Superior Survival with Allogeneic Hematopoietic Stem Cell Transplantation versus Chemotherapy for High-Risk Adult Acute Lymphoblastic Leukemia in PDT-ALL-2016 Pediatric-Inspired Cohort

doi:10.21203/rs.3.rs-4008818/v1

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult high-risk acute lymphoblastic leukemia (HR-ALL) remained elusive in the pediatric-inspired regimen era. We conducted a cohort study on the outcome of allo-HSCT post-consolidation versus chemotherapy for HR-ALL in the first complete remission in PDT-ALL-2016 pediatric-inspired cohort. A total of 245 patients with HR-ALL were enrolled, according to donor availability and patients’ preferences, among which 159 received allo-HSCT after consolidation therapy, and 86 received post-remission chemotherapy. With a median follow-up of 43.6 months, the 3-year overall survival (OS) in allo-HSCT cohort was 77.1% (70.6–84.2%), and 51.7% (41.7–64.1%) in chemotherapy cohort, respectively (p < .001). In multivariate analysis, allo-HSCT cohort showed superior OS (HR = 0.33, 0.21–0.54, p < .001), event-free-survival (EFS, HR = 0.36, 0.23–0.56, p < .001), cumulative incidence of relapse (CIR, HR = 0.13, 0.07–0.22, p < .001), and increased non-relapse mortality (NRM, HR = 4.06, 1.23–13.4, p = .021), compared to chemotherapy cohort. Notably, allo-HSCT improved the outcome of minimal residue disease (MRD)-positive subset (OS, HR = 0.42,0.20–0.90, p = .025), as well as MRD-negative subset (OS, HR = 0.21, 0.10–0.43, p < .001). Our study demonstrates that allo-HSCT post-consolidation, compared to chemotherapy, could further improve survival of HR-ALL in pediatric-inspired cohort, regardless of MRD status.

Health sciences/Diseases/Cancer/Cancer therapy/Chemotherapy

Biological sciences/Cancer/Haematological cancer/Leukaemia/Acute lymphocytic leukaemia

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has undergone gradual changes in adult acute lymphoblastic leukemia (ALL). In the era of conventional adult chemotherapy regimen, the MRC UKALLXII/ E2993 study and others have demonstrated that allo-HSCT is superior to consolidation chemotherapy in adult ALL patients in first complete remission (CR1)^[1–4]. This supports the critical role of allo-HSCT as a post-remission treatment for adult ALL, including standard risk (SR) and high risk (HR) ALL.

As pediatric-inspired regimen remarkably improved the survival of adolescents and young adult ALL (AYA ALL)^[5–7], allo-HSCT was less pronounced as post-remission therapy. Several studies compared outcomes between pediatric-like regimen and allo-HSCT in adult ALL, revealing that allo-HSCT does not exhibit superiority over pediatric-inspired regimen^{[8, 9]}. Recently, a meta-analysis including 13 trials and 3161 patients demonstrated the superiority of pediatric-inspired chemotherapy over allo-HSCT for adult ALL in CR1^[10]. However, these studies did not provide a clear conclusion regarding the benefit of allo-HSCT in HR-ALL. So far, research focusing on allo-HSCT in HR-ALL has been limited and controversial. The PETHEMA ALL-HR-11 study showed that avoiding allo-HSCT did not hamper the outcomes of HR-ALL patients^{[11, 12]}. The GRAALL 2003/2005 study found that allo-HSCT could improve the survival in the minimal residual disease (MRD)-positive subgroup, but not in the MRD-negative population^[13]. Despite the controversy surrounding allo-HSCT for the HR-ALL patients within pediatric-inspired regimen, our previous study illustrated that allo-HSCT showed superiority for certain high-risk ALL, such as IKZF1 deletion plus CD20 positive B-ALL^[14].

The issue that remains to be addressed for adult HR-ALL patients is how to integrate pediatric regimen and allo-HSCT into a total-therapy regimen. Hypothesizing of double benefits of pediatric-inspired chemotherapy and allo-HSCT, we designed a PDT-ALL-2016 pediatric-inspired protocol, in which allo-HSCT was allocated post-consolidation, instead of post-remission, as a total-therapy regimen. In present study, for the first time, we demonstrated that allo-HSCT post-consolidation exhibited superior survival versus chemotherapy for HR-ALL regardless of MRD status, in the PDT-ALL-2016 pediatric-inspired cohort.

PDT-ALL-2016 cohort

Patients in this study were enrolled from PDT-ALL-2016 pediatric-inspired cohort, a GRAALL-2003 backbone, PEG-asparaginase-intensified, pediatric-inspired regimen^{[15, 16]}, whose detailed protocol was attached in the supplemental data.

PDT-ALL-2016 cohort contain a total of 411 adult ALL patients, all of whom were diagnosed at Nanfang Hospital from January 2016 to December 2021, with outcomes updated in January 2023. Inclusion criteria for this study encompassed patients with any high-risk features, all of whom achieved complete remission (CR) and received allo-HSCT at CR1. High risk features included:(1) withe blood cell count (WBC) count ≥ 30×10⁹/L for B-ALL or 100×10⁹/L for T-ALL; (2) presence of t(9;22), t(1;19), t(4;11) or any other 11q23 rearrangements; (3) complex karyotype, hypodiploid, or near-triploid; (4) pro-B or early T-cell precursor (ETP) immunophenotype; (5) Philadelphia chromosome-like (Ph-like) or IKZF1-deleted (IKZF1del) subtype. For HR-ALL, allo-HSCT was recommended in our protocol. According to their individual preferences and decisions and the donor availability (the HLA donor should younger than 45 years^[17]), patients were assigned to either the chemotherapy cohort or the transplant cohort after consolidation therapy.

CR was defined as disappearance of leukemic blasts in the peripheral blood and < 5% blasts in the bone marrow (BM) aspirate, recovery of blood cell count, and lack of extramedullary disease. MRD evaluation took place after induction (day 45). MRD assessment was determined by 8-color flow cytometry according to the standardized EuroFlow methodology as previously described^[18], cutoff values of MRD positive were defined as 0.01%. BM samples were used for the monitoring of MRD.

Transplant modalities

HR-ALL patients in CR1 after induction therapy and consolidation chemotherapy received allo-HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), unrelated-donor (MUD) or haploidentical related donor (HID). Donor selection was based on patients' biological characteristics and patients or guardians consent^[19]. Conditioning regimens consist of BuCy (busulfan and cyclophosphamide) and TBI/Cy (total body irradiation, cyclophosphamide) as previously reported^[20]. Acute and chronic graft-versus-host diseases (GVHD) were diagnosed and graded according to previously reported criteria. Cyclosporine A (CsA) combined with methotrexate (MTX) were used for GVHD prophylaxis in patients with MSD transplant. CsA + MTX + antithymocyte globulin and mycophenolate were used in patients undergoing MUD or HID allo-HSCT^[21].

Statistical methods

Associations between categorical variables were assessed by a Fisher exact test, while the Wilcoxon two sample test was performed to test for differences between continuous variables. Overall survival (OS) was measured from the date of CR1 to the date of death or last follow-up. Event-free survival (EFS) was measured from the date of CR1 to the date of event occurred or at the last follow-up. Relapse or death by any cause were considered as events in the EFS analysis. Cumulative incidence of relapse (CIR) was calculated from the date of CR1 to the date of relapse, considering non-relapse mortality (NRM) as a competing event. This analysis aimed to compare the outcomes between transplantation and chemotherapy, to avoid bias form other therapies, patients who received immunotherapy when they relapsed, such as chimeric antigen receptor T-Cell (CAR-T) therapy or CD3/CD19 bispecific T cell engager (Blinatumomab), were censored at the time of starting immunotherapy. The left-truncated Kaplan-Meier method was used to compare survival between the allo-HSCT and chemotherapy cohorts, as previous reported^{[9, 22–24]}. Probabilities of NRM and CIR were generated using cumulative incidence estimates to account for competing risks and compared by Gray’s test. To adjust for differences in baseline characteristics, left-truncated Cox proportional hazards regression was used to compare the two cohorts.

The data that support the findings of this study are available from the corresponding author ([email protected]) upon reasonable request.

Patients’ characteristics

Out of the 411 patients in the PDT-ALL-2016 pediatric-inspired cohort, 293 were classified as HR-ALL, among whom 277 achieved CR1 after induction therapy. Finally, a total of 253 patients were enrolled in this analysis, excluding 32 patients who received transplantation at a non-CR1. According to donor availability and patients’ preference, 159 underwent allo-HSCT, and the other 86 received post-remission chemotherapy (Fig. 1).

Characteristics of patients in the allo-HSCT cohort and patients in the chemotherapy cohort were summarized in Table 1, which showed comparable baseline characteristics.

Among the 159 allo-HSCT recipients, 93 underwent transplantation from HID, and 66 from MSD or MUD. Ninety-three patients received TBI-based conditioning regimen, while 66 patients received non-TBI-based regimen. Peripheral blood was the stem cell source in 87 patients, and the combination of peripheral blood and bone marrow in 72 patients. For GVHD prophylaxis, 54 patients received CSA + MTX, 93 received CSA + MMF + MTX + ATG, and 12 received CSA + MMF + MTX + ATG + PT-CY (Table 1).

General outcomes

In the entire cohort, with a median follow-up time of 43.6 (3.5–82.5) months, 78 patients died, including 54 attributed to relapse and 24 to NRM (3 in the chemotherapy cohort, and 21 in the allo-HSCT cohort). The causes of the 21 NRM cases in the allo-HSCT cohort consist of acute or chronic GVHD (N = 10), infection (N = 8), graft failure (N = 2) and secondary primary malignancy (N = 1).

Seventy-five patients experienced relapse during the follow-up period, with 14 of them received CAR-T therapy or Blinatumomab, we aimed to compare the outcomes between transplantation and chemotherapy, to avoid bias form other therapies these patients were censored at the time of immunotherapy (N _allo−HSCT=3, N _chemotherapy=11; Fig. 1).

For entire cohort, the 3-yr OS was 66.5% (60.4–73.2%), 3-yr EFS was 52.4% (45.9–59.9%), 3-yr CIR was 31.0% (26.8–39.0%) and 3-yr NRM was 11.7% (7.9–11.2%, Table 2).

Outcome of allo-HSCT versus Chemotherapy Cohorts

The 3-yr OS and EFS were significantly superior in allo-HSCT cohort compared to the chemotherapy cohort (Table 2). The estimated 3-yr OS was 77.1% (70.6–84.2%) and 51.7% (41.7–64.1%) in allo-HSCT and chemotherapy cohorts (Fig. 2A), respectively (HR = 0.33, 0.21–0.54, p < .001). The 3-year EFS in the allo-HSCT cohort (69.2%, 62.0-77.2%) was also superior to the chemotherapy cohort (38.1%, 28.9–50.2%, Fig. 2B), with an HR of 0.36 (0.23–0.56, p < .001). The 3-yr CIR was 13.0% (8.2–18.8%) in the allo-HSCT cohort and 54.2% (42.6–64.3%) in the chemotherapy cohort (HR = 0.14, 0.08–0.23, p < .001) (Table 2). Meanwhile, the 3-yr NRM in allo-HSCT cohort was 11.8% (9.5–20.5%).

Outcomes of allo-HSCT versus chemotherapy cohort in MRD-negative/positive subsets

To further address the role of transplantation in different MRD statuses, particularly for MRD-negative subset, subgroup analysis were conducted. In the MRD-positive subset (allo-HSCT, N = 65; chemotherapy, N = 36), patients who received allo-HSCT exhibited longer EFS and OS along with lower CIR, compared to the chemotherapy cohort (3-yr OS, 69.8% vs. 36.7%, P<0.001; 3-yr EFS, 60.1% vs. 19.2%, P<0.001; 3-yr CIR, 15.7% vs. 72.3%, P<0.001; Table S1, Fig. 3AB). Notably, patients who achieved MRD-negative also benefit from transplantation. In the MRD-negative subset (allo-HSCT, n = 94; CT, n = 50), the allo-HSCT cohort exhibited longer EFS, OS, and lower CIR, compared with chemotherapy cohort (3-yr OS, 82.1% vs. 63.2%, P = 0.030; 3-yr EFS, 75.5% vs. 51.2%, P = 0.010; 3-yr CIR, 11.2% vs. 42.6%, P<0.001;Table S1, Fig. 3CD). Collectively, allo-HSCT post-consolidation proved beneficial for HR-ALL patients regardless of the MRD statuses.

Multivariate analysis

In multivariate analysis for entire cohort (Table 3), allo-HSCT was a protective factors for OS (HR = 0.32, 0.19–0.53, P < 0.001), EFS (HR = 0.37, 0.24–0.58, P < 0.001) and CIR (HR = 0.13, 0.07–0.22, P < 0.001), and negatively affected NRM (HR = 4.06, 1.23–13.4, P < 0.001). Meanwhile, in MRD-negative or positive subsets, allo-HSCT also led to superior OS, EFS and CIR in the multivariate analysis (Table S2, S3).

Allo-HSCT is still a recommended therapeutic strategy for HR-ALL patients at CR1. However, emerging evidence indicates that the survival for HR-ALL patients may not be further improved by allo-HSCT when receiving a pediatric-inspired chemotherapy, particularly in the MRD-negative subset. In present study, our data showed that post-consolidation transplantation exhibited superior survival compared to chemotherapy for HR-ALL in the PDT-ALL-2016 pediatric-inspired cohort. In this study, we included very high risk subtype, such as IKZF1 deletion and Ph-like ALL and more patients had detective MRD at 45 days, even though, the survival of the entire cohort and chemotherapy cohort was comparable with other reports^{[11, 13]}. These findings suggested that the integrated pediatric-inspired chemotherapy and post-consolidation allo-HSCT may be the optimal therapy for adult HR-ALL. Of note, this study is the first to demonstrate the advantage of post-consolidation allo-HSCT for HR-ALL patients in the context of pediatric-inspired regimen, irrespective of MRD status.

The efficacy of allo-HSCT has been debated since using pediatric-inspired regimen in adult ALL. This controversy arises from several aspects, firstly, the survival rate of AYA ALL patients has been significantly improved by pediatric-inspired regimen. Secondly, it’s well-established that a weaker graft-versus-leukemia (GVL) effect was yielded post-allo-HSCT in ALL compared to myeloid neoplasms (MNs)^[25–27], as evidenced by a poor response to donor lymphocyte infusion (DLI) in ALL ^[28–30]. Another unresolved question pertains to bridging the gap between the time required for immune reconstitution for GVL (3 months for cellular immunity, and 12 months for full immune reconstitution^[31–33]), and early relapse after allo-HSCT (MRD-positive occurs within the first 3 months^[34] and relapse manifest within 9 months^{[35, 36]}). In present protocol, we speculated that adequate and effective treatment with pediatric-inspired regimen could induce durable remission to avoid early relapse, and subsequently spare enough time to reconstitute the immune system to exert GVL effect. Furthermore, the importance of a sufficient dose of asparaginase for better survival in AYA ALL has been widely accepted, with patients received more than 20 weeks of asparaginase showing better survival compared to those with a lower cumulative dose^[37–40]. Based on these studies, we scheduled allo-HSCT after 4 blocks of consolidation therapy, ensuring patients receive a sufficient dose of asparaginase and achieve a deeper remission. Our previous study, the PASS-ALL study, illustrated that this integrated total-therapy yielded durable or deeper MRD response (d/d MRD) in HR-ALL. We found that, as pre-transplantation chemotherapy, pediatric-inspired regimen resulted in significant longer time-to-positive MRD than adult protocol^[16].

In terms of HR-ALL, the chemotherapy alone may be insufficient to maintain the remission status, even for patients who achieved MRD-negative status. While many studies argue that allo-HSCT is unnecessary for the MRD-negative subset in the era of pediatric-inspired regimen, we advocate for a more cautious acceptance of this conclusion. In fact, even for patients who achieved MRD-negative status, more sensitive techniques, such as next-generation sequencing-based MRD, may detect residual leukemic cells^{[41, 42]}. These surviving leukemic cells, which are resistant to prior chemotherapy, increase the risk of relapse, necessitating immunotherapy interventions such as CAR-T, Blinatumomab^{[43, 44]} or allo-HSCT. The ECOG-ACRIN E1910 study exemplifies this, demonstrating an inferior survival for chemotherapy cohort versus immunotherapy cohort, in ALL patients who achieved MRD-negative after induction^[45]. Correspondingly, we showed that survival of the MRD-negative subset can be improved by allo-HSCT. In contrast to the GRAALL 2003/2005 post-hoc study, which found that allo-HSCT improved survival for MRD-positive HR-ALL but not for the MRD-negative subgroup^[13]. This discrepancy may arise from differences in transplant modality between the two studies. Specifically, 57.1% of patients in our study underwent HID transplants among the allo-HSCT cohort, while patients in the GRAALL 2003/2005 study received MSD or MUD transplants, with none undergoing HID transplants^[13]. Previous research had demonstrated that the GVL effect of HID was stronger than that in MSD/MUD transplant^{[2, 46]}.

Additionally, another limitation associated with allo-HSCT is the high NRM. Allo-HSCT’ s ability to reduce the relapse rate was offset by the excessively high NRM of transplantation^{[9, 11, 24]}. In present study, the 3-year NRM was 11.8% (9.5–20.5%), a relatively low rate compared with other reports^{[8, 47–49]}, which might benefit from experienced management of allo-HSCT in our center. Furthermore, our earlier study also showed the low transplantation NRM of 11.0% (7.6–15.0%) in SR-ALL patients^[20]. Due to an acceptable NRM, the reduced relapse rate among allo-HSCT cohort can be translated into improved survival, especially for the MRD-negative subset.

Limitations in our study included that this is a single-center analysis, and a multi-center study is needed in the future. In conclusion, we demonstrated that allo-HSCT still had an irreplaceable role in adult HR-ALL post-remission therapy in the pediatric-inspired regimen era. We highlighted the importance of total therapy for adult HR-ALL, and the post-consolidation allo-HSCT should be considered for patients who achieved MRD-negative.

Funding

This study was supported by the National Natural Science Foundation of China (NSFC82170163, 81970147 to HSZ), the Science and Technology Planning Project of Guangdong Province (No. 2017A030313601 to HSZ).

Acknowledgments

Financial disclosure: This study was supported by the National Natural Science Foundation of China (NSFC82170163, 81970147 to HSZ), the Science and Technology Planning Project of Guangdong Province (No. 2017A030313601 to HSZ). We appreciate all members of our study team for their cooperation. We thank all the nurses and physicians for providing exceptional care to the patients, and the patients and their families for participating in this study. Conflict of interest statement: There are no conflicts of interest to report.

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Table 1. Patients Characteristics

Total = 253	Allo-HSCT (N = 159)	Chemotherapy (N = 86)	p
Age	29.1 (18.0-60.2)	28.1 (18.0-68.7)	.435
Sex
Male	68 (42.8%)	37 (43%)	.999
Female	91 (57.2%)	49 (57%)
Immuno-type
T-ALL	41 (25.8%)	20 (23.3%)	.967
ETP	30 (18.1%)	14 (16.2%)	.546
B-ALL	118 (74.2%)	66 (76.7%)	.845
Pro-B	24 (15.0%)	14 (116.2%)	.540
Clinical features
CNSL at presentation	8 (5.0%)	7 (8.1%)	.491
High WBC ^a	62 (39.0%)	41 (47.7%)	.239
>30×10⁹ for B-ALL	53 (33.3%)	33 (38.3%)
>100×10⁹ for T-ALL	9 (5.7%)	8 (9.4%)
Cytogenetic features
Non/ other	66 (41.5%)	41 (47.6%)	.888
MLLr	7 (4.4%)	3 (3.4%)
E2Ar	3 (1.8%)	4 (4.6%)
IGHdel	9 (5.6%)	5 (5.8%)
Ph+	44 (27.6%)	26 (30.2%)
CK	20 (12.5%)	4 (4.6%)
Missing	10 (6.2%)	3 (3.4%)
Ph-like
No	137 (86.2%)	75 (87.2%)	.974
Yes	22 (13.8%)	11 (12.8%)
IKZF1 deletion
No	132 (83%)	73 (84.9%)	.845
Yes	27 (17%)	13 (15.1%)
MRD at day 45
Negative	94 (59.1%)	50 (58.1%)	.990
Positive	65 (40.9%)	36 (41.9%)
Donor type
HID	93 (58.49%)
MSD/MUD	66 (41.51%)
Reconstitution
Neutrophil	12.54 ± 2.25
Platelet	14.29 ± 4.28
GVHD prophylaxis
CSA + MTX	93 (58.49%)
CSA + MMF + MTX + ATG	12 (7.55%)
CSA + MMF + MTX + ATG + PT-CY	54 (33.96%)
Donor sex
F-M	23 (14.47%)
Other	136 (85.53%)
Stem cell source
PB	87 (54.7%)
PB + BM	72 (45.3%)
Conditioning regimen
Non-TBI based	66 (41.51%)
TBI based	93 (58.49%)
Abbreviations: CNSL, central nervous system leukemia; WBC, white blood cell; Ph+, Philadelphia chromosome positive; MLLr, MLL rearrangement; E2Ar, E2A rearrangement; CK, complex karyotype; a, For B-ALL, WBC>30×10⁹/L; for T-ALL, WBC> 100×10⁹/L; MRD, minimal residual disease; HID, haploidentical related donor; MSD, HLA-matched sibling donor; MUD, HLA-matched unrelated-donor; GVHD, graft versus-host disease; F-M, female to male; P, peripheral blood stem cells; M, marrow stem cells; BF, busulfan + fludarabine; BuCy, busulfan + cyclophosphamide; TBI + Cy + VP16, total body irradiation + cyclophosphamide + etoposide;

Table 2 Comparison of outcomes between allo-HSCT and chemotherapy cohort

Outcome	Total	Allo-HSCT	Chemotherapy	P
OS				<0.001
3-year	66.5 (60.4–73.2)	77.1 (70.6–84.2)	51.7 (41.7–64.1)
5-year	63.0 (56.6–70.1)	75.1 (68.3–82.6)	44.9 (33.5–58.6)
EFS				<0.001
3-year	52.4 (45.9–59.9)	69.2 (62.0-77.2)	38.1 (28.9–50.2)
5-year	47.8 (41.1–55.6)	64.5 (56.7–73.5)	32.0 (22.7–45.1)
CIR				<0.001
3-year	31.0 (26.8–39.0)	13.0 (8.2–18.8)	54.2 (42.6–64.3)
5-year	34.9 (28.4–41.5)	20.9 (13.0-30.1)	63.7 (50.7–74.1)
NRM				<0.001
3-year	11.7 (7.9–11.2)	11.8 (9.5–20.5)	2.1 (0.8–9.6)
5-year	11.7 (7.9–11.2)	14.6 (11.0-23.4)	2.1 (0.8–9.6)
Abbreviations: allo-HSCT, allognetic hematopoietic stem cell transplantation; OS, Overall survival; EFS, Event-free survival; CIR, Cumulative incidence of relapse; NRM, Non-relapse mortality

Table 3. Multivariate analysis.

	Number	EFS	OS	CIR	NRM
Age
≥35	101 (43.5%)	Ref
<35	131 (56.5%)	0.82 (0.52–1.28, p = .372)	0.55 (0.33–0.91, p = .021)	0.87 (0.45–1.65, p = .661)	0.50 (0.19–1.28, p = .151)
Immuno-type
T-ALL	52 (22.4%)	Ref
B-ALL	180 (77.6%)	1.53 (0.79-3.00, p = .210)	1.32 (0.59–2.94, p = .500)	1.65 (0.68–3.98, p = .270)	1.22 (0.40–3.72, p = .731)
CNSL at presentation
No	217 (93.5%)	Ref
Yes	15 (6.5%)	1.10 (0.47–2.58, p = .832)	1.11 (0.42–2.88, p = .837)	1.72 (0.63–4.69, p = .292)	NA
High WBC ^a
No	136 (58.6%)	Ref
Yes	96 (41.4%)	1.63 (1.06–2.50, p = .027)	1.39 (0.86–2.25, p = .180)	1.88 (1.02–3.48, p = .044)	1.05 (0.43–2.56, p = .923)
Cytogenetic features
Non / other	130 (56.0%)	Ref
Ph	71 (30.6%)	1.12 (0.66–1.91, p = .675)	1.35 (0.72–2.53, p = .346)	1.35 (0.68–2.68, p = .401)	1.16 (0.39–3.41, p = .791)
MLL	10 (4.3%)	1.92 (0.75–4.90, p = .172)	3.38 (1.26–9.11, p = .016)	2.87 (0.92–8.98, p = .070)	NA
E2A	7 (3.0%)	2.11 (0.77–5.83, p = .148)	1.90 (0.55–6.63, p = .312)	1.61 (0.29–8.89, p = .595)	2.19 (0.21–22.9, p = .924)
IGHdel	14 (6.0%)	1.19 (0.51–2.73, p = .690)	1.68 (0.70–4.02, p = .247)	1.52 (0.51–3.89, p = .384)	1.10 (0.25–4.25, p = .904)
CK
No	208 (89.7%)	Ref
Yes	24 (10.3%)	1.23 (0.59–2.55, p = .587)	1.35 (0.61–2.98, p = .464)	2.37 (1.02–5.50, p = .044)	0.29 (0.04–2.37, p = .250)
Allo-HSCT
No	85 (36.6%)	Ref
Yes	147 (63.4%)	0.37 (0.24–0.58, p < .001)	0.32 (0.19–0.53, p < .001)	0.13 (0.07–0.22, p < .001)	4.06 (1.23–13.4, p = .021)
Ph-like
No	198 (85.3%)	Ref
Yes	34 (14.7%)	2.28 (1.26–4.12, p = .007)	2.39 (1.18–4.82, p = .015)	2.86 (1.32–6.21, p = .008)	1.41 (0.46–4.30, p = .551)
IKZF1mut/del
No	193 (83.2%)	Ref
Yes	39 (16.8%)	1.22 (0.72–2.09, p = .459)	1.46 (0.81–2.63, p = .204)	1.34 (0.71–2.56, p = .372)	1.72 (0.65–4.55, p = .272)
MRD
Negative	140 (60.3%)	Ref
Positive	92 (39.7%)	1.99 (1.32–3.02, p = .001)	2.52 (1.56–4.06, p < .001)	1.72 (1.01–2.98, p = .049)	1.42(0.56–3.57, p = .462)
Abbreviations: CNSL, central nervous system leukemia; WBC, white blood cell; Ph+, Philadelphia chromosome positive; MLLr, MLL rearrangement; E2Ar, E2A rearrangement; CK, complex karyotype; OS, Overall survival; EFS, Event-free survival; CIR, Cumulative incidence of relapse; NRM, Non-relapse mortality a, For B-ALL, WBC>30×10⁹/L; for T-ALL, WBC> 100×10⁹/L.

There is NO conflict of interest to disclose.

Superior Survival with Allogeneic Hematopoietic Stem Cell Transplantation versus Chemotherapy for High-Risk Adult Acute Lymphoblastic Leukemia in PDT-ALL-2016 Pediatric-Inspired Cohort

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