Long Term Follow-Up of a Randomized Trial Comparing Response Adapted (RA), Non-Cross Resistant Induction and Consolidation with Idarubicin/Cytarabine (IDAC) Followed by Mitoxantone/Etoposide (NOVE) Compared with Consolidation with High Dose Cytarabine (HDAC) in Adult Patients with AML. A Study by the Canadian Leukemia Studies Group (CLSG).
Authors: Van der Jagt Richard H. , Robinson K. , Sheridan D.P. , Delage R. , Larratt L.M. , Yetisir L. , Wells G. 
Published: October 2019

Background: Previously the CLSG studied response adapted rx (RA) using idarubicin 12mg/m2 d1-3/cytarabine 200mg/m2 d1-7(IDAC); followed by IDAC and mitoxantrone 10mg/m2/etoposide 100mg/2 d1-5(NOVE) if in CR afer IDAC, or NOVEx2 if they had persistent blasts at d 14 or on recovery. The 10 year follow-up demonstrated that RA rx appeared to have an encouraging response and lead to longer survival. We elected to compare consolidation with RA vs high dose ara-c(HDAC).

Methods: Pts. with newly dx’d AML were included who were: age 15–80, with ECOG performance status 0–2, with no hx of HIV, CML or MDS>3 mos, and had bilirubin<85mmol/l(5.0mg/dl), creatinine<220 mmol/l(2.2mg/dl), no previous chemorx or radiorx for another malignancy, and an ejection fraction≥40%. Pts were given induction with (IDAC). Pts with persistent marrow blasts at d14, or after recovery, were given (NOVE). Pts in CR were randomized to obtain consolidation rx with: either IDAC followed by NOVE-arm A, or HDACx2-arm B, and if they required NOVE to obtain CR, HDACx2-arm C, or NOVEx2-arm D. HDAC was given at a 3 gms/m2 q12h on days 1,3,5 if pts were ≤ 60 and 1gm/m2 on days 1,3,5 if>60. Dosage adjustments were made to idarubicin according to bilirubin, to etoposide according to AST, and to HDAC according to ALP and creatinine. Pts with M3 were rx’d with ATRA x45d after achieving CR, prior to consolidation. Pts. were stratified according to age and # of inductions required to achieve CR, and were followed for death, relapse, or BMT. All pts were followed until death. Pts were also followed for quality of life using the SF-36 and FLIC surveys which pts completed at baseline,1,4, and 12 mos post rx. Data was analysed by an independent data monitoring committee comprised of a non-blinded statistician, and hematologist and oncologist not participating in the study who were blinded to rx allocation. Analyses was done on intent-to-rx basis using the group sequential design with early stopping boundaries. Survival was summarized using Kaplan-Meier curves and comparisons were made using the log rank test.

Results: 503 pts were recruited from 5/96 until 12/01 of whom 461were assessable and 296 were randomized. 201 pts were age≤60 and 95 were>60. Median follow-up since randomization was 64 mos. Comparing RA(arms A+D) vs HDAC(armsC+D), DFS in pts<60 was 32 vs. 23 mos(p=.46) and median OS was not yet reached vs.60 mos(p=.46). Median DFS in RA pts>60 was 20 vs.13 mos following HDAC(p=.15). For those pts >60 disease free at 6 mos, median DFS was 27 mos after RA vs.10 mos post HDAC(p=.05). There was a trend towards higher mortality in BMT patients <60, following HDAC, as the DFS post BMT in RA pts was 36 mos vs.17 mos post HDAC(p=.16). D14 marrow was a significant predictor of both DFS and OS in all pts (p=.0001).

Conclusion: This study suggests that RA consolidation is advantageous over HDAC, particularly in patients >60 and in those <60 who get a BMT. Thus in the next CLSG trial, RA rx has been adopted as standard rx in pts>60.