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Effect of eligibility criteria on outcomes in AML
Table 2. Univariate associations between ineligibility and overall sur- vival.
Table 3. Univariate associations between baseline characteristics and ineligibility. Median (range) or numbers (N) (%) reported for summary.
Factor
No ineligible characteristic
1 ineligible characteristic
2 ineligible characterisics
3 ineligible characteristics
No ineligible characteristic
1 or more ineligible characteristic
HR: Hazard ratio; CI: Confidence Interval.
N (%)
HR (95% CI)
P
-
<0.001 0.0013 0.051 - <0.001
Factor
2014
2015
2016
Female
Male
De novo
Secondary
Favorable cytogenetic risk Intermediate cytogenetic risk Adverse cytogenetic risk Unknown cytogenetic risk TRM score
High intensity therapy
Intermediate intensity therapy
Low intensity therapy Alive past day 28
Died on or before day 28 CR without MRD
CR with MRD
CRi/CRp with or without MRD Refractory
Missing
No ineligible 1 or more P characteristic ineligible
(n=220) characteristics (n=144)
220 (60)
106 (29) 1.68 (1.26, 2.25)
31 (9) 7 (2) 220 (60)
2.12 (1.34, 3.34) 2.26 (1, 5.14) Reference
68 (31) 76 (35) 76 (35) 98 (45) 121 (55) 135 (61) 85 (39) 12 (5) 134 (61) 67 (30) 7 (3)
4 (0, 73)
143 (65)
31 (14)
46 (21) 209 (96) 8 (4) 121 (55) 24 (11) 28 (13) 34 (15) 13 (6)
42 (29) 0.77 55 (38)
47 (33)
52 (36) 0.13 91 (64)
Reference
144 (40) 1.79 (1.37, 2.33)
and cytogenetic risk, the rate of CR without MRD was significantly higher in eligible patients (55% vs. 38%). Partly as a consequence, although eligible patients com- prised 60% of our population, they comprised 74% of the 140 patients who received allogeneic hematopoietic cell transplantation (HCT) (P=0.004). It is interesting to observe that 39 “ineligible” patients went on to allogeneic HCT, but notably 30 met only one ineligibility criterion at diagnosis.
Ineligibility is associated with decreased survival (Table 4)
A multivariable Cox regression model indicated that the presence of one more ineligible factors was associated with decreased overall survival (HR 1.45, 95% CI: 1.08- 1.93) (Table 4), even after accounting for known prognos- tic factors. Considered as a time-dependent variable, HCT was associated with improved survival (HR 0.67, 95% CI: 0.49-0.93). Tests of interaction between HCT and ineligibility indicated no evidence of a difference in the association between transplant and outcome between eligible and ineligible patients (HR 0.99, P=0.99).
We also examined the effect of participation in clinical trials in our cohort. Many of the clinical trials on which our patients were enrolled were investigator-initiated tri- als which commonly had more lenient inclusion criteria than the “standard” eligibility criteria defined for the cur- rent analysis, perhaps leading our trial patients to have worse prognoses than those more typically enrolled. Examples of clinical trials enrolling during this time peri- od that targeted patients with a high treatment-related mortality include reduced-dose CPX-35112 and a random- ized trial for reduced versus full-dose CLAG-M.13 In fact, despite the relation between shorter survival and ineligi- bility for clinical trials, participation in a clinical trial (207 patients, 56% of the cohort) was not associated with improvement in survival (HR 1.01, 95% CI: 0.76-1.33). Furthermore, of the 207 patients treated on study, 74 (36%) were ineligible by at least one criterion, and the effect of eligibility on overall survival was similar in patients treated on or off a trial (interaction P=0.15).
Discussion
Because overly strict eligibility criteria for clinical trials may lead to unrepresentative study populations, we set out to examine the frequency of characteristics associated with ineligibility. We observed a high percentage of patients with at least one ineligible characteristic (40%), though this finding is somewhat less than the 50-85%
7 (5) 0.96
45 (31) 99 (69)
<0.001
86 (60) 45 (31) 6 (4) 6 (0, 73) 69 (48) 28 (19) 47 (33)
<0.001
0.0035
130 (92) 0.06 12 (8)
54 (38)
17 (12) 23 (16) 35 (24) 15 (10)
0.014
TRM: treatment-related mortality; CR: complete remission; CRi: CR with incomplete neutrophil recovery; CRp: CR with incomplete platelet recovery; MRD: measurable residual disease,as detected by multiparameter flow cytometry.
ineligible patients identified in the Lichtman analysis of solid tumor trial candidates and less than the 88% ineligi- ble identified in the Statler analysis of AML patients treat- ed with chemotherapy.4,6 Our analysis excluded a subset of patients who received palliative care alone or unknown treatment in the community. Because of the nature of oncology trials, the Lichtman analysis notably also included age over 75 as an exclusion criterion, which was a characteristic of 14% of our final cohort.
Cardiac disease was uncommon in our cohort, at least based on history of CHF (4%) or MI (5%) and decreased EF within 3 months of leukemia diagnosis (2%). The Lichtman analysis was comparable, with CHF/cardiomy- opathy observed in 5-11% of patients and prior MI in 1- 5%, depending on cancer type.4 In our analysis, EF assess- ment was done on a routine basis for most patients prior to planned receipt of an anthracycline during induction chemotherapy, even though most cardiac toxicity is only seen after high cumulative anthracycline doses.14 EF eval- uation can be expensive and can delay the initiation of life-saving chemotherapy, and these results suggest that it is unnecessary more often than not.15 In contrast, a previ- ous analysis of 97 randomized controlled trials in hema- tologic malignancies, not limited to AML and MDS, determined that cardiac eligibility criteria were signifi- cantly associated with observed adverse events in a way that hepatic and renal eligibility criteria were not.16
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