A recent study published in Leukemia suggests that relaxing eligibility criteria in clinical trials could benefit patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who are typically excluded due to comorbidities. The research indicates that these patients, often deemed "unfit" for standard trials, can safely participate and potentially benefit from investigational therapies.
Study Design and Patient Population
The study, led by Guillermo Montalban Bravo, MD, from the University of Texas MD Anderson Cancer Center, enrolled patients with AML and MDS who would typically be excluded from traditional clinical trials due to factors such as organ dysfunction (serum creatinine >2 mg/dL or total bilirubin >2 mg/dL), poor performance status (Eastern Cooperative Oncology Group Performance Status of 3-4), or other comorbidities. Patients were treated with azacitidine, a hypomethylating agent, with or without vorinostat, a histone deacetylase inhibitor, both known for acceptable toxicity profiles.
The initial exploratory study included 30 patients (14 with AML and 16 with MDS) randomized to receive azacitidine (75 mg/m2 daily for five days) with or without vorinostat (200 mg three times daily). Treatment continued for up to 12 cycles. An expanded study then included 79 patients randomized to azacitidine alone or azacitidine plus vorinostat.
Key Findings
The 60-day survival rate in the exploratory study was 83%. Patients with AML and MDS experienced similar overall survival (OS; 5.9 vs. 7.9 months; hazard ratio [HR] = 0.67; 95% CI 0.32-1.4; p=0.308) and event-free survival (EFS; 3.5 vs. 4.4 months; HR=0.74; 95% CI 0.34-1.57; p=0.432). The overall response rate (ORR) was 40%, with 27% achieving complete response (CR).
In the expanded study, 60-day survival was 79%. Patients with MDS experienced longer median OS (10.6 vs. 4.4 months; HR=0.5; 95% CI 0.1-8.3; p=0.07) and significantly longer EFS (5.7 vs. 2.9 months; HR=0.1; 95% CI 0.3-0.8; p=0.04) compared with patients with AML. The ORR was 47%, with 25% achieving CR.
Safety and Tolerability
In the exploratory study, 70% of patients experienced at least one adverse event (AE), most commonly gastrointestinal toxicity and febrile neutropenia. In the expanded study, 82% experienced at least one AE, with grade 3 fatigue, dyspnea, and neutropenic fever being the most common. The stopping rule for toxicity was not met in either study.
Implications for Clinical Trial Design
"These findings suggest relaxation of [organ dysfunction, poor performance status, and other comorbidities] exclusion criteria may increase the pool of clinical trial candidates and allow access to potential beneficial therapies for patients with an otherwise dismal prognosis," Dr. Montalban Bravo and authors concluded. They also noted that stringent criteria might limit access to beneficial therapies and our ability to extrapolate safety and efficacy outcomes to patients with unfavorable clinical features.
Study Limitations
The authors acknowledged limitations, including the heterogeneous patient population, which limits the ability to extrapolate outcomes to specific patient populations. Additionally, quality of life was not assessed, an important clinical outcome in this patient population.
