Empiric Definition of Eligibility Criteria for Clinical Trials in Relapsed/Refractory AML: Analysis of 1,892 Patients from HOVON/SAKK and SWOG
Authors: Walter Roland B. , Othus Megan , Löwenberg Bob , Ossenkoppele Gert J , Petersdorf Stephen H. , Pabst Thomas , Vekemans Marie-Christianne , Appelbaum Frederick R. , Erba Harry P. , Estey Elihu H. 
Published: October 2019

Background: Therapeutic resistance, i.e. the failure to achieve complete remission (CR) or relapse from CR, is common in adult acute myeloid leukemia (AML). It is well recognized that the likelihood of complete remission (CR) and survival after receipt of therapy for relapsed/refractory AML (Òsalvage therapyÓ) varies widely with prior response duration being the primary predictor of both outcomes. One approach to salvage therapy trials would permit inclusion regardless of prior CR duration (CRD) given the possibility that a new drug might only be effective with longer CRD and that even with longer CRD standard therapies are hardly satisfactory. A second, more common approach relies on CRD to create a ÒhomogenousÓ population to facilitate data interpretation; yet, various arbitrary CRD cut-points have been used. This work examines whether a particular CRD might be used based on the relation between CRD and subsequent survival.

Methods: We used information on patients with newly diagnosed AML other than acute promyelocytic leukemia receiving curative-intent treatment on 5 trials conducted by the Dutch-Belgian Cooperative Trial Group for Hematology/Oncology and the Swiss Group for Clinical Cancer Research (HOVON/SAKK; n=1,306) or on the SWOG S0106 trial (n=586). Failure was considered as completion of induction therapy without CR (CRD=0) or as relapse from CR. Survival after failure (SAF) was measured from the date of completing protocol induction therapy without report of CR or from the date of relapse, with SAF measured until the date of death from any cause with patients last known to be alive censored at the date of last contact. SAF was estimated using the Kaplan-Meier method. Cox regression was used to analyze the association between SAF and CR duration; the latter was modeled both quantitatively and categorically. Regression analyses with all three cohorts were stratified by cohort.

Results: Among the 1,892 patients, 1,026 (54%) patients (median age: 48 years [range: 15-77 years]) failed induction therapy (n=430) or had a first CR duration of 2 years or less (n=596) and were included in our analyses. In the total patient cohort as well as in both treatment sites, longer CR duration was associated with longer SAF. In the total patient cohort, there was no evidence that the SAF for patients with first CR duration of 6 months or less was different or better than the SAF for patients who were primary refractory to induction therapy (see table). The same conclusion could be drawn when analyzing patients treated on HOVON/SAKK trials as separate cohort. In the SWOG cohort, there was no evidence that SAF with patients with first CR duration of 9 months or less was different or better than SAF of patients who were refractory to induction therapy.

Conclusions: Limitations of this work include incomplete information about whether primary induction failures received 1 or 2 induction courses before failure was declared and about the therapy received after failure, as well as the presence of inter-cohort heterogeneity. Nonetheless, assuming SAF is a crucial endpoint and using data to establish its relation with CRD, our study indicates that patients who are primary refractory to 1-2 courses of intensive induction chemotherapy or who relapse within 6 months have distinctly different SAF than patients who relapse after a CR duration of more than 6 months. Regardless of whether these 2 subsets are deemed equally eligible for trials, our data could form the basis for rational stratification of patients enrolled on a trial for relapsed/refractory AML.

Table 1: Hazard ratio (95% confidence interval) for Cox regression models for survival after failure (SAF). HOVON/SAKK(n=685) SWOG(n=341) All Patients(n=1,026) Failed Induction (Reference) (Reference) (Reference) CR 0-3 months 0.92 (0.69-1.23) 1.70 (0.96-3.02) 1.08 (0.83-1.40) CR 3-6 months 1.05 (0.83-1.32) 1.67 (1.07-2.62) 1.20 (0.98-1.47) CR 6-9 months 0.64 (0.51-0.81) 1.25 (0.84-1.87) 0.77 (0.63-0.94) CR 9-12 months 0.43 (0.31-0.59) 0.88 (0.59-1.30) 0.56 (0.43-0.72) CR 1-2 years 0.39 (0.30-0.52) 0.55 (0.36-0.83) 0.45 (0.35-0.56)

Disclosures

Petersdorf: Author deceased: Author recently deceased Other.