Impact of Combining Targeted Agents with High-Dose Cytarabine-Based Induction Chemotherapy on Acute Myeloid Leukemia Outcomes: The M.D. Anderson Cancer Center Experience
Authors: Quintás-Cardama Alfonso , Kantarjian Hagop M. , Garcia-Manero Guillermo , Brandt Mark , Faderl Stefan , Pierce Sherry , Borthakur Gautam , Ravandi Farhad , Cortes Jorge E. 
Published: October 2019

Abstract
Abstract 1539

Background:
Standard AML therapy with cytarabine and an anthracycline produces a complete remission (CR) rate of 60%–70% but cure rates of only 15%–25%. AI (ara-C 1.5g/m2x3d and idarubicin 12mg/m2x3d), the standard induction chemotherapeutic backbone used at M.D. Anderson Cancer Center for AML, consists of idarubicin 12 mg/m2/day on days 1–3 and cytarabine 1.5 g/m2 IV over 24 hours daily on days 1–4 (days 1–3 only if age >60 years). In recent years several targeted agents have been combined with IA in an attempt to improve outcomes.

Patients & Methods:
We reviewed all the AI-based protocols used at our institution over the last decade to identify combinations that may improve outcomes over standard AI. Only trials that enrolled >20 pts (age 15–70 years) were analyzed, including AI alone (n=486) and in combination with sorafenib (BAY; n=56), interleukin-11 (IL-11; n=37), lisofylline (Liso; n=24), vorinostat (SAHA; n=58), tipifarnib (Zarn; n=84), G-CSF+/−ATRA (G+/−ATRA; n=115). Patients with core-binding factor AML or acute promyelocytic leukemia were excluded.

Results:
The combination of AI with BAY (84%), lisofylline (67%), SAHA (76%) and G+/−ATRA (76%; no difference regardless of the addition of ATRA) produced higher CR rates than IA alone (61%; p=0.0001), which for BAY and SAHA was also accompanied by improved early death (ED; 8-wk mortality) rate and median overall survival (OS) (5%/not reached [NR] & 5%/68wks) compared to AI alone (15%/48wks) (Table 1, Figure 1). AI+Zarn produced similar CR (61%) but improved ED rate & OS (8%/54wks) while AI+G+/−ATRA also rendered a better OS (83wks) than AI. Of note, both BAY (80%) and SAHA (79%) but not G+/−ATRA (57%) included a higher number of pts younger than 60 yrs compared to AI (55%). However, when only pts <60 years were considered, the CR/OS rates were still superior for BAY (87%/NR), SAHA (76%/68wks), and G+/−ATRA (86%/115wks) compared with AI (71%/67wks). A similar trend was observed for pts ≥60 years (73%/64wks for BAY, 67%/32wks for SAHA, 61%/34wks for G+/−ATRA, and 49%/29 for AI) but the low number of pts in the BAY (n=11), and SAHA (n=12), albeit not in the G+/−ATRA group (n=49), limits the value of this comparison.
When the analysis was limited to pts with unfavorable cytogenetics (−5, −7, complex) BAY (75%/NR), SAHA (69%/43wks), G+/−ATRA (80%/23wks) also improved the outcomes produced by AI (50%/21wks) with better ED rates (0%, 5%, 12.5% and 19%, respectively).
Of the latter targeted agents, sorafenib and SAHA showed remarkable activity in FLT3-mutated AML. CR/OS rates for pts with FLT3-ITD were 94%/67wks for BAY, 91%/77wks for SAHA (no FLT3 mutational data for G+/−ATRA) and 64%/48wks for AI (AI vs BAY or SAHA, p=0.001 for CR and p=0.001 for OS).

Conclusion:
Long-term follow-up suggests that IA combined with sorafenib, SAHA, or G+/−ATRA may improve outcomes in pts with AML, including those with adverse karyotypes and those older than 60 years, compared with AI alone. AI+Sorafenib and (surprisingly) AI+SAHA showed remarkable activity against FLT3-mutated AML. Randomized studies are warranted to confirm these observations.

Disclosures:
No relevant conflicts of interest to declare.