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Effect of eligibility criteria on outcomes in AML
TRM,8 the difference in TRM between eligible and ineli- gible patients was small when contrasted with the much greater differences in survival. This suggests much of the survival difference reflected the considerably higher rate of CR without MRD in eligible patients (55% vs. 38%), since achievement of CR without MRD is associated with longer survival.19 Since cytogenetic risk was similar in eligible and ineligible patients and since none of our ineligibility criteria are known to be associated with resistance to therapy, another explanation is needed for this higher CR without MRD rate. One possibility is the much less frequent use of intense induction in ineligible patients. Ineligible patients were also much less likely to receive allogeneic HCT. Hence while electing not to give ineligible patients intense induction may reduce TRM, this effect may be considerably less than the entailed loss of efficacy (e.g., decreased rate of CR without MRD) and resultant loss of ability to receive HCT.
Most patients with AML are given standard treatment (off trial) in community centers. An important question is whether the effect of “ineligibility” is the same in com- munity and academic centers. Patients treated in commu- nity centers are older, have more comorbidities, and trav- el less distance for treatment than those at academic cen- ters.20 Although after accounting for these factors survival remained better in academic centers, the negative effect of covariates such as comorbidities and shorter distance traveled was similar in both settings, suggesting that the effect of ineligibility is similar in community and academ- ic centers. Nonetheless, the pre-selection of patients inherent in a retrospective study from an academic med- ical center undoubtedly adds to the effect of ineligibility in evaluating the relevance of clinical trial outcomes.
As noted in the results, many of the patients entered on trials at our center would have been ineligible for typical trials. The lack of a linkage between participation in a trial and fulfillment of standard eligibility criteria may partial- ly explain the failure of our trials to improve survival, although the trials themselves may have been at fault. Though participation in clinical trials is encouraged, it is also true that not all trials lead to improved outcomes for patients. Patients with characteristics that make them ineligible for most trials may be the very population who would benefit most from novel therapies that are avail- able only within the context of a trial. Additionally, improvements in supportive care over time will benefit
all patients, regardless of eligibility. Investigators at MD Anderson Cancer Center published the results of a clinical trial for patients with AML and MDS who were by defi- nition not eligible for standard clinical trials,21 but we are not aware of any other similar studies either completed or enrolling. Future studies with broader inclusion criteria could also include a “correction factor” to help compen- sate for the expected worse outcomes of patients who would not meet standard eligibility. The recent Food and Drug Admistration approvals in the AML arena have changed the landscape of treatment options, but the real world use of these drugs may not mimic the cohort stud- ied in the clinical trials leading to approval.
Even the possibility of less benefit for “ineligible” patients may not be sufficient justification for their con- tinued exclusion from trials. For many patients with AML, standard treatment is unsatisfactory. Hence, once properly informed, many patients would prefer to enroll on trials rather than receive standard therapy. Extended to many cancers, this fact underlies the “right-to-try” movement. We understand patients are often ineligible for trials because the trials’ sponsors realize inclusion would lead to less encouraging results, harming chances for regulatory approval. A possible means to reconcile the interests of patients and of sponsors would be to make regulatory approval of new drugs might be made conditional on subsequent conduct of trials in patients underrepresented in the trials prompting initial approval, thus potentially increasing the applicability of results to the substantial numbers of patients currently considered “ineligible.”
Disclosures
This study was presented, in part, at the American Society of Hematology 2019 annual meeting in Orlando, FL, USA.
Contributions
MEMP and EHE: conceived and designed the study; data collection was performed by MEMP, SM, KMG, and CS; sta- tistical analysis was performed by MO. The remaining authors enrolled patients and provided feedback and revisions. The final manuscript was approved by all authors.
Funding
The study was supported in part by a Cancer Consortium Grant from the National Institutes of Health (P30 CA015704).
References
1. Network NCC. Acute Myeloid Leukemia (version 2.2019). https://www.nccn.org/ professionals/physician_gls/pdf/aml.pdf. Accessed April 12, 2019.
2. Srikanthan A, Vera-Badillo F, Ethier J, et al. Evolution in the eligibility criteria of ran- domized controlled trials for systemic can- cer therapies. Cancer Treat Rev. 2016; 43:67-73.
3. Kim ES, Bruinooge SS, Roberts S, et al. Broadening eligibility criteria to make clini- cal trials more representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. J Clin Oncol. 2017;35(33):3737-3744.
4. Lichtman SM, Harvey RD, Damiette Smit MA, et al. Modernizing clinical trial eligibil- ity criteria: recommendations of the American Society of Clinical Oncology- Friends of Cancer Research Organ
Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group. J Clin Oncol. 2017;35(33):3753- 3759.
5. Statler A, Othus M, Erba HP, et al. Comparable outcomes of patients eligible vs ineligible for SWOG leukemia studies. Blood. 2018;131(25):2782-2788.
6. Statler A, Hobbs BP, Radivoyevitch T, et al. The impact of comorbidities and organ dysfunction commonly used for clinical trial eligibility criteria on outcome in acute myeloid leukemia (AML) patients receiving induction chemotherapy. Blood. 2019; 134(Suppl 1):S16.
7. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000; 96(13):4075-4083.
8.Walter RB, Othus M, Borthakur G, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29(33):4417-4423.
9. Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodys- plastic syndrome. Leukemia. 2019; 33(2):379-389.
10.DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17.
11. R: A language and environment for statisti- cal computing. R Foundation for Statistical Computing [computer program]. R Foundation for Statistical Computing,
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