A Multicenter Randomized Trial Comparing Response-Adapted (RA), Non-Cross-Resistant Induction and Consolidation with Idarubicin/Cytarabine (IDAC) Followed by Mitoxantrone/Etoposide (NOVE) Compared with Consolidation with High Dose Cytarabine (HDAC) in Adult Patients with AML. A Study by the Canadian Leukemia Studies Group (CLSG).

Background: A CLSG pilot rx’d 140 pts.with Response Adapted Rx(RA) with Idarubicin 12 mg/m² d1-3 & Ara-C 200 mg/m2 d1-7(IDAC);followed by IDAC II, then Mitoxantrone10 mg/m²&VP-16 100 mg/m²d1-5(NOVE), if in CR after IDAC, & NOVE x2 if they had persistent blasts @ d14 or @ recovery. CR rate was 74% in pts age15–80.DFS and OS were favourable @ 20 mos & 47 mos in pts ≤ 60. A CALGB study demonstrated the advantage of consolidation with high dose Ara-C(HDAC).We chose to compare HDAC with RA.

Methods: All pts with AML, age15–80, with a performance of 0–2,were included except those with a hx of MDS>3 mos,bili>85 mmol/l, creatinine>220 mmol/l, hx of chemoRx or radiation Rx for another malignancy,CML, ejection fraction<40%,or HIV+. Pts were randomized in CR to obtain consolidation Rx with: either IDAC followed by NOVE - Arm A, or 2 cycles of HDAC as given by the CALGB-Arm B, and if they required NOVE to obtain CR-2 cycles of HDAC-Arm C, or 2 cycles of NOVE - Arm D. HDAC was given at 3 g/m2 if pts were ≤ 60 and 1 g/m2 if >60. Dosage adjustments were made to VP-16 according to ↑ AST, to Idarubicin according to↑ bilirubin, and to HDAC according to ↑ ALP and/or ↑ creatinine. Pts with M3 were to be treated at least 45 days with ATRA. Pts were stratified according to age and # of inductions required to achieve CR and were followed until death, relapse, or BMT. Pts were followed for quality of life using both the SF-36 and the FLIC surveys which pts completed at baseline,1,4 and 12 mos post discharge from consolidation. Data went through annual analyses by an independent data monitoring committee comprised of a non-blinded statistician, a hematologist, and a an oncologist not participating in the study who were blinded to treatment allocation. Their analysis was done using group sequential design with early stopping boundaries.

Results: The comparison was made between the RA approach (Arms A+D) vs. consolidation with HDAC (Arms B+C). Analysis was done on an intent-to-treat basis. 503 patients were recruited into the study from 5/96 until 12/01, of whom 461 were assessable. 201 age ≤ 60 and 95 age > 60 were randomized with a median time since randomization of 65.7 mos.Median DFS in RA pts > 60 was 20 mos vs. 13.3 mos in the HDAC arm (p=.15). The overall DFS hazard ratio was 0.72 (0.47, 1.13), p=0.153. For those RA pts > 60 and disease free at 6 mos, the median DFS was 27.3 mos vs. 10.2 mos in the HDAC arm with the hazard ratio of 0.57 (0.33, 1.02), p=0.056. Median DFS in pts ≤ 60 was 32 mos in pts randomized to RA and was 22.8 mos in the HDAC arm. Median OS in pts ≤ 60 has not yet been reached in pts randomized to RA and was 60.2 mos in the HDAC arm. In the RA pts > 60 the median OS was 21.1 mos vs. 19 mos in the HDAC arm. Notably, there is a trend in 117 pts ≤ 60 undergoing BMT to have lower mortality if treated with RA 21 (41.2%), rather than with HDAC 37 (56.1%), p=0.11.

Conclusion: Although this study was not sufficiently powered to detect a statistically significant difference at the 0.05 level it suggests that RA therapy is advantageous over HDAC consolidation therapy, particularly for pts > 60 and for those who may get a BMT.