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Low-Dose Cytarabine plus Quizartinib versus Low-Dose Cytarabine Monotherapy in Older Patients with Acute Myeloid Leukemia: The LI-1 Trial

2020 Year in Review - AML

For many patients aged ≥60 years with acute myeloid leukemia (AML), intensive remission induction chemotherapy is often not appropriate. Patients may be treated with hypomethylating agents or low-dose cytarabine (LDAC), but either way, survival in these patients is poor. This study examines the possibility of improving outcomes by adding an additional agent, quizartinib (AC220), to LDAC for treating these patients. This second-generation class 3 receptor tyrosine kinase inhibitor is orally administered and has demonstrated highly potent FLT3 inhibitory activity. When it has been examined as monotherapy, quizartinib has demonstrated acceptable toxicity and potential activity in AML regardless of a patient’s FLT3 status.

This study, named “Low Intensity-1” or LI-1, was sponsored by the United Kingdom’s National Cancer Research Institute Working Group and aimed to assess the efficacy of quizartinib given concomitantly with LDAC versus LDAC alone in patients aged ≥60 years who could not be treated with intensive therapy. The study employed a “pick-a-winner” design because it allowed for several treatments to be evaluated in a randomized fashion. The goal was to double the 2-year survival for this patient population from 11% to 22% (hazard ratio [HR], 0.69). Interim assessments were completed upon recruitment of 50 patients per arm and again upon recruitment of 100 patients per arm.

Patients from Denmark (1%), New Zealand (11%), and the United Kingdom (88%) were randomized; the median age of these patients was 77 years (range, 60-89 years). Of the patient population, 64% were male, 63% had de novo AML, 25% had secondary AML, and 11% had a diagnosis of high-risk myelodysplastic syndrome. The risk categories distribution of patients according to baseline cytogenetics was 2% favorable, 66% intermediate, 27% adverse, and 5% unknown. Although investigators were not informed of the disease FLT3 status, FLT3-internal tandem duplication (ITD) mutation was identified in 27 patients. A median of 2 courses was delivered in either arm (mean, 2.7 LDAC, 3.0 LDAC plus quizartinib; range for both, 1-12).

For the total population, overall complete response/complete response with incomplete count recovery (CR/CRi) was achieved in 26 of the 202 patients, or 13%. For the LDAC plus quizartinib arm and the LDAC-alone arm, overall response was achieved in 16% and 10% of patients, respectively. Thirty-day mortality for LDAC plus quizartinib versus LDAC was not significantly different (10% vs 15%; HR, 0.71; 95% confidence interval [CI], 0.32-1.60; P = .415); nor was 2-year overall survival (OS; 11% vs 17%; HR, 0.87; 95% CI, 0.64-1.19; P = .381). Median OS time was 5.5 months with LDAC plus quizartinib and 3.8 months with LDAC (HR, 0.89; 95% CI, 0.66-1.21; P = .46).

In the FLT3-ITD subgroup, 13 of 27 patients (48%) were included in the LDAC plus quizartinib arm and the rest in the LDAC monotherapy arm. In that subgroup, LDAC plus quizartinib resulted in an improved response, with a CR/CRi rate for LDAC plus quizartinib of 38% versus LDAC monotherapy of 0%. OS was also improved at 2 years with LDAC plus quizartinib versus LDAC alone (HR, 0.36; 95% CI, 0.16-0.85; P = .04).

For the majority of patients in both arms, cause of death was resistant/recurrent disease (64% with LDAC plus quizartinib and 66% with LDAC alone). Relapses occurred in 17 patients, 13 of which were in the LDAC plus quizartinib arm, but the number of patients was too low to reliably determine relapse-free survival. Quizartinib was associated with cardiac toxicities during the first course (8.7%, grades 1/2; 2.2%, grades 3/4); however, there were no cardiac-related deaths.

For all elderly patients with AML and for patients with AML and wild-type FLT3 status, the addition of quizartinib to LDAC did not result in improved survival. However, for the subgroup of elderly AML patients with FLT3-ITD, response and survival were improved with the addition of the FLT3 tyrosine kinase inhibitor quizartinib to treatment with LDAC. Quizartinib was well-tolerated and had an acceptable toxicity profile.


Dennis M, Thomas I, Ariti C, et al. A Randomised Evaluation of Low-Dose ARA-C plus AC220 (Quizartinib) versus Low-Dose ARA-C in Older Patients with Acute Myeloid Leukemia: Results from the LI-1 Trial. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S137.

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