Friday, June 9, 2023
|
Variable |
n or median |
% or range |
|---|---|---|
| Sex | ||
| Female | 204 | 43.3 |
| Male | 267 | 56.7 |
| Age, y | 68 | 60-85 |
| ECOG performance status | ||
| 0 | 205 | 43.5 |
| 1 | 200 | 42.5 |
| 2 | 52 | 11 |
| 3 | 9 | 1.9 |
| NA | 5 | 1.1 |
| HCT comorbidity index | ||
| 0 | 354 | 75.2 |
| 1 | 108 | 22.9 |
| NA | 9 | 1.9 |
| Type of AML | ||
| De novo | 390 | 82.8 |
| Post–MDS | 68 | 14.4 |
| Treatment related | 13 | 2.8 |
| WBC, ×109/L | 5.3 | 0.3-546.6 |
| Cytogenetic risk* | ||
| Good | 13 | 2.8 |
| Intermediate | 339 | 72 |
| Poor | 84 | 17.8 |
| NA | 35 | 7.4 |
| ELN2017 | ||
| Favorable | 133 | 28.2 |
| Intermediate | 129 | 27.4 |
| Adverse | 195 | 41.4 |
| NA | 14 | 3 |
| Follow-up, months (IQR) | 44.8 | 43.0-49.9 |
| CR/CRp | ||
| After 1 course | 311 | 66 |
| After 2 courses | 30 | 6.4 |
| No | 130 | 27.6 |
Table 1. Characteristics of the study cohort
IQR, interquartile range; MDS, myelodysplastic syndrome; NA, not available. Defined in supplemental Table 1, with details in supplemental Table 4.
|
Variable |
Odds ratio |
95% CI |
P |
|---|---|---|---|
| Non–poor cytogenetics (n = 387) | |||
| Log (WBC) | 0.69 | 0.58-0.82 | <.0001 |
| NPM1 mutation | 2.25 | 1.15-4.51 | .02 |
| NRAS mutation | 0.46 | 0.23-0.91 | .02 |
| SETBP1 mutation | 0.16 | 0.02-0.87 | .04 |
| RUNX1 mutation | 0.43 | 0.23-0.81 | .009 |
| ASXL1 mutation | 0.52 | 0.28-0.98 | .04 |
| Poor risk cytogenetics (n = 84) | |||
| Log (WBC) | 0.61 | 0.41-0.87 | .009 |
Table 2. Multivariate logistic regression for CR/CRp achievement according to cytogenetic risk
|
Variable |
HR |
95% CI |
P |
|---|---|---|---|
| Non–poor risk cytogenetics (n = 387) | |||
| NPM1 mutation | 0.57 | 0.41-0.77 | .0004 |
| FLT3-ITD low ratio | 1.85 | 1.31-2.62 | .0005 |
| FLT3-ITD high ratio | 3.51 | 2.03-6.08 | <.0001 |
| NRAS mutation | 1.54 | 1.07-2.20 | .019 |
| ASXL1 mutation | 1.89 | 1.34-2.67 | .0003 |
| DNMT3A mutation | 1.86 | 1.40-2.47 | <.0001 |
| Poor risk cytogenetics (n = 84) | |||
| KRAS mutation | 3.60 | 1.68-7.72 | .001 |
| TP53 mutation | 2.49 | 1.53-4.04 | .0003 |
Table 3. Multivariate Cox models for OS in patients according to cytogenetic risk
| Training cohort | Validation cohorts | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ALFA1200 (n = 471) | AMLSG (n = 223) | HDF (n = 141) | SAL (n = 466) | |||||||||
| n (%) | 2-y OS (95% CI) | P | n (%) | 2-y OS (95% CI) | P | n (%) | 2-y OS (95% CI ) | P | n (%) | 2-y OS (95% CI) | P | |
| Go-go* | 184 (39.1) | 66.1% (59.5-73.3) | <10−5 | 84 (37.7) | 44.8 (35.3-56.9) | .0006 | 44 (31.2) | 43.4 (30.7-61.4) | .06 | 171 (36.7) | 35.5 (28.9-43.5) | .02 |
| Slow-go | 251 (53.3) | 39.1% (33.5-45.7) | Ref. | 113 (50.7) | 21.9 (15.4-31.2) | Ref. | 78 (55.3) | 29.9 (21.2-42.2) | Ref. | 243 (52.1) | 28.2 (20.1-31.2) | Ref. |
| No-go | 36 (7.6) | 2.8% (0.4-19.2) | <10−5 | 26 (11.6) | 3.8 (0.5-26.2) | 3 × 10−5 | 19 (13.5) | 10.5 (2.8-39.1) | .01 | 52 (11.2) | 2.0 (0.2-13.9) | <10−5 |
| Overall log-rank test | <10−5 | <10−5 | .003 | <10−5 | ||||||||
Table 4. Repartition and outcome per ALFA decision tool tier in the ALFA1200 training cohort and validation cohorts
P values by overall log-rank test and from pairwise log-rank tests considering the slow-go group as reference (Ref.)
*Go-go tier: non–poor cytogenetics, NPM1 mutated and at most 1 mutation among FLT3-ITD low, DNMT3A, ASXL1, or NRAS OR non–poor cytogenetics and NPM1, FLT3-ITD, DNMT3A, ASXL1, and NRAS all wild-type; no-go tier: poor-risk cytogenetic with KRAS and/or TP53 mutation; slow-go: all others.
This activity is intended for hematologists, oncologists, internists, geneticists, geriatricians, and other clinicians caring for patients with acute myeloid leukemia.
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Abstract
To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10−4) allelic ratio, DNMT3A (HR, 1.86; P < 10−4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a “go-go” tier with a 2-year OS of 66.1%, 7.6% to the “no-go” group (2-year OS 2.8%), and 3.3% of to the “slow-go” group (2-year OS of 39.1%; P < 10−5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10−5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.
Introduction
Acute myeloid leukemia (AML) is mostly diagnosed in patients ≥60 years of age.[1] Recent improvements in survival have been confined to younger adults with AML.[2] Intensive chemotherapy, with or without allogeneic stem cell transplantation (HSCT), remains the standard of care of AML for all adults, including older, fit patients.[3,4]
Recurrent cytogenetic and genetic lesions are key prognostic factors in patients with AML treated intensively, but the prognostic value of oncogenetic lesions has mostly been studied in younger adults.[5-8] Yet, major interactions occur between age, oncogenetics, and treatment outcome.[9-12] The genomic landscape of AML in older patients also differs from that in younger adults.[9,13-16] After earlier studies focusing on the prognostic value of NPM1 orFLT3 mutations in older patients with AML,[17-21] several studies, including those conducted by our group, have interrogated the prognostic value of a broader spectrum of recurrent genetic lesions in this population.[22-24] However, none of these studies reproducibly identified subsets with patients with outcomes contrasting enough to guide upfront decisions between intensive chemotherapies and alternative investigational approaches.
In recent years, 7 + 3-based induction chemotherapy has been increasingly challenged by less intensive options, notably the combination of hypomethylating agents and venetoclax.[16] To design future randomized studies of intensive and less intensive therapies in fit older patients with AML, specific decision tools must be developed to identity the minority of patients in whom 7 + 3 is unequivocally beneficial (“go-go”) or futile (“no-go”) among most older, fit patients with AML (“slow-go” group).
In this study, we leveraged the results of a 37-gene panel in 471 patients with AML aged ≥60 years and treated with intensive chemotherapy in the prospective, multicenter, ALFA1200 study (registered at www.clincialtrials.gov as #NCT01966497)[24] to design a very simple 3-tier decision tool, which we validated in 3 independent cohorts.
