Skip to main content
Download PDF

Intensified conditioning containing decitabine versus standard myeloablative conditioning for adult patients with KMT2A-rearranged leukemia: a multicenter retrospective study

BMC Medicine volume 22, Article number: 605 (2024) Cite this article

Abstract

Background

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended for patients with KMT2A-rearranged (KMT2A-r) leukemia whereas relapse remains high. We aimed to determine whether intensified conditioning containing decitabine (Dec) could reduce relapse compared with standard myeloablative conditioning in adult patients with KMT2A-r leukemia.

Methods

We performed a multicenter retrospective study at seven institutions in China. Eligible patients were aged 14 years or older at transplantation, had a diagnosis of KMT2A-r leukemia, and underwent the first allo-HSCT. Standard myeloablative conditioning regimens (standard group) included BuCy (busulfan 3.2 mg/kg/day on days -7 to -4; cyclophosphamide 60 mg/kg/day on days -3 to -2) and TBI-Cy (total body irradiation 4.5 Gy/day on days -5 to -4; Cy 60 mg/kg/day on days -3 to -2). Intensified conditioning regimens containing Dec (intensified group) consisted of Dec-BuCy (Dec 20 mg/m2/day on days -14 to -10; the same dose of BuCy) and Dec-TBI-Cy (Dec 20 mg/m2/day on days -10 to -6; the same dose of TBI-Cy).

Results

Between April 2009 and December 2019, 218 patients were included in this study, of whom 105 were in the intensified group and 113 were in the standard group. The 3-year cumulative incidence of relapse was 17.6% and 34.5%, overall survival was 71.3% and 61.0%, disease-free survival was 70.1% and 56.0%, and non-relapse mortality was 12.3% and 9.5% in the intensified and standard groups, respectively (P = 0.001; P = 0.034; P = 0.005; P = 0.629). Subgroup analysis showed that the relapse rate of intensified conditioning was lower than that of standard conditioning in multiple subgroups, including different leukemia types, disease status at transplantation, high-risk cytogenetics and Bu-based regimens. There was no difference in regimen-related toxicity, engraftment, or graft-versus-host disease between the intensified and standard groups.

Conclusions

These results suggest that intensified conditioning containing Dec might be a better strategy than standard myeloablative conditioning for adult patients with KMT2A-r leukemia undergoing allo-HSCT.

Peer Review reports

Background

Rearrangements of the lysine methyltransferase 2A gene (KMT2A, also known as MLL, MLL-1, HRX or ALL-1) on chromosome 11q23, are found in 70–80% of acute leukemia in infants, 5–25% in children, and 5–10% in adults [1,2,3,4,5]. KMT2A rearrangements define a distinct leukemia with a relatively poor prognosis [6, 7], which is phenotypically characterized as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and mixed-phenotype acute leukemia (MPAL) [1, 8]. Compared with conventional chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved the prognosis of adult patients with KMT2A-rearranged (KMT2A-r) leukemia, with the 3-year overall survival (OS) of 40–60% and 10–20%, respectively [6, 9,10,11,12,13]. Nonetheless, relapse post-transplantation in this population remains high, with the 3-year cumulative incidence of relapse of 25–40% [10, 13].

In addition to disease-associated factors, the intensity of conditioning is an essential factor affecting relapse post-transplantation [13,14,15,16]. Some studies suggested that standard myeloablative conditioning regimens including busulfan plus cyclophosphamide (BuCy) and total body irradiation plus cyclophosphamide (TBI-Cy) resulted in lower relapse rates than reduced-intensity conditioning regimens in hematological malignancies, whereas the prognosis of high-risk acute leukemia patients treated with standard myeloablative conditioning was unsatisfactory [13, 16]. The addition of anti-leukemic agents such as decitabine (Dec) or other targeted drugs to standard myeloablative conditioning, composing the intensified conditioning, was reported to achieve improved outcomes [17,18,19]. Dec is a hypomethylating agent broadly used for the treatment of myelodysplastic syndrome (MDS) and AML [20]. Owing to its low organ toxicity, Dec was given in combination with standard myeloablative conditioning following allo-HSCT and contributed to favorable outcomes for patients with high-risk acute leukemia [16, 21,22,23]. However, the efficacy of intensified conditioning containing Dec in patients with KMT2A-r leukemia has not yet been investigated. In this multicenter retrospective study, we aimed to determine whether intensified conditioning containing Dec resulted in lower relapse compared with standard myeloablative conditioning in adult patients with KMT2A-r leukemia undergoing allo-HSCT.

Methods

Study design and patients

The clinical information of 218 adult patients with KMT2A-r leukemia was collected from April 2009 to December 2019 at seven institutions in China. Patients were eligible for analysis if they were aged 14 years or older at transplantation, had a diagnosis of KMT2A-r leukemia, and underwent the first allo-HSCT. KMT2A rearrangements were identified using karyotype analysis, fluorescence in situ hybridization, reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing. Details of the follow-up data were obtained from medical records and telephone follow-up. All surviving patients were followed up at a maximum of five years post-transplantation. This study was approved by the ethics committee review board at each participating center and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all the patients.

Conditioning and transplantation

The intensity of conditioning was graded according to published guidelines: generally, standard myeloablative conditioning regimens comprised BuCy, TBI-Cy and associated modified regimens, and intensified conditioning regimens included the addition of a drug, such as idarubicin, etoposide, fludarabine, melphalan, Dec or TBI, to a standard myeloablative conditioning [18, 24]. In this study, standard myeloablative conditioning regimens were as follows: BuCy (Bu 3.2 mg/kg/day on days −7 to −4; Cy 60 mg/kg/day on days −3 to −2) and TBI-Cy (TBI 4.5 Gy/day on days −5 to −4; Cy 60 mg/kg/day on days −3 to −2) [25], and intensified conditioning regimens containing Dec consisted of Dec-BuCy (Dec 20 mg/m2/day on days −14 to −10; the same dose of BuCy) and Dec-TBI-Cy (Dec 20 mg/m2/day on days −10 to −6; the same dose of TBI-Cy).

An HLA-matched sibling donor (MSD) was considered first, followed by an HLA-matched unrelated donor (MUD). If both were unavailable, patients would receive transplantation from an HLA-haploidentical related donor (HID) [18]. MSD or MUD recipients were transplanted with peripheral blood stem cell grafts, and HID recipients were transplanted with a combination of bone marrow and peripheral blood stem cell grafts. Cyclosporin A, methotrexate, and mycophenolate were administered to patients receiving MSD transplantation. Cyclosporin A, methotrexate, antithymocyte immunoglobulin and/or mycophenolate were administered to patients receiving MUD or HID transplantation for graft-versus-host disease (GVHD) prophylaxis [26]. Post-transplant Cy regimen was not administered for GVHD prophylaxis in this study.

Definitions and endpoints

The cytogenetics risk stratification of KMT2A-r leukemia was defined according to the National Comprehensive Cancer Network guidelines: AML patients with t(9;11) or KMT2A-partial tandem duplication (PTD) were defined as intermediate-risk, whereas AML patients with t(v;11q23.3) and ALL patients with any KMT2A rearrangement were defined as high-risk [27, 28]. Some KMT2A rearrangements were listed below with former names: t(4;11)/KMT2A-AFF1 referred to former MLL-AF4; t(6;11)/KMT2A-AFDN referred to former MLL-AF6; t(9;11)/KMT2A-MLLT3 referred to former MLL-AF9; t(10;11)/KMT2A-MLLT10 referred to former MLL-AF10; and t(11;19)(q23;p13.1)/KMT2A-ELL referred to former MLL-ELL [29]. Complete remission (CR) was defined as less than 5% blasts in bone marrow, with the absence of circulating blasts and extramedullary disease. Partial remission (PR) was defined as 5%−25% blasts with at least 50% decrease in bone marrow. Non-remission (NR) was defined as a failure to obtain CR or PR [27, 28]. Patients in first complete remission (CR1) or at least second complete remission (≥ CR2) at transplantation were categorized into the CR group, and those in PR or NR at transplantation were assigned to the non-CR group. Measurable residual disease (MRD) was evaluated by eight-color multi-parameter flow cytometry (MFC) with a threshold of 0.01%. MRD was also monitored by quantitative PCR for KMT2A assessment with a threshold of 0.001%. Subjects were defined as MRD positivity if they had two consecutive positive results using MFC or PCR or were both positive in a single sample.

The evaluation endpoints included relapse, OS, disease-free survival (DFS), non-relapse mortality (NRM), regimen-related toxicity (RRT), disease response, engraftment and GVHD. Relapse was defined as either the reappearance of blasts in the blood or 5% leukemic blasts in bone marrow or evidence of extramedullary disease. OS was defined as time from allo-HSCT until death from any cause or last follow-up. DFS was defined as time from allo-HSCT to relapse, death from any cause or last follow-up. NRM was defined as time from allo-HSCT to death without relapse. Neutrophil engraftment was defined as the first of three consecutive days with absolute neutrophil counts exceeding 0.5 × 109/L. Platelet engraftment was defined as the first of three consecutive days with absolute platelet counts exceeding 20 × 109/L without a platelet transfusion. Acute GVHD (aGVHD) and chronic GVHD (cGVHD) were graded according to published guidelines [30, 31]. RRT was assessed within 28 days after transplantation and was graded according to Bearman’s criteria [32].

Statistical analysis

Categorical variables were compared between the two groups using the chi-square test or Fisher’s exact test. Continuous variables were compared using the Mann–Whitney U test. OS and DFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Cumulative incidence curves were used to estimate the probabilities of relapse, NRM, and GVHD in a competing risk setting [33]. Relapse was a competing risk for NRM and vice versa. Competing risks for GVHD included death without GVHD and relapse. The comparison of the cumulative incidence in the presence of a competing risk was done using the Fine and Gray model [34]. Cox proportional hazard model was used to analyze risk factors for time-to-event variables. The following variables were included in univariable analysis: patient age, patient gender, leukemia type, cytogenetics, white blood cell (WBC) at diagnosis, year of transplantation, hematopoietic cell transplantation-comorbidity index (HCT-CI), disease status at transplantation, donor type and conditioning. Only variables with P < 0.10 were included in the multivariable analysis. SPSS version 25.0 and R version 4.3.1 were used for data analysis. Two-sided P values < 0.05 were considered statistically significant.

Results

Patient and transplant characteristics

Between April 2009 and December 2019, a total of 218 adult patients with KMT2A-r leukemia were included in this study, 167 (76.6%) of whom were diagnosed with KMT2A-r AML, 48 (22.0%) with KMT2A-r ALL and 3 (1.4%) with KMT2A-r MPAL. KMT2A rearrangements with ≥ 5% occurrence were t(9;11)/KMT2A-MLLT3, t(6;11)/KMT2A-AFDN, t(4;11)/KMT2A-AFF1, KMT2A-PTD, t(11;19)(q23;p13.1)/KMT2A-ELL, and t(10;11)/KMT2A-MLLT10. With respect to cytogenetic risk, 54 (24.8%), 161 (73.9%), and 3 (1.4%) patients had intermediate-risk, high-risk and unknown cytogenetics, respectively. One hundred and eighty-one (83.0%) patients achieved CR (176 in CR1 and 5 in CR2), 11 (5.0%) achieved PR and 26 (11.9%) had NR at transplantation. Of the 181 patients in CR at transplantation, 121 had available MRD assessment, and the rate of MRD positivity at transplantation was 30.6%. Patients were classified into two groups on the basis that whether they received a conditioning regimen containing Dec: 105 patients were in the group of intensified conditioning containing Dec (intensified group), and 113 patients were in the group of standard myeloablative conditioning (standard group). The distributions of patient and transplant characteristics between the two groups were well balanced (Table 1).

Table 1 Patient and transplant characteristics
Full size table

Patient and transplant characteristics classified by leukemia type are shown in Additional file 1: Table S1. Distribution of KMT2A rearrangements differed by leukemia type, with t(9;11) most common in KMT2A-r AML, and t(4;11) most common in KMT2A-r ALL. Besides, 113 (67.7%) KMT2A-r AML patients and all KMT2A-r ALL patients had high-risk cytogenetics. WBC ≥ 100 × 109/L was more frequent in KMT2A-r ALL than KMT2A-r AML. KMT2A-r AML patients were more often treated with Bu-based conditionings, while KMT2A-r ALL patients were more often treated with TBI-based conditionings.

Regimen-related toxicity

RRT within 28 days post-transplantation was similar between the intensified and standard groups. The most common RRT was oral mucosa, detected in 102 (46.8%) patients. Grade 3 or worse RRT occurred in 11 (10.5%) patients in the intensified group, and 10 (8.8%) patients in the standard group. One (1.0%) patient in the intensified group died of heart toxicity, and one (0.9%) patient in the standard group died of kidney toxicity (Table 2).

Table 2 Regimen-related toxicity
Full size table

Response, engraftment and GVHD

Except for the two patients who died of RRT within 28 days post-transplantation, 216 patients were evaluable for response and engraftment, and all of them achieved CR on day + 30 post-transplantation. A total of 205 patients (102 in the intensified group and 103 in the standard group) had available MRD assessment on day + 30 post-transplantation. The rate of MRD positivity on day + 30 post-transplantation was 9.8%, along with 4.9% in the intensified group and 14.6% in the standard group (P = 0.036).

The median time to neutrophil engraftment was 11.5 (IQR, 11–13) and 11 (11–13) days, and the median time to platelet engraftment was 12 (12–14) and 12 (11–14) days in the intensified and standard groups, respectively (P = 0.261; P = 0.423). The 100-day cumulative incidence of grade II-IV aGVHD was 37.4% (95% CI, 28.1–46.6) and 33.9% (25.3–42.8; HR 1.07 [95% CI, 0.69–1.68]; P = 0.722), and grade III-IV aGVHD was 10.5% (5.6–17.3) and 10.7% (5.8–17.3; HR 0.99 [95% CI, 0.44–2.25]; P = 0.999) in the intensified and standard groups, respectively. The 3-year cumulative incidence of overall cGVHD was 35.4% (95% CI, 25.5–45.4) and 35.6% (26.5–44.7; HR 0.72 [95% CI, 0.45–1.15]; P = 0.760), and extensive cGVHD was 13.5% (7.3–21.7) and 14.9% (8.9–22.3; HR 0.68 [95% CI, 0.32–1.44]; P = 0.625) in the two groups, respectively.

Relapse and survival

Fifty-two patients (23.9%) experienced relapse with a median relapse time of 6.7 (IQR, 3.0–13.9) months, including 14 (13.3%) in the intensified group and 38 (33.6%) in the standard group. The 3-year cumulative incidence of relapse was 26.4% (95% CI, 20.2–33.0) for the entire cohort, along with 17.6% (10.0–27.1) in the intensified group and 34.5% (25.4–43.9) in the standard group, respectively (HR 0.36 [95% CI, 0.19–0.66]; P = 0.001). With a median follow-up of 38.1 months after transplantation, 155 (71.1%) patients survived and 63 (28.9%) died, including 23 in the intensified group and 40 in the standard group. The causes of death included relapse (n = 42; 12 in the intensified group and 30 in the standard group), infections (n = 11; seven in the intensified group and four in the standard group), GVHD (n = 6; two in the intensified group and four in the standard group), and organ failure (n = 4; two in each group). The 3-year OS was 65.9% (95% CI, 59.2–73.4) in total, along with 71.3% (61.6–82.4) and 61.0% (52.1–71.5) in the intensified and standard groups, respectively (HR 0.58 [95% CI, 0.35–0.97]; P = 0.034). The 3-year DFS was 62.8% (95% CI, 56.1–70.3), along with 70.1% (60.6–81.2) and 56.0% (47.0–66.6) in the two groups, respectively (HR 0.51 [95% CI, 0.31–0.82]; P = 0.005). The 3-year NRM was 10.8% (95% CI, 6.8–15.7), along with 12.3% (6.3–20.3) and 9.5% (4.8–16.0) in the two groups, respectively (HR 1.09 [95% CI, 0.46–2.56]; P = 0.629) (Fig. 1). Subgroup analysis showed that the relapse rate of intensified conditioning was lower than that of standard conditioning in multiple subgroups, including the subgroups of patients with different gender, leukemia types, WBC at diagnosis and disease status at transplantation, as well as patients with high-risk cytogenetics, allo-HSCT in 2009–2014, HCT-CI ≤ 2, MSD and HID transplantation, and Bu-based regimens (Fig. 2).

Fig. 1
figure 1

Outcomes classified by conditioning. (A) Cumulative incidence of relapse. (B) Overall survival. (C) Disease-free survival. (D) Non-relapse mortality

Full size image
Fig. 2
figure 2

Subgroup analysis of relapse in patients receiving intensified conditioning or standard conditioning. Abbreviations: AML acute myeloid leukemia, ALL acute lymphoblastic leukemia, WBC white blood cell, HCT-CI hematopoietic cell transplantation-comorbidity index, CR complete remission, MSD HLA-matched sibling donor, MUD HLA-matched unrelated donor, HID HLA-haploidentical related donor, Bu busulfan, TBI total body irradiation

Full size image

The outcomes in KMT2A-r AML and KMT2A-r ALL patients are shown in Table 3. The 3-year cumulative incidence of relapse was 26.8% (95%CI 19.6–34.6) and 27.4% (15.0–41.2; HR 1.10 [95% CI, 0.58–2.10];P = 0.706), and OS was 63.0% (55.1–72.1) and 72.2% (59.8–87.0; HR 0.83 [95% CI, 0.44–1.56]; P = 0.560) in KMT2A-r AML and KMT2A-r ALL patients, respectively. Moreover, we evaluated the prognostic impact of disease status at transplantation and cytogenetics. Among the patients allografted in CR and non-CR, the 3-year cumulative incidence of relapse was 23.4% (95% CI, 16.8–30.7) and 40.5% (24.6–55.9; HR 0.49 [95% CI, 0.27–0.89]; P = 0.024), 3-year OS was 69.2% (61.8–77.5) and 51.1% (37.2–70.2; HR 0.50 [95%CI, 0.29–0.87]; P = 0.011), respectively. With respect to cytogenetic risk, for the total cohort, the high-risk cytogenetics group had worse relapse and survival than the non-high-risk cytogenetics group, with 3-year cumulative incidence of relapse of 30.0% (95% CI, 22.4–37.9) and 16.3% (7.5–28.0; HR 2.16 [95% CI, 1.02–4.60]; P = 0.041), and 3-year OS of 60.7% (52.6–70.0) and 81.0% (71.0–92.4; HR 2.00 [95% CI, 1.01–3.92]; P = 0.041), respectively. Similarly, among the patients receiving standard conditioning, the high-risk cytogenetics group had inferior 3-year cumulative relapse (40.9% [95% CI, 29.4–52.0] vs 17.6% [6.2–33.7]; HR 3.08 [95% CI, 1.20–7.90]; P = 0.014) and 3-year OS (53.9% [43.3–67.0] vs 79.2% [65.6–95.6]; HR 2.46 [95% CI, 1.03–5.88]; P = 0.035) than the non-high-risk cytogenetics group. However, among the patients receiving intensified conditioning, outcomes were not different between the two cytogenetics groups (3-year cumulative incidence of relapse: 18.4% [95% CI, 9.6–29.5] vs 14.6% [3.4–33.7]; HR 1.11 [95% CI, 0.31–3.98]; P = 0.889; 3-year OS: 67.8% [56.4–81.5] vs 83.4% [69.5–100.0]; HR 1.50 [0.51–4.40]; P = 0.460).

Table 3 Outcomes in KMT2A-r AML and KMT2A-r ALL patients
Full size table

In multivariate analysis, allo-HSCT in CR was a protective factor for relapse (HR 0.47 [95% CI, 0.25–0.90], P = 0.022) and OS (HR 0.54 [95% CI, 0.30–0.98], P = 0.043). The intensified conditioning was a protective factor for relapse (HR 0.32 [95% CI, 0.17–0.59], P = 0.001), OS (HR 0.49 [95% CI, 0.29–0.83], P = 0.008), and DFS (HR 0.45 [95% CI, 0.28–0.74], P = 0.001), whereas high-risk cytogenetics was an adverse factor for relapse (HR 2.58 [95% CI, 1.20–5.53], P = 0.015), OS (HR 2.16 [95% CI, 1.09–4.26], P = 0.027), and DFS (HR 2.17 [95% CI, 1.16–4.04], P = 0.015). Allo-HSCT in 2015–2019 was associated with superior OS (HR 0.50 [95% CI, 0.29–0.87], P = 0.015), DFS (HR 0.54 [95% CI, 0.33–0.90], P = 0.018) and NRM (HR 0.33 [95% CI, 0.13–0.81], P = 0.016), whereas HCT-CI > 2 were associated with inferior OS (HR 2.77 [95% CI, 1.37–5.59], P = 0.005), DFS (HR 2.55 [95% CI, 1.31–4.96], P = 0.006) and NRM (HR 4.01 [95% CI, 1.43–11.29], P = 0.008) (Table 4).

Table 4 Univariable and multivariable analyses for relapse and survival post-transplantation
Full size table

Discussion

In this larger-cohort multicenter retrospective study, our results indicated that intensified conditioning containing Dec might have superior outcomes than standard myeloablative conditioning in adult patients with KMT2A-r leukemia.

Allo-HSCT is recommended for patients with KMT2A-r leukemia [9,10,11,12,13]. In adult patients with KMT2A-r leukemia who received a standard myeloablative conditioning or reduced-intensity conditioning, the 3-year OS post-transplantation was reported to be 40–60%, along with 50–60% for patients allografted in CR and 30–45% in non-CR, respectively [9, 10, 12, 13]. In this study, all patients received a standard myeloablative conditioning or intensified conditioning containing Dec, and the 3-year OS was 65.9% for the entire cohort, along with 69.2% for patients allografted in CR and 51.1% in non-CR. Although cross-study comparisons should be made with caution, our results were better than the previous reports, both for the patients in CR and those in non-CR at transplantation [9, 10, 12, 13]. Meanwhile, the OS for the entire cohort was also significantly superior to the previous study in which patients received a standard myeloablative conditioning or intensified conditioning without Dec [11]. Nevertheless, these results should be interpreted with caution and warranted further investigation in large-cohort prospective studies. Moreover, our results showed a superior OS in the intensified group than the standard group. The specific mechanism by which the intensified conditioning containing Dec was effective in KMT2A-r leukemia was not fully understood. Some studies indicated that patients with KMT2A-r leukemia had aberrant promotor hypermethylation of CpG islands, and that Dec resulted in genome-wide demethylation by incorporating into DNA, and in turn, restored expression of tumor suppressor genes [35, 36]. Besides, Dec was reported to exert synergistic anti-leukemia effects with DNA alkylation agents [37, 38], which might partially explain the efficacy of intensified conditioning containing Dec in treating KMT2A-r leukemia.

Relapse remains the major cause of mortality post-transplantation in acute leukemia, especially in KMT2A-r leukemia. Some studies indicated the intensity-dependent effect of conditionings on relapse post-transplantation [13,14,15,16], in which Pigneux et al. reported that standard myeloablative conditioning had lower relapse than reduced-intensity conditioning in adult patients with KMT2A-r AML [13]. Hypomethylating agents such as Dec were reported to prevent relapse post-transplantation, as a conditioning regimen or maintenance therapy after allo-HSCT [16, 21,22,23, 39]. In terms of the conditioning regimen, several studies suggested that intensified conditioning containing Dec had superior outcomes than standard myeloablative conditioning in high-risk acute leukemia [16, 21,22,23]. Our recent randomized, multicenter study demonstrated that granulocyte-colony stimulating factor combined with Dec-BuCy was associated with a lower 2-year relapse rate than BuCy in MDS or secondary AML evolving from MDS [23]. Wang et al. reported a reduced 3-year relapse rate in the Dec group (Dec plus modified BuCy and Dec plus busulfan-fludarabine) compared with the non-Dec group (modified BuCy and busulfan-fludarabine) in high-risk MDS and AML [22]. This study focused on whether the specific population with KMT2A-r leukemia benefited from intensified conditioning containing Dec. Our results showed a significantly decreased 3-year relapse in the intensified group compared with standard group. Furthermore, subgroup analysis of relapse favored intensified conditioning compared with standard conditioning in multiple subgroups, including different leukemia types, disease status at transplantation, high-risk cytogenetics and Bu-based regimens. To further determine the value of Dec in KMT2A-r leukemia, a new randomized controlled trial (NCT03596892) to compare the efficacy and safety of Dec-BuCy with BuCy conditioning for KMT2A-r leukemia patients undergoing allo-HSCT is ongoing.

A major concern with intensified conditioning is RRT. Some studies suggested that the intensified conditioning had higher NRM in spite of lower relapse than standard myeloablative conditioning, resulting in a similar OS between the two regimens [40]. Therefore, the challenge is to develop new intensified regimens with both sufficient anti-leukemic effects and less toxicity. In our study, the RRT and NRM were similar between the intensified and standard groups. These results suggested that Dec might have low toxicity and that intensified conditioning containing Dec was well tolerated in adult patients with KMT2A-r leukemia.

KMT2A-r leukemia is a heterogeneous disease characterized by various fusion partners and different leukemia types. There are more than 100 fusion partners in this disease [29], and increasing researches revealed the prognostic value of KMT2A rearrangements [13, 41, 42]. Balgobind et al. reported that t(4;11), t(6;11), t(10;19), and t(11;19) were associated with worse prognosis in KMT2A-r AML patients [41]. Krauter et al. demonstrated that translocations other than t(9;11) were adverse risk factors for OS and that t(6;11) had a negative impact on relapse-free survival [42]. In this study, high-risk cytogenetics were identified as a poor factor for relapse, OS, and DFS. Surprisingly, among the patients receiving intensified conditioning containing Dec, outcomes were not different between the high-risk and non-high-risk cytogenetics groups, suggesting that the intensified conditioning containing Dec might overcome the adverse impact of high-risk cytogenetics. Moreover, KMT2A-r leukemia affected the myeloid lineage, lymphoid lineage, or both. With respect to the prognostic impact of leukemia types, similar outcomes were reported in KMT2A-r AML and KMT2A-r ALL [10]. Consistent with the previous study, our data showed that leukemia types did not affect prognosis, which implied that KMT2A-r AML, KMT2A-r ALL and KMT2A-r MPAL might share some biological features and required further investigation.

Our study was limited by its retrospective collection of data over a 10-year period, and failed to include non-KMT2A-r leukemia patients with other cytogenetics as a control group. Additionally, the relatively small sample sizes of some subgroups might result in low test power.

Conclusions

This study suggests that intensified conditioning containing Dec might be a better choice than standard myeloablative conditioning for adult patients with KMT2A-r leukemia undergoing allo-HSCT, which requires further confirmation in prospective, randomized controlled studies.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

aGVHD:

Acute graft-versus-host disease

allo-HSCT:

Allogeneic hematopoietic stem cell transplantation

ALL:

Acute lymphoblastic leukemia

AML:

Acute myeloid leukemia

BuCy:

Busulfan plus cyclophosphamide

cGVHD:

Chronic graft-versus-host disease

CR:

Complete remission

Dec:

Decitabine

DFS:

Disease-free survival

HCT-CI:

Hematopoietic cell transplantation-comorbidity index

HID:

HLA-haploidentical related donor

KMT2A-r:

KMT2A-rearranged

MDS:

Myelodysplastic syndrome

MFC:

Multi-parameter flow cytometry

MPAL:

Mixed-phenotype acute leukemia

MRD:

Measurable residual disease

MSD:

HLA-matched sibling donor

MUD:

HLA-matched unrelated donor

NR:

Non-remission

NRM:

Non-relapse mortality

OS:

Overall survival

PR :

Partial remission

PTD:

Partial tandem duplication

RRT:

Regimen-related toxicity

RT-PCR:

Reverse transcription polymerase chain reaction

TBI-Cy:

Total body irradiation plus cyclophosphamide

WBC:

White blood cell

References

  1. Issa GC, Aldoss I, DiPersio J, et al. The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia. Nature. 2023;615(7954):920–4.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Khabirova E, Jardine L, Coorens THH, et al. Single-cell transcriptomics reveals a distinct developmental state of KMT2A-rearranged infant B-cell acute lymphoblastic leukemia. Nat Med. 2022;28(4):743–51.

    Article  PubMed  PubMed Central  Google Scholar 

  3. van Weelderen RE, Klein K, Harrison CJ, et al. Measurable Residual Disease and Fusion Partner Independently Predict Survival and Relapse Risk in Childhood KMT2A-Rearranged Acute Myeloid Leukemia: A Study by the International Berlin-Frankfurt-Münster Study Group. J Clin Oncol. 2023;41(16):2963–74.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Attarbaschi A, Möricke A, Harrison CJ, et al. Outcomes of Childhood Noninfant Acute Lymphoblastic Leukemia With 11q23/KMT2A Rearrangements in a Modern Therapy Era: A Retrospective International Study. J Clin Oncol. 2023;41(7):1404–22.

    Article  PubMed  Google Scholar 

  5. Li X, Song Y. Structure, function and inhibition of critical protein-protein interactions involving mixed lineage leukemia 1 and its fusion oncoproteins. J Hematol Oncol. 2021;14(1):56.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Issa GC, Zarka J, Sasaki K, et al. Predictors of outcomes in adults with acute myeloid leukemia and KMT2A rearrangements. Blood Cancer J. 2021;11(9):162.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Aubrey BJ, Cutler JA, Bourgeois W, et al. IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia. Nat Cancer. 2022;3(5):595–613.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Iacobucci I, Mullighan CG. KMT2A-rearranged leukemia: the shapeshifter. Blood. 2022;140(17):1833–5.

    Article  PubMed  Google Scholar 

  9. Yang H, Huang S, Zhu CY, et al. The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation Over Chemotherapy Alone in the Treatment of Acute Myeloid Leukemia Patients with Mixed Lineage Leukemia (MLL) Rearrangements. Med Sci Monit. 2016;22:2315–23.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wang Y, Liu QF, Qin YZ, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of patients with mixed-lineage-leukemia-rearranged acute leukemia: Results from a prospective, multi-center study. Am J Hematol. 2014;89(2):130–6.

    Article  PubMed  Google Scholar 

  11. Qi HZ, Xu N, Xu J, et al. Allogeneic hematopoietic stem cell transplantation overcomes the poor prognosis in MLL-rearranged solid tumor therapy related-acute myeloid leukemia. Am J Cancer Res. 2021;11(4):1683–96.

    PubMed  PubMed Central  Google Scholar 

  12. Esteve J, Giebel S, Labopin M, et al. Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT. Leukemia. 2021;35(8):2232–42.

  13. Pigneux A, Labopin M, Maertens J, et al. Outcome of allogeneic hematopoietic stem-cell transplantation for adult patients with AML and 11q23/MLL rearrangement (MLL-r AML). Leukemia. 2015;29(12):2375–81.

    Article  PubMed  Google Scholar 

  14. Hourigan CS, Dillon LW, Gui G, et al. Impact of Conditioning Intensity of Allogeneic Transplantation for Acute Myeloid Leukemia With Genomic Evidence of Residual Disease. J Clin Oncol. 2020;38(12):1273–83.

    Article  PubMed  Google Scholar 

  15. Spyridonidis A, Labopin M, Savani BN, et al. Redefining and measuring transplant conditioning intensity in current era: a study in acute myeloid leukemia patients. Bone Marrow Transplant. 2020;55(6):1114–25.

    Article  PubMed  Google Scholar 

  16. Tang X, Valdez BC, Ma Y, et al. Low-dose decitabine as part of a modified Bu-Cy conditioning regimen improves survival in AML patients with active disease undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2021;56(7):1674–82.

    Article  PubMed  Google Scholar 

  17. Yu S, Huang F, Fan Z, et al. Haploidentical versus HLA-matched sibling transplantation for refractory acute leukemia undergoing sequential intensified conditioning followed by DLI: an analysis from two prospective data. J Hematol Oncol. 2020;13(1):18.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Zhang XH, Chen J, Han MZ, et al. The consensus from The Chinese Society of Hematology on indications, conditioning regimens and donor selection for allogeneic hematopoietic stem cell transplantation: 2021 update. J Hematol Oncol. 2021;14(1):145.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wang Y, Chang YJ, Chen J, Consensus on the monitoring, treatment, and prevention of leukaemia relapse after allogeneic haematopoietic stem cell transplantation in China, et al. update. Cancer Lett. 2024;2024:217264.

    Article  Google Scholar 

  20. Stomper J, Rotondo JC, Greve G, et al. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. Leukemia. 2021;35(7):1873–89.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li Z, Shi W, Lu X, et al. Decitabine-Intensified Modified Busulfan/Cyclophosphamide Conditioning Regimen Improves Survival in Acute Myeloid Leukemia Patients Undergoing Related Donor Hematopoietic Stem Cell Transplantation: A Propensity Score Matched Analysis. Front Oncol. 2022;12:844937.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wang QY, Li Y, Liang ZY, et al. Decitabine-Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft versus Host Disease. Cancer Manag Res. 2019;11:10195–203.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Xuan L, Dai M, Jiang E, et al. The effect of granulocyte-colony stimulating factor, decitabine, and busulfan-cyclophosphamide versus busulfan-cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2023;10(3):e178–90.

    Article  PubMed  Google Scholar 

  24. Saad A, de Lima M, Anand S, et al. Hematopoietic Cell Transplantation, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(5):599–634.

  25. Zhang H, Fan Z, Huang F, et al. Busulfan Plus Cyclophosphamide Versus Total Body Irradiation Plus Cyclophosphamide for Adults Acute B Lymphoblastic Leukemia: An Open-Label, Multicenter. Phase III Trial J Clin Oncol. 2023;41(2):343–53.

    PubMed  Google Scholar 

  26. Xuan L, Wang Y, Yang K, et al. Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2023;10(8):e600–11.

    Article  PubMed  Google Scholar 

  27. Pollyea DA, Altman JK, Assi R, et al. Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21(5):503–13.

    Article  PubMed  Google Scholar 

  28. Brown PA, Shah B, Advani A, et al. Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(9):1079–109.

    Article  PubMed  Google Scholar 

  29. Meyer C, Larghero P, Almeida Lopes B, et al. The KMT2A recombinome of acute leukemias in 2023. Leukemia. 2023;37(5):988–1005.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995;15(6):825–8.

  31. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2015;21(3):389–401.e1.

  32. Bearman SI, Appelbaum FR, Buckner CD, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol. 1988;6(10):1562–8.

    Article  PubMed  Google Scholar 

  33. Gooley TA, Leisenring W, Crowley J, et al. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18(6):695–706.

    Article  PubMed  Google Scholar 

  34. Austin PC, Fine JP. Practical recommendations for reporting Fine-Gray model analyses for competing risk data. Stat Med. 2017;36(27):4391–400.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Touzart A, Mayakonda A, Smith C, et al. Epigenetic analysis of patients with T-ALL identifies poor outcomes and a hypomethylating agent-responsive subgroup. Sci Transl Med. 2021;13(595):eabc4834.

    Article  PubMed  Google Scholar 

  36. Prada-Arismendy J, Arroyave JC, Röthlisberger S. Molecular biomarkers in acute myeloid leukemia. Blood Rev. 2017;31(1):63–76.

    Article  PubMed  Google Scholar 

  37. Valdez BC, Tang X, Li Y, et al. Epigenetic modification enhances the cytotoxicity of busulfan and4-hydroperoxycyclophosphamide in AML cells. Exp Hematol. 2018;67:49-59.e1.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Qin T, Youssef EM, Jelinek J, et al. Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res. 2007;13(14):4225–32.

    Article  PubMed  Google Scholar 

  39. Wei AH, Döhner H, Pocock C, et al. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020;383(26):2526–37.

    Article  PubMed  Google Scholar 

  40. Zhang R, Lu X, Wang H, et al. Idarubicin-Intensified Hematopoietic Cell Transplantation Improves Relapse and Survival of High-Risk Acute Leukemia Patients with Minimal Residual Disease. Biol Blood Marrow Transplant. 2019;25(1):47–55.

    Article  PubMed  Google Scholar 

  41. Balgobind BV, Raimondi SC, Harbott J, et al. Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study. Blood. 2009;114(12):2489–96.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Krauter J, Wagner K, Schäfer I, et al. Prognostic factors in adult patients up to 60 years old with acute myeloid leukemia and translocations of chromosome band 11q23: individual patient data-based meta-analysis of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2009;27(18):3000–6.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the faculty members who participated in this study.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82293634, 82170213, 82370216), National Key Research and Development Program (No. 2021YFC2500300-4, 2022YFC2502600-5), and Natural Science Foundation of Guangdong Province (No. 2024A1515010794).

Author information

Author notes

  1. Zhongli Hu, Zinan Feng and Shiqi Liu these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Zhongli Hu, Zinan Feng, Shiqi Liu, Zhiping Fan, Fen Huang, Na Xu, Ren Lin, Hua Jin, Qifa Liu & Li Xuan

  2. Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China

    Zhongli Hu, Zinan Feng, Shiqi Liu, Zhiping Fan, Fen Huang, Na Xu, Ren Lin, Hua Jin, Qifa Liu & Li Xuan

  3. Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China

    Hai He, Ruijuan Sun & Qifa Liu

  4. Department of Hematology, Maoming People’s Hospital, Maoming, China

    Ying Dong & Xiong Zhang

  5. Department of Hematology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Yiqing Li

  6. Department of Hematology, Hunan Provincial People’s Hospital, Changsha, China

    Can Liu

  7. Department of Hematology, the Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, China

    Yunxin Zeng

  8. Department of Hematology, the First People Hospital of Chenzhou, Chenzhou, China

    Ping Zhu

Authors
  1. Zhongli Hu
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Zinan Feng
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Shiqi Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Hai He
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Ying Dong
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Zhiping Fan
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Yiqing Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Fen Huang
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Na Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Can Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Yunxin Zeng
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Ping Zhu
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Ren Lin
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Hua Jin
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Xiong Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Ruijuan Sun
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Qifa Liu
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Li Xuan
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

LX, QFL, RJS, and XZ were responsible for the conception and design. LX, QFL, RJS, and XZ were responsible for the development of methodology. ZLH, ZNF, SQL, HH, YD, ZPF, YQL, FH, NX, CL, YXZ, PZ, RL and HJ were responsible for the acquisition of data. ZLH, ZNF and SQL were responsible for the analysis and interpretation of data. LX, QFL, RJS, XZ, ZLH, ZNF and SQL were responsible for the writing, review, and/or revision of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiong Zhang, Ruijuan Sun, Qifa Liu or Li Xuan.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee review board at each participating center and was conducted in accordance with the principles of the Declaration of Helsinki. The reference number for the ethics committee was NFEC-2009–23. Written informed consent was obtained from all the patients.

Consent for publication

All of the authors agreed to submit and publish the final manuscript.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hu, Z., Feng, Z., Liu, S. et al. Intensified conditioning containing decitabine versus standard myeloablative conditioning for adult patients with KMT2A-rearranged leukemia: a multicenter retrospective study. BMC Med 22, 605 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-024-03830-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12916-024-03830-0

Keywords

BMC Medicine

ISSN: 1741-7015

Contact us