Post-induction consolidation therapy is essential for patients with acute myeloid leukemia (AML) in first complete remission (CR1) in case of disease recurrence.
Consolidation therapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) are the most frequent post-induction therapies. Since a suitable donor is not always available after achieving CR1 and medical resource is limited, one or more courses of consolidation chemotherapy have to be given to patients with AML after achieving CR before proceeding to allo-HSCT as “bridging” therapy to allo-HSCT. Theoretically, pre-transplant consolidation chemotherapy reduces leukemia cell burden, thereby potentially improving transplant outcomes by decreasing relapse rate. However, the toxicity of consolidation chemotherapy might increase the risk of transplant-related mortality. Although this is a debating issue for all hematologists, no prospective studies have been conducted to answer this question. [1-3]
Two large retrospective registry studies showed that pre-transplant consolidation chemotherapy with cytarabine before human leukocyte antigen (HLA)-matched HSCT with myeloablative conditioning for patients with AML in CR1 was not associated with improved outcomes compared with proceeding directly to allo-HSCT after CR1.
Similarly, for patients with AML in CR1 who received HSCT with reduced-intensity conditioning or non-myeloablative conditioning, patients did not benefit from pre-transplant consolidation therapy. [4,5] However, a recently published study reported that patients with one or two courses of high-dose cytarabine before allo-HSCT had better HSCT outcomes when compared with patients without consolidation, although HLA-matched donors and mismatched donors were all included in the study. [6,7] Another retrospective study showed that patients in minimal residual disease (MRD)-negative CR1 undergoing allo-HSCT who received pre-transplant consolidation demonstrated better outcomes.  MRD before HLA-matched HSCT is a robust prognostic marker for the patient with AML in CR1 in previous data.  Therefore, the value of consolidation chemotherapy before allo-HSCT remains controversial. It remains an issue whether MRD plays a role in directing the decision to proceed immediately to HSCT or to consolidation therapy before HSCT. [10-17]
First, we focused on the effects of the number of pre-transplant consolidation chemotherapies on the outcomes of patients with AML in CR1 after
HLA-matched sibling stem cell transplantation (MSDT). In addition, owing to the stratification based on MRD in patients with AML who received MSDT, it remains an issue whether pre-transplant consolidation chemotherapy has different effects on transplant outcomes between pre-transplant MRD-negative and -positive patients receiving MSDT. In other words, whether pre-transplant consolidation therapy could offset leukemia cell burden that MRD harbors. Therefore, our multicenter study further compared the effects of pre-transplant consolidation therapy between MRD-negative patients and -positive patients with AML in CR1 who received MSDT. Methods
This retrospective, multicenter study across China was approved by the Medical Ethic Committee of Peking University People's Hospital ( Hospital ethic committee clinic medicine No. 17). The medical ethic committee of First Affiliated Hospital of Soochow University and Nanfang Hospital approved data were used for the study. All data were collected by transplant center personnel according to the same case report form following written informed consent from patients in accordance with the centers’ ethical research guidelines. All patients signed informed consent forms before the start of HSCT. The accuracy of data was assured by clinic doctors from the three transplant centers: Peking University People's Hospital, First Affiliated Hospital of Soochow University, and Nanfang Hospital.
All patients with AML received induction chemotherapy and post-remission therapy as described
in the Chinese guidelines published in 2011. The data of 373 patients with AML who met the following criteria were collected in this retrospective study: (1) in their first morphologic remission, (2) receiving MSDT in the three HSCT centers mentioned above in China from 2012 to 2016, and (3) with written informed consent. The exclusion criteria were as follows: (1) patients who refused written informed consent and (2) patients who achieved CR1 after more than three courses of induction chemotherapy for direct HSCT.  Transplant protocol
Unmanipulated MSDT was performed as previously reported by our group.
The conditioning regimen was as follows: hydroxycarbamide (80 mg/kg) orally on day –10; cytarabine (2 g·m  −2·day −1) on day –9; busulfan (3.2 mg·kg −1·day −1) IV on days –8 to –6; cyclophosphamide (1.8 g·m −2·day −1), IV on days –5 to –4; methyl chloride hexamethylene urea nitrate (250 mg·m −2·day −1), orally once on day –3. Granulocyte colony-stimulating factor (G-CSF; 5 μg/kg of body weight per day for 5 days) was used to mobilize the bone marrow (BM) and peripheral blood (PB). The target mononuclear cell count was >6 × 10 8/kg of recipient weight. Unmanipulated BM (harvested on day 4 after G-CSF) and PB stem cells (harvested on day 5 after G-CSF) were infused into the recipient on the day of collection. Patients received both BM and PB as a stem cell source. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A, a short course of methotrexate, and low-dose mycophenolate mofetil. [20-22] Multicolor flow cytometry (MFC) detection of MRD
MFC was performed for patients at the Peking University People's Hospital on BM aspirate samples obtained at the time of diagnosis, 1 month after every course of chemotherapy, and < 1 month before HSCT. A panel of eight antibody combinations recognizing cluster of differentiation (CD)7, CD11b, CD13, CD14, CD16, CD19, CD33, CD34, CD38, CD41, CD45, CD56, CD61, CD64, CD71, CD117, CD123, and HLA-DR was used for MRD detection. The standardized assays and quality controls were previously described.
When a patient had abnormal leukemia-associated immunophenotype (LAIP) at diagnosis, positive MRD was defined as a cell population carrying at least two LAIP markers at diagnosis. When a patient did not have LAIP at diagnosis, positive MRD was identified as a cell population that deviated from the normal patterns of antigen expression on specific cell lineages at specific stages of maturation. A lower limit of detection of 0.01% was targeted. Once MFC-based MRD was identified, the abnormal cell population was calculated as a percentage of total CD45 [23-25] + white cell events. Any measurable level of MRD was considered positive. MFC-based MRD less than 1 month before HSCT was defined as pre-transplantation minimal residual disease (pre-MRD) in the study. [23,26] Outcomes
The primary endpoint of this study was the cumulative incidence of AML relapse, and the secondary endpoints were the cumulative incidence of non-relapse mortality (NRM) and the probabilities of overall survival (OS) and leukemia-free survival (LFS), all of which were calculated from the time of HSCT. Acute GVHD (aGVHD) and chronic GVHD (cGVHD) were diagnosed and graded according to standard international criteria.
Primary engraftment failure was defined as a recovery of absolute neutrophil count ≤ 0.5 × 10 [27,28] 9/L, and platelet counts ≤ 20 × 10 9/L by + 30 days after allo-HSCT. Secondary engraftment failure was defined as a decrease in blood cell count to the above-described levels for at least 30 consecutive days after successful engraftment. Relapse was defined according to histological criteria. All patients were followed up through our outpatient clinic, medical records in the hospital, and by telephone. Statistical analysis
Patient characteristics were compared among different groups using the
χ 2-test for categorical variables and the t-test for continuous variables. The probabilities of OS and LFS were estimated using the Kaplan-Meier method, and the cumulative incidences of NRM and relapse were calculated using cumulative incidence estimates. NRM was defined as death without relapse and was treated as a competing risk for relapse, whereas relapse was considered a competing risk for NRM. The time to engraftment was defined as the time from transplantation to successful engraftment, and the time to GVHD was defined as the time from transplantation to GVHD onset. The number of consolidation chemotherapy courses, pre-MRD status, aGVHD grade, cGVHD, neutrophil engraftment, platelet engraftment, and all variables in Table 1 were included in the univariate analysis. Further, those variables with P < 0.1 were included in a Cox proportional hazards model. Unless otherwise stated, a P value < 0.05 was considered statistically significant. Competing risk analysis was performed using R software ( ). Other statistical analyses were performed using SPSS 22.0 (Mathsoft, Seattle, WA, USA). https://www.r-project.org/
Table 1 -
Characteristics of patients with acute myeloid leukemia in the first complete remission.
≤ 2 consolidation
≥ 3 consolidation
Number of patients (
Median cycles of consolidation therapy (
Median age (years)
n (%) 52.8
FLT3-ITD mutation (%)
ABO matched grafts,
Cell compositions in allografts,
BM + PB
Infused nuclear cells (10
8/kg, range) 7.87 (2.27–28.55)
+ cells (10 8/kg, range) 3.00 (0.41–14.74)
DLI after HSCT,
n (%) 40 (10.7)
BM: Bone marrow; DLI: Donor lymphocyte infusion; DR sex: Donor-recipient sex-matched grafts; HLA: Human leukocyte antigen; F-F: Female to female; F-M: Female to male; MSDT: HLA-matched sibling transplantation; M-M: Male to male; M-F: Male to female; PB: Peripheral blood.
Patient characteristics and overall outcome
Three hundred and seventy-three patients with AML in CR1 who underwent MSDT (
n = 373) were included in this retrospective study. Table 1 summarizes the characteristics of these patients stratified by the number of consolidation chemotherapies of which donor-recipient sex-matched grafts and cell compositions in allografts showed significant differences.
With a median follow-up of 969 days after transplantation (range, 27–3123 days), the 5-year cumulative incidences of NRM and relapse were 9.5% and 15.1%, respectively. The 5-year probabilities for LFS and OS were 76.6% and 84.2%, respectively. The median time of neutrophil and platelet engraftment was 14 and 12 days post-HSCT, respectively. The cumulative 100-day incidence of aGVHD grades II–IV was 14.5%. The 4-year cumulative incidence of cGVHD was 47.2%.
Effect of pre-transplant consolidation therapy on MSDT
All enrolled 373 patients were stratified into two groups: consolidation chemotherapy ≤ 2 courses
vs. ≥ 3 courses, and we analyzed their transplant outcomes according to the number of pre-transplant consolidation chemotherapy they received. All patients underwent neutrophil engraftment. Patients with consolidation chemotherapy ≤ 2 courses pre-transplant had similar probabilities of platelet engraftment as those patients with pre-transplant consolidation chemotherapy ≥ 3 courses (98.9% vs. 100.0%, P = 0.064).
The cumulative 100-day incidence of aGVHD grades II to IV for patients with consolidation chemotherapy ≤ 2 courses was higher than those patients with ≥ 3 courses pre-transplant (19.4%
vs. 8.7%, P = 0.004). The 4-year cumulative incidence of cGVHD in patients with consolidation chemotherapy ≤ 2 courses was comparable to that in patients with consolidation chemotherapy ≥ 3 courses (44.5% vs. 46.5%, P = 0.272).
In the MSDT setting, pre-transplant consolidation chemotherapy patients who have received was associated with transplant outcomes. The incidence of LFS and OS in patients with ≥ 3 courses of consolidation chemotherapy was higher than that in patients with ≤ 2 courses of consolidation chemotherapy (LFS, 85.6%
vs. 67.0%, P < 0.001; OS, 89.2% vs. 78.5%, P = 0.007). The cumulative incidence of relapse (CIR) and NRM in patients with ≥ 3 courses of consolidation chemotherapy was lower than that in patients with ≤ 2 courses of consolidation chemotherapy (CIR, 10.5% vs. 19.6%, P = 0.020; NRM, 4.2% vs. 14.9%, P = 0.001) [ Figure 1]. Figure 1:
OS (A), LFS (B), NRM (C), and relapse (D) were compared between AML patients in CR1 with consolidation chemotherapy ≤ 2 courses and ≥ 3 courses in MSDT setting. AML: Acute myeloid leukemia; CR1: First complete remission; HLA: Human leukocyte antigen; LFS: Leukemia-free survival; MSDT:
HLA-matched sibling stem cell transplantation; NRM: Non-relapse mortality; OS: Overall survival.
Stepwise forward Cox proportional hazards regression models were used to compare risks for OS, LFS, relapse rate, and NRM in multivariate analyses adjusting for the effects of other significant covariates. More than two courses of consolidation chemotherapy pre-transplant in MSDT were positively associated with probabilities of LFS (hazard ratio [HR] 0.403, 95% confidence interval [CI] 0.250–0.650,
P < 0.001), OS (HR 0.469, 95% CI 0.267–0.824, P = 0.008), cumulative incidence of NRM (HR 0.278, 95% CI 0.120–0.643, P = 0.003), and CIR (HR 0.504, 95% CI 0.280–0.907, P = 0.022) in univariate analysis, and the results were also been confirmed in multivariate analyses (LFS, HR 0.405, 95% CI 0.256–0.853, P = 0.003; OS, HR 0.454 95% CI 0.220–0.935, P = 0.032; NRM, HR 0.320, 95% CI 0.108–0.948, P = 0.040; relapse, HR 0.427, 95% CI 0.205–0.889, P = 0.023) [ Table 2].
Table 2 -
Multivariate analysis of consolidation chemotherapy with all variables in MSDT setting.
P value HR
Consolidation therapy no.
Infused nuclear cells
Consolidation therapy no.
Infused nuclear cells
PLT graft Yes or no
Consolidation therapy no.
PLT graft Yes or no
Consolidation therapy no.
PLT graft Yes or no
All variables were first included in the univariate analysis; only variables with
P < 0.1 were included in the Cox proportional hazards model with time-dependent variables.aGVHD: Acute GVHD; cGVHD: Chronic GVHD; CI: Confidence interval; GVHD: Graft- vs.-host disease; HR: Hazard ratio; HLA: Human leukocyte antigen; MRD: Minimal residual disease; MSDT: HLA-matched sibling stem cell transplantation; MFC: Multicolor flow cytometry; NRM: Non-relapse mortality; OS: Overall survival. Effects of pre-transplant consolidation on outcomes of patients with AML receiving MSDT according to different pre-MRD status
To observe the effect of pre-MRD on outcomes of MSDT, all patients with AML undergoing MSDT with complete pre-MRD data were classified into the pre-MRD-positive group (
n = 26) and -negative groups ( n = 183). Although only 209 patients from Peking University People's Hospital detected MFC-based MRD, the number of patients accounted for 56% of the entire population, reflecting the real-world situation to some extent. Patients in the pre-MRD-positive and -negative groups had comparable probabilities of LFS (68.8% vs. 80.3% P = 0.078), cumulative incidences of relapse (23.5% vs. 13.7%, P = 0.076), and NRM (9.1% vs. 6.7%, P = 0.652), but the pre-MRD-negative group had better OS (72.7% vs. 87.0%, P = 0.025).
Considering the negative effect of pre-MRD on transplant outcomes in the MSDT settings, we investigated whether there were differences in the effects of pre-transplant consolidation on outcomes of AML cases according to different pre-MRD status. For pre-MRD-positive patients in the MSDT setting (26 patients), the incidence of OS and LFS of those with ≥ 3 courses of consolidation chemotherapy was 80.8% and 81.3%, respectively, in contrast to patients with ≤ 2 courses of consolidation chemotherapy (OS 60.0%, LFS 50.0%). The CIR and NRM of patients with ≥ 3 courses and ≤ 2 courses of consolidation chemotherapy were 0%
vs. 21.8% and 18.8% vs. 29.4% [ Figure 2E–H]. Among the 26 pre-MRD-positive patients receiving MSDT, ten patients received ≤ 2 courses of consolidation chemotherapy, and 16 patients had ≥ 3 courses of consolidation chemotherapy. Of the 16 patients with ≥ 3 courses of consolidation chemotherapy, ten had collected complete MRD data detected by flow cytometry from the second course of chemotherapy to the third course of consolidation chemotherapy. Another additional consolidation therapy decreased the MRD by 1 log in three of ten patients [ Table 3]. Figure 2:
OS (A, E), LFS (B, F), NRM (D, H), and relapse (C,G) were compared between AML patients in CR1 with consolidation chemotherapy ≤ 2 courses and ≥ 3 courses according to different pre-MRD status by flow cytometry in MSDT setting. AML: Acute myeloid leukemia; CR1: First complete remission; HLA: Human leukocyte antigen; LFS: Leukemia-free survival; MSDT:
HLA-matched sibling stem cell transplantation; NRM: Non-relapse mortality; OS: Overall survival; pre-MRD: Pre-transplantation minimal residual disease; preMRDneg: Pre-transplantation minimal residual disease negative; preMRDpos: Pre-transplantation minimal residual disease positive.
Table 3 -
Effect of pre-transplant consolidation therapy on MSDT.
≤ 2 consolidation (%)
≥ 3 consolidation (%)
aGVHD II to IV
19.4 ± 2.8
8.7 ± 2.2
44.5 ± 5.5
46.5 ± 7.5
67.0 ± 3.6
85.6 ± 2.7
78.5 ± 3.2
89.2 ± 2.4
19.6 ± 3.2
10.5 ± 2.4
14.9 ± 2.8
4.2 ± 1.6
Values were shown as mean ± standard deviation. aGVHD: Acute GVHD; cGVHD: Chronic GVHD; CIR: Cumulative incidence of relapse; GVHD: Graft-
vs.-host disease; LFS: Leukemia-free survival; MSDT: HLA- matched sibling stem cell transplantation; NRM: Non-relapse mortality; OS: Overall survival.
Among the 183 pre-MRD-negative patients receiving MSDT, those patients with ≥ 3 courses of consolidation chemotherapy had a better LFS (85.9%
vs. 67.7%, P = 0.003) and a lower CIR (9.6% vs. 23.3%, P = 0.013) compared to patients with ≤ 2 courses of consolidation chemotherapy, but the two groups had a comparable probability of NRM (4.9% vs. 10.9%, P = 0.127) [ Figure 2A–D]. In addition, the probabilities of OS between the two groups were 90.0% (≥3 courses) and 80.3% (≤2 courses), respectively ( P = 0.051). Among the 183 pre-MRD-negative patients receiving MSDT, 57 patients received ≤ 2 courses of consolidation chemotherapy, and 126 patients had ≥ 3 courses of consolidation chemotherapy. Of the 126 patients with ≥ 3 courses of consolidation chemotherapy, 81 had collected complete MRD data detected by flow cytometry from induction chemotherapy to the third course of consolidation chemotherapy. However, only three patients had positive MRD after the second course of consolidation therapy, and another additional consolidation therapy rendered the MRD of two patients negative. Discussion
Our study is a multicenter retrospective study, showing that patients with pre-transplant consolidation chemotherapy ≥ 3 courses achieved better transplant outcomes than those with consolidation chemotherapy ≤ 2 courses in the MSDT setting. In the pre-MRD-negative patient subgroup, patients who underwent MSDT with ≥ 3 courses of consolidation chemotherapy had a better probability of LFS and a lower CIR than those with ≤ 2 courses. Our results provide new insights into the controversial value of consolidation chemotherapy pre-transplantation,
suggesting that ≥ 3 courses of consolidation chemotherapy pre-transplant benefit patients with AML in CR1 who undergo HLA-matched allografts. [29,30]
Multicenter data demonstrated that patients with AML in CR1 who received ≥ 3 courses of consolidation chemotherapy before MSDT achieved a better probability of LFS and lower cumulative incidences of NRM and relapse rate than those receiving ≤ 2 courses of consolidation chemotherapy. Theoretically, pre-transplant consolidation chemotherapy should reduce leukemia cell burden, and further decrease relapse rate to improve LFS. However, data from the centers showed that patients with AML in CR1 with more than three courses of consolidation chemotherapy before MSDT had a lower cumulative incidence of NRM. According to the NRM data, more pre-transplant consolidation therapy did not increase the chemotherapy toxicities, but whether other factors affected the NRM rate was undefined. First, there were only 21 patients with pre-transplant consolidation chemotherapy ≥ 5 courses, so it might be because most patients did not suffer sufficient chemotherapy toxicities to affect their outcomes. Second, as a multicenter study, the difference in tackling complications after allo-HSCT in different centers might lead to different outcomes to some extent. Third, the two groups are not comparable for all characteristics; in particular, the group with ≥ 3 courses of consolidation chemotherapy almost exclusively received a combination of PB and BM as stem cell sources, while it was only 53% in the group with less than two courses of consolidation chemotherapy. Zhao
et al reported that PB as a stem cell source was an independent risk factor for grades III-IV aGVHD and LFS in MSDT. 
Several researchers have demonstrated that for patients with AML in CR1 who underwent myeloablative conditioning
or non-myeloablative conditioning [4,5] allo-HSCT using allografts either from a matched related donor, a matched unrelated donor, or an umbilical cord blood donor, the outcomes were comparable between patients receiving pre-transplant consolidation chemotherapy with cytarabine and those proceeding directly to transplantation after achieving CR. In contrast to the above studies, we found a beneficial effect of more consolidation chemotherapy pre-transplant on outcomes in the MSDT setting, in accordance with previously published data. [6,7] Several reasons might contribute to the different results between others [8,9,32] and our study. First, Tallman [4-7] et al and Cahn  et al studies included patients across more than 100 centers with different conditioning regimens, whereas our study used the same conditioning regimen, making it easier to compare among homogenous samples. Second, the studies of Tallman  et al and Cahn  et al compared transplant outcomes of different groups defined by doses of cytarabine, while another two studies regarding RIC MSDT compared transplant outcomes based on exposure to cytarabine as post-remission consolidation. Our study first focused on the number of consolidation chemotherapy pre-transplant administered to the patients. More recently, a meta-analysis showed no significant benefit of post-remission consolidation chemotherapy in patients with AML who received allo-HSCT.  Unfortunately, a recent study reported by Rashidi  et al and How  et al was not included in this meta-analysis. Rashidi  et al showed that in AML patients undergoing allo-HSCT in MRD-negative CR1, a history of prior consolidation was associated with favorable outcomes. 
According to published data, MFC-based positive pre-MRD predicted worse outcomes of HSCT in the MSDT setting.
However, for those pre-MRD-negative patients, whether more consolidation chemotherapy is required remains an issue. We observed that pre-MRD-negative patients with AML in CR1 receiving MSDT with ≥ 3 courses of consolidation chemotherapy had better outcomes than those with ≤ 2 courses. [10-17] The cytogenetics of patients at first diagnosis was comparable between the two groups. The results reported by Rashidi  et al and our study confirmed that the number of consolidation courses still matters despite MRD negativity in patients with AML in CR1. However, in our study, the benefits were only noticeable in cases with ≥ 3 courses of consolidation chemotherapy. It is possible that previous treatments before allo-HSCT reflect the depth of remission, although pre-MRD has not been detected by MFC in this study, and MRD evaluation by next-generation sequencing (NGS) might clarify this issue in the future. More consolidation chemotherapy might help eradicate these residual leukemia cells pre-transplantation in pre-MRD-negative patients with AML. These residual leukemia cells could not be eradicated by conditioning regimens and recovered by immune cells, including T cells and natural killer cells, because many studies have demonstrated the negative effects of positive pre-MRD on outcomes in MSDT settings.  However, there were only 26 pre-MRD-positive patients in the available data, which is insufficient to draw a definitive conclusion. [10-17,33]
There are some limitations of this study. First, since our study is a multicenter retrospective study, experience in these centers is different. Second, patients receiving the highest number of consolidation courses are potentially selected and represent a lower risk because they did not relapse earlier. We also considered that high-risk patients who relapsed prior to HSCT would lead to an inherent bias. When designing the study, in order to decrease the effect, the patients in the second CR and refractory patients in CR1 were excluded from the study. Therefore, patients who relapsed early or died from consolidation therapy were precluded from transplantation, which might have led to deviation from the real world. However, a prospective study is required to eliminate this inherent bias. Third, MRD data pre-transplant were only collected by one center, and there were only 26 pre-MRD-positive patients receiving MSDT; thus, the statistical power is not sufficient to make a definitive conclusion. Data from more centers are required to confirm the conclusion. Fourth, for MRD, NGS is more sensitive than multicolor flow cytometry; therefore, it would be more predictive to evaluate MRD by combining multicolor flow cytometry and NGS. However, a prospective study involving pre-MRD and consolidation therapy before transplantation is required to draw definitive conclusions.
In conclusion, our results, indicate that patients with AML in CR1 benefit from more than two courses of pre-transplant consolidation chemotherapy in the MSDT setting. Furthermore, these results suggest that multicenter, prospective studies are warranted to further elucidate the effects of pre-transplant consolidation chemotherapy on clinical outcomes in different allogeneic transplantation protocols.
We thank all the faculty members that participated in these studies.
This work was supported by grants from the National Key Research and Development Program of China (No. 2019YFC0840606) from the Ministry of Science and Technology, the National Natural Science Foundation of China (No. 82070189, 81621001 and 82270227), CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2019-I2M-5-034).
Conflicts of interest
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