Modified Intensive Induction Treatment for Elderly Acute Myeloid Leukemia Patients Based on Peripheral Blast Clearance Rate: A Phase II Single-Arm Study
Authors: Li Ya , Li Xiaoyang , Zhu Hongming , Zhang Yunxiang , Chen Yu , Chen Qiusheng , Zheng Yu , Li Junmin 
Published: November 2021

Abstract
Background
Outcomes and prognosis of older patients with acute myeloid leukemia (AML) are fairly dismal and poor tolerance to regimens hinders treatment decision-making to expand to the greatest extent. Nevertheless, it is still indicated that a certain proportion of elder patients may benefit from intensive therapies [1], after which the insistent need for algorithms to select elder patients fit for intensive regimens has emerged. Based on the previous achievement, monitoring the peripheral blast clearance rate on the day 5 of induction chemotherapy (D5-PBCR) showed its promising value in younger patients [2]. Along with the increasingly important comprehensive geriatric assessment (CGA), we conducted this trial in fit elderly AML patients to confirm the non-inferior efficacy of modified intensive treatment on the basis of D5-PBCR.
Materials and methods
This multiple-center, single-arm, phase 2 trial of early intervention according to D5-PBCR results with modified "3+7" regimen was performed at Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China) and the other two hospitals in Shanghai. Patients aged 60-75 years were assessed via CGA and required to be fit for intensive chemotherapy. Eligible patients had newly diagnosed AML with more than 0·5% blasts detected in the peripheral blood and adequate end-organ function. The initial induction included idarubicin (6 mg/m² for 3 days) and cytarabine (100 mg/m² for 7 days). Peripheral blood specimens were collected before and on day 5 of induction and analyzed by multi-parameter flow cytometry to calculate the D5-PBCR. D5-PRCR (+) patients received extra IDA (6 mg/m² for 2 days) starting from induction day 6 with the absence of contraindications. Responders received another "2+5" regimens and at least two cycles of mediate dose cytarabine or even allogeneic stem cell transplantation, if eligible. The primary endpoint was composite complete remission (CR/CRi), and secondary endpoints were overall survival, event-free survival, early mortality, minimal residual disease after one cycle of induction, drug toxicity, and safety. The trial was registered in the Chinese Clinical Trial Register (ChiCTR-OPC-16008955).
Results
Between March 30, 2016, and June 30, 2021, a total of 120 eligible patients were enrolled in the trial (Fig.1). Fifty-nine (49.2%) patients were D5-PBCR (+), of which seventeen patients were ineligible for extra idarubicin due to severe infection or unstable hemodynamic parameters and one patient was lost to follow-up. None of the patients in the D5-PBCR (-) group discontinued induction due to adverse events, and three patients were lost to follow-up. The composite complete remission rate after one course of induction for all patients was 62.6% (62/99), with 65.5% (38/58) and 58.5% (24/41) for D5-PBCR (-) and D5-PBCR (+) groups, respectively (P=0.497). At a median follow-up of 24.3 months (95% CI 10.4-38.2), median overall survival (OS) was 20.0 months (95% CI 15.2-24.8) and 13.6 months (95% CI 9.8-17.4), and the median event-free survival (EFS) was 7.8 months (95% CI 2.5-13.1) and 6.6 months (95% CI 4.3-8.9), respectively (Fig.2). Neither the OS nor EFS showed significant differences between the two groups. The total 30-day mortality rate of the two cohorts was 6.8% (7/103). The median platelet recovery time (PLT&gt;50×109/L) after induction therapy in CR/CRi was different between patients with D5-PBCR(-) and D5-PBCR(+) (22 days vs 26 days, P=0.000, Fig.2F). There was a trend but no significant difference in the recovery time of neutrophils (ANC&gt;0.5×109/L) in two cohorts (21 days vs 23 days, P=0.025, Fig.2E). The incidence of adverse events during the first induction was comparable between the two groups and key adverse events of grade ≥3 included pneumonia(37%), sepsis (7%), and γ-glutamyl transpeptidase(GGT) increase (6%) in the entire cohort(Table.1).
Conclusion:
"3+7" regimen modified by the composition of D5-PBCR and CGA was safe and tolerable in fit older patients with AML. The efficacy and safety of induction were non-inferior compared with the results of existing trials, along with a relatively lower dose of IDA. We considered there may be reserved probability for combining other emerging drugs to challenge higher remission rate in fit AML with additional investigation.
Keywords: acute myeloid leukemia; elderly; induction therapy; non-inferior; flow cytometry; D5-PBCR.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.