Original Article

Volume 000, Number 000, July 2025, pages 000-000

Does Time Matter From Diagnosis to Induction in Acute Myeloid Leukemia?

Acute myeloid leukemia (AML) is an aggressive hematological malignancy, which accounts for approximately 80% of acute leukemias [1, 2]. Without treatment, the median survival ranges from a few weeks to several months [3]. Leukemia develops from the serial acquisition of somatic mutations in hematopoietic stem and progenitor cells with the capacity to regenerate the neoplastic clone [4, 5]. AML is a very heterogenous disease [6, 7]. Recent advances and our better understanding of the pathogenesis, molecular testing, and the development of novel therapies have brought us to a new era regarding the diagnosis, classification, and treatment of patients with AML [7]. Within the past few decades, genomic studies based on next-generation sequencing (NGS) have further dissected the molecular profile of AML and changed the landscape of AML treatment [4, 5]. The accumulation of molecular information provides a powerful understanding and prognostic insight about AML. An international expert panel from the European LeukemiaNet (ELN) published a well-validated risk stratification tool which is largely based on the comprehensive molecular and cytogenetic analysis at the time of diagnosis for patients receiving intensive chemotherapy [8], as well as an updated molecular risk stratification for patients receiving less intensive chemotherapy [9].

Morphological diagnosis of AML can be made in a few hours; however, results of comprehensive molecular and cytogenetic analysis on the other hand can take longer processing time, up to 2 weeks. Historically, the general recommendation is to initiate induction chemotherapy immediately after the diagnosis is confirmed due to the aggressive and acute nature of AML, especially for those with hyperleukocytosis [10]. Many clinicians wait for comprehensive molecular testing before initiating systemic treatment, utilizing hydroxyurea (HU) as a bridge for blast reduction to stabilize patients with hyperleukocytosis [11]. The optimal timing from diagnosis to treatment (TDT) remains unclear, perhaps due to the lack of prospective randomized clinical trials looking into TDT and corresponding outcomes. A comprehensive molecular and cytogenetic analysis at diagnosis can impact treatment decision and intensity [8, 9, 12-15], even for older patients [16, 17]. This is observed especially in the era of newer and targeted therapies, like liposomal daunorubicin and cytarabine (Vyxeos) for high risk/secondary AML [18], venetoclax combined with hypomethylating agents [2, 19-22], gemtuzumab ozogamicin (GO) for favorable risk AML [23], FLT3 inhibitors with or without chemotherapy for AML with FLT3 mutation [24-26], ivosidenib and azacitidine in IDH1-mutated AML [27], IDH2 inhibition in IDH-mutated AML [28], and menin inhibitors targeting driver mutations in AML such as KMT2A and NPM1 [29].

In this study, we performed a retrospective analysis to assess the complete remission (CR) and overall survival (OS) in relation to the timing of treatment initiation.

A retrospective cohort analysis was conducted at SUNY Upstate University Hospital using EPIC’s Slicer Dicer search tool, and records were reviewed in EPIC from January 2010 to June 2024. We selected all patients fulfilling the following criteria: at least 18 years old; diagnosed with AML; who received intensive or non-intensive chemotherapy. Patients with acute promyelocytic leukemia and those who did not receive any chemotherapy were excluded. The study protocol was approved by SUNY Upstate Medical University’s Institutional Review Board Committee. The study was conducted in compliance with the ethical standards of the responsible institution on human subjects as well as with the Helsinki Declaration.

Patients’ characteristics were analyzed by descriptive statistical methods. CR and early death (ED) were expressed as percentage and compared by the χ² test, whereas for OS, univariate Kaplan-Meier survival curves were plotted to estimate survival over time for each group, with differences assessed by the log-rank test. Pearson’s Chi-square tests were performed for categorical variables. A multivariate Cox proportional hazards model was used to evaluate the independent effects of each covariate and time to death. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were reported while controlling for all other predictors. A significance level of 0.05 was used for all analyses. Likelihood ratios were calculated using logistic regression model. All statistical calculations were done using Statistical Analysis System (SAS) software, version 9.4. OS was calculated from diagnosis until death from any cause. For patients who did not die during the follow-up period, OS was censored on the date of last known follow-up. TDT was defined as time from diagnosis of AML (confirmation by peripheral blood or bone marrow samples) and the beginning of chemotherapy. Use of HU was allowed prior to initiating systemic treatment and was not counted into treatment initiation. Response criteria post chemotherapy induction were evaluated and categorized into CR and no response: CR (CR with incomplete hematological recovery (CRh) and CR with partial hematological recovery (CRi) considered as CR) and partial response was considered as no response.

TDT was stratified into three cohorts: chemotherapy induction between 1 - 5, 6 - 10, and 11+ days. Based on the ELN 2022 risk stratification system, patients were divided into three risk categories: favorable, intermediate, or adverse.

The characteristics of the 187 patients and the comparison of TDT are presented in Table 1. The median age at diagnosis was 63 years old. Of the patients, 34% were younger than age of 60, 50% were males, and 82% were White. Seventy-two percent had de novo AML. According to the ELN 2022 risk stratification, 20%, 36%, and 40% of patients had favorable, intermediate, and adverse risk, respectively. ELN risk stratification could not be calculated in 4% of the patients. In our institution, the median times for NGS and karyotype results were found to be 11 - 14 and 7 - 14 days, respectively. Fifty out of 187 (27%) patients had white blood cell (WBC) counts > 50 (× 10³/µL) at diagnosis. The majority of them (96%) had early treatment initiation (TDT 1 - 10), while only two patients (4%) had delayed treatment initiation (TDT 11+).

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Table 1. Descriptive Characteristics of Patients and Comparison of TDT

The median TDT was 5.4 days. Notably, the majority of patients (n = 130) received chemotherapy within days 1 - 5. Intensive chemotherapy in our study was administered to 62% (n = 116) and included 7 + 3, Vyxeos and FLAG-Ida regimens. Non-intensive chemotherapy was administered to 37% (n = 71) and included the following: venetoclax combined with hypomethylating agents, hypomethylating agents alone, and low-dose cytarabine. Table 2 presents the OS for all TDT groups. The median OS was 20.5 months for TDT 1 - 5, 18 months for TDT 6 - 10, and 10.4 months for TDT 11+.

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Table 2. Overall Survival in Months by Time to Induction for All Patients

HR for OS vs. TDT is shown in Table 3. An induction time of 1 - 5 days decreased the risk of death compared to an induction time of 11 days or more, which showed statistical significance (HR = 0.567, 95% CI: 0.325 - 0.989). There was no statistical difference in OS between the days 1 - 5 and 6 - 10 (HR = 1.072, 95% CI: 0.577 - 1.992). Kaplan-Meier estimates of OS according to TDT are illustrated in Figure 1.

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Table 3. HR for Overall Survival vs. Time to Induction

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Figure 1. Kaplan-Meier estimates of overall survival according TDT. TDT: timing from diagnosis to treatment.

Table 4 presents the reasons for delay in initiating chemotherapy 11+ days after diagnosis.

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Table 4. Reasons for Delay in Initiating Chemotherapy 11+ Days After Diagnosis

The logistic regression model that predicted remission status using timing to induction was statistically significant (χ²(2) = 6.440, P = 0.040). Our model suggested that the odds of CR decreased in those who had induction 11+ days from diagnosis by 0.3 times compared to those who had induction 1 to 5 days from diagnosis. This relationship was statistically significant (OR = 0.32, 95% CI: 0.125 - 0.796; P = 0.003). Our model also suggested that the odds of CR increased in those who began induction 6 to 10 days from diagnosis by 1.1 times compared to those who had induction 1 to 5 days from diagnosis; however, this relationship was not statistically significant (OR = 1.13, 95% CI: 0.442 - 2.907; P = 0.157).

A multivariate analysis was performed to evaluate the independent effects of each covariate and survival. There was no statistical significance in survival between TDT 1 - 5, 6 - 10, or 11+ days. Patients younger than age of 60 trended toward better survival but without statistical significance. Notably, based on the year of diagnosis, patients with a diagnosis of AML in 2020 and after had a better OS. Our model suggested that patients who were diagnosed between 2015 and 2020 had an increased risk of death by 2.2 times compared to patients who were diagnosed in 2020 or later after controlling for all other predictors. This relationship was statistically significant (HR = 2.157, 95% CI: 1.311 - 3.575). Our model also suggested that patients who were diagnosed in 2020 or later had a decreased risk of death by 0.4 times compared to patients who were diagnosed before 2015 after controlling for all other predictors. This relationship was also statistically significant (HR = 0.395, 95% CI: 0.203 - 0.802). Figure 2 presents a forest plot for multivariate analysis, and Table 5 presents the HRs.

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Figure 2. Forest plot of adjusted hazard ratios and 95% confidence interval for each predictor.

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Table 5. aORs for Overall Survival vs. Predictors

Amongst the 90 deaths recorded during the follow-up period, there were 13 deaths within 30 days, all of which occurred in TDT 1 - 5 group. No EDs within 30 days were seen in TDT 6 - 10 or 11+.

Table 6 presents the EDs within 30 days, within 90 days, and after 90 days.

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Table 6. Early Death by Time to Induction for AML

Table 7 summarizes the remission status, chemotherapy intensity, days to platelet and neutrophil recovery, and transplant status for different TDT groups.

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Table 7. Clinical Outcomes Based on TDT Groups

Traditionally, the general recommendations are to start chemotherapy induction for AML patients as soon as possible due to the worries of poor outcomes when delaying therapy or untreated AML as shown in previous observational series [3, 30]. Though thus far, there have been no prospective randomized clinical trials to explicitly confirm the optimal timing to initiating treatment, perhaps due to ethical reasons.

In review of available studies that have investigated TDT and clinical outcomes, some limitations are noted. An Eastern Cooperative Oncology Group (ECOG) study in 300+ AML patients older than 55 years showed significantly lower CR with treatment delay, but no difference in OS, though patients with secondary AML were excluded in this study [30]. A mutual study between Cleveland Clinic and the MD Anderson Cancer Center that included 1,317 AML patients showed no difference in OS and remission status, except for younger patients in whom treatment was delayed by 5 days or more, both OS and CR were significantly lower, though in this study patients with leukocytosis > 50 × 10⁹/L were excluded [31], and almost half of the patients had secondary AML which is proportionally higher than the reported percentage in the literature. Another retrospective study done in Toulouse center, France including 599 patients without excluding patients with high WBC counts showed no difference in OS or CR in both univariate and multivariate analyses between all TDT groups [32]. In a large German study that included 2,263 AML patients, the median TDT was 3 days, the majority of patients had de novo AML (75%), and no significant difference in outcomes (remission status, OS, ED) was observed between TDT groups [3]. A large systematic review of 13 studies showed highly variable results [33].

In our study, 72% had de novo AML, which is very similar to the available literature. Patients with leukocytosis > 50 × 10⁹/L were not excluded, and use of HU prior to initiating chemotherapy was allowed. The majority of patients (48/50, 96%) with leukocytosis > 50 × 10⁹/L were treated early (TDT 1 - 10) and only two patients (4%) had delayed treatment initiation 11+ days after diagnosis in order to achieve cytoreduction prior to initiating venetoclax-based regimen to avoid tumor lysis syndrome [34]. Although the two patients with hyperleukocytosis who had delayed treatment had OS > 6 months, it is not advised to delay initiating cytoreductive therapy for patients with hyperleukocytosis to avoid complications like spontaneous tumor lysis syndrome(TLS) and organs failure [35-37].

The majority of patients (70%) received induction chemotherapy within 5 days from diagnosis, which has shown superior CR and OS - only in univariate analysis - in comparison to patients who had treatment induction after 10 days from diagnosis; however, no difference in OS was seen between TDT groups when multivariate analysis was performed. In comparison to patients who initiated treatment early (TDT 1 - 5), patients who initiated therapy later (TDT 11+) were less likely to achieve CR (45% vs. 73%; P < 0.05), though they were older (mean 71.2 vs. 61.9), less likely to receive intensive chemotherapy (30% vs. 71%), less likely to receive allogeneic stem cell transplant (11% vs. 75%), and had higher TP53 mutations/deletions (15% vs. 5%). This suggests that age is a potential confounder. Thirteen EDs within 30 days were reported in TDT 1 - 5, whereas none were reported in TDT 6 - 10 or 11+, though no statistical correlation could be made due to small sample size. Notably, patients who were initiated on treatment in 2020 and after had better OS which likely is attributed to our better understanding of AML molecular profiling, improvement in supportive care, and the development of targeted therapies (e.g., FLT3 inhibitors, menin inhibitors, and others).

In conclusion, with the availability of newer and targeted therapies for AML, our best course of action and treatment recommendations are increasingly based on molecular profiling, highlighting the importance of obtaining and implementing comprehensive profiling at diagnosis for optimal risk stratification and management. Concordant to other studies listed above, our study suggests no statistically significant difference in OS based on timing to chemotherapy initiation.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Not applicable.

Author Contributions

Osama Batayneh and Teresa Gentile contributed to the study design, literacy search, conceptualization, methodology, writing and editing the manuscript, data collection and analysis. Deevyashali Parekh, Michael Sandhu, and Carina Hernandez contributed to the literacy search, conceptualization, methodology, writing and editing the manuscript, and data collection. Margarita Vazquez Almonte, Angela Gupta, and Danielle Passafiume contributed to the literacy search, conceptualization, writing and editing the manuscript, and data collection. Cristina Hamacher contributed to the literacy search, conceptualization, methodology, writing and editing the manuscript. Safa Afridi and Sanjay Rao Gergal GopalakrishnaRao contributed to the literacy search, methodology, writing and editing the manuscript, and data collection. Alyssa Cortese and Alexanda Goodman contributed to the literacy search, methodology, data collection, writing and editing the manuscript. Kelsey Christo contributed to the literacy search, methodology, conceptualization, writing and editing the manuscript. Josh Wallace contributed to the study design, conceptualization, methodology, data analysis, creating tables and graphs.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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