Patient disposition
Eight-hundred-twenty patients from the database of the SAL-AML registry fulfilled the criteria and were included in the analyses (Fig. 1). 178 patients were treated with approximately 6 g/m2 cytarabine per cycle (median 5.9 (IQR, 5.7–8.6) g/m²), corresponding to 6 applications of 1 g/m² cytarabine, compared to 642 patients who received approximately 18 g/m² cytarabine per cycle (median 17.6 (IQR, 16.5–18.0) g/m²), which corresponds to 6 applications at 3 g/m² (Table 1). Only 2.8% or 1.6% received additional agents during consolidation. Thus, the selected cohort was almost exclusively treated with single-agent cytarabine for consolidation. IDAC-treated patients were older (median (IQR) 58.5 (49–62) vs. 50 (41–56) years, p < 0.001) and had significantly more often secondary and therapy-related AML, as well as more adverse and less favorable genetic risk features according to the ELN 2017 classification (Table 1). Of note, 116 core binding factor AML (CBF-AML) were treated with HiDAC, while only 20 received IDAC for consolidation. Furthermore, IDAC-treated patients had more comorbidities according to HCT-CI score (HCT-CI ≥ 2 43.8 vs. 22.3%, p < 0.001). Eighty respectively 90% of patients have been induced with the 7 + 3 regimen. Based on German recommendations, the number of induction cycles differed significantly with more patients within the HiDAC cohort receiving 2 cycles (76.8 vs. 61.2%, p < 0.001). Likewise, the median number of consolidation cycles was different with two (IQR, 1–3) in the IDAC group and three (IQR, 2–3) among HiDAC-treated patients. As a result of more unfavorable risk patients in elderly patients > 60 years, significantly more patients treated with IDAC received allogeneic hematopoietic cell transplantation in first remission (37.6 vs. 19.8%, p < 0.001). Whereas the rate of transplantation after relapse was higher among HiDAC-treated patients (30.8 vs. 20.2%, p = 0.007).
Table 1
Patient and treatment characteristics of all patients. HiDAC/IDAC, high-dose/intermediate-dose cytarabine; IQR, interquartile range; sAML, secondary AML; tAML, treatment-related AML; HCT-CI, Hematopoietic Cell Transplantation-Comorbidity Index; 7 + 3, induction treatment with standard-dose cytarabine for 7 d and daunorubicin for 3 d; HAM, high-dose cytarabine plus mitoxantrone; HCT, hematopoietic cell transplantation; CR1, first complete remission.
| IDAC (n = 178) | HiDAC (n = 642) |
Age at initial diagnosis (years, median (IQR)) | 58.5 years (IQR, 49–62) | 50.0 years (IQR, 41–56) |
Female sex, no./no. Available (%) | 88/178 (49.4%) | 314/642 (48.9%) |
AML type, no./no. available (%) de novo AML sAML tAML | 147/178 (82.6%) 9/178 (5.1) 22/178 (12.4) | 594/640 (92.8%) 20/640 (3.1) 26/640 (4.1) |
ELN-Risk 2017 group, no./no. available (%) Favorable Intermediate Adverse | 67/165 (40.6) 74/165 (44.8) 24/165 (14.5) | 336/600 (56) 225/600 (37.5) 39/600 (6.5) |
Core binding factor AML | 20/168 (11.9) | 116/604 (19.2) |
Complex karyotype, no./no. available (%) | 15/168 (8.9) | 29/609 (4.8) |
FLT3-ITD | 38/161 (23.6) | 123/595 (20.7) |
NPM1 mut | 68/168 (40.5) | 280/612 (45.8) |
HCT-CI 0–1 2–4 | 100/178 (56.2) 78/178 (43.8) | 498/641 (77.7) 143/641 (22.3) |
Induction therapy 1 cycle 7 + 3 2 cycles 7 + 3 7 + 3 / HAM others | 67/178 (37.6) 75/178 (42.1) 8/178 (4.5) 28/178 (15.7) | 151/642 (23.5) 428/642 (66.7) 33/642 (5.1) 30/642 (4.7) |
Number of consolidation cycles (median (IQR)) | 2 (IQR,1–3) | 3 (IQR,2–3) |
Cytarabine dose per chemo-consolidation cycle (median (IQR)) | 5891.85 mg/m² per cycle | 17580.38 mg/m² per cycle |
Additional substances | 2.8% | 1.6% |
Allogeneic HCT in CR1 | 67/178 (37.6) | 127/642 (19.8) |
Allogeneic HCT salvage | 36/178 (20.2) | 198/642 (30.8) |
Effect of cytarabine dose on outcome
To explore the impact of cytarabine dose in post-remission therapy after intensive induction treatment on survival, propensity score weights were estimated for the average treatment effects, which allowed adjusting for imbalances in prognostic variables and estimating adjusted Kaplan-Meier curves. There was no difference in RFS with a 2-year survival probability of 55.3% in HiDAC- versus 55.6% in IDAC-treated patients (HR = 0.935, p = 0.69) (Fig. 2A). Also for OS there were no significant differences with a 2-year OS probability of 84.7% in HiDAC vs. 80.6% in IDAC group (HR = 1.101, p = 0.65). To exclude the influence of allogeneic hematopoietic cell transplantation, we next assessed outcome with censoring on the date of allogeneic hematopoietic cell transplantation in first remission. In fact, there was no significant survival difference in dependence of cytarabine dosage, neither for RFS (2-year RFS HiDAC vs. IDAC, 52.3 vs. 49.7%, HR = 1.008, p = 0.97) nor OS (2-year OS HiDAC vs. IDAC, 86.3 vs. 84.1%, HR = 0.999, p = 1.00) (Fig. 2B).
Looking at the subgroup of patients with favorable genetic features according to the ELN 2017 classification, which comprised 336 patients treated with HiDAC and 67 with IDAC, no significance difference for RFS (2-year RFS HiDAC vs. IDAC, 65.0 vs. 57.3%, HR = 1.151, p = 0.59) and OS was found (2-year OS HiDAC vs. IDAC, 90.1 vs. 87.5%, HR = 1.092, p = 0.82) (Fig. 3A). Though there was no significant difference in the rate of allogeneic hematopoietic cell transplantation in this subgroup, for better comparison we also censored the ELN favorable cohort on the date of transplantation in first remission. A trend for superior RFS for HiDAC-treated patients appeared with a 2-year survival rate of 62.7% compared to 47.0% for patients consolidated with IDAC, which, however, did not reach statistical significance (HR = 1.453, p = 0.16) (Fig. 3B). For OS, there was no significant difference in dependence of cytarabine dose (2-year OS HiDAC vs. IDAC, 89.9 vs. 85.3%, HR = 1.326, p = 0.51) (Fig. 3B). Given previously reported evidence suggesting that HiDAC for consolidation is beneficial for core binding factor leukemia3,9, we specifically assessed the subgroup of core binding factor AML. With only 20 patients in the IDAC and 116 patients in the HiDAC group, there was no significant difference for RFS and OS (2-year RFS HiDAC vs. IDAC, 59.5 vs. 38.2%, HR 1.742, p = 0.16; 2-year OS HiDAC vs. IDAC, 86.6 vs. 97%, HR 1.101, p = 0.86), though the small patient number prohibit any conclusion for this subgroup (data not shown). For AML patients at intermediate risk according to ELN 2017 classification, again there was no significant difference in terms of RFS and OS in dependence of cytarabine dose (Fig. 4A). Given the significant differences in the number of allogeneic-transplanted patients between both cohorts, this subgroup was also censored on the date of allogeneic hematopoietic cell transplantation in first remission. There was a trend for inferior probability of RFS for ELN intermediate risk patients treated with HiDAC compared to IDAC, which, however, was not statistically significant (2-year RFS HiDAC vs. IDAC, 40.6 vs. 55.7%, HR = 0.626, p = 0.11) (Fig. 4B). Still, there was no difference in OS (2-year OS HiDAC vs. IDAC, 84.8 vs. 85.0%, HR = 0.979, p = 0.96) (Fig. 4B). For ELN adverse risk AML patients, there were no significant differences in outcome in dependence of cytarabine dose, though the numbers of patients were in both groups expectedly low (Fig. S1).
Finally, in multivariable analysis accounting for the influence of ELN risk, number of induction cycles, age, sex, performance and comorbidities, as well as AML type, the dose of cytarabine in post-remission therapy remained not prognostically significant for outcome (Table 2).
Table 2
Hazard ratio for relapse-free and overall survival according to multivariable Cox regression models. HiDAC/IDAC, high-dose/intermediate-dose cytarabine; sAML, secondary AML; tAML, treatment-related AML; ECOG, clinical performance status according to ECOG criteria; HCT-CI, Hematopoietic Cell Transplantation-Comorbidity Index; 7 + 3, induction treatment with standard-dose cytarabine for 7 d and daunorubicin for 3 d; CR1, first complete remission.
| Relapse-free survival | Overall survival |
| Hazard ratio | 95% CI | p | Hazard ratio | 95% CI | p |
Cytarabine dose | | | | | | |
HiDAC | Reference | | | Reference | | |
IDAC | 0.900 | 0.650–1.246 | 0.530 | 1.094 | 0.721–1.660 | 0.670 |
ELN risk group | | | | | | |
Intermediate | Reference | | | Reference | | |
Favourable | 0.704 | 0.514–0.965 | 0.029 | 0.435 | 0.273–0.694 | < 0.001 |
Adverse | 1.147 | 0.745–1.767 | 0.540 | 1.771 | 0.988–3.174 | 0.055 |
Number of 7 + 3 induction cycles | | | | | | |
1 cycle | 1.603 | 1.195–2.151 | 0.002 | 1.758 | 1.221–2.532 | 0.002 |
2 cycles | Reference | | | Reference | | |
Age (per 10 years) | 1.012 | 0.999–1.025 | 0.120 | 1.021 | 1.001–1.041 | 0.036 |
Sex, Male | 1.151 | 0.860–1.539 | 0.350 | 1.163 | 0.788–1.718 | 0.450 |
ECOG, >1 | 1.071 | 0.704–1.629 | 0.750 | 1.653 | 1.001–2.728 | 0.050 |
HCT-CI, >1 | 1.220 | 0.887–1.677 | 0.220 | 1.425 | 0.968–2.099 | 0.072 |
AML type | | | | | | |
de novo | Reference | | | Reference | | |
sAML | 0.807 | 0.462–1.410 | 0.450 | 1.033 | 0.548–1.947 | 0.920 |
tAML | 1.266 | 0.795–2.015 | 0.320 | 1.215 | 0.657–2.246 | 0.540 |