Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial

Abstract

Risk assessment in acute myeloid leukemia (AML) using pretreatment characteristics may be improved by incorporating parameters of early response to therapy. In the 1992 trial of the German AML Cooperative Group (AMLCG), the amount of residual leukemic blasts in bone marrow was assessed one week after the first induction course (day 16 blasts). A total of 449 patients 16 to 76 years of age (median, 53 years) with de novo AML entered the trial and were evaluable. Treatment included TAD/HAM (thioguanine, cytosine arabinoside, and daunorubicin/high-dose cytosine arabinoside and mitoxantrone) double induction, TAD consolidation, and randomly either maintenance therapy or S-HAM consolidation. Cytogenetics were favorable, intermediate, unfavorable and not available in 10.0%, 48.3%, 13.1%, and 28.5%, respectively. Day 16 blasts ranged from 0% to 100% (median, 5%, mean ؎ SD, 18.6 ؎ 28.5%). Complete remission (CR) rate was 72.6%, 17.6% had persistent leukemia (PL), and 9.8% succumbed to hypoplastic death. Median overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) were 18, 9, and 15 months with 28.4%, 21.6%, and 30.1% at 5 years, respectively. As a continuous variable, day 16 blasts were related to CR rate (P < 0.0001), PL rate (P < 0.0001), OS (P < 0.0001), EFS (P < 0.0001), and RFS (P ‫؍‬ 0.0049). Multivariate analyses identified the following parameters to be associated with the respective end points. CR rate: day 16 blasts (P < .0001), age (P ‫؍‬ .0036), and LDH (P ‫؍‬ .0072); OS: unfavorable cytogenetics (P < .0001), day 16 blasts (P < .0001), age (P < .0001), and LDH (P ‫؍‬ .0040); EFS: unfavorable cytogenetics (P < .0001), LDH (P < .0001), day 16 blasts (P < .0001), and age (P ‫؍‬ .0061); RFS: unfavorable cytogenetics (P < .0001), LDH (P < .0001), and day 16 blasts (P ‫؍‬ .0359). The prognostic significance of day 16 blasts is independent of pretherapeutic parameters and predicts outcome even in patients achieving a CR. (Blood. 2003;101:64-70)

Routine interim disease assessment in patients undergoing induction chemotherapy for acute myeloid leukemia: Can we do better?

“…In a GOELAMS study of over 800 patients with AML, patients with 5 or >5% marrow blasts achieved overall CR rates, 5-year event free survival (EFS), relapse free survival (RFS) and overall survival (OS) rates of 92 vs. 69% (P < 0.0001), 48 vs. 25% (P < 0.0001), 53 vs. 37% (P 5 0.0016), and 55 vs. 36% (P < 0.0001), respectively [13]. In the German AML Cooperative Group (AMLCG) 1992 trial, day 16 blast percentage (<10 vs. 10%) significantly correlated with CR rate (P < 0.0001), EFS (P < 0.0001), RFS (P < 0.0049), and OS (P < 0.0001) [1].…”

“…Early bone marrow (BM) evaluation (during aplasia or at "day 14") in patients with AML undergoing conventional induction therapy has been adopted from clinical practice in pediatric lymphoblastic leukemia (ALL) [1,2]. While it has been shown that early persistence of AML correlates with decreased complete remission (CR) rates and overall survival (OS), unlike in ALL, there are no data to indicate that early initiation of salvage therapy positively influences outcome.…”

Day 15 bone marrow driven double induction in young adult patients with acute myeloid leukemia: Feasibility, toxicity, and therapeutic results

“…The timing was established on the basis of previous observations, which did clearly demonstrate that patients with absence or low blast count D15 BM, which reflects major sensitivity to induction therapy, had a significantly better clinical outcome when compared with those of persistent leukemia [13][14][15][16]. As DI, we decided to use the FLAG regimen, which has been proven as useful and safe for poor prognosis AML as well as for high-risk MDS.…”

“…Prognostic evaluation of cytogenetics was made according to UK Medical Research Council criteria [19]. Favorable karyotype included t(8;21) and inv (16) [20]. In all cases, diagnosis was confirmed by immunophenotypic study, as previously described [21].…”

“…A threshold value of 10% at days 14-15 from the beginning of chemotherapy is highly prognostically relevant, in that the degree to which the blasts are cleared from the marrow in response to the first course of chemotherapy represents a surrogate for chemoresistance [16,17]. To achieve better therapeutic results, avoiding unnecessary toxicity, from 2007, we decided to administer DI only to patients with persistent leukemia, defined as over 10% of blasts in the BM at day 15 (D15) morphological and/or immunophenotypic examination.…”