Assessing Role of Comorbidities in Treatment Selection for Older Patients with Acute Myeloid Leukemia
Authors: Grenet Justin , Easwar Neela , Jain Akriti G. , Burkart Madelyn , Ma Xiaoyue , Christos Paul , Ritchie Ellen K. , Samuel Michael , Kaner Justin D. , Canaani Jonathan , Goldberg Aaron D. , Dinner Shira N. , Sweet Kendra L. , Roboz Gail J. , Desai Pinkal 
Published: December 2024

Background: The treatment (Rx) of acute myeloid leukemia (AML) in older patients (pts) is complicated by adverse biologic risk, comorbidities and reduced tolerance to intensive chemotherapy (IC). Among pts 60-75 yrs, assessment of fitness is essential in choosing IC vs. non-intensive (non IC) therapy. Recent guidelines acknowledge the lack of standardized frameworks in assessing fitness. The Ferrara score (FS) and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) are the closest we have in assessing pre-induction and pre-transplant fitness, respectively. We chose to investigate comorbidities in older AML pts to understand whether clinical decisions on Rx choice (IC vs. non IC) and transplant decision correlated with FS or HCT-CI respectively.

Methods: This is a multicenter retrospective study drawing from 4 large U.S. academic medical centers (Weill Cornell, Moffitt, MSKCC, Northwestern). Eligibility included pts aged 60-75 who received CPX-351, 7+3, or HMA+V as frontline Rx for AML from 2013-2022. The Ferrara score was assessed prior to induction Rx and HCT-CI post-induction, prior to possible transplant.

Statistical considerations: To evaluate the association between individual Ferrara criteria and selection of frontline AML Rx, the chi-square or Fisher's exact test were used, as appropriate, and Wilcoxon rank-sum test was performed on total HCT-CI score for transplant decision. For the primary (binary) outcome variable of selection status of frontline AML Rx, multivariable logistic regression analysis was performed to evaluate the effect of total FS on selection of frontline AML Rx.

Results: In total, 298 pts were included (191 pts received IC and 98 pts HMA+V). Overall, 57.8% and 42.2% were male and female respectively, and 60.9% were &lt;70 and 39.1% 70-75 yrs old. The HMA+V cohort (vs. IC) had higher prevalence of several key comorbidities, including CHF/EF&lt;50% (7.22% vs 1.57%, p=0.03), severe pulmonary disease (13.3% vs 2.62%, p&lt;0.001), active resistant infection (5.10% vs 1.05%, p=0.04), and ECOG &gt;/=3 status (5.10% vs 1.05%, p=0.04). Consequently, HMA+V pts were more likely to have FS 1 or 2: 26.0% vs 7.33% (p&lt;0.001), and conversely, 74.0% of HMA+V vs 92.7% of IC pts had a FS 0. As expected, compared to a FS of 0, pts with a score of 1 or 2 had a higher probability of Rx with HMA+V (OR 4.45, 95% CI 2.19 - 9.05, p&lt;0.001). Severe cardiac disease (aOR 5.55, 95% CI 1.40 - 22.0, p=0.01) and severe pulmonary disease (aOR 6.18, 95% CI 2.13 - 17.9, p=0.001) were the only two individual comorbidities found to significantly predict AML Rx selection. Among pts who had FS 0 and got HMA+V (n=71), 59 (83.1%) had any one of the following: adverse ELN risk, prior myeloid malignancy, prior HMA Rx, and TP53 status, while 16.9% of pts who got HMA+V had no comorbidities or adverse features. Adjusting for age, ELN risk, prior myeloid malignancy, prior HMA Rx, and TP53 status, pts with FS 1 or 2 were significantly more likely to receive Rx with HMA+V (aOR 6.06, 95% CI 2.60 - 14.1, p&lt;0.001).

There was no significant difference in HCTCI score after induction Rx (p=0.37) between HMA+V vs IC cohorts. Severe renal dysfunction was the only comorbidity more prevalent in the HMA+V cohort: 9.28% vs 1.57% (p=0.004). Pts who received IC were more likely to undergo transplant: 54.7% vs 18.6% (p&lt;0.001). This could not be explained by CR rates: among 177 (61.5%) pts who achieved CR/CRi, 69.4% of IC pts vs 31.1% of HMA+V pts underwent transplant (p&lt;0.001). Furthermore, there was no difference in total HCTCI score among pts who underwent HSCT vs. who did not (p=0.54). Interestingly, FS pre induction was significantly correlated to HSCT with lower probability of HSCT in pts with FS 1 or 2 vs 0: 15.4% vs 47.0% (p&lt;0.001).

Conclusion:Our analysis showed Ferrara criteria is correlated with upfront AML Rx choice, however a significant proportion of HMA+V treated pts had a score of 0 and adverse biological risk did not always explain the Rx choice. While current clinical trials continue to use these criteria for determination of IC vs. non-IC eligibility, FS does not reflect all the factors that influence Rx selection in the real world. In addition, non-IC pts receive significantly less HSCT compared to IC pts even in CR and with equivalent HCTCI scores and may be strongly affected by their fitness at the time of presentation rather than after induction. Survival analyses by fitness scores on a larger pt group is pending and will be presented at the meeting.