Impact of Combining Targeted Agents with High-Dose Cytarabine-Based Induction Chemotherapy on Acute Myeloid Leukemia Outcomes: The M.D. Anderson Cancer Center Experience

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.Table 1Outcomes of pts with AML treated with AI-based regimensRegimensAIAI+BAYAI+IL11AI+LISOAI+SAHAAI+ZARNAIG+/-ATRAp valueN%N%N%N%N%N%N%Response RateCR29661%4784%1951%1667%4374%5161%8776%0.001CRp214%24%13%00%610%810%00%ED7415%12%719%625%35%78%2017%NR9520%611%1027%28%610%1821%87%Total4865637245884115Pts age 0–5926655%4580%924%1250%4679%8095%6657%0.00001Pts age ≥6022045%1120%2876%1250%1221%45%4943%0.0001Median CRD (Weeks)635839264272820.0852-year39%34%29%13%50%46%42%5-year28%0%44%31%Median OS (Weeks)48NR2033685483<0.0012-year32%63%12%21%32%39%42%5-year18%8%31%20% [Display omitted] 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.