2nd cycle Remission Achievement with 7+3 Is Associated with Shorter Survival in Adults with Newly Diagnosed Acute Myeloid Leukemia: Analysis of Recent SWOG Trials

Background: Intensive chemotherapy will induce a complete morphologic remission (CR) in many adults with acute myeloid leukemia (AML). Whether it matters that a remission is obtained early, i.e. with the first cycle of chemotherapy, has remained controversial. Data from historic and contemporary trials with double induction chemotherapies showed patients who achieved a CR with the first induction cycle were less likely to relapse than those requiring 2 courses of therapy to enter CR. Contrasting these findings, an analysis of 6 ECOG (now ECOG-ACRIN) trials conducted between 1983 and 1993 indicated patients who achieved a CR after 1 or 2 cycles of induction chemotherapy had similar prognoses. The relationship between timing of remission achievement and outcome has not been examined in contemporary cohorts of people treated with 7+3 for AML. Here, we used data from adults participating in 5 SWOG trials between 1983 and 2015 and studied the association between prognosis and need for 7+3 reinduction therapy and how it has changed over time.Patients and Methods: We analyzed 1247 patients randomized to 7+3 arms on 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocol gave 7+3 per contemporary standard, which changed over time: in S8600, S9031, and S9033, the cytarabine and daunorubin doses were 200mg/m2 and 45mg/m2, in S0106 100mg/m2 and 60mg/m2, and in S1203 100mg/m2 and 90mg/m2. CR was defined morphologically. Overall survival (OS) was measured from the date of study registration/randomization to date of death due to any cause; patients last known to be alive were censored at the date of last contact. Relapse-free survival (RFS) was measured from the date of CR to the first of relapse from CR or death due to any cause; patients last known to be alive in CR were censored at the date of last contact. OS and RFS were estimated using the Kaplan-Meier method. Multivariable Cox regression models included covariates (modeled quantitatively unless otherwise specified): age at study registration, gender, cytogenetic risk, pre-study white blood cell counts (WBC), pre-study platelets, pre-study marrow blasts, type of AML (secondary vs. de novo), indicator of receiving reinduction and study/protocol. We analyzed study/protocol separately and also grouped the studies by twenty-year period (S8600/S9031/S9333 representing 1980s and 1990s vs. S0106/S1203 representing 2000s and 2010s).Results: In multivariable analysis in the older studies, CR achievement only upon reinduction chemotherapy was not significantly associated with OS (hazard ratio (HR)=1.19 [95% confidence interval: 0.89-1.59], P=0.25) or RFS (HR=1.15 [0.86-1.54], P=0.34). These findings are similar to those reported by Rowe and colleagues on 1,980 adults with newly-diagnosed AML treated on 6 consecutive ECOG trials conducted in the 1980s and early 1990s. In contrast, in the contemporary studies we found receiving 2 cycles of induction chemotherapy before CR is documented was associated with worse OS (HR=1.82 [1.24-2.66], P=0.002) and RFS (HR=1.90 [1.34-2.70], P<0.001). Models evaluating the statistical interaction between the two time periods was significant (OS P=0.046; RFS P=0.016). One trial, S0106, had MRD data (n=70). Among patients with CR on the first cycle, having a negative MRD test (n=55) was associated with statistically significantly better OS (P=0.049) and a trend toward better RFS (P=0.098) compared to having a positive MRD test (n=15).Conclusion: These findings indicate adults with newly-diagnosed AML treated on more recent cooperative group trials who achieve remissions early, i.e. with the first cycle of 7+3 chemotherapy, have better survival outlooks than those who need 2 cycles of chemotherapy to enter a CR, even after adjustment for other risk factors. Need for a second cycle of induction therapy may therefore serve as a post-treatment prognostic factor to refine risk-stratification of adults with AML undergoing curative-intent therapy.Support: NIH/NCI grants CA180888 and CA180819Acknowledgment: The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106.Figure. Figure.

Duke Scholars

Author Harry Paul Erba Medicine, Hematologic Malignancies and Cellular Therapy