Cost-Effectiveness of Allogeneic Hematopoietic Stem Cell Transplantation Versus Consolidation Chemotherapy for Patients with Intermediate Risk Acute Myeloid Leukemia

*GG and JPB considered as co-senior authors

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic modality for many patients with acute myeloid leukemia (AML). However, due to the morbidity and mortality associated with HSCT in AML, an individualized approach based on patient and disease characteristics is essential. While patients with favorable risk AML per the European LeukemiaNet (ELN) classification can be cured without HSCT, there remains uncertainty whether intermediate risk patients should proceed to HSCT or continue with standard consolidation chemotherapy (CCT). The ETAL-1 trial (Bornhauser et al, JAMA Oncology 2023) randomized patients 18-60 years with newly diagnosed AML in first remission after induction therapy to consolidation with either HSCT or CCT. The trial demonstrated an improved disease-free survival (DFS) but not overall survival (OS) with HSCT. However, the health economic implications comparing an upfront HSCT strategy with a delayed HSCT strategy (i.e., at time of relapse) are unknown.

Methods: We performed a partitioned survival analysis of patients with intermediate risk AML per ELN 2017 criteria enrolled in the ETAL-1 trial (median start age 48 years), with patients receiving either HSCT upfront or up to 3 cycles of CCT with high-dose cytarabine, followed by HSCT only if necessary. All patients in the ETAL-1 trial who were randomized to the CCT arm received HSCT at the time of first relapse. Patterns and costs of subsequent lines of therapy, supportive care, and utilities were based on the original ETAL-1 trial or derived from published literature if not reported in the original trial. We used patient-level data derived from the Kaplan-Meier curves and at-risk tables for DFS and OS from the original trial to reconstruct the survival function for both treatment arms. As HSCT is a potentially curative therapeutic modality we calculated a time-dependent, AML-attributable background mortality rate starting at month 48, when follow-up of patients on the trial ended. Effectiveness was captured in quality adjusted life-years (QALY). AML- and HSCT-specific utilities, and costs were derived from the literature and adjusted for inflation to 2022 US dollars. Gamma distributions were used to parameterize costs and beta-PERT distributions for transition probabilities and utilities. The primary outcome was the incremental net monetary benefit (iNMB) for HSCT compared to CCT at a willingness-to-pay threshold (WTP) of $150,000/QALY over a lifetime time-horizon and from a US health system perspective. All variables were varied ±20% in deterministic and probabilistic sensitivity analyses, with the latter employing 10,000 Monte Carlo iterations to simultaneously propagate uncertainty in all parameters.

Results: The 2-year DFS and OS in our model was 68% and 82% in the HSCT arm and 38% and 82% in the CCT arm, respectively, which was comparable to the original trial (2-year DFS: 70% with HSCT and 39% with CCT; 2-year OS: 76% with HSCT and 83% with CCT). HSCT and CCT incurred total costs of $1.8 and $2.1 million while accruing 9.7 and 9.9 QALYs, respectively. HSCT was the cost-effective strategy with an iNMB of $270,000 [95% credible interval $60,000-$460,000], driven by significant differences in cost and non-significant point estimate differences in QALYs.

One-way sensitivity analyses showed that our model was most sensitive to the monthly costs of care of patients with AML in remission in the CCT arm as well as the probability of proceeding to a salvage HSCT in the CCT arm. In all one-way sensitivity analyses, variation of any model parameter by ±20% continued to yield a positive iNMB consistent with upfront HSCT being the cost-effective strategy. A salvage HSCT rate of <14.2% after CCT would be necessary to make delayed HSCT the cost-effective strategy. Upfront HSCT was the cost-effective strategy in 100% of 10,000 Monte Carlo iterations at a WTP threshold of $150,000/QALY.

Conclusion: In conclusion, we conducted a partitioned survival analysis based on the randomized ETAL-1 trial and showed that for patients 18-60 years with intermediate risk AML proceeding to HSCT in first remission is more likely to be cost-effective than a delayed HSCT transplant strategy (i.e., CCT followed by HSCT at the time of relapse). These findings are specifically driven by the disproportionately lower total cost of upfront HSCT than delayed HSCT.