Salvage Reinduction Chemotherapy Versus Alternative Regimens after Failed AML Intensive Induction Regimen, a Single Center Experience

Background: Intensive induction chemotherapy (Ind-CTX) remains the standard initial treatment for fit patients diagnosed with acute myeloid leukemia (AML). Nonresponse to Ind-CTX is associated with poor prognosis, and further strategies such as reinduction CTX (Reind-CTX) with an intensive CTX regimen or using a less intensive regimen may be offered. The difference in outcome between these strategies is largely unknown. We aim to compare outcomes between Reind-CTX and alternative regimens in AML patients with nonresponse to first-line Ind-CTX.

Methods: We conducted a single-center retrospective cohort study to compare overall survival (OS), event-free survival (EFS), and the clinical response rate for AML in adult patients (≥18 years) who were refractory to first-line Ind-CTX. Patients were included if had a non-response (blasts >5%) on day 14-28 bone marrow aspirate and received a subsequent salvage therapy. Acute promyelocytic leukemia was excluded. Ind-CTX included 7+3 +/- midostaurin or FLAG +/- Idarubicin. Reind-CTX included 7+3, 5+2, etoposide + cytarabine + mitoxantrone (MEC), or salvage high-dose cytarabine 2-3 gm/m² q12hr for four-six days. Baseline variables were collected and included: age, gender, ethnicity, comorbidities, subtypes of AML, cytogenetics, BCR:ABL1 status, FLT3 status, mutational profile based on DNA and RNA next-generation sequencing, ECOG performance status, all treatment lines and responses, and follow-up data. Response to first-line treatment included composite complete response (CCR) (complete response (CR) + complete response with incomplete count recovery (Cri)) and responses assessed by MRD by flow cytometry (MRD-FC) or real-time PCR. EFS was defined from the date of first therapy to the date of the second refractoriness, progression, or death. OS was defined from the date of first therapy to the date of death. The Kaplan-Meier method was used to estimate survival probabilities, and a log-rank test was used to test for differences according to the salvage regimen. Multivariable regression was used to adjust outcomes.

Results: Between 4/2017 and 9/2023, 730 AML patients were treated at Cleveland Clinic Foundation, Ohio. During the study period, 98 patients had no response to Ind-CTX; sixty-six patients (67%) received Reind-CTX, fifteen patients (15%) received venetoclax in combination with a hypomethylating agent (Ven+HMA), and seventeen patients (17%) received other treatments, including HMA. The most common Ind-CTX and Reind-CTX were 7+3 followed by 5+2 (27%). The most common salvage Ven+HMA was Ven+Azacitidine (80%). The median age at diagnosis for Reind-CTX was 64 years [IQR: 57-68], 59 years for Ven+HMA [IQR: 57-69], and 55 years for others [IQR: 42-68]. High-risk cytogenetics was seen in 25%, 47%, and 56% of patients in Reind-CTX, Ven+HMA, and other treatment groups, respectively. On multivariable logistic regression, Reind-CTX was more likely to achieve CCR compared to Ven+HMA (odds ratio (OR): 0.2, 95% CI 0.05-0.66) and other treatments (OR: 0.33, 95% CI 0.1-1.02) (P=0.011). The crude CCR rates were 65%, 27%, and 35% for Reind-CTX, Ven+HMA, and other treatments, respectively.

With a median follow-up period of 34.7 months (range: 4.99 - 75.2). On multivariable Cox proportional hazards model (CPH), OS was not different in the Reind-CTX compared to Ven+HMA (mortality hazard ratio (HR): 0.58, 95%CI: 0.23-1.46) and other treatments (mortality hazard ratio (HR): 1.64, 95%CI: 0.83-3.21) (P=0.13). For EFS, the median follow-up was 34 months (range: 2.17 - 73.03). On CPH, Reind-CTX was associated with a similar EFS compared to Ven+HMA (HR: 1.12, 95%CI: 0.5-2.5), and other treatments (HR: 1.82, 95%CI 0.96-3.46) (P=0.2).

Conclusion: Patients who received salvage Reind-CTX after a failed AML Ind-CTX had a higher response rate compared to patients who received Ven+HMA or other treatments. However, this was not translated into a superior long-term OS or EFS. Because of the higher CCR rates, Reind-CTX might have a utility in AML patients planned for an early allogeneic transplant.