High Risk of Relapse with Intermediate Dose Cytarabine for Consolidation in Young Favorable Risk AML Patients Following Induction with 7+3

Introduction

CALGB study in 1994 reported improved leukemia free survival (LFS) with sequential courses of high dose cytarabine (HIDAC- 3 gm/m², q12h on days 1, 3 and 5) compared to lower doses of 100 mg/m² and 400 mg/m² per day. Following this study, HIDAC has been commonly used for chemotherapy consolidation in AML patients 60 years or younger. More recently, several groups investigated the role of intermediate dose cytarabine (IDAC-1.5 gm/m² q12h D 1, 3 and 5 or D 1-3) in this population and reported equivalent outcomes for IDAC compared to HIDAC (Table 1). ELN guidelines published in January 2017 recommend IDAC for consolidation therapy in young (<60 years) favorable risk AML patients. Following these studies and ELN publication, consolidation protocols for AML patients 60 years or younger were changed from HIDAC to IDAC at Singapore General Hospital (SGH) in 2011 and at University of Minnesota Medical Center (UMMC) in February 2017. NCCN continues to recommend HIDAC as category 1 recommendation for consolidation of patients in this setting. We performed a combined analysis of outcomes in young favorable risk AML patients to assess impact of this change in practice on outcomes at our institutions as a quality initiative.

Methods

Patients 60 years or younger with ELN favorable risk AML between 2004 and 2015 at SGH and between September 2015 and March 2018 at UMMC, who underwent induction therapy with 7+3 regimen (idarubicin 12 mg/m² D1-3 or daunorubicin 60 - 90 mg/m² and cytarabine 100 mg/m² continuous infusion from D1-7) and consolidation with cytarabine monotherapy were identified. These dates were chosen to allow reasonably equal time distribution before and after change in our practice. We extracted relevant outcomes data using chart review. We used Chi-square testing and applied Kaplan-Meier survival analysis to detect differences in relapse and survival outcomes.

Results

Of 67 ELN favorable risk patients 60 years or younger, 42 received HIDAC and 25 received IDAC. Median age was 39 years (range 16-59). 64 patients received 1 induction cycle and 3 patients received 2 induction cycles to achieve complete remission. Median LFS and overall survival (OS) with HIDAC vs IDAC were not-reached (NR, median time for follow up = 6.9 years) vs 1.35 years (p=0.004) and NR vs 2.27 years (p=0.001) respectively (Figure 1). Cumulative incidence of relapse at 2 years was 23.8% for HIDAC and 60% for IDAC groups (p=0.003). 3-year LFS and OS for HIDAC vs IDAC groups were 71% vs 36% (p=0.06) and 90% vs 48% (p=0.002).

Discussion

Historical data suggests chemotherapy consolidation with 3-4 cycles of HIDAC achieves long-term LFS of 60 - 70 % in young favorable risk AML patients. While the outcomes in HIDAC group in this study are comparable to historical data with good outcomes, a significantly larger proportion of patients in the IDAC group had early relapse (60%) and death. A major difference between the patients in this study and the other studies which showed similar outcomes with HIDAC and IDAC is the mode of induction. Data from large randomized studies in AML (Table 1) that suggest similar efficacy of IDAC compared to HIDAC used higher intensity induction regimens (frequently double induction therapy) compared to 7+3 and/or used other agents in combination with Ara-C for consolidation. These data are not broadly applicable in patients who receive a single cycle of 7+3 for induction, when selecting dose of Ara-C as monotherapy for consolidation. Furthermore, studies that used 7+3 for induction therapy showed benefit for HIDAC compared with multi-agent chemotherapy that included IDAC (Table 1).

Conclusion

Using single agent IDAC for post remission therapy is associated with higher rates of relapse and poor overall survival compared to HIDAC among young, ELN favorable risk AML patients who achieve complete remission following 7+3. The large randomized studies that suggested equivalency of IDAC to HIDAC for post remission therapy in AML patients, either used more than one cycle of intensive induction regimen and/or used cytarabine in combination with an anthracycline for consolidation. Hence, ELN guidelines should be cautiously interpreted given the above limitations in generalizability. Our study suggests that HIDAC, rather than IDAC, is the preferred chemotherapy consolidation regimen in young, favorable risk AML patients following standard 7+3 induction.

Foot note: BK & NAAH contributed equally. FH & ZL contributed equally.

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