Forty-Year Analysis of Randomized Clinical Trials in Patients with Acute Myeloid Leukemia Treated with Remission Induction Chemotherapy
Authors: Patel Sagar S. , Radivoyevitch Tomas , Gerds Aaron T. , Majhail Navneet S. , Carraway Hetty E. , Advani Anjali S. , Nazha Aziz , Maciejewski Jaroslaw P. , Kalaycio Matt , Sekeres Mikkael A. , Mukherjee Sudipto 
Published: October 2019

Abstract
Several population-based cancer registries have consistently reported improvements in overall survival (OS) for patients (pts) with AML treated with intensive chemotherapy (IC) across all age groups extending up to the age of 80 years. While major advances in supportive care and greater numbers of allogeneic transplantations have contributed to improvements in OS in AML, the role of experimental IC regimens has not been comprehensively analyzed. We conducted a systematic review of all phase three randomized clinical trials (RCTs) in AML conducted over the past forty years to evaluate the contribution of experimental IC regimens in clinical outcomes, along with OS in these pts based on the Surveillance, Epidemiology, and End Results (SEER) database.
The following electronic databases were searched for eligible non-acute promyelocytic leukemia trials covering the period from 1973 to 2016: Cochrane Controlled Trials Register, PubMed, Embase databases and American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) websites for conference abstracts. Analyses were restricted to phase three RCTs using IC regimens. The principal outcomes examined in the experimental arms (EAs) and control arms (CAs) included complete remission (CR) rates, leukemia-free survival (LFS), and OS. Outcomes were stratified by age and cytogenetic risk, in studies where information was available. RCTs were classified as including younger or older AML pts based on whether >65% of the patients in a study were < 60 or ≥ 60 years (yrs) old, respectively. We also evaluated the outcomes of pts diagnosed with AML outside of clinical trials by analyzing survival trends of 61,000 AML pts in SEER registry.
A total of 71 studies comprising 36,796 AML pts were included. The majority of pts in RCTs were < 60 years (68.6%); 54.3% were male. Eligibility criteria for study entry across all RCTs included a mean ECOG performance status of 2-3, mean upper limit (UL) of serum creatinine of 2.3 mg/dl and mean UL of serum bilirubin of 2.6 mg/dl. Mean CR (stratified by age and cytogenetics), mean LFS, OS and treatment-related mortality were similar between EA and CA cohorts (Table 1). Over the study period, there was no trend towards improved CR in EAs and CAs in both younger and older AML trials or even when stratified by cytogenetic risk groups. Similarly, no significant change in LFS trend was observed over time in the EAs and CAs in both younger and older pts. However, over time EAs in younger and older AML trials had a significant increase in median OS, at a rate of 29.52 days/yr (d/yr) (6.84-51.84; P=.01), and 13.68 d/yr (1.8-25.92; P=.05), respectively (Figure 1). For those in CAs, the corresponding rates for younger and older pts was 32.76 d/yr (8.64-56.88; P=.009) and 12.24 d/yr (2.88-27.93; P=.10), respectively. By comparison, there was a significant trend towards improvement in median OS over time in the SEER cohort for younger pts, defined as < 60 yrs (18.36 d/yr; 30-212.4, P<.0001). For the older SEER cohort (≥ 60 yrs) although the survival trend was statistically significant (0.36 d/yr; 0.36-0.72, P=.003) due to large patient numbers, this improved survival was not clinically meaningful (Figure 2).
This systematic review of evidence from phase three RCTs in AML suggests a minimal improvement in OS with use of experimental IC regimens, with gains mostly seen in younger pts. No significant improvements in LFS trends were observed in any age group, demonstrating a lack of aggregate clinical efficacy of experimental drugs over this time period. Greater survival gains in OS in pts enrolled in CAs of RCTs as compared to the SEER population suggests a strong selection bias in RCTs, thereby limiting extrapolation of study findings to the real world population.

Disclosures
Carraway: Celgene Corporation: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.