Survival Benefit of Novel Drug Combinations Using Hypomethylating Agents for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: A Systemic Review

Background - Acute myeloid leukemia (AML) in elderly patients (>65 years) is associated with poor prognosis with median overall survival (mOS) of 6 months. Hypomethylating agents (Azacytidine (Aza) and Decitabine) are used in elderly patients who are not candidates for intensive chemotherapy. Aza has resulted in complete remission/complete remission with incomplete hematologic recovery (CR/CRi) of 18-27.8% and mOS of 10.4-24.5 months. Decitabine resulted in CR/CRi of 18-47% and mOS of 7.7-8 months. We conducted a systemic review to assess survival benefit of novel combination drug regimens (CDR) involving hypomethylating agent (HMA) in elderly patients with newly diagnosed AML. Methods - Comprehensive literature search was conducted in Medline, Embase and Cochrane database. We included phase I/II studies only that used CDR involving HMA. Results - Initial database search (since inception) lead to 975 studies. After exclusion (duplicates, case reports, relapsed/refractory AML) final analysis included 17 studies(n=540) Ten phase I/II CDR studies involving Aza (n=334) were included. The various drugs used in combination included valproic acid/all trans retinoic acid (n= 42 ,CR/CRi=26.2% mOS= 18.1 m), thalidomide (n= 14,CR/CRi= 29%, mOS= 13.2 m ), gemtuzumab ozogamicin (GO) (n= 142,CR/CRi = 35-44%, mOS= 11 m), lenalidomide (n= 45,CR/CRi=28-44% , mOS= 3-8.2 m), panobinostat (n=38,CR/CRi=10-22.4%, mOS= 8 m), midostaurin (n=12,CR/CRi=25%, mOS=6 m) , entinostat (n=18 ,CR/CRi=0% ,mOS= 6 m ), Seven phase I/II CDR studies(n=206) involving decitabine were included. Drugs used in combination included low dose cytarabine and aclarubicin (n= 85 ,CR/CRi = 64.7% , mOS= 10-12 m ), tosedostat (n=17 ,CR/CRi= 59% mOS= 11.5 m ), bexarotene(n= 4 ,CR/CRi= 0% mOS= 9.2 m), valproic acid(n= 62 ,CR/CRi= 9% mOS= 7.4m) , GO (n= 40,CR/CRi= 45% , mOS= 7m ),bortezomib (n= 10,CR/CRi= 50% ), vorinostat(n = 31,CR/CRi= 30%). Seven studies reported outcomes for patients with adverse cytogenetics separately. Of these, Aza with lenalidomide (n= 11) had a mOS of 9.5 months and with panobinostat (n=12) the overall response rate was 25% and mOS of 7 months. Similarly, decitabine with vorinostat (n = 8) and tosedostat(n =12) resulted in CR/CRi of 25% and 43% respectively. Long term outcomes for these CDR with decitabine were not reported. In two additional studies, valproic acid/all trans retinoic acid given with AZA and low dose cytarabine & aclarubicin with decitabine(p=0.023) showed poor outcome