)/del(7q) and/or -5/del(5q) were overall poor but improved with alloSCT. There was no difference in mOS following induction with IC vs HMA+ven in pts age 60-75 and in pts who had alloSCT after induction. There was also no difference in mOS following induction with IC vs HMA+ven in pts with a concomitant de novo ontogeny defining or TP53 co-mutation.