LDAC plus AC220: Results from the LI-1 trial in older patients with AML

Low dose cytarabine (LDAC) is the current standard treatment for older patients with acute myeloid leukemia (AML). This was established by the AML14 trial, in which 10–20% of patients had a complete response (CR) and a median 18-month increase in overall survival (OS). However, this response rate is modest and, therefore, alternative treatment strategies are required.

Quizartinib (AC220), was initially studied in 2012 as a second-generation receptor tyrosine kinase (RTK) inhibitor with a primary effect on FLT3, although it had some activity on KIT and other associated RTKs. The phase II interim analysis presented by Mark Levis at the American Society of Hematology (ASH) Annual Meeting & Exposition 2012 showed AC220 to be well tolerated and demonstrated a 30–36% response rate in the non-FLT3 internal tandem duplication (ITD) population. Most current studies are focused on its use in the FTL3-ITD population, where it remains well tolerated and is a highly effective monotherapy in the relapsed/refractory (R/R) setting. This was demonstrated by the results of the phase III QuANTUM-R trial (NCT02039726), which compared AC220 with salvage chemotherapy in patients with R/R FLT3-ITD AML.  However, the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have decided not to grant approval to quizartinib for the treatment of patients with FLT3-ITD-positive R/R AML, as results of the QuANTUM-R trial failed to show that the benefits of the treatment outweigh the risks. The treatment was licensed for use in Japan in October 2019. Click here to read the FDA’s decision and here to read the EMA’s decision.  

During the 25th European Hematology Association (EHA) Annual Congress 2020, Mike Dennis presented an oral abstract on the results from the phase II, randomized, LI-1 trial, comparing LDAC with or without AC220 in older patients with AML.

Study design and patient characteristics

• Patients with AML or higher-risk myelodysplastic syndromes > 60 years of age were randomized 1:1 to receive LDAC or LDAC + AC220
• Dosage:
  • LDAC, 20 mg twice-daily, subcutaneously, on Days 1–10 every 4–6-weeks
  • AC220, 90 mg once daily, orally, on Days 1–21 every 4 weeks
  • In 2017, a dose amendment of AC220 to 60 mg reduced cardiotoxicity
• The median follow-up was 13.1 months
• Primary endpoints: OS, CR, and duration of response
• Secondary endpoints: Toxicity, supportive care assessments, and quality of life
• Baseline characteristics were broadly similar; key differences can be seen in Table 1
  • The population was very mature, with a median age of 77 years
  • 26.8% of patients had adverse cytogenetics
  • 15.8% of patients had FLT3-ITD mutations

Table 1. Baseline characteristics¹

 Results

• The median number of treatment courses for both cohorts were 2 (range, 1–12)
• Responses can be seen in Table 2
  • The overall response rate (ORR), defined as the proportion of patients with a CR or a CR with incomplete count recovery (CRi), was higher for the LDAC + AC220 cohort compared with the LDAC alone cohort (16% vs 10%, respectively; p = 0.2)
  • The 30-day mortality was lower for the LDAC + AC220 cohort compared with the LDAC alone cohort (10% vs 15%, respectively; p = 0.4)
  • Although there appeared to be an improvement in 1-year survival with the addition of AC220, there was no improvement in survival at two years

Table 2. Response to treatment¹

•  Overall survival data can be seen in Table 3
  • Median OS was not significantly different between the two treatment arms
  • Relapse-free survival was significantly lower in the LDAC + AC220 cohort (6.8 months) vs the LDAC alone cohort (19.3 months); HR 3.40 CI, 1.20–9.60, p = 0.021

Table 3. Overall survival¹

•  Subgroup analysis for patients with FLT3-ITD showed a significant improvement for the LDAC + AC220 cohort (n = 13) compared with the LDAC alone cohort (n = 14) in terms of
  • ORR rates: 38% vs 0%, respectively (HR, 0.36; CI, 0.16–0.85; p = 0.05)
  • median OS: 13.7 vs 4.2 months, respectively (HR, 0.36; CI 0.16–0.85; p = 0.020)

Safety

• Grade 3 or 4 toxicities occurred mainly in treatment Course 1
  • The most common toxicity reported was cardiac in nature (~n = 9) but occurred mainly in the 90 mg AC220 dose group.
  • One patient in the 60 mg dose group had a cardiac event that was possibly related to investigational medicinal product, though they had a complex sepsis, hypokalemia, and a cardiac rhythm disturbance
• Significantly more blood transfusions were used for the LDAC + AC220 group compared with the LDAC group (p < 0.05) during Course 1 and 2
• The most common cause of death across both arms was resistant/recurrent leukemia, followed by infection and hemorrhage (Table 4)

Table 4. Cause of death¹

Conclusion

The addition of AC220 to LDAC for frail, elderly patients with AML was well tolerated and increased ORR, with no increase in 30-day mortality. However, there was no significant difference in overall survival. For patients with FLT3-ITD mutations, the addition of AC220 to LDAC significantly increased ORR and 2-year overall survival. LDAC is an inadequate therapy for elderly patients with AML who have FLT3-ITDs, therefore, further evaluation of AC220 combination strategies in this patient population should continue.