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A risk score system for stratifying the risk of relapse in B cell acute lymphocytic leukemia patients after allogenic stem cell transplantation

Cao, Le-Qing1; Zhou, Yang1; Liu, Yan-Rong1; Xu, Lan-Ping1; Zhang, Xiao-Hui1; Wang, Yu1; Chen, Huan1; Chen, Yu-Hong1; Wang, Feng-Rong1; Han, Wei1; Sun, Yu-Qian1; Yan, Chen-Hua1; Tang, Fei-Fei1; Mo, Xiao-Dong1; Liu, Kai-Yan1; Fan, Qiao-Zhen1; Chang, Ying-Jun1; Huang, Xiao-Jun1,2,3

Editor(s): Lyu, Peng

Author Information
doi: 10.1097/CM9.0000000000001402
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Abstract

Introduction

Outcomes of acute lymphoblastic leukemia (ALL) have improved with the development of treatment measures.[1,2] However, relapse remains the major cause of treatment failure in patients with ALL who either exclusively received chemotherapy or additionally underwent allogeneic stem cell transplantation (allo-SCT).[3,4] For allo-SCT cases, almost all available studies have demonstrated that positive measurable/minimal residual disease (MRD) before[5–12] and after[13–25] transplantation was related to a higher cumulative incidence of relapse (CIR) in both adult and pediatric ALL. A previous study[18] also showed that the positive MRD at the time points, including days +30, +60, +90, +180, and +365 after allo-SCT, were inversely correlated with event-free survival and positively correlated with CIR in pediatric ALL. More recently, we reported the association of both quantitative and qualitative pre-transplantation MRD (pre-MRD)[11] as well as post-transplantation MRD (post-MRD)[25] with increased CIR and inferior survival in patients with ALL who underwent haploidentical allograft transplantation.

For patients with ALL who underwent allo-SCT, other variables in addition to post-MRD have also been demonstrated to be associated with leukemia relapse. For example, patients in the first complete remission (CR1) have better outcomes than those in CR2 or those with advanced disease stage.[26–35] Meanwhile, studies reported by others[26,28,32,36–44] and us[45,46] have shown that the onset of graft-versus-host disease (GVHD) after allo-SCT can reduce CIR. Recent studies found that acute graft-versus-host disease (aGVHD) or chronic graft-versus-host disease (cGVHD) could reduce CIR for patients with positive post-MRD[47] as well as for patients transplanted with advanced disease (≥CR3 or active disease).[39]

However, there are rare data regarding the prognostic significance of the combination of disease status with pre-MRD or post-MRD and GVHD in patients with ALL who are receiving allo-SCT. In addition, long-term survival has improved in patients with ALL who undergo current treatment regimens, but outcomes for T cell ALL are still worse than those for B cell acute lymphocytic leukemia (B-ALL).[48,49] Therefore, we attempted to establish a risk score based on pre-MRD or post-MRD determined by multiparametric flow cytometry (MFC) and disease status as well as cGVHD to explore whether it could predict transplant outcomes more precisely in patients with B-ALL after allo-SCT.

Materials and Methods

Ethical approval

This study met the guidelines of the Helsinki Declaration of 1975 and was approved by the Ethics Committee of Peking University People's Hospital (No. 2014PHB086-01). Informed consent was obtained from all patients or their guardians, and donors.

Patients and study design

This is a retrospective study. A total of 477 patients at the Peking University People's Hospital from December 2010 to December 2015 were enrolled. Donor selection and transplant protocol were performed as previously described.[50] Patients with B-ALL who underwent allo-SCT were included, and patients who lost follow-ups were excluded.

Transplant protocol

Granulocyte colony-stimulating factor (G-CSF; 5 μg per kilogram of body weight per day for 5 days) was used to mobilize granulocytes from the bone marrow (G-BM) and the peripheral blood (G-PB). The target mononuclear cell count was ≥6 × 108 per kilogram of recipient weight. Unmanipulated BM (harvested on day 4 after G-CSF) and PB stem cells (PBSCs, harvested on day 5 after G-CSF) were infused into the recipient on the day of collection. All patients who underwent haploidentical blood and marrow transplantation (HBMT) or HLA-matched sibling donor transplantation (MSDT) received both G-BM and G-PB, while patients who underwent HLA-matched unrelated donor transplantation (MUDT) received G-PB.

The conditioning therapy for the HBMT group was as follows: cytarabine (4 g·m−2·d−1) intravenously on days −10 to −9; busulfan (3.2 mg·kg−1·d−1) intravenously on days −8 to −6; cyclophosphamide (1.8 g·m−2·d−1) intravenously on days −5 to −4; semustine (Me-CCNU, 250 mg·m−2·d−1) orally once on day −3; and anti-T-lymphocyte globulins (ATG, thymoglobulin, 2.5 mg·kg−1·d−1, Genzyme Polyclonals, SAS, France) intravenously on days −5 to −2. MSDT patients received hydroxycarbamide (80 mg·kg−1·d−1) orally on day −10 and a lower dose of cytarabine (2 g·m−2·d−1) on day −9, but otherwise, an identical regimen to that of the HBMT patients without ATG was used. In the MUDT group, patients received the same regimen as the MSDT group but with the addition of ATG, as in the HBMT group. All patients received immunosuppressive agents, including cyclosporine A, mycophenolate mofetil, and short-term methotrexate, to prevent GVHD.[51–53]

MFC detection of MRD

The first day after stem cell infusion was defined as day 1. Multicolor MFC was performed in all patients on bone marrow aspirate samples that were obtained as part of the baseline assessment at diagnosis, across the duration of chemotherapy, before and around days +30, +60, +90, +120, and +180 or more after transplantation.[54–58] In this study, we focused on MRD status pre- and post-transplantation. Different antibody combinations were used as described previously.[17,59] Residual disease ≥0.001% detected by MFC at any time point before and after allo-SCT was considered pre-MRD or post-MRD positive (MRD+), while persistent negative MRD at all time points after transplantation was defined as MRD negative (MRD).[11,46]

Prevention and treatment of relapse

Once MRD turned positive or hematological relapse occurred, some measures were taken to prevent or treat relapse, including immunosuppression tapering, targeted drugs (such as tyrosine kinase inhibitors), interferon, donor lymphocyte infusion (DLI) with previous chemotherapy, and chimeric antigen receptor T cell immunotherapy.[46,60]

Definitions and assessments

The diagnostic criteria for ALL followed the World Health Organization 2008 criteria.[61] The primary study endpoint was the cumulative incidence of leukemia relapse. The secondary endpoints were the cumulative incidences of non-relapse mortality (NRM), the probabilities of leukemia-free survival (LFS), and overall survival (OS). Neutrophil engraftment was defined as an absolute neutrophil count ≥0.5 × 109/L for three consecutive days, and platelet engraftment was defined as ≥20 × 109/L for seven consecutive days without platelet transfusion. aGVHD, cGVHD, NRM, relapse, LFS, and OS were defined as described previously.[62,63] Patients with confirmed MRD were not classified as having a relapse.

Statistical analysis

Descriptive statistics, including the frequency (proportions) for categorical variables and the median (range) for quantitative variables, were used to describe the patient demographic and clinical characteristics. LFS, OS, NRM, and relapse incidence curves were estimated with the Kaplan–Meier method. Separate analyses were performed for six landmarks, namely samples from days +30, +60, +90, +120, and +180 or more after allo-HSCT. In each landmark analysis, time was measured from the date of sampling. Cumulative incidence curves were used in a competing risk setting, with relapse treated as a competing event, to calculate NRM probabilities. Only variables with P < 0.1 were included in a Cox proportional hazards model with time-dependent variables. Only variables with P < 0.1 were included in a Cox proportional hazards model with time-dependent variables, while the P < 0.05 was defined as significant in the multivariate analysis.

Finally, the risk score system included three significant prognostic factors, disease status, post-MRD, and cGVHD status, which, based on the results of the multivariate analysis, would be established. This risk score system ranged from 0 to 3 (0 for no risk factor, 1 for any one of the three risk factors, 2 for any two of the three risk factors, and 3 for all three risk factors). Calculations were performed using the SPSS 16.0 statistical package (SPSS Inc., Chicago, IL, USA).

Results

Patient characteristics

The characteristics and outcomes of the 477 patients with B-ALL who underwent allo-HSCT are outlined in Table 1. There were 163 (34.2%) patients with positive Philadelphia chromosome (Ph) and 314 (65.8%) patients with negative Ph. The median age of the patients was 26 years, ranging from 2.5 to 63.0 years. Of all patients, 423 (88.7%) achieved CR1 before transplantation, and 54 (11.3%) achieved CR2 or CR3. There were 118 patients with pre-MRD+ and 77 patients with post-MRD+, and the subsequent pre-emptive interventions are shown in Figure 1.

Table 1 - Demographic and clinical characteristics of patients with B-ALL underwent allo-SCT (n = 477).
Parameters Values
Age (years) 26 (2.5–63.0)
Gender
 Male 267 (56.0)
 Female 210 (44.0)
ALL type
 Ph positive 163 (34.2)
 Ph negative 314 (65.8)
Disease status
 CR1 423 (88.7)
 CR >1 54 (11.3)
Transplant type
 HBMT 340 (71.3)
 MSDT 127 (26.6)
 MUDT 10 (2.1)
Conditioning regimen
 MA 477 (100)
Donor-recipient sex match
 Male-male 170 (35.6)
 Male-female 130 (27.3)
 Female-male 96 (20.1)
 Female-female 81 (17.0)
ABO matched
 Matched 259 (54.3)
 Major mismatched 98 (20.5)
 Minor mismatched 93 (19.5)
 Bidirectional mismatched 27 (5.7)
Infused cell doses
 MNC (×106/kg) 7.9 (2.5–20.1)
 CD34+ cells (×106/kg) 2.5 (0.4–12.7)
Engraftment (yes or no)
 Neutrophil 477 (100)
 Platelet 455 (95.4)
Engraftment (days)
 Neutrophil 13 (9–26)
 Platelets 14 (7–506)
Acute GVHD grades
 I 128 (26.8)
 II 95 (19.9)
 III 19 (4.0)
 IV 9 (1.9)
Chronic GVHD (n = 197)
 Clinical extensive 44 (9.2)
Median follow-up for surviving patients (days) 1816 (1277–3107)
Data are presented as median (range), or n (%). ALL: Acute lymphoblastic leukaemia; allo-SCT: allogeneic stem cell transplantation; CR: Complete remission; CR1: First complete remission; GVHD: graft-versus-host disease; HBMT: Haploidentical blood and marrow transplantation; MA: Myeloablative conditioning regimen; MNC: Mononuclear cell; MSDT: HLA-matched sibling donor transplantation; MUDT: HLA-matched unrelated donor transplantation; Ph: Philadelphia chromosome.

Figure 1
Figure 1:
Pre-emptive intervention for patients with positive post-MRD after allo-SCT. allo-SCT: Allogeneic stem cell transplantation; CAR-T: Chimeric antigen receptor T cell immunotherapy; Che-DLI: DLI with previous chemotherapy; DLI: Donor lymphocyte infusion; GVHD: Graft-versus-host disease; IFN: Interferon; MRD: Minimal residual disease; TKI: Tyrosine kinase inhibitor.

By the end of the follow-up time, June 30, 2019, there was a median follow-up duration of 1570 (24–3107) days for all patients and 1816 (1277–3107) days for surviving patients; a total of 143 patients died, and the causes of death were relapse (53.8%), infection (28.7%), poor graft function (4.9%), GVHD (2.8%), and other causes (9.8%). All patients achieved neutrophil engraftment, and 95.4% of patients achieved platelet engraftment. The 100-day cumulative incidence of Grades III–IV aGVHD was 5.9% (95% confidence interval [CI] 3.7%–8.1%), while the 5-year cumulative incidence of cGVHD was 48% (95% CI 43.1%–52.9%); the transplant outcomes are listed in Table 2.

Table 2 - Transplant outcomes for B-ALL patients who underwent allo-SCT in different sub-group cases.
Parameters n 5-year relapse 5-year OS 5-year LFS 5-year NRM
Total patients 477 20.7 (17.0–24.4) 70.4 (66.3–74.5) 65.6 (61.3–69.9) 13.9 (10.8–17.0)
Pre-MRD
 Negative 359 15.5 (12.3–18.7) 73.3 (68.6–78.0) 69.0 (64.1–73.9) 16.1 (12.1–20.1)
 Positive 118 36.4 (27.7–45.1) 61.8 (53.0–70.6) 55.3 (46.1–64.5) 7.6 (2.8–12.4)
Post-MRD
 Negative 400 11.9 (8.7–15.1) 76.0 (71.7–80.3) 72.8 (68.3–77.3) 15.5 (11.9–19.1)
 Positive 77 66.6 (61.1–72.1) 41.5 (52.5–30.5) 28.2 (17.6–38.8) 5.2 (0.2–10.2)
Risk score system
 0 159 6.3 (2.6–10.0) 85.7 (80.0–91.4) 83.2 (77.1–89.3) 10.6 (5.5–15.7)
 1 235 16.6 (11.7–21.5) 69.2 (62.7–75.7) 66.6 (60.5–72.7) 17.1 (12.2–22.0)
 2 72 55.9 (43.9–67.5) 36.6 (24.8–48.4) 31.8 (20.8–42.8) 12.3 (4.7–19.9)
 3 11 81.8 (55.3–100.0) 27.3 (1.0–53.6) 18.2 (0–40.9) 0
Data are presented as percentage of incidence (95% confidence interval).
Indicates P < 0.05 compared with patients with pre-MRD positive.
Indicates P < 0.05 compared with patients with pre-MRD positive.
Indicates P < 0.05 compared with patients with the other three risk scores. allo-SCT: Allogeneic stem cell transplantation; B-ALL: B cell acute lymphocytic leukemia; CI: Confidence interval; HR: Hazard ratio; LFS: Leukemia-free survival; MRD: Minimal residual disease; NRM: Non-relapse mortality; OS: Overall survival.

Variables associated with outcomes

Univariate analysis showed the following: (i) disease status (CR1 vs. CR ≥2) was related to CIR, LFS, and OS; (ii) pre-MRD (positive vs. negative), post-MRD (positive vs. negative), and cGVHD (yes or no) were associated with CIR, LFS, OS, and NRM; (iii) platelet engraftment (yes or no) and aGVHD III–IV (yes or no) were associated with LFS, OS, and NRM; while aGVHD (yes or no) was related to CIR. The multivariate analysis showed that patients with post-MRD+ suffered higher CIR (66.6% vs. 11.9%, P < 0.001), lower LFS (28.2% vs. 72.8%, P < 0.001), and OS (41.5% vs. 76.0%, P < 0.001) than those with post-MRD. Patients with post-MRD+ showed a trend of higher NRM than those with post-MRD (5.2% vs. 15.5%, P = 0.057) in the univariate analysis, but there was no significance in the multivariate analysis. The landmark analysis showed that post-MRD at all time points (days +30, +60, +90, +120, and +180 or more) was inversely correlated with OS as well as LFS and positively correlated with CIR, but there was no relationship with NRM [Table 3].

Table 3 - Transplant outcomes for B-ALL patients at different time points after allo-SCT.
MRD status at different time points 5-year relapse P value 5-year OS P value 5-year LFS P value 5-year NRM P value
+30 days <0.001 <0.001 <0.001 0.416
 MRD 21.7 (17.6–25.8) 72.6 (68.5–76.7) 67.7 (63.4–72.0) 13.5 (10.4–16.6)
 MRD+ 52.3 (28.2–76.4) 36.8 (15.0–58.6) 36.8 (15.0–58.6) 18.9 (0–38.5)
+60 days <0.001 <0.001 <0.001 0.792
 MRD 21.6 (17.5–25.7) 73.3 (69.2–77.4) 68.3 (64.0–72.6) 12.6 (9.5–15.7)
 MRD+ 61.1 (35.8–86.4) 33.3 (9.4–57.2) 33.3 (9.4–57.2) 11.1 (0–31.7)
+90 days <0.001 0.002 <0.001 0.230
 MRD 20.4 (16.5–24.3) 75.4 (71.3–79.5) 70.7 (66.4–75.0) 11.0 (8.1–13.0)
 MRD+ 70.0 (46.9–93.1) 42.8 (18.5–67.1) 30.0 (6.9–53.1) 0
+120 days <0.001 <0.001 <0.001 0.285
 MRD 19.8 (15.9–23.7) 76.8 (72.9–80.7) 71.5 (67.2–75.8) 10.7 (7.8–13.6)
 MRD+ 73.3 (51.0–95.6) 26.7 (4.4–49.0) 26.7 (4.4–49.0) 0
+180 or more days <0.001 <0.001 <0.001 0.066
 MRD 13.9 (10.2–17.6) 82.8 (79.1–86.0) 79.1 (75.0–83.2) 8.2 (5.5–10.9)
 MRD+ 75.0 (60.7–89.3) 33.6 (14.8–52.4) 25.0 (10.7–39.3) 0
Data are presented as percentage of incidence (95% confidence interval). allo-SCT: Allogeneic stem cell transplantation; B-ALL: B cell acute lymphocytic leukaemia; LFS: Leukemia-free survival; MRD: Minimal residual disease; NRM: Non-relapse mortality; OS: Overall survival.

In this study, a total of 77 patients had positive post-MRD, of which 60 were treated with pre-emptive interventions [Figure 1]. The CIR of the intervention group showed a lower incidence than that of the non-intervention group (68.1% vs. 75.2%), but the difference was not statistically significant (P = 0.394). Meanwhile, the OS (41.4% vs. 11.8%, P = 0.002) and LFS (31.9% vs. 15.7%, P = 0.039) were better and the TRM was lower (0% vs. 29.8%, P < 0.001) in the intervention group than those in the non-intervention group.

The multivariate analysis also showed that higher disease status (≥CR2 vs. CR1) and the occurrence of cGVHD (without cGVHD vs. with cGVHD) were associated with higher CIR (P = 0.004, P < 0.001), worse OS (P = 0.009, P < 0.001), and LFS (P = 0.017, P < 0.001). Patients without platelet (PLT) engraftment and with Grades III–IV aGVHD had higher NRM (P < 0.001, P < 0.001), lower OS (P < 0.001, P = 0.005), and LFS (P < 0.001, P = 0.022) than patients with PLT engraftment and without Grades III–IV aGVHD.

Improving relapse risk stratification with post-MRD, CR, and cGVHD status

Considering the effects of disease status, post-MRD, and cGVHD on relapse, we performed sub-group analyses to confirm whether the combination of the above risk factors could achieve further stratification of relapse and survival.

First, as shown in Table 4, the combination of CR and post-MRD status could stratify patients with different incidences of relapse. For patients with post-MRD+, there was a tendency for patients transplanted in ≥CR2 to have a higher CIR than those in CR1 (80.0% vs. 63.3%, P = 0.096). Similar results were obtained in patients with post-MRD, in which patients transplanted in ≥CR2 had a higher CIR than those transplanted in CR1 (25.3% vs. 10.5%, P = 0.007).

Table 4 - The effects of pairwise combination of post-MRD, disease status, and cGVHD on transplant outcomes.
Sub-groups 5-year relapse P value 5-year OS P value 5-year LFS P value 5-year NRM P value
Status of post-MRD and CR <0.001 <0.001 <0.001 0.408
 Post-MRD+ and CR1 63.3 (50.4–76.2) 36.5 (21.8–51.2) 30.3 (18.3–42.3) 6.5 (0.2–12.8)
 Post-MRD+ and ≥CR2 80.0 (57.7–100.0) 25.0 (2.3–47.7) 20.0 (0–40.2) 0
 Post-MRD and CR1 10.5 (7.4–13.6) 77.5 (73.2–81.8) 74.4 (69.9–78.9) 14.9 (11.2–18.6)
 Post-MRD and ≥CR2 25.3 (10.0–40.6) 55.4 (37.6–73.2) 56.8 (40.1–73.5) 18.0 (5.8–30.2)
Status of post-MRD and cGVHD <0.001 <0.001 <0.001 0.004
 Post-MRD+ and cGVHD 61.3 (32.9–89.7) 54.5 (32.5–76.5) 33.8 (8.7–58.9) 5.0 (0–14.8)
 Post-MRD+ and no cGVHD 69.2 (56.7–81.7) 33.5 (20.6–46.4) 25.6 (14.0–37.2) 5.3 (0–11.2)
 Post-MRD and cGVHD 6.3 (2.8–10.0) 85.7 (80.2–91.2) 83.5 (77.8–89.2) 10.3 (5.6–15.0)
 Post-MRD and no cGVHD 16.3 (11.4–21.2) 68.4 (62.3–74.5) 64.5 (58.2–70.8) 19.6 (14.3–24.9)
Status of CR and cGVHD <0.001 <0.001 <0.001 0.050
 CR1 and cGVHD 10.5 (5.8–15.2) 82.1 (75.8–88.4) 79.3 (73.0–85.6) 10.2 (5.5–14.9)
 CR1 and no cGVHD 23.7 (18.4–29.0) 64.2 (58.1–70.3) 60.0 (53.9–66.1) 16.6 (11.9–21.3)
 ≥CR2 and cGVHD 21.1 (2.1–40.1) 73.3 (53.3–93.3) 73.7 (53.9–93.5) 5.3 (0–15.7)
 ≥CR2 and no cGVHD 50.4 (32.4–68.4) 33.3 (15.2–51.3) 32.5 (16.0–49.0) 17.1 (4.4–29.8)
Data are presented as percentage of incidence (95% confidence interval). cGVHD: Chronic graft-versus-host disease; CI: Confidence interval; CR: Complete remission; LFS: Leukemia-free survival; MRD: Minimal residual disease; NRM: Non-relapse mortality; OS: Overall survival.

Second, we made four sub-groups based on the post-MRD and cGVHD status of all patients. As shown in Table 4, patients with post-MRD who developed cGVHD had a lower CIR than patients without cGVHD (6.3% vs. 16.3%, P < 0.001); meanwhile, patients with post-MRD+ who developed cGVHD had similar CIR compared to patients without cGVHD (61.3% vs. 69.2%, P = 0.159).

Third, the results of our study showed that patients transplanted in ≥CR2 had higher CIR than those in CR1, and further stratification analysis showed that patients transplanted in ≥CR2 who developed cGVHD could achieve the same relapse rate as patients transplanted in CR1 without cGVHD (21.1% vs. 23.7%, P = 0.631) [Table 4].

Risk score for relapse in the entire cohort

We chose three factors (including disease status, post-MRD status, and cGVHD status) to formulate a risk score according to the results of the multivariate analysis: 0 corresponded to patients in CR1, with post-MRD and with cGVHD, while 1 corresponded to patients in ≥CR2, with post-MRD+ but without cGVHD. All patients were divided into four sub-groups based on their score (0, 1, 2, or 3).

As expected, our study concluded that the 5-year CIR increased with increasing risk score: 6.3% (score 0), 16.6% (score 1), 55.9% (score 2), and 81.8% (score 3); the 5-year OS (85.7% vs. 69.2% vs. 36.6% vs. 27.3%) and 5-year LFS (83.2% vs. 66.6% vs. 31.8% vs. 18.2%) decreased with increasing risk score, and all relationships were statistically significant. Multivariate analysis showed that the risk score was an independent risk factor associated with CIR, LFS, and OS [Tables 2 and 5, and Figure 2].

Table 5 - Univariate and multivariate analysis of variables related to transplant outcomes among all patients.
Univariate analysis Multivariate analysis
Covariates HR 95% CI P value HR 95% CI P value
Relapse
 Pre-MRD (positive vs. negative) 2.724 1.824–4.068 <0.001 1.576 1.031–2.409 0.036
 Risk score system
  0 1 1
  1 3.348 1.616–6.938 0.001 3.062 1.525–6.148 0.002
  2 15.707 7.596–32.479 <0.001 12.195 5.979–24.870 <0.001
  3 31.916 12.598–80.854 <0.001 25.356 10.135–63.435 <0.001
 Acute GVHD (yes or no) 0.650 0.431–0.980 0.040
LFS
 Pre-MRD (positive vs. negative) 1.605 1.153–2.234 0.005
 Risk score system
  0 1 1
  1 2.411 1.533–3.792 <0.001 2.094 1.335–3.284 0.001
  2 6.556 4.036–10.649 <0.001 5.279 3.244–8.591 <0.001
  3 10.246 4.765–22.031 <0.001 11.070 5.158–23.761 <0.001
 Platelet engraftment (yes or no) 0.060 0.037–0.098 <0.001 0.079 0.048–0.129 <0.001
 Acute GVHD III–IV (yes or no) 1.751 0.993–3.091 0.053 1.854 1.048–3.282 0.034
NRM
 Pre-MRD (positive vs. negative) 0.507 0.251–1.026 0.059
 Risk score system
  0 1
  1 1.856 1.037–3.322 0.037
  2 0.256
  3 0.962
 Platelet engraftment (yes or no) 0.024 0.013–0.044 <0.001 0.025 0.014–0.045 <0.001
 Acute GVHD III–IV (yes or no) 4.022 2.099–7.705 <0.001 3.502 1.797–6.826 <0.001
OS
 Pre-MRD (positive vs. negative) 1.536 1.081–2.182 0.017
 Risk score system
  0 1 1
  1 2.311 1.425–3.748 0.001 2.109 1.295–3.433 0.003
  2 6.565 3.936–10.949 <0.001 5.262 3.118–8.880 <0.001
  3 8.412 3.735–18.949 <0.001 9.533 4.221–21.527 <0.001
 Platelet engraftment (yes or no) 0.041 0.025–0.069 <0.001 0.055 0.033–0.093 <0.001
 Acute GVHD III–IV (yes or no) 2.064 1.166–3.654 0.013 2.189 1.231–3.894 0.008
Results were calculated by Cox proportional hazards model.
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. CI: Confidence interval; GVHD: Chronic graft-versus-host disease; HR: Hazard ratio; LFS: Leukemia-free survival; MRD: Minimal residual disease; NRM: Non-relapse mortality; OS: Overall survival.

Figure 2
Figure 2:
The effect of risk score on relapse (A), LFS (B), OS (C), and NRM (D) in all patients with B-ALL after allo-SCT. allo-SCT: Allogeneic stem cell transplantation; B-ALL: B cell acute lymphocytic leukemia; LFS: Leukemia-free survival; NRM: Non-relapse mortality; OS: Overall survival.

Discussion

Our study analyzed the prognostic factors associated with transplant outcomes in patients with B-ALL who received allografts, and the results were as follows: (i) the factors associated with increased CIR and inferior survival were disease status, post-MRD, and cGVHD status; and (ii) a scoring system that could predict relapse and survival was established. These results added further evidence to the inferences that disease status, post-MRD status, and cGVHD status can predict relapse in patients with B-ALL receiving allo-SCT, and that the onset of cGVHD could improve the outcomes of patients in ≥CR2 and/or those with post-MRD+. Moreover, the scoring system could stratify patients with different risks of relapse more precisely than using one indicator.

Consistent with previous studies,[14,16–20,23,25,64] our study showed that patients with post-MRD+ suffered higher CIR and poorer survival than post-MRD patients. In addition, we also found that post-MRD+ at different time points was related to a higher incidence of relapse and a lower probability of LFS and OS, which was consistent with the results of Bader et al.[18] The above results suggested that patients with positive post-MRD had a poor prognosis. Previous studies[57,65] have illustrated that pre-emptive interventions (such as DLI and interferon) are effective treatments to reduce the CIR for patients with acute leukemia or myelodysplastic syndrome who become post-MRD positive after allo-SCT. Our study showed that pre-emptive interventions had a tendency to reduce the CIR for patients with positive post-MRD compared to no intervention, but the difference was not statistically significant because the non-intervention patients could not receive interventions to prevent relapse for active infection or GVHD, or were not willing to receive the interventions. In addition, patients died for other reasons before hematological relapse. Therefore, for ALL patients with positive post-MRD, aggressive measures should be taken to remove the MRD to reduce relapse.

Previous studies have demonstrated that disease status pre-transplant[26–30,32,34,66] is related to outcomes in patients with ALL after allo-SCT. The same results were arrived at in our study: patients transplanted in ≥CR2 had a higher CIR than those in CR1. Moreover, patients transplanted in ≥CR2 were more likely to be post-MRD positive than those in CR1 (P = 0.016) in this study, which might be a reason why being in ≥CR2 was related to a higher CIR. Previous studies[26,32,37,38,40,41,66–68] also demonstrated that GVHD had a graft-versus-leukemia effect, but Grades III–IV aGVHD were accompanied by a higher NRM than cases without Grades III–IV aGVHD.[39,69] We also concluded that patients with Grades III–IV aGVHD had a higher NRM and poorer OS and LFS than those without Grades III–IV aGVHD, but there was no correlation with relapse. The results revealed that cGVHD instead of aGVHD could reduce the CIR and improve OS and LFS. A possible reason might be that the time of relapse for most patients was >100 days after transplantation, with a median time of relapse of 322 (45–1678) days after transplantation.

Considering the above results, we formulated a scoring system to predict transplant outcomes. The model consisted of three parameters: disease status, post-MRD status, and cGVHD status. The results indicated that the higher the score was, the higher the CIR, and the lower the LFS and OS, but there was no correlation with NRM [Figure 2]. Overall, all patients in this study had B-ALL, and the study contained a large sample size of patients undergoing HBMT. Some new insights can be drawn from these findings. First, the scoring system together with findings from our previous study[11] could help predict transplant outcomes precisely in ALL patients receiving allo-SCT. Second, for patients in ≥CR2 pre-transplant and/or with post-MRD+, we can reduce relapse by inducing cGVHD. However, it is important to undertake some caution in interpreting the scoring system. First, these data were derived from an allo-SCT setting, including HBMT, MSDT, and few MUDT cases, whereas further evidence under different transplant modalities is required to confirm the results. Second, we focused on total cGVHD in this study, but cGVHD may occur before, during, or after the post-MRD turns positive; as such, the effect of cGVHD occurring at different time points on outcomes needs to be further explored.

There are some limitations to this study. First, post-MRD was detected by MFC in this study, but specific biomarkers in patients with B-ALL, such as BCR/ABL, were not taken into account. Second, clinical intervention while MRD turned positive in some patients would affect clinical outcomes, which was an interfering factor for the risk score system. Finally, this was a single-center and retrospective study, and a multicenter study is needed to provide a large sample study with adequate statistical power.

In conclusion, our study indicated that disease status, post-MRD status, and cGVHD status were related to transplant outcomes in patients with B-ALL receiving allo-SCT. The most important accomplishment of this study was the formulation of a new scoring system with the three variables mentioned above; this scoring system could further stratify patients with different risks of relapse and guide treatment more precisely.

Funding

This work was partly supported by grants from the Beijing Municipal Science and Technology Commission (No. Z181100009618032), the National Key Research and Development Program of China (No. 2017YFA0104500), the National Natural Science Foundation of China (Nos. 81670186, 82070185), and the Peking University Clinical Scientist Program (No. BMU2019LCKXJ003).

Conflicts of interest

None.

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Keywords:

B cell acute lymphocytic leukemia; Allogeneic stem cell transplantation; Minimal residual disease; Disease status; chronic graft-versus host disease; Patient outcome

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