Survival Benefit of Novel Drug Combinations Using Hypomethylating Agents for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: A Systemic Review
Authors: Tenneti Pavan , Maher Keri R , Bakr Mohamed Mokhtar , Zahid Umar , Malik Saad Ullah , Faridi Warda , Anwer Faiz 
Published: October 2019

Abstract
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 through multivariable cox model analysis.
Five studies reported response rates for subgroup of patients with secondary AML using HMA. Of these, Aza with lenalidomide (n= 16) had a CR/CRi = 27% with median response duration of 21.3 weeks, a CR/CRi of 0% with entinostat (n= 18) and CR/CRi of 22% with thalidomide(n=9). Decitabine given with tosadostat (n= 10) had CR/CRi of 60% and with bortezomib(n=3) the CR/CRi was 66%. The long term outcomes were not reported for these patients.
Conclusion - Novel combinations involving Aza with valproic acid/all trans retinoic acid, thalidomide, or GO showed similar CR/CRi and mOS compared to Aza alone. Tosedostat, low dose cytarabine, and aclarubicin given in combination with decitabine showed best results with superior CR/CRi and mOS compared to decitabine alone. Bexarotene with decitabine also improved mOS over decitabine alone despite lower CR/CRi. In patients with adverse cytogenetics, Aza with lenalidomide or panobinostat showed superior CR/CRi and mOS. Decitabine given with vorinostat and tosedostat also showed superior CR/CRi.
In patients with secondary AML, Aza in combination with lenalidomide or thalidomide and decitabine with tosedostat or bortezomib showed superior CR/CRi. These CDR for patients with adverse cytogenetics and secondary AML need further testing in studies designed with this specific patient population in which long term outcomes are also measured. These CDR need to be evaluated in large, randomized, prospective studies to assess definitive benefit.

Disclosures
No relevant conflicts of interest to declare.