Are Strict Eligibility Criteria Keeping Patients From Clinical Trial Participation?

Eligibility criteria for clinical trials of leukemia therapies may be overly restrictive, limiting trial results’ applicability to real-world clinical practice and leading to unbalanced accrual of specific patient populations, according to a study published in Blood.

“Non-essential eligibility criteria, specifically those associated with missing documentation, can be less restrictive, thus expanding patient enrollment and avoiding protocol deviations,” Abby Statler, MPH, MA, of the Taussig Cancer Institute at the Cleveland Clinic, and co-authors wrote.

The investigators analyzed patients enrolled in 13 phase II, II/III, and III SWOG (Southwest Oncology Group) Leukemia Committee trials open since 2005 to identify and categorize reasons for trial ineligibility, then compared toxicity and outcomes between ineligible and eligible patients.

A total of 2,361 patients were included in the trials. All had acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute lymphocytic leukemia, myelodysplastic syndromes, or chronic myeloid leukemia. A majority of these patients (n=2,114; 90%) were considered “eligible” and fully met trial inclusion and exclusion criteria. The remaining 247 (10%) were deemed ineligible, but were initially registered as eligible despite having violated at least one criterion.

Of the ineligible population, 78 were excluded from this analysis and 169 who were treated on the protocols despite being ineligible were included. Most of the excluded patients (n=57; 73%) did not have the disease of interest.

Of those who were included, the primary reasons for ineligibility were:

  • missing baseline documentation (n=101; 60%)
  • acceptable laboratory values outside the protocol-defined time window (n=27; 16%)
  • out of window bone marrow (BM) biopsy (n=15; 9%)

The most common types of missing baseline documentation were:

  • specimens required for correlative studies (n=59; 58%)
  • enumeration of BM promyelocytes (n=19; 19%) in non-APL AML trials
  • pathology report not submitted (n=9; 9%)
  • inadequate BM/dry tap (n=7; 7%)

Comparing ineligible and eligible populations, baseline characteristics were similar, except for Eastern Cooperative Oncology Group (ECOG) performance status score in two studies, S0325 (p=0.02) and S0530 (p=0.002). However, in multivariable analyses, neither the proportion of patients with ECOG ≥2 (odds ratio [OR] = 0.60; 95% CI 0.32-1.15; p=0.12) nor the rate of grade five serious adverse events (AEs; OR=0.69; 95% CI 0.17-2.99; p=0.62) differed between the groups.

Because most ineligible patients were excluded for “administrative reasons, it is not surprising that there were no significant differences” in these baseline findings, the authors noted.

There were some significant differences in the rates of grade 3 to 5 AEs between ineligible and eligible patients: Grade 4 blood/marrow disorders were less frequent in ineligible patients in S0333 (75% vs. 30%; p=0.01) and S0805 (79% vs. 33%; p=0.01), but more frequent in S1117 (57% vs. 76%; p=0.048).

In both univariate and multivariable analyses, rates of complete remission (CR) were similar between ineligible and eligible patients, except for two protocols, S0325 and S0703 (TABLE 1).

There was no difference in overall survival (OS) between ineligible and eligible patients across all protocols (p=0.25). This finding remained even when trials “for which the majority of patients would be expected to have prolonged survival” were excluded (S0325 for CML and S0521 for APL; p=0.09).

As seen in TABLE 2, eligibility status also was not significantly associated with OS when the researchers controlled for age, sex, study design, and disease (hazard ratio = 1.12; 95% CI 0.89-1.40; p=0.37).

“Comparing the ineligible patients due to missing documentation … [with] the eligible patients did not change our results, [including OS, CR, and toxicity], suggesting those patients ineligible due to missing documentation may perform similarly to the eligible patients,” the researchers wrote.

The study is limited in its retrospective design, and these findings may not be generalizable to the larger leukemia population. Because this study was limited to patients who were actually enrolled on SWOG trials, the authors noted that “it likely underestimates the true numbers of patients who could have been eligible for these protocols had the eligibility criteria been expanded slightly (e.g., allowing one extra week for BM assessment).”

If similar clinically insignificant criteria are modified by clinical trials in the U.S., “access to novel treatments could increase dramatically, ultimately improving the generalizability of these trials’ results, minimizing protocol violations, and accelerating the time it takes to bring new products to market,” the authors concluded.

The corresponding authors report financial support from Celgene, Incyte, Jazz, Novartis, Amgen, Daiichi Sankyo, ImmunoGen, Macrogen, Ono, Pfizer, Seattle Genetics, Sunesis, Millennium/ Takeda, Agios, Juno, Astellas, Celator, and Janssen. Mikkael A. Sekeres, MD, MS, editor in chief of ASH Clinical News, is a corresponding author of the study.


Statler A, Othus M, Erba HP, et al. Comparable outcomes of patients eligible versus ineligible for SWOG leukemia studies. Blood. 2018 April 4. [Epub ahead of print]