Prognosis and Application of Day 14 Bone Marrow Results in Acute Myeloid Leukemia Induction

Introduction:

The 2017 National Comprehensive Cancer Network (NCCN) guidelines for Acute Myeloid Leukemia (AML) recommend performing a bone marrow aspirate (BMA) and trephine biopsy (BMTB) 14-21 days after starting induction therapy (commonly referred to as a "Day 14 [D14] marrow"). Those who do not achieve a hypoplastic marrow, with cellularity <10-20% and blasts <5-10%, are recommended to undergo a second induction cycle (IC). We performed a retrospective analysis to determine the impact of day 14 bone marrow (D14 BM) characteristics in predicting remission, association with overall survival (OS) and the impact of a second IC based on D14 BM results.

Methods:

Patients with AML aged 18-70 years undergoing induction therapy with standard "7+3" regimens at Vancouver General Hospital or University of Alberta Hospital from 2007-2015 and 2005-2015 respectively were included. D14 cellularity was determined on BMTB and blast percentage (blast %) was assessed by morphology on BMA and BMTB. We examined outcomes by three D14 risk categories: 1. blast % (<5/≥5%), 2. cellularity (<20%/≥20%) or 3. blast % and cellularity (< 5% blasts or <20% cellularity/ ≥5% blasts and ≥20% cellularity). Overall response rate was determined at peripheral count recovery and defined as complete remission (CR) or CR with incomplete count recovery (CRi), (Cheson B J Clin Onc 2003; 21(24):4642-9). Differences in categorical variables were determined using Mantel-Haenszel tests. Binary logistic regression was used to determine association between D14 BM and other covariates on CR/CRi rate. Cox regression was used to determine association between covariates with OS.

Results:

546 patients were identified with 486 (89.0%) undergoing a D14 BM (Table 1). On the D14 BM, 190 patients had blasts ≥5%, 96 had cellularity ≥20% (with 12 patients also having blasts <5%) and 84 had both blasts ≥5% and cellularity ≥20%. The CR/CRi rate stratified by D14 categories was: 87% vs. 56%, p<0.001 (< 5% vs. ≥ 5% blasts), 79% vs. 57%, p<0.001 (< 20% vs. ≥20% cellularity) and 79% vs. 54%, p<0.001 (<5% blasts or <20% cellularity vs. ≥5% blasts and ≥20% cellularity).

In univariate analysis, D14 low-risk categories were associated with higher CR/CRi rates (D14 blasts <5%, OR 5.4, 95% CI 3.5-8.4, p<0.001, D14 cellularity <20%, OR 2.9, 95% CI 1.8-4.6, p<0.001 and D14 blasts <5% or cellularity <20%, OR 3.4, 95% CI 2.1-5.5, p<0.001) and improved OS (D14 blasts <5%, HR 0.66, 95% CI 0.51-0.84, p<0.001, D14 cellularity <20% ,HR 0.55, 95% CI 0.42-0.73, p<0.001 and D14 blasts <5% or D14 cellularity<20% ,HR 0.52, 95% CI 0.39-0.70, p<0.001). In multivariate analysis, the diagnostic cytogenetics and D14 blasts <5% predicted CR/CRi at count recovery whereas age, cytogenetics and D14 blasts <5% were significantly associated with improved OS (Table 2). The risk category using both blast % and cellularity was not included in the multivariate model due to multicollinearity with D14 blast % and cellularity.

131 patients (27%) underwent a second IC, most commonly with etoposide/cyclophosphamide (n=48) or mitoxantrone/etoposide (n=48) regimens based upon the results of the D14 BM. CR/CRi rates for patients receiving 1 vs. 2 ICs in high risk D14 groups were: 43% vs. 62%, p=0.01 (D14 blasts ≥ 5%), 67% vs. 55%, p=0.33 (D14 cellularity >20%) and 38% vs. 55%, p=0.35 (D14 blasts ≥5% and cellularity ≥20%). In patients with ≥5% residual blasts on D14 marrow but <20% cellularity there was significant variation in use of D14 BM results with only 49/106 (46.2%) patients undergoing a second IC. In this group, a second IC improved CR/CRi (43.9% vs. 72.0%, P=0.004) but there was no difference in OS (HR 1.08, 95% CI 0.63-1.86, p=0.77). Furthermore, in this group leukemia free survival following CR/CRi was worse in patients that received a second IC (HR 2.24, 95% CI 1.00-4.98, p=0.05).

Conclusion:

D14 BM results are prognostic for achievement of CR/CRi following induction therapy for AML. D14 blasts <5% predicted CR/CRi in multivariate analysis, despite possible confounding of this analysis by the use of second IC based on D14 BM results. In addition, D14 blasts <5% are prognostic for OS in multivariate analysis including other recognized prognostic factors. For patients with residual blasts but hypocellular marrow on D14 BM, second IC was associated with greater CR/CRi rates but no difference in OS. This finding suggests that for this subset of patients, treatment decisions based on D14 BM may not significantly improve OS.

View largeDownload slide

View largeDownload slide

Close modal